Kumpulan Jurnal Jantung

THE EGYPTIAN HEART JOURNAL
(EHJ)
Volume 62
Number 2
June 2010
TABLE OF CONTENTS
Page
Echocardiography:
Usefulness of Tissue Doppler Imaging Versus Radionuclide Scintigraphy in Evaluation of
Right Ventricular Myocardial Involvement in Acute Inferior Wall Myocardial Infarction
Randa Aly, Sameh El Maraghi, Ahmed El Sherif
205
Value of Tissue Doppler Imaging in Assessing Effect of Hypertension on Systolic and Diastolic
Function
Nagwa Elmahalawy, Inas Eweida, Iman Esmat, Fadia Elzoghby
219
Hypertension:
Impaired Endothelial Function is a Novel Marker of Subclinical Organ Damage in Hypertensive
Patients
Mohammed A Abdel Wahab
225
Importance of Inflammatory Cytokines and Endothelial Peptides in Predicting Hypertensive

Left Ventricular Hypertrophy
Omyma G Ahmed, Hatem A Helmy, Osama A Ibrahiem, Marwa A Ahmed, Asma F Hassan
231
Ambulatory Arterial Stiffness Index and its Correlation with Target Organ Damage in Patients
with Essential Hypertension
Mohamed M Saad, Mohammed A Abdel Wahab
243
Relevance of Homocysteine on Brachial Flow-Mediated Vasodilation and Carotid and Femoral

Intima-Media Thickness in Siblings of Hypertensive Patients
Mohamed Fahmy Elnoamany, Hala Mahfouz Badran, Hesham Hasan Ebraheem,
Ahmed Ashraf Reda, Neven Abelmonem Elsheekh
249
Coronary Heart Disease:

Significant Value of Oxidized LDL Serum Level in Diabetic Coronary Artery Disease Patients
Ihab Mostafa Abdel-Fattah, Hesham Hassan, Walaa Farid, Maather El Shafie, Mostafa Hamed,
Abdallah Mostafa
261
Effect of Glucose Insulin Infusion on High Sensitivity C-Reactive Protein and Left Ventricular
Global Systolic Function in Diabetic Patients Presenting with ST Segment Elevation Myocardial
Infarction (STEMI)
Osama Abdel Aziz Rifaie, Iman Esmat Sayed Ibrahim, Ahmed Mohammed Onsy,
George Ghaly Girgus
267
Serum Adiponectin Levels in Patients with Coronary Artery Disease

Mohamed Fahmy Elnoamany, Ihab Mohamed Abdelfa ttah, Ashraf Abdelraouf Dawood,
Abdalla Mostafa Kamal, Samah Abdelsamea Zahran
277
Clinical Implications of Adipocytokine, Serum Resisten in Diabetics with Coronary Artery

Disease
Mahmoud Soliman, Waleed Fathey, Adel Abdel Elghany, Amira Abd El Kader, Gehan Kamal
289
(B)
Page
Cardiomyopathy:
Pacing Induced Cardiomyopathy, Diagnosis and Prevalence
Amr El-Hadidy, Khaled Farouk, Hamdy Saber, Ahmed El-Sherief
297
Multigated Radionuclide Study of Systolic Function after Cardiac Resynchronization Therapy

Ahmed Abd El-Aziz, Ashraf W Andraos
307
Interventional:
Cobalt Chromium Coronary Stents and Drug-Eluting Stents in Real Practice
Ali A Youssef, Hanan M Kamal, Hon-Kan Yip, Cheng-Hsu Yang, Chi-Ling Hang, Yuan-Kai Hsieh,
Chih-Yuan Fang, Chiung-Jen Wu
315
Immediate Versus Next Day Coronary Angioplasty in Non-ST Segment Elevation Acute
Coronary Syndrome Patients
Walid Maamoun
323
Molecular Biology:
Association between Transforming Growth Factor-1 Gene C-509T and T869C Polymorphisms
and the Rheumatic Heart Disease in Egypt
Hanan M Kamal, Gehan Hussein, Howayda Hassoba, Nesrin Mosad, Mosleh A Ismail,
Amal A Gad
329
The Association of PvuII Lipoprotein Lipase Gene Polymorphism with Coronary Artery
Disease in Egyptian Southern Territory
Hanan M Ahmed, Doaa A Fouad, Omar Herdan, Hala K Elshereef, Lubena M Tag,
Ebtsam Farouk, Madleen A Atia, Hebat Alla G Rashed, Waffaa Tohamy El-Sherif, Eman Mosaad
339
Electrophysiology:
A Wolf in a Sheeps Skin Atrial Flutter with 1:1 Nodo-Ventricular Conduction Secondary to
Sympathomimetic Inhalant (Salbutamol) in a Young Patient with Acute Bronchial Asthma:
A Case Report with Literature Review
Mohammed Fakhry Abdulmohsen
349
The Predictive Value of E/E' Ratio and Left Atrial Appendage Function for Atrial Fibrillation
Recurrence after Successful Cardioversion
Khalid M Abd El Salam
355
Valvular Heart Disease:

Intermediate-Term Follow-up Results of Pulmonary Balloon Valvuloplasty; Insights from
Doppler Tissue Imaging; Mansoura Experience
Mohamed Matter, Hala Almarsafawy, Mona Hafez, Mohamed Magdy Abou Elkhier,
Mohamed Eltahan
363
Arrhythmia:
Assessment of NT-pro-BNP Levels in Patients with Atrial Fibrillation before and after
Cardioversion and their Relation to Left Atrial Function
Islam A El-Sherbiny, Tamer M Mostafa, Mahmoud H Shah, Ismail M Ibrahim
371
(C)
Page
General Medicine:
Cardiac Autonomic Neuropathy in Type 1 Diabetic Patients:
Prevalence and Utility of Corrected QT Interval in ECG for Diagnosis
Soha M Abd El Dayem, Ahmed A Battah, Randa Ali Soliman
383
Pro-BNP Study of Patients Referred for Echocardiographic Assessment of Left Ventricular

Diastolic Function
Dina YI Nassar, Salama H Omar, Ahmed Said A Zaky, Aida Korayem, Ahmed Dawood,
Aad Baher El-Badawy, Hoda El-Khateeb, M Sherif Hashem
389
Ischemic HD:
Predictors of in-Hospital Mortality in Patients with Cardiogenic Shock Complicating Acute
Myocardial Infarction
Mohammed Saad, Alia Abdel-Fattah, Ahmed Abdel-Aziz, Amr Elhadidy, Gert Richardt
395
Pediatric:
Leptin Axis and Plasma Ghrelin in Children with Congenital Cyanotic Heart Diseases
Yasser F Ali, Sanaa M Abdel Salam, Hadeel MA Rahman, Rehab A Karam
407
Egypt Heart J 62 (2): 205-218, June 2010
Usefulness of Tissue Doppler Imaging Versus Radionuclide Scintigraphy

in Evaluation of Right Ventricular Myocardial Involvement in Acute
Inferior Wall Myocardial Infarction
RANDA ALY, MD*; SAMEH EL MARAGHI, MD**; AHMED EL SHERIF, MD*
Background: Right ventricular (RV) infarction is accompanied with approximately 30%-50% of inferior wall myocardial
infarction (MI). The early diagnosis of right ventricular infarction complicating inferior wall MI can reduce morbidity and
mortality.
Aim of the Work: The objective of our study was to assess the usefulness of tissue Doppler imaging in evaluation of RV
MI in patients with a first acute inferior MI in comparison to First Pass Radionuclide Angiography (FPRNA) which is the gold
standard method and finally to make a confirmative study by coronary angiography.
Patients and Methods: Twenty five patients (pts) with acute inferior wall MI as defined by chest pain, ECG evidence of
inferior MI (elevated ST segment of 1m in leads II, III, aVF), elevated cardiac markers, were subjected to full history of CAD,
clinical examination, left 12-leads ECG, right chest leads, cardiac markers, tissue Doppler imaging (to measure myocardial
performance index "MPI" and systolic myocardial velocity "Sm"), 1st pass radionuclide angiography (to measure RV ejection
fraction) and coronary angiography to define the occluded vessel and to localize the occlusion of RCA either before or after
the right ventricular branch.
Results: Based on the nuclear study (FPRNA) our 25 pts were divided into to 13 pts with RV ejection fraction 45%
(57.385.9) and 12 pts with RV ejection fraction <45% (37.083.2). From the 1 st 13 pts, 12 showed by TDI, myocardial
performance index <0.7 (0.480.07) and Sm 12cm/s (13.891.02cm/s). From the 2nd 12 pts 10 exhibited by TDI, myocardial
performance index 0.7 and Sm <12cm/s (0.810.4 and 9.271.7cm/s respectively). Based on the coronary angiography our
25 pts were divided into to 11 pts in whom the acute occlusion of the RCA before the RV branch and 14 pts who had the acute
occlusion was in coronary vessel other than the RCA before the RV branch (Lt. Cx, LAD, RCA after the right ventricular
branch). From the 1st 11 pts, 10 shown by TDI, myocardial performance index 0.7 and Sm <12cm/s and 1 showed normal
myocardial performance index and Sm. From the 2nd 14 pts 13 showed by tissue Doppler imaging normal myocardial performance
index and Sm and 1 showed myocardial performance index 0.7 and Sm <12cm/s.
Conclusion: There is a significant correlation between tissue Doppler imaging and FPRNA in the ability to detect RVMI
by a sensitivity 90.9% and specificity 85.7% p-value 0.0001. There is a good correlation between the tissue Doppler imaging
and coronary angiography in the ability to detect RVMI (sensitivity 90.9% and specificity 92.9% p-value <0.0001). In comparison
to FPRNA as a calibration method to assess RVEF, tissue Doppler imaging is considered a new, easy, bed side and less expensive
technique in assessment of RVEF.
Key Words: Tissue Doppler Imaging Peak myocardial systolic velocity Myocardial performance index First pass radionuclide
angiography Right ventricular myocardial infarction Inferior wall MI.
Introduction
infarction. The most reliable ECG finding is STsegment elevation in right pericardial leads (V3R,
V4R, V5R) particularly V4R, with associated STsegment elevation 1-mm in the inferior leads II,
III, aVF [1] . It is imperative to record the ECG
through the accessory right pericardial leads as
early as possible due to 48% of the patients had
resolution of electrocardiographic changes within
10 hrs of the onset of symptoms [2].
Right ventricular myocardial infarction (RV

MI) complicates 30-50% of inferior wall myocardial infarction and 10% of anterior wall myocardial
The Department of Critical Care, Cairo* and Beni Suef**
Universities.
Manuscript received 10 Fep., 2010; revised 11 March 2010;
accepted 13 March 2010.
Address for Correspondence: Dr. Randa Aly,
The Department of Critical Care, Cairo University.
Two dimensional echocardiography is not feasible in assessment RV function. In addition two
205
dimensional echocardiography doesn't provide

hemodynamic information about right ventricular
filling and pressures, which can be derived from
Doppler echocardiography studies [3].
ence for RVEF, and has often been performed in

concern with other measurements of right ventricular function as a calibration method [19,20].
Aim of Work:
The objective of our study is to assess the
usefulness of tissue Doppler imaging in evaluation
of RVMI in patients with a first acute inferior
myocardial infarction in comparison to First Pass
Radionuclide Angiography (FPRNA) which is the
gold standard method. (Finally to make a confirmative study by coronary angiography).
Radionuclide ventriculography (RNV) is considered the gold standard for estimating the right
ventricular ejection fraction (RVEF) and is also
useful in detecting wall-motion abnormalities.
Abnormal RV function in patients with inferior
wall myocardial infarction has been demonstrated
by both first-pass and gated blood pool scanning
[4].
Patients and Methods
Interest in recognizing RVMI non-invasively

has grown because of the therapeutic implications
of distinguishing patients with RV dysfunction
from those with the more usual clinical presentation
of left ventricular (LV) dysfunction. Patients with
RVMI associated with inferior infarctions have
much higher rates of significant hypotension, bradycardia requiring pacing support, and in-hospital
mortality than isolated inferior infarctions [5].
The study population consisted of twenty five

patients (pts) admitted to the critical care department, (Kasr El-Aini Hospitals) Cairo University,
from the period of April 2006 to December 2007
with acute inferior wall myocardial infarction
diagnosed by:
1- Typical chest pain.
2- Electrocardiographic evidence (ST segment
elevation of 1mm in inferior leads (II, III,
aVF), and
In approximately 30% of patients with inferior

MI, RVMI develops [6]. In patients with RVMI,
the risk of death in the hospital is high and major
complications are greater [7,8]. For early diagnosis,
ECG and two-dimensional echocardiography [9,10]
are used. However, it is difficult to assess both RV
anatomy and function with reliable conventional
echocardiographic examination because of its complex structure. In most cases, the visual assessment
of the RV free wall by echocardiography leads to
an underestimation of hypokinesia, due to an asymmetric contraction of the RV walls toward its center
[11] . The recent utilization of tissue Doppler in
echocardiography has also increased, providing
another means to detect RVMI. It has been shown
that the tricuspid annulus systolic velocity decreases
in patients with inferior MIs compared to those
with anterior MIs, and in those with RVMIs compared to those without RVMIs [12]. A decrease in
the systolic velocity at the tricuspid annulus not
only allows for diagnosis of RVMI but also suggests
worse mortality outcome [13]. Another echocardiographically obtained value that can aid in diagnosis
of RVMI is the myocardial performance index
(MPI) [13].
3- Creatinine kinase 210IU and creatinine kinase

fraction MB 20IU (normal upper limit = 6U/L).
Exclusion criteria:
1- Inferior wall re-infarction.
2- Cardiomyopathies.
3- Rheumatic heart diseases.
4- Pulmonary hypertension.
5- Chronic obstructive pulmonary disease (COPD).
6- Pregnancy.
7- Cardiac pacing.
All patients were subjected to:
Complete history taking including risk factors of
coronary artery disease (CAD).
Full clinical examination.
Standard 12-leads electrocardiogram (ECG),
Right chest leads ECG (V3R, V4R, V5R).
Right ventricular function is less often measured

than LV function, but has been shown to hold
clinical diagnostic and prognostic importance in
many disorders [14-18] . Owing to its accuracy,
FPRNA has become a non invasive standard refer-
Cardiac markers (CK, CKMB, LDH).

Routine laboratory investigations including:
Blood glucose, Complete blood count (CBC),
Kidney functions tests, electrolytes.
206
Randa Al y, et al
Imaging studies:
All pts underwent conventional transthoracic
Echocardiographic examination as well as tissue
Doppler study, nuclear imaging to assess right
ventricular function with Tc-99m Sestamibi, and
coronary angiography.
Isovolumic relaxation time (IVRT):

Measured in (msec) by Pulsed-Doppler from
the end of systolic wave to the beginning of E
wave (N: 60ms).
Ejection time (ET):
Measured in (msec) by Pulsed-Doppler as the
period of aortic or pulmonary valve opening or the
time of peak myocardial systolic velocity (N:
250ms).
A- Echocardiographic examination:
All patients underwent echocardiographic examination, including the routine transthoracic and
tissue Doppler study.
Myocardial performance index (MPI):

Calculated by the following equation:
Each patient was examined in the left lateral

decubitus position according to the recommendations of the American Society of Echocardiography.
Images obtained from each part of the examination
together with standard ECG were stored on videotape for subsequent analysis. The study was conducted using an ATL HDI 5000 colored echocardiographic machine with tissue Doppler imaging
software incorporated in the device using a 3.5MHz.
transducer.
IVRT + IVCT
MPI = (N: 0.39)
ET
Peak myocardial systolic velocity (Sm):

Measured in Cm/s by drawing a perpendicular
line from the summit of the systolic wave to the
baseline (N: 12-17cm/s).
B- Nuclear imaging:
Myocardial nuclear imaging was done within
one week from the onset of admission following
stabilization of the patient's medical condition.
A- Routine echocardiographic study:

The following parameters were measured to
exclude cardiac myopathies and to give an idea
about right ventricular size:
First pass radionuclide angiography (FPRNA):

First pass technique was used to assess the RV
ejection fraction by injecting 25-30mCi Tc-99m
Sestamibi intravenously. Intravenous access should
be obtained using a large-bore indwelling polyethylene catheter, either a 18-or 20-gauge catheter in
an external jugular vein or a 14- or 16-gauge in a
medial antecubital vein.
1- Left ventricular end diastolic dimension

(LVEDD).
2- Left ventricular end systolic dimension (LVESD).
3- Ejection fraction (EF): Calculated by the equation using modified Simpson's method from
apical four and/or two chamber view by 2-D
study (normal range 55%-75%).
The images are acquired in anterior view, (the

acquisition duration should be set for at least 30
seconds in order to allow for complete transition
through the central circulation then processed and
analyzed using the frame method for RV, which
creates a representative ventricular volumes cycles
by summing frames of several (usually 2 or 4 for
RV) cardiac cycles, aligned by matching their ED
to get the right ventricular by semi-automated
method.
LVEDV LVESV
EF = x 100
LVEDV
4- Right ventricular dimensions (normal range

1.7-2.7cm).
B- Tissue Doppler study:
Tissue Doppler Imaging (TDI) was done in the
pulsed modality from the apical 4 chamber view
placing the sample volume of the Doppler cursor
at the lateral tricuspid annulus to determine the
following parameters (in a pt. with HR 70bpm):
C- Coronary angiography:
The procedure was performed using Integris H
300 (Philips, NL) catheterization laboratory. The
diagnostic procedure was performed via right
femoral artery using seldinger's technique after
giving xylocaine for local anaethesia, with JL F6,
F7 and C3.5, C4 to visualize the left system. And
JR F6, F7 and C3, C4 to visualize the right system.
Isovolumic contraction time (IVCT):

Measured in (msec) by Pulsed-Doppler from
the end of A wave to the beginning of systolic
wave (N: 50ms).
207
Views were taken in the right oblique with

caudal and cranial angulations, in left oblique with
cranial and caudal (spider) angulations, lateral
projections and additional projection when needed.
Patients with acute inferior wall MI and concomitant RV infarction could be detected by the
following:
I- Electrocardiogram (ECG) that showed presence
of ST-segment elevation in the right chest leads
(V3R, V4R, V5R).
II- Pulsed wave tissue Doppler echocardiography
at the lateral tricuspid annulus that showed the
following parameters:
Peak myocardial systolic velocity (Sm)
<12cm/s.
Myocardial performance index (MPI) 0.7.
Statistical methods:
Data were collected on special format, verified
and then coded prior to analysis.
All continuous data were expressed as mean
SD, categorical data were expressed as frequency
in tables.
Chi-square test and kappa for assessing agreement
between two methods in categorical data.
III- First pass radionuclide angiography (FPRNA)

that showed right ventricular ejection fraction
(RVEF) <45%.
IV- Coronary angiography that showed right coronary artery (RCA) occlusion before giving the
RV branch.
Sensitivity, specificity, positive and negative

predictive values together with Odds ratio.
Sens = [TP + FN] / TP.
Spec = [TN + FP] / TN.
Positive predictive value = [TP + FP] / TP.
We excluded pts with acuter inferior MI in who

RV involvement is unlikely because of:
ECG: Absence of ST-segment elevation in V3R,
V4R, V5R in the first 10 hours.
Peak myocardial systolic velocity 12cm/s.
Myocardial performance index <0.7.
Right ventricular ejection fraction by first pass
protocol 45%.
The occluded coronary artery is the RCA after
giving the right ventricular branch or a coronary
artery other than the RCA (Lt. Cx, LAD).
Negative predictive value = [TN + FN] / TN.

Where:
TP = True positive.
FP = False positive.
TN = true negative.
FN = False negative.
p-value <0.05 considered significant (CI is 95%).
All analysis has been performed using SPSS 12
and graphics by Microsoft excel.
The following parameters were analyzed:

1- Risk factors:
Sixteen (64%) out of our 25 pts were smokers,
13 (52%) were hypertensives, 10 (40%) were diabetics, positive family history for CAD was found
in 9 pts (36%), 8 (32%) had dyslipidaemia and 6
(24%) were obese (Fig. 2).
Results
Our study group includes 25 pts with a mean
age of 53.49.9 ys, (range from 30-75 ys), 21 males
(84%) and 4 females (16%), presented by acute
inferior wall MI (Fig. 1).
16%
70
84%
60
64
52
50
40
36
40
30
32
24
20
10
Female
Male
Smoking HTN
Hyper- Obesity
cholesterolaemia
Figure 2: Risk factors in acute inferior wall MI.
Figure 1: The percentage of males and females in the study

group.
208
DM
FH
Randa Al y, et al
2- ECG:
Out of the 25 pts nine (36%), showed STsegment elevation in right chest leads (V3R, V4R,
V5R).
to 41%) was found in 13 (52%) and 12 pts (48%)

respectively.
As shown in Table (3):
o Thirteen patients (52%) showed normal RV
ejection fraction by FPRNA (RVEF 45%)
(mean 57.385.9, ranging from 49% to 67%)
from which 12 patients (92.3%) exhibited normal myocardial performance index and Sm by
tissue doppler imaging (mean 0.480.07, ranging from 0.36 to 0.62 and mean 13.891.02,
ranging from 13.1 to 16.9cm/s respectively)
and only 1 patient (7.7%) exhibited MPI, Sm
0.7 and <12cm/s respectively.
o Twelve patients (48%) showed impaired right
ventricular ejection fraction by FPRNA (RVEF
<45%) (mean 37.083.2, ranging from 30 to
41%) from which 10 patient (83.3%) exhibited
myocardial performance index 0.7 and Sm
<12cm/s by tissue doppler imaging (mean
0.810.04, ranging from 0.77 to 0.91 and mean
9.271.7, ranging from 5.7 to 11.1cm/s respectively) and 2 patients (16.7%) exhibited normal
myocardial performance index and Sm (<0.7
and 12cm/s respectively).
3- Complications (Table 1):

Out of whole group 4 pts (16%) showed smooth
course during the hospital stay.
Table 1.
ST
AT
VT
SB
HB
BP
Re-inferior
8
32%
4
16%
1
4%
9
36%
8
32%
9
36%
1
4%
ST: Sinus tachycardia.

AT: Atrial tachycardia.
VT: Ventricular tachycardia.
SB: Sinus bradycardia.

HB: Heart block.
BP : Blood pressure.
4- Pulsed wave tissue Doppler parameters:

As shown in Table (2) the study group showed
variable levels in the tissue Doppler parameters
including peak myocardial systolic velocity (Sm),
isovolumetric relaxation time (IVRT), isovolumetric
contraction time (IVCT), ejection time (ET) and
myocardial performance index (MPI).
Table 3: Agreement between the 2 techniques; tissue Doppler

imaging (TDI) and FPRNA in detection of right
ventricular involvement with acute inferior wall MI
Table 2: Variable levels of tissue Doppler parameters.
Peak myocardial systolic velocity

(Sm) cm/sec
Isovolumetric relaxation time (ms)
Isovolumetric contraction time (ms)
Ejection time (ms)
Myocardial performance index
Mean SD
Range
11.852.68
5.7-16.90
79.016.38
83.4820.50
268.441.85
0.620.17
51.0-111.0
51.0-123.0
207-342
0.36-0.91
FPRNA
TDI:
ve for right ventricular
involvement (14 pts)
Out of our 25 pts an Sm 12Cm/s and myocardial performance index <0.7 were found in 14 pts
(56%) with a mean of 13.891.02 (range 13.1 to
16.9) and 0.480.07 (range 0.36 to 0.62) respectively. While Sm <12Cm/s and myocardial performance index 0.7 were found in 11 pts (44%) with
a mean of 9.271.7 (range 5.7 to 11.1) and 0.81
0.04 (range 0.77 to 0.91) respectively.
+ve for right ventricular

involvement (11 pts)
ve for right
ventricular
involvement
(13 pts)
+ve for right

ventricular
involvement
(12 pts)
12 pts (92.3%)
2 pts (16.7%)
1 pt (7.7%)
10 pts (83.3%)
(Kappa = 0.759, p: 0.0001).
A significant agreement between the two methods

(FPRNA, TDI) in assessment of right ventricular
systolic function, sensitivity 90.9%, specificity
85.7%, +ve predictive value 83.3% and ve predictive value 92.3%, (p-value 0.0001), (Fig. 3).
5- First pass radionuclide angiography (FPRNA)

and detection of RVEF:
The study group showed variable RV ejection
fraction ranging from 30 to 67% (mean 47.64
11.36).
6- Coronary angiography (Fig 8):

Prevalence of the coronary arteries that is responsible for acute inferior wall myocardial infarction
in the study group:
o Twenty pts (80%) had inferior wall MI due to
RCA occlusion, from whom 11 (55%) had the
Right ventricular ejection fraction 45% with

a mean of 57.385.9 (range from 49 to 67%) and
<45% with a mean of 37.083.2 (range from 30
209
occlusion site before and 9 (45%) had it after

the right ventricular branch respectively.
o Four pts (16%) had inferior wall MI due to
occlusion of dominant Lt. Cx.
o One pt. (4%) infarcted due to occlusion of the
middle part of a long LAD artery, wrapping
around the apex.
and 6 (66.67%) had additional variable chronic

overlaping lesions not responsible for the acute
insult (5 in LAD, 2 in Lt. Cx).
o Four pts (28.57%) showed an acute occlusion
of the proximal Lt. Cx artery, out of them 2
(50%) showed isolated acute occlusion and 2
(50%) had overlapping chronic LAD lesions.
o The last pt (7.14%) showed isolated acute occlusion at the mid segment of a long LAD that
was wrapping around the apex.
Based on the occluded artery and the level of

occlusion our pts showed an RCA occlusion before
the RV branch in 11 (44%) while the remaining 14
pts (56%) had the occlusion site after the RV branch
in 9 pts (36%), the Lt. Cx artery in 4 pts (16%)
and the LAD artery in 1 pt. (4%).
1.00
0.75
Sensitivity
Out of 11 pts with RCA occlusion before the RV

branch 2 (18.18%) had isolated acute RCA occlusion and 9 (81.82%) had additional chronic
overlapping lesions (master table) not responsible
for the acute insult (7 had LAD variable lesions,
5 had Lt. Cx variable lesions).
0.50
0.25
0.00
0.00
Regarding the 14 pts in whom the site of acute

occlusion was in the RCA after giving the right
ventricular branch, Lt. Cx or LAD:
o Out of the nine pts (64.29%) who had the acute
occlusion of the RCA after the right ventricular
branch, 3 (33.33%) had isolated RCA occlusion
0.25
0.50
1-specificity
0.75
Figure 3: ROC curve to assess the newly introduced method

(TDI) against FPRNA for detection of right ventricular involvement in acute inferior wall myocardial
infarction (Area under the curve 0.88).
Study group (25 pts)
20 pts (RCA)
4 pts (Lt. Cx)
2 pts
(isolated Lt. Cx)
11 pts
(before the right ventricular branch)
1 pt (LAD)
2 pts
(overlapped by LAD lesions)
9 pts
(after the right ventricular branch)
3 pts
(isolated RCA)
2 pts
(isolated RCA)
1.00
6 pts
(overlapped by Lt. Cx, LAD lesions)
9 pts
(overlapped by Lt. Cx. LAD lesions)
Figure 4: Diagrammatic representation of the arteries involved in our studied pt.
210
Randa Al y, et al
Correlation between the tissue doppler imaging

and coronary angiography results:
Out of the 11 pts who showed acute occlusion
of the RCA before the right ventricular branch 10
pts (90.9%) showed myocardial performance index
0.7 and Sm <12cm/s by tissue Doppler imaging
(RV involvement with acute inferior wall MI) and
the other one (9.1%) showed normal myocardial
performance index & Sm.
wall MI, (sensitivity 90.9%, specificity 92.9%,

+ve predictive value 90.9% and ve predictive
value 92.9%, p-value 0.0001) (Fig. 5).
1.00
Sensitivity
0.75
Out of the remaining 14 pts (acute occlusion

of other than the RCA before the RV branch) 13
(92.9%) showed normal myocardial performance
index and Sm by tissue Doppler imaging and 1
(7.1%) showed myocardial performance index 0.7
and Sm <12cm/s.
0.50
0.25
Specificity
0.00
0.00
0.25
0.50
1-specificity
0.75
1.00
Figure 5: ROC curve to assess the newly introduced method

(TDI) against coronary angiography for detection
of right ventricular involvement in inferior wall
myocardial infarction (Area under the curve 0.91).
There is a good agreement between the tissue

Doppler imaging and coronary angiography in
evaluation of RV involvement with acute inferior
Figure 6: Pt No. (11) ECG showing acute inferior wall MI without RV infarction as seen in the right chest leads.
211
Figure 7: Coronary angiography showing the acute occlusion of

the RCA after the right ventricular branch.
Figure 8: Pt no (.) Tissue Doppler

imaging showing Sm = 12.8
cm/s, IVRT=51 ms, IVCT
= 51 ms, ET = 282 and MPI
= 0.36.
Figure 9: Pt no (.) Showing normal

right ventricular ejection
fraction (67%) by the FPRNA.
212
Randa Al y, et al
Figure 10: ECG showing acute inferior wall MI complicaed by CHB with RV infarction as seen in the right chest leads.
Figure 11: Coronary angiography

showing the acute occlusion of the RCA before
the right ventricular
branch.
Figure 12: Tissue Doppler imaging showing Sm=8.1 cm/s, IVRT=63 ms, IVCT=114 ms, ET=222 ms and MPI=0.8.
213
myocardial infarction and concomitant right ventricular involvement, and the peak myocardial
systolic velocity of <12cm/s and myocardial performance index of 0.7 can define right ventricular
infarction.
These findings are in agreement with the previous several studies that studied the effect of first
acute inferior myocardial infarction on the global
right ventricular function [30,31]. Alam et al [32],
in 1999 found a significant reduction of the peak
systolic velocity at the lateral tricuspid annulus in
first acute inferior MI, compared to both normal
subjects and patients with acute anterior MI.
However, the authors didn't report any predictive
value for peak systolic velocity at the lateral tricuspid annulus used for the identification of right
ventricular function. Moreover, it was found that
pts with inferior MI and RV involvement (on the
basis of ECG signs) had lower systolic peak velocities at the lateral tricuspid annulus than those
without ECG evidence of right ventricular infarction.
Figure 13: Showing impaired right ventricular ejection fraction

(40%) by the FPRNA.
Discussion
Based on the peak systolic velocity at the tricuspid annulus as an indicator to right ventricular
systolic function in inferior wall myocardial infarction Alam et al [12] in 2000 prospectively studied
thirty eight patients with a first acute inferior
myocardial infarction compared with 33 patients
with a first anterior MI and 24 age-matched healthy
individuals. Association of right ventricular infarction in inferior myocardial infarction was defined
as the presence of 1-mm ST-segment elevation
at the right precordial lead V4R of the electrocardiograms. From the echocardiographic apical 4chamber views, the peak systolic velocity of the
tricuspid annulus at the right ventricular free wall
was recorded with the use of pulsed-wave Doppler
tissue imaging. The peak systolic velocity of the
tricuspid annulus was significantly reduced in
inferior MI compared with that in healthy individuals (11.7 Vs 16.3cm/s, p<0.001) and patients with
anterior MI (11.7 Vs 13.8cm/s, p<0.001). Patients
with inferior MI were divided into 2 subgroups:
those with and those without ECG signs of RV
infarction. Compared with patients without ECG
signs of RV infarction, those with RV MI had a
significantly decreased peak systolic tricuspid
annular velocity (9.9 Vs 13.9cm/s, p<0.001). This
study is in agreement with that of ours which used
the peak myocardial systolic velocity to differentiate
between pts with and those without right ventricular
infraction (9.27 Vs 13.89cm/s respectively).
Previous studies using pulsed tissue Doppler

in healthy adults have established normal reference
values for adults at the level of the right ventricular
free wall and at the lateral tricuspid annulus and
concluded that a peak systolic annular velocity
<11.5cm/sec predicted right ventricular systolic
dysfunction (RV ejection fraction <45%) with a
sensitivity of 90% and a specificity of 85% [21].
Experimental studies, have reported that in
normal conditions, the right ventricle, unlike the
left ventricle, starts its diastolic filling without an
isovolumic relaxation time (IVRT) since it works
against a lower vascular impedance [22-24]. Accordingly, several studies in humans have confirmed
that TD-derived IVRT (measured at the left of the
right ventricular free wall or at the lateral tricuspid
annulus) is very short or even absent in healthy
subjects [25-28].
However, Sengupta et al [29] in 2002 studied
the right ventricular function in healthy subjects
and reported marked variations in tissue velocities
among the different right ventricular segments.
They referred this to the complex geometry of the
right ventricle and the variable loading and unloading characteristics of its different wall.
Our study revealed impaired global right ventricular function in patients with acute inferior wall
214
Randa Al y, et al
Our study is also in agreement with a study

done by Abdurrahman Oguzhan et al [33] in 2003.
This study was undertaken to determine the RV
function as assessed by Doppler tissue imaging in
patients with RV infarction. During the study
period, 35 patients were evaluated: 14 had an
inferior MI with RV infarction and 21 without RV
involvement. Twenty age-matched healthy subjects
served as control. The diagnosis of RV infarction
was defined by ST segment elevation of 1-mm
in lead V4R. One week later, they found that the
systolic velocity at the lateral tricuspid annulus
using TDI was significantly reduced in patients
with inferior MI with RV involvement compared
with those in healthy individuals (7.81 Vs.
142cm/s, p<0.002) and patients with inferior MI
but without RV involvement (7.81 Vs. 101cm/s,
p<0.002). The agreement of our results with those
of Oguzhan may be attributed to the use of the
same technique of tissue doppler imaging after a
fixed period from the onset of the inferior wall
myocardial infarction (nearly 5 days). In addition,
the number of the pts who showed RVMI in that
study was nearly similar to our pts that showed
RVMI by tissue Doppler imaging (14 Vs 11 respectively).
MI, anterior MI, valvular heart disease and in the

control group respectively. These results were in
agreement with ours regarding assessment of the
RV systolic function by FPRNA.
Dell Italia and Lembo et al [36] in 1998 assessed
RVMI by first pass radionculide ventriculograms
in 27 pts who met hemodynamic criteria for RVMI.
They found that early assessment by first pass
resting radinculide ventriculography demonstrated
a significant reduction in RV systolic function
(307%), a figure that was slightly less than that
reported in our pts (37.083.2%). This may be due
to the early assessment of the RV ejection fraction
of their pts after MI (period of stunning), and may
also be due to the larger number of studied pts who
met hemodynamic criteria of RVMI than our pts
(27 Vs 12 respectively).
Konishi et al [37] in 1987 studied the incidence
and prognosis of RV infarction by RVN in 50
consecutive cases of acute MI within thirty-six
hours of symptoms and one month after onset.
Right ventricular infarction was absent in all 25
patients with anterior MI and was found in 15 out
of the 25 patients with inferior MI, accompanied
by a marked reduction in RV ejection fraction
(288%), but was notably alleviated one month
later with improvement of RV ejection fraction
(397%) and wall motion. This finding seems to
be specific to the RV infarction. The observed
lower RV ejection fraction in pts with RVMI than
that reported in our studied pts who showed RVMI
by RNV (288% Vs 37.083.2% respectively)
may be attributed to the early examination of their
pts compared with ours (36 hrs Vs 5 days), and
when they were evaluated later, the RV ejection
fraction started to improve.
Munusamy et al [34] in 2001 prospectively

studied thirty patients with first acute Inferior wall
MI with a mean age of 50.58.5 ys compared to
patients with first acute anterior wall MI and to
age matched controls. RV involvement in inferior
wall MI was diagnosed by standard criteria. Using
pulsed-wave Doppler tissue imaging, the peak
systolic velocity of the tricuspid annulus was
significantly reduced in inferior wall MI compared
with healthy individuals (12cm/s V. 14.5cm/s,
p<0.001) and patients with anterior wall MI (12cm/s
V. 14.5cm/s, p<0.001). Patients with inferior wall
MI were divided into 2 subgroups: those with and
those without ECG signs of RVMI. Compared to
patients without signs of RVMI, those with RVMI
also had a significantly decreased peak systolic
tricuspid annular velocity (10.3cm/s Vs 13.3cm/s,
p<0.001). These findings are in agreement with
our study, in a nearly close number of studied pts
and mean age (30 Vs 25 pts, 50.58.5 Vs 53.49.9
ys respectively).
Tobinick et al [38] in 1989 measured RV ejection

fraction from high frequency time-activity curves
obtained during the initial passage of an intravenous
bolus of 99mTc pyrophosphate. In 22 normal controls RV ejection fraction averaged 524%, while
in 24 pts with acute anterior or lateral infarction
RV ejection fraction was normal (5610%). Nineteen pts with acute inferior wall MI were further
divided into two groups: those with and without
concomitant RV infarction based on ECG criteria
and hemodynamic affection. Compared to the group
without RV infarction (12 pts), patients with RV
infarction (7 pts) showed a significantly lower RV
ejection fraction by FPRNV (395% Vs 519%,
p<0.001). These findings were in agreement with
ours using the same radioactive isotope and high
Zheng Zhang et al [35] in 1990 studied 15 pts

with RVMI, 9 with anterior MI, 5 with valvular
heart disease and 19 as a control group. Using
FPRNA RV ejection fraction was 297%, 4310%,
3014% and 466% in pts with right ventricular
215
frequency time activity curves to differentiate

between pts with impaired RV ejection fraction
those with normal RV ejection fraction in inferior
wall MI (37.083.2% Vs 57.385.9% respectively).
RCA than in those with distal right or Lt.Cx coronary artery. They proposed the value of <12cm/sec
for peak systolic velocity of the RV free wall as
the cutoff for the identification of RVMI and proximal RCA disease with high sensitivity & specificity. These findings are in agreement with ours with
similar high sensitivity & specificity (90.2, 92.9%
respectively).
Starting MR et al [39] in 1984 studied the radionuclide criteria for identifying hemodynamically
significant right ventricular infarction in 33 consecutive men with acute inferior transmural infarction within 36 hours of the onset of symptoms.
They found that a right ventricular EF of 35% can
separate 2 groups. Those with and those without
RVMI the lower RV (35%) to define RVMI than
in our pts (41%) detected by the same technique
may be due to that their studied pts with RVMI
was significantly lower than the number of our pts
with RVMI (6 Vs 12 respectively).
In 1999 Rafeeq et al [43] in 2005 studied twenty

patients who experienced a first acute inferior MI.
RVMI was detected in 10 patients, and the IRA in
these patients was the proximal RCA. After stabilization of the pts clinical conditions the right
ventricular Sm was observed to be significantly
low (<12cm/s) in pts with RVMIs in pts with
proximal RCA compared to those without RVMIs
(distal RCA & LCX). The myocardial performance
index was higher in patients with RVMI than in
those without RVMI (0.800.10 Vs 0.250.11).
These findings were in agreement with that of ours
and this agreement may be due to: the similar
number of pts to our studied pts (20 Vs 25), the
close mean age to that of our pts (55.311 Vs
53.49.9 ys) and lastly due to the TDI which was
performed after coronary angiography when pts
became hemodynamically stables.
To detect right ventricular systolic dysfunction

by tissue doppler imaging versus FPRNV Meluzin
et al [40] in 2001 studied 44 pts and they found
that the peak systolic velocity at the tricuspid
annulus was significantly lower than that in healthy
subjects (10.32.6cm/s Vs 15.52.6cm/s). Two
hours after tissue doppler imaging patients were
subjected to FPRNV by injecting technetium 99m
(Tc) pertechnetate. The authors concluded that the
systolic annular velocity <11.5cm/s can predict
RV systolic dysfunction (EF <45%), and that there
was a significant correlation between the peak
systolic annular velocity by tissue doppler imaging
and right ventricular ejection fraction by FPRNV
(r=0.648, p<0.001) with a sensitivity 90% and
specificity 85%. This study is in agreement with
ours that used the two methods to detect right
ventricular ejection fraction (sensitivity 90.9%,
specificity 85.7%).
Dokainish and Gin et al [44] in 2002, echocardographic variables including studied TDI to detect,
RVMI. Fifty patients with a first ST elevation
inferior wall myocardial infarction underwent
echocardiographic examination with tissue doppler
imaging and coronary angiography within 48 hours
of infarction. RVMI was determined by the presence
of the infarct culprit lesion (ICL) proximal to the
first RV branch of the RCA on angiography. Out
of the 50 patients included in the study. 22 (44%)
had the ICL proximal to the first RV branch of the
RCA (Group 1, RVMI), while the other 28 had the
ICL distal to the first RV branch of the RCA or in
an artery other than the RCA (Group 2, No RVMI).
According to Pavan et al [41] in 2006 using

linear regression analysis and sensitivity analysis
were used to analyze the data. RV EF measured
by nuclear ventriculography was significantly
correlated with myocardial performance index
(r=0.55, p 0.005). These findings were in agreement with our results which used the MPI derived
by tissue doppler imaging as an indicator for detection of RV involvement with inferior wall MI.
Conclusion
In comparison to FPRNA as a calibration method
to assess RVEF, tissue doppler imaging is considered a new, easy, and less expensive bed side
technique in assessment of RVEF.
According to zdemir et al [42] in 2003, in a

study of sixty patients who experienced a first
acute inferior myocardial infarction and underwent
coronary angiography to diagnose the infarctrelated artery (IRA) the peak systolic velocity
obtained from the RV free wall by TDI was significantly lower in pts in whom the IRA was proximal
We can detect right ventricular ejection fraction

by TDI-derived peak myocardial systolic velocity
(Sm) at the lateral tricuspid annulus and myocardial performance index (summation of IVRT +
IVCT divided by ET).
216
Randa Al y, et al
8- Berger PB, Ryan TJ: Inferior myocardial infarction: High
risk subgroups. Circulation 1990; 81: 401-411.
Right ventricular myocardial infarction can be

predicted by a Sm <12 cm/s and myocardial
performance index 0.7 obtained by TDI.
9- Lopez-Sendon J, Lopez de Sa E, Roldan I, et al: Inversion

of normal interatrial septum convexity in acute myocardial
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First pass radionuclide angiography can separte

patients with from those without RVMI by a right
ventricular ejection fraction 41%.
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infarction as an independent predictor of prognosis after
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328: 981-988.
There is a significant correlation between tissue

doppler imaging and FPRNA in the ability to
detect RVMI by a sensitivity 90.9% and specificity 85.7% p-value 0.0001.
11- Lopez-Sendon J, Garcia-Fernandez MA, Coma-Canella

I, et al: Segmental right ventricular function after acute
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218
Value of Tissue Doppler Imaging in Assessing Effect of Hypertension on

Systolic and Diastolic Function
NAGWA ELMAHALAWY, MD; INAS EWEIDA, MD; IMAN ESMAT, MD;
FADIA ELZOGHBY, MBBCh
Introduction: In patients with hypertension and preserved left ventricular (LV) systolic function, hypertension has been
linked to a gradual development of diastolic LV dysfunction, referred to as diastolic heart failure [1]. The combination of the
study of mitral inflow and TDI study can reliably evaluate the presence of elevated LV end-diastolic pressure [2].
Aim of the Study: To assess the impact of hypertension on both systolic function and diastolic function using pulsed Doppler
and tissue Doppler echocardiography in hypertensive patients with preserved global LV systolic function (EF).
Patients and Methods: We studied two groups of subjects:
Group 1: Included 30 patients (14 men and 16 women) with history of hypertension.
Group 2: Included 20 subjects (9 men and 11 women) with no history of hypertension and normal findings on two-dimensional
echocardiography.
Exclusion Criteria Included: Coronary heart disease, Cardiac arrhythmias, valvular heart disease, abnormal LV ejection
fraction (LVEF 55%).
All patients were subjected to the following: History taking, physical examination, twelve lead ECG, Echocardiographic
study: The measurements of LV dimensions, ejection fractions (%) and LV fractional shortening (%) were performed to evaluate
the systolic functions, EF >55% is considered normal. Wall thickness and LV diameter were derived from M-mode echocardiograms
according to the recommendations of the American Society of the Echocardiography.
Diastolic function assessment using pulsed wave conventional Doppler, The peak E (early rapid ventricular filling) wave velocity:
The peak A (late ventricular filling) wave velocity, diastolic dysfunction is considered if E/A ratio <1. Tissue Doppler study
was done Was done using the echocardiographic Vingmed Vivid 5 machine, to assess systolic and diastolic function of the left
ventricle by measuring tissue Doppler velocities at mitral annulus, using pulsed-wave tissue Doppler myocardial velocity.
Systolic dysfunction is considered if peak systolic velocity is <4.4cm/sec [3]. Diastolic dysfunction is considered if ETDI/ATDI
reversed [4].
Statistical Analysis: All statistical analyses were performed using SPSS for Windows (version 11.0, SPSS Inc., Chicago,
Illinois).
Results: The study included 50 patients:
Group I : Thirty patients with hypertension mean age 54.17.7 year recruited from the outpatient clinic of Ain Shams University
Hospitals.
Group II: Twenty subjects as control with mean age 50.19.2 years.
There was a higher mean SBP and DBP among hypertensive cases compared to controls and the difference is highly
significant statistically p<0.01.
The Department of Cardiology, Ain Shams University,

Cairo, Egypt.
Manuscript received 20 March, 2010; revised 25 April, 2010;
accepted 26 April 2010.
Address for Correspondence: Dr. Nagwa Elmahalawy,
The Department of Cardiology, Ain Shams University,
Cairo, Egypt.
219
Value of Tissue Doppler Imaging in Assessing Effect of Hypertension

There was a lower mean EF among cases with hypertension compared to controls and the difference is highly significant
statistically. p<0.01. There was a higher mean LV mass (211.757.5) LV mass index (111.232.4) among cases compared to
controls and the difference was highly significant statistically. p<0.01.
There was lower LV mass among cases on ACE as antihypertensive medication.
We classified the hypertensive group into two subgroups:
Group A-1: Those with diastolic dys function by the conventional echo Doppler defined by reversed E/A ratio.
Group A-2: Those with normal diastolic function by the conventional echo Doppler defined by E/A ratio 1.
There was significant difference between the level of systolic blood pressure in both sub groups, being higher in pts with
diastolic dysfunction (15940mmhg) p<0.001. There was a higher percentage of diastolic dysfunction among cases with LVH
compared to cases with no LVH by Echo cardiography but the difference was not significant statistically. p>0.05.
There was a lower mean S wave among cases with LVH compared to cases with no LVH but the difference is not significant
statistically. p>0.05. There was a higher mean E wave, A wave among cases with LVH compared to cases with no LVH but the
difference was not significant statistically. p>0.05.
Conclusion: Tissue Doppler Imaging is a useful tool, being preload independent it can accurately evaluate the systolic and
diastolic function. Pulsed Wave Tissue Doppler Imaging is superior to conventional Doppler in early detection of systolic and
diastolic dysfunction in hypertensive patients.
Key Words: Tissue Doppler Hypertension LVH Diastolic function.
Introduction
The patients were recruited from the outpatient

clinic of Ain-Shams University hospitals.
Numerous studies have focused on sub clinical

diastolic dysfunction in patients with hypertension
and preserved global LV systolic function; however,
in these studies, systolic function was not assessed
quantitatively [5].
Exclusion criteria:
1- Coronary heart disease.
2- Cardiac arrhythmias.
3- Valvular heart disease.
Echocardiography using TDI reveals that hypertensive patients with preserved global LV systolic function often have combined impairment of
systolic function and diastolic function [6].
Abnormal LV ejection fraction (LVEF 55%).

All patients were subjected to the following:
1- Carful history taking:
Included age, diabetes mellitus, smoking, history of hypertension, its duration, whether or not
on regular treatment, and the type of medications.
Aim of the work:

To assess the impact of hypertension on both
systolic function and diastolic function using pulsed
Doppler and tissue Doppler echocardiography in
hypertensive patients with preserved global LV
systolic function (EF).
1- Group 1: Included 30 patients (14 men and 16

women) with history of hypertension.
Physical examination:
Systolic and diastolic blood pressures were
measured by sphygmomanometer in the sitting
position: Patients were considered to be hypertensive, when systolic blood pressure values were
>140mm Hg and/or diastolic blood pressure
>90mm Hg or if known hypertensive on medications.
2- Group 2: Included 20 subjects (9 men and 11

women) with no history of hypertension and
normal findings on two-dimensional echocardiography.
12-lead ECG:
Which was analysed with special interest for
presence or absence of left ventricular hypertrophy
and to detect any ischemic changes.

We studied two groups of subjects:
220
Nagw a Elmahalawy, et al
Transthoracic echocardiography:
Was done using Vingmed Vivid 5 machine with
use of echo transducer 2.5MHz. All the study
population was examined in the supine or the left
lateral decubitus position. The standard views were
the parasternal long axis, parasternal short axis
view, apical 4-chamber view, and apical 2-chamber
view.
The ratio between the early filling and the late

filling waves (N=1-2).
Diastolic dysfunction is considered if E/A ratio
<1.
Tissue Doppler imaging:
Was done using the Echocardiographic Vingmed
Vivid 5 machine, to assess systolic and diastolic
function of the left ventricle by measuring tissue
Doppler velocities at mitral annulus, using pulsedwave tissue Doppler myocardial velocity.
Wall thickness and LV diameter were derived

from M-mode echocardiograms according to the
recommendations of the American Society of the
Echocardiography with the formula of Devereux
[7].
LVIDd is the left ventricular internal dimension

in diastole.
Tissue Doppler velocities were measured in 2

views. The apical 4 chamber view to assess septal
and anterior points and apical 2 chamber view to
assess the inferior and lateral points on mitral
annulus. In those 4 positions we recorded the peak
systolic velocity (Sm), peak early velocity wave
(Em), and peak atrial systolic velocity wave (Am).
IVSd is the interventricular septal thickness in

diastole.
Systolic dysfunction is considered if peak systolic

velocity is <4.4cm/sec [9,10].
PWTd is the posterior wall thickness in diastole.
Diastolic dysfunction is considered if ETDI/ATDI

reversed [9,10].
LVM = 0.8 (1.04 X {(LVIDd + IVSd + PWTd)3 (LVIDd)3}

+ 0.6 g
Where:
1.04 is the specific gravity of the myocardium,

and 0.8 is the correction factor.
Staistical analysis:
All statistical analyses were performed using
SPSS for Windows (version 11.0, SPSS Inc., Chicago, Illinois).
Systolic function assessment:

Ejection fraction (EF%) was calculated as percentage change of left ventricular chamber volumes
between diastole and systole from apical four-and
two-chamber views using modified biplane Simpson's rule [8].
Comparisons between the groups were made

by student t-test for continuous variables and chisquare test for categorical variables.
A p-value of less than 0.05 was considered to
indicate statistical significance.
Ejection fraction >55% indicated a normal

systolic function and 55% is considered systolic
dysfunction [8].
A p-value of less than 0.001 was considered

highly significant.
Diastolic function assessment:

Pulsed-wave Doppler echocardiography was
used to evaluate diastolic LV function; Doppler
studies were recorded from the apical 4-chamber
view, with a sample volume positioned within the
inflow portion of the LV,midway between the
annular margins of the mitral valve.
Results
The study included two groups:
1- Group I: Thirty patients with hypertension:
Those patients had age range from 40-70 years
with mean age 54.17.7 years.
Waves measured by pulsed Conventional Doppler:
The patients were recruited from the outpatient

clinic of Ain Shams University Hospitals.
The peak E (early rapid ventricular filling) wave

velocity.
2- Group II: Twenty subjects as control with age

range from 40-70 years mean age 50.19.2
years.
The peak A (late ventricular filling) wave velocity.

E/A ratio.
221

Table 1: Clinical characteristics of the hypertensive patients.
Characteristics
Number
Mean (total) S.D.
Range (total)
Male
Female
Age
Sex
Percent
54.17.7 years
40-70 years
14
16
7
4
8
Smoking
D.M.
Dyslipidemia
Table 4: Comparison of the systolic blood pressure between

the two subgroup of cases with hypertension.
Cases with
Cases with normal
diastolic
diastolic function
dysfunction
46.7
53.3
23.3
13.3
26.6
159.41
40mmHg
Mean
Control
SD
Significiant
0.6 <0.001
Table 5: Distribution of medications of hypertension among

cases.
Significiant
Mean SD
SBP 158.3 16.4 113.5 7.4 11.4 <0.01

DBP 97.0 5.9 75.0 5.1 13.4 <0.01
There was significant difference between the

level of systolic blood pressure in both sub groups
p<0.001.
Table 2: Comparison between cases and controls as regards

mean SBP, DBP.
Cases
129.23
60mmHg
No.
Percentage
8
9
2
1
4
1
1
2
1
1
26.7
30.0
6.7
3.3
13.3
3.3
3.3
6.7
3.3
3.3
1st time to be diagnosed

ACE
Ca antagonist
Diuretics
B blockers
ACE + diuretics
ACE + B blockers
ACE + B + diuretic
B blocker + ca antagonist
B blocker + diuretic
HS
HS
p<0.01 Highly significant.
There was a higher mean SBP and DBP among

hypertensive cases compared to controls and the
difference is highly significant statistically p<0.01.
EF, LVM, LVMI .
Table 6: Effect of medication on the mean LVMI.

Cases
EF
LVM
LVMI
Control
Mean
SD
Mean
SD
60.5
210.7
111.2
32.4
4.8
57.5
65.3
150.5
81.7
6.9
33.3
18.0
p<0.05 Significant.
Significiant
<0.05
<0.01
<0.01
Sign
HS
HS
LVMI
1st time to be diagnosed N=9
ACE
N=8
B blockers
N=4
Combination N=9
p<0.01 Highly significant.
Mean
SD
124.7
95.8
124.5
105.5
26.2
17
46.7
23
There was lower LVMI among cases on ACE

as antihypertensive medication.
There was a lower mean EF among cases compared to controls and the difference is significant
statistically p<0.05.
There was a higher LVMI in cases 1st time to

be diagnosed as hypertensive, But the difference
was not significant statistically p>0.05.
There was a higher mean LVM, LVMI among

cases compared to controls and the difference is
highly significant statistically p<0.01.

LVH.
We classified the hypertensive group into two

subgroups:
Group A: Those with diastolic dys function by the
conventional echo Doppler defined by
reversed E/A ratio.
LVMI
No.
X2
Significant
Cases N=30
Control N=20
11
0
36.7
9.4
<0.01
HS
There was a higher percentage of LVH 36.7%

among cases compared to 0% among controls and
the difference is highly significant statistically
p<0.01.
Group B: Those with normal diastolic function by

the conventional echo Doppler defined
by E/A ratio 1.
222
Nagw a Elmahalawy, et al
Table 8: Comparison between cases with and without LVH
as regards the mean S wave, E wave, A wave E/A
ratio by tissue doppler.
Tissue Doppler
Mean SD
Table 10: Mitral annular septal velocities by TDI.

Item
Hypertensive
Control
Mean SD
Mean SD
8.13
9.51
9.55
1.07
8.46
10.52
9.80
1.32
Significant
Sm cm/s
Em cm/s
Am cm/s
Em/Am cm/s
1
1.25
1.8
0.19
0.6
1.1
0.98
0.2
Significant
<0.001
<0.001
<0.001
<0.001
Sign
Sign
Sign
Sign
S wave:
No LVH
LVH
N=19
N=11
8.3
7.4
2.5 1.0
2.2
>0.05
NS
E wave:
No LVH
LVH
N=19
N=11
9.3
9.4
2.8 0.03 >0.05

2.5
NS
A wave:
No LVH
LVH
N=19
N=11
9.8
9.9
3.2 0.02 >0.05

3.0
NS
There was a highly significant decrease in the

systolic and diastolic myocardial velocities in
hypertensive group in comparison to the control
group in mitral annular septal velocities p<0.001.
E/A ratio:
No LVH
LVH
N=19
N=11
1.05
1.02
0.3 0.2
0.3
NS
Table 11: Mitral annular lateral velocities.

Hypertensive
There was a lower mean S wave among cases

with LVH compared to cases with no LVH but the
difference is not significant statistically p>0.05.
Sm cm/s
Em cm/s
Am cm/s
Em/Am cm/s
There is a higher mean E wave, A wave among

cases with LVH compared to cases with no LVH
but the difference is not significant statistically
p>0.05.
Control
Item
E/A ratio
p
Significant
Mean
SD
Mean
SD
0.92
0.11
1.22
0.16
<0.001
>0.005
NS
Mean SD
Mean
SD
8.34
9.8
9.98
1.07
8.77
11.91
9.99
1.41
0.12
3
1
2
1.9
1.29
2.3
0.2
Significant
0.001
0.001
0.001
0.001
Sign
Sign
Sign
Sign
There was a highly significant decrease in

systolic and diastolic myocardial velocities in the
hypertensive group in comparison to the control
group in mitral annular lateral velocities p<0.001.
Table 9: Comparison between the two groups as regard E/A

ratio by Conventional Echo Doppler.
Hypertensive
Control
Item
8.57
8.75
7.12
8
7
6
5
There was significant difference between the

two groups as regard E/A ratio measured by Echo
Doppler.
4
3
2
1.4
1.22
0.92
1.2
0
Hypertensive
Hypertensive
with diastolic
with normal
dysfunction diastolic function
0.6
E/A ratio
1
0.8
ean Sm
>0.05
Control
subject
Figure 2: Mean TDI Systolic mitral annular velocities in

hypertensive with normal diastolic function, hypertensive with diastolic dysfunction and in control
subjects.
0.4
0.2
0
There was a highly significant difference between hypertensive patients with normal diastolic
function, hypertensive with abnormal diastolic
function and control subjects p<0.001.
Figure 1: Comparison as regards E/A ratio by Conventional

Echo Doppler, between hypertensive (1.22) and
control (0.92) as regards E/A ratio by Conventional
Echo Doppler.
223

5- Caruana L, Petrie MC, Davie AP, et al: Do patients with
suspected heart failure and preserved left ventricular
systolic function suffer from "diastolic heart failure" or
from misdiagnosis? A prospective descriptive study. BMJ
2000; 321: 215-8.
Conclusion
Tissue Doppler Imaging is a useful method,
beeing preload independent that can accurately
evaluate the systolic and diastolic function.
6- Manolis Bountioukos, Arend FL Schinkel, Jeroen J Bax,

et al: The impact of hypertension on systolic and diastolic
left ventricular function. Tissue Doppler Echocardiographic study. Am Heart J 2006; 151 (6): 1323.e7-1323.e12.
Pulsed Wave Tissue Doppler Imaging is superior

to conventional Doppler early detection of systolic
and diastolic dysfunction in hypertensive patients.
7- Devereux RB, Casal D, Klifield P, et al: Echocardiographic

determination of left ventricular mass in man: Anatomic
validation of method. Circulation 1986; 55: 613.
References
1- Aurigemma GP, Gaasch WH: Clinical practice. Diastolic
heart failure. N Engl J Med 2004; 351: 1097-1105.
8- Schiller NB, Shah PM, Crawford M, et al: Recommendations for quantification of the left ventricle by twod i m e n s i o n a l e c h o c a r d i o g r a p h y. J A m S o c
Echocardiography 1989; 2: 358.
2- De Boeck BW, Cramer MJ, Oh JK, et al: Spectral pulsed

tissue Doppler imaging in diastole: A tool to increase our
insight in and assessment of diastolic relaxation of the
left ventricle. Am Heart J 2003; 146: 411-419.
9- Pai RG, Gill KS, et al: Amplitudes,durations,and timings

of apically directed left ventricular myocardial velocities,
I. Their normal pattern and coupling to ventricular filling
and ejection. J Am Soc Echocardiography 1998; 11: 105111.
3- Garcia-Fernandez MA, Azevedo J, Mareno M, et al:

Regional diastolic function in ischemic heart disease using
pulsed wave TDI. Eur Heart J 1999; 20: 496-505.
4- Pai RG, Gill KS, et al: Amplitudes,durations,and timings
of apically directed left ventricular myocardial velocities,
II: Systolic and diastolic asynchrony in patients with left
ventricular hypertrophy. J Am Soc Echocardiogr 1998;
11: 112-118.
10- Garcia E,Perna E, Eduardo F, et al: Reduced systolic

performance by tissue Doppler in patients with preserved
and abnormal ejection fraction: New insights in chronic
heart failure. Echocardiography 2004 Feb; 21 (2): 205.
224
Impaired Endothelial Function is a Novel Marker of Subclinical Organ

Damage in Hypertensive Patients
MOHAMMED A ABDEL WAHAB, MD
Background: It is universally accepted that disturbed endothelial cell biology, variably including injury, damage, and
dysfunction, forms part of the early pathogenesis of atherosclerosis. Therefore, the assessment of endothelial dysfunction by
either noninvasive or invasive means may represent a clinically relevant tool to predict the overall vascular risk.
Aim: To evaluate the correlation between endothelial dysfunction and multiple target organ damage (TOD), we measured
endothelial function using high-resolution ultrasonography in hypertensive patients with or without TOD.
Patients and Methods: 50 hypertensive patients were divided into four groups as follows: Hypertensive patients with no
TOD (Group I, n=12); hypertensive patients with 1 TOD (Group II, n=12); hypertensive patients with 2 TOD (Group III, n=13)
and hypertensive patients 3 TOD (Group IV, n=13). Endothelial function was assessed by endothelium-dependent flow-mediated
dilatation (FMD) and -independent vasodilation (after sublingual administration of nitroglycerin) of the brachial artery using
high-resolution vascular ultrasound. We also assessed the intima-media thickness (IMT) of the common carotid, fundus
examination and left ventricular mass index (LVMI).
Results: FMD was inversely associated with the number of affected organs. FMD was lower in the patient groups with >/=3
TOD (Group V: 3.890.66% Vs Group III: 5.615.52%, p=0.039), 2 TOD (Group III: 5.615.52%, Vs Group II: 10.52 4.78,
p=0.026) and 1 TOD as compared with patients with no TOD (Group I: 16.086.4% Vs Group II, p=0.015). There was a
significant relationship between FMD and intima-media thickness (IMT), fundus retinopathy, LVMI and microalbuminuria.
Conclusion: These findings suggested that reduced FMD was associated with the number of TOD and may be considered
an indicator for evaluating TOD and may be a useful marker for detection of the efficacy of different anti-hypertensive treatment
in prevention of progression of TOD or even improving them.
Key Words: Endothelial Hypertensive Dilatation TOD.
Introduction
Flow-mediated endothelium-dependent (FMD)

vasodilation in the brachial artery is impaired in
patients with hypertension [3].
Impaired endothelium-dependent vasomotion

is a diffuse disease process resulting in abnormal
regulation of blood vessel tone and loss of several
atheroprotective effects of the normal endothelium
[1]. It is generally accepted that disturbed endothelial cell biology, variably including injury, damage,
and dysfunction, forms part of the early pathogenesis of atherosclerosis. Therefore, the assessment
of endothelial dysfunction by either noninvasive
or invasive means may represent a clinically relevant tool to predict the overall vascular risk [2].
The occurrence of major cardiovascular events

is usually the result of long term exposure to
hypertension and other cardiovascular risk factors,
and is often preceded by the development of asymptomatic functional and structural abnormalities,
this so called subclinical organ damage phase, is
potentially reversible and in turn represent a strong
independent predictor of unfavorable outcome.
This sub-clinical organ damage is described before
[4], including; Electrocardiographic left ventricular
hypertrophy (LVH), Echocardiographic LVH, Carotid wall thickening, Carotid femoral pulse wave
velocity >12m/s., Ankle brachial blood pressure
index <0.9, slight increase in serum creatinine,
low estimated glomerular filtration rate and Microalbuminuria.
The Department of Cardiology, Minya University.

Manuscript received 20 Feb., 2010; revised 13 March 2010;
Address for Correspondence: Dr. Mohammed A Abdel Wahab,
Cardiology Department, Minya University.
225
Impaired Endothelial Function is a Novel Marker of Subclinical Organ Damage
4th scan was taken 4 minutes after administration

of 400mg of GTN spray sublingually.

57 hypertensive patients were divided into four
groups as follows: Hypertensive patients with no
TOD (Group I, n=20); hypertensive patients with
1 TOD (Group II, n=12); hypertensive patients
with 2 TOD (Group III, n=12) and hypertensive
patients 3 TOD (Group IV, n=13).
o FMD percentage was calculating by the following equation:

2nd Scan 1st Scan
FMD% = x 100
1st Scan
o GTN percentage was calculating by the following equation:
Exclusion criteria include: Tobacco smoking,

previous myocardial infarction, coronary bypass
graft, cardiac valve disease, stroke, diabetes, dyslipidemia and obesity. All the participant were
subjected to: History taking, clinical examination,
office blood pressure measurement (Blood pressure
140/90 and above was considered hypertensive),
measurement of body mass index and body surface
area, laboratory investigation (Fasting and post
prandial blood sugar, lipogram, blood urea nitrogen,
serum creatinine, and quantification of albumin in
urine), and ambulatory blood pressure monitoring
(ABPM) device (model: TM 2430 Space Labs Inc).
4th Scan 3rd Scan

3rd Scan
o Dilatation percentage was calculating by the

following equation:
FMD%
DilRatio = x 100
GTN MD%
Echocardiography evaluation of the LVMI:

Was done according to the recommendations of
the American Society of Echocardiography (ASE)
as follows:
LV mass in grams = 0.8 {1.04 [(LVIDD +
PWTD + IVSTD)3 (LVIDD)3]} + 0.6g.
Colored duplex ultrasound to measure the

Intima-media thickness (IMT): The end-diastolic
IMT of both common carotid artery was measured
from the leading edge of the 1st echogenic line to
the leading edge of the 2nd echogenic line 10mm
caudal to the bulb using Hewlett Packard Sonos
1000 system, with 7.5Hz linear array transducers,
with the patient in the supine position and the neck
in slight hyperextension. A Plaque was defined as
presence of a focal thickening greater than 1.5mm
and plaques were sought in the entire extra-cranial
carotid tree.
And then indexing the LVM to height 2.7 and

BSA.
Assessment of micro-albuminuria:
Urinary albumin and creatinine concentrations
were determined on a morning spot-urine sample.
Urine albumin was determined by the ELISA method {(disease related group) DRG Microalbumin
ELISA (EIA-2361) USA}, whereas urinary creatinine was assessed by the kinetic Jaff method
with the Autoanalyzer Modular (Hitachi-Roche
Diagnostics, Manneheim, Germany). The urinary
albumin-to-creatinine ratio (ACR) was then calculated. MA was defined as an ACR of 30 to 299mg/g.
(referrence).
Colored duplex ultrasound to test the endothelial functions: Colored duplex ultrasound was
done for all subjects.The mean right brachial artery
antero-posterior diameter was measured 3-5cm
above the elbow, between media and adventitia
from 4 cycles synchronized with the end-diastole
at the R wave peaks [5].
Funduscopic retinal examination:

Subjects were graded according to Modified
Scheie Classification (reference):
A basic scan of the flow was taken.

2nd scan was taken after applying a pneumatic
tourniquet of 250-300mmHg. (Using mercurial
sphygmomanometer) for about 4.5sec. The scan
was taken 60 seconds after releasing the tourniquet measuring the maximum FMD.
Grade 0 No changes.
3 rd scan was taken after 15 minutes of rest to

allow recovery of the artery after FMD and that
was the basic of Glyceryl trinitrate (GTN)mediated dilatation (GTN-MD) reading.
Grade 3 Grade 2 + retinal hemorrhages and/or

exudate.
Grade 1 Minimal arteriolar narrowing.

Grade 2 Obvious arteriolar narrowing with focal
irregularities.
Grade 4 Grade 3 + swollen optic nerve (Malignant

hypertension).
226
GTN MD
Statistical method:
Data were analyzed using the Statistical Package
for the Social Sciences (SPSS), version 16 for
Window. All continuous data were expressed as
mean SD. A Students t-test was used to compare
continuous variables in the two groups while the
Mann-Whitney test was used to compare the nonparametric variables. A Pearsons correlation coefficient was used to study the correlation between
to parameters. Differences were considered significant at a two-tailed p0.05.

Results
There is a siginificant decrease in FMD and
dilatation ratio in group 2 (TOD 1) compared with
group 1 (TOD 0). Also, IMT and LVMI is significantly increased in group 2 compared to group 1
(Table 1).
Table 1: Comparison between patients of group 1 and 2.

TOD1 Group 2 n=12
TOD0 Group 1 n=20

p
Age
Office SBP
Office DBP
Mean 24h SBP
Mean 24h DBP
LVMI
Microalbuminuria
RCCA-IMT
LCCA-IMT
MCCA-IMT
FMD%
Dil. ratio
Mean
SD
Mean
SD
49.5000
159.17
94.1667
143.00
91.8333
37.6108
9.8025
0.0647
0.0667
0.0675
10.5183
57.8292
5.76037
9.49482
8.74729
7.04531
8.03213
7.81482
4.38317
0.01240
0.00984
0.00965
4.78047
19.57399
45.2500
127.35
77.5000
123.05
74.8000
27.7180
8.2510
0.0551
0.0580
0.0575
16.0790
94.7980
7.88653
5.32398
6.38666
6.65286
6.63008
3.10460
2.54444
0.00561
0.01143
0.00786
6.48300
40.06131
There is a significant decrease in FMD and

tendency for significant decrease in dilatation ratio
in group 3 (TOD 2) compared with group 2 (TOD
1). Also, IMT is significantly increased in group
3 compared to group 2 (Table 2).
0.115
<0.001
<0.001
<0.001
<0.001
<0.001
0.213
0.005
0.034
0.003
0.015
0.006
There is a significant decrease in dilatation

ratio in group 4 (TOD 3&4) compared with group
3 (TOD 2). Also, IMT of left CCA is significantly
increased in group 4 compared to group 3 (Table
3).

TOD1 Group 2 n=12
TOD2 Group 3 n=12

p
Age
Office SBP
Office DBP
Mean 24h SBP
Mean 24h DBP
LVMI
Microalbuminuria
RCCA-IMT
LCCA-IMT
MCCA-IMT
FMD%
Dil. ratio
Mean
SD
Mean
SD
49.5000
159.17
94.1667
143.00
91.8333
37.6108
9.8025
.0647
.0667
.0675
10.5183
57.8292
5.76037
9.49482
8.74729
7.04531
8.03213
7.81482
4.38317
.01240
.00984
.00965
4.78047
19.57399
46.6667
1.67.08
97.0833
154.75
94.2500
37.9225
19.5150
.0887
.0862
.0908
5.6092
38.1533
8.54223
22.908
9.40462
26.16078
11.19355
8.50475
22.66484
.04988
.02401
.03204
5.24979
27.08285
227
0.351
0.281
0.440
0.147
0.550
0.926
0.159
0.120
0.016
0.024
0.026
0.054

TOD2 Group 3 n=12
TOD3&4 Group 4 n=13

p
BMI
Age
Office SBP
Office DBP
Mean 24h SBP
Mean 24h DBP
AASI
LVMI
Microalbuminuria
RCCA-IMT
LCCA-IMT
MCCA-IMT
FMD%
Dil. ratio
Mean
SD
Mean
SD
24.67
46.67
167.08
97.08
154.75
94.25
0.731
37.92
19.52
0.089
0.086
0.091
5.61
38.15
3.06
8.54
22.91
9.40
26.16
11.19
0.097
8.50
22.66
0.050
0.024
0.032
5.25
27.08
25.62
48.54
178.46
104.23
151.77
92.92
0.813
59.56
78.00
0.097
0.108
0.106
3.89
64.99
2.79
5.25
13.45
12.05
11.45
5.59
0.070
12.66
58.97
0.021
0.023
.012
2.66
36.19
125
Also, the endothelial dependant flow mediated

dilatation is significant negatively correlated with
LVMI (Fig. 1 & Table 4), LCCA-IMT and MCCAIMT (Fig. 2 & Table 4). Furthermore, it was found
to be negatively correlated with the level of microalbuminuria, whoever such results not reached
statistical significance (Fig. 3 & Table 4).
LVMI
p=0.0001
75
50
25
0
0
10
20
30
% FMD
40
50
250
p
0.249
0.384
0.173
0.183
0.276
0.278
0.037
0.001
0.152
0.129
0.05
0.02
0.25
Micro albuminria
FMD%
r
MA
200
p=0.15
150
100
50
0
CCA IMT
0.20
60
Figure 2: Correlation between FMD and the mean common

carotid artery IMT (CCA IMT).
Table 4: Correlation of FMD.
CCA IMT
LVMI
100
Also the endothelial dependant flow mediated

dilatation is significant negatively correlated with
hypertensive retinopathy. (p<0.029 and Spearman
r=0.26) and (p<0.0001 & Spearman r=0.466)
respectively.
Age
LVMI
MA
RCCA
LCCA
MCCA
0.425
0.512
0.140
0.114
0.712
0.708
0.25
< 0.001
0.04
0.570
0.029
0.124
0.306
0.048
p=0.018
10
20
30
40
% FMD
50
60
Figure 3: Correlation between FMD and microalbuminuria.
0.15
0.10
Discussion
0.05
Impaired endothelium-dependent vaso-motion

is a diffuse disease process resulting in abnormal
regulation of blood vessel tone and loss of several
atheroprotective effects of the normal endothelium
[1].
0.00
0
10
20
30
% FMD
40
50
60
Figure 1: Correlation between FMD and LVMI.
228
Results of this study revealed that FMD is

associated with the number of target organ damage
in an inverse manner i.e the more the number of
organs affected, the less FMD. This result is in
agreement with [6] who concluded that reduced
FMD was associated with the number of TOD and
may be considered an indicator for evaluating
TOD.
endothelial function evaluated by measuring the

forearm vascular responses to intrabrachial infusion
of acetylcholine (endothelial dependant vasodilatation). The response to acetylcholine, were significantly blunted and minimal forearm vascular
resistances were increased in hypertensive patients
compared with controls. However, no correlation
was found between urinary albumin excretion and
vasodilatation in response to acetylcholine [11].
Also, others found that the microalbuminuria in
essential hypertension is weakly related to the
vasodilator response to Ach [12].
This result may be explained by the result of

another study [7] who concluded that the relationship between endothelial dysfunction and adverse
outcome is likely to be due not only to destabilization of established disease in high-risk populations but also to its impact on the evolution of the
atherosclerotic substrate.
Results of the current study found significant

positive correlation between the FMD% and the
common carotid artery intima media thickness
(CCA-IMT) where the (r=0.278, and 0.276 where
the p=0.02 and 0.02) for the mean and left common
carotid artery intima media thickness respectively.
Results of the current study found that FMD%,

was significant negatively correlated with the left
ventricular mass index (p=0.001).
Also in agreement with the current study several

studies [13,14] found significant association between
the carotid artery IMT and endothelial dependant
FMD. Moreover, others found that FMD was negatively related with IMT and LVMI respectively
[15] . Furthermore, It was found FMD% was inversely correlated with age, baseline vessel diameter
and carotid artery intima-media thickness in hypertensive elderly patients [1].
In agreement with results of the current study,

another study enrolled 65 never-treated hypertensive patients, the left ventricular mass index (LVMI)
was calculated, also the endothelial function was
tested as the responses of forearm vasculature to
acetylcholine (ACh), an endothelium-dependent
vasodilator. ACh was infused into the brachial
artery, a negative significant relationship between
LVMI and the FMD% during ACh infusions
(r=0.554; p<0.0001) (8).
References
1- Saka B, Oflaz H, Erten N, Bahat G, Dursun M, Pamukcu
B, Mercanoglu F, Meric M, Karan MA: Non-invasive
evaluation of endothelial function in hypertensive elderly
patients. Arch Gerontol Geriatr 2005 Jan-Feb; 40 (1): 6171.
Also the correlation between LVMI with FMD

was studied in newly discovered never treated
subjects with essential hypertension, and it was
found that the LVMI showed a significant negative
correlation with FMD% (r=0.61, p<0.05) [9].
2- Meyer AA, Kundt G, Steiner M, Schuff-Werner P, Kienast

W: Impaired flow-mediated vasodilation, carotid artery
intima-media thickening, and elevated endothelial plasma
markers in obese children: The impact of cardiovascular
risk factors. Pediatrics 2006 May; 117 (5): 1560-7.
Also the endothelial function was assessed in

32 hypertensive patients, using the reactive hyperemia method of the brachial artery. Flow mediated
dilatation was considerably higher in the control
group than in hypertensive patients with left ventricular hypertrophy [10].
3- Motoyama T, Kawano H, Hirai N, Tsunoda R, Moriyama

Y, Miyao Y, Sakamoto T, Yoshimura M, Kugiyama K,
Yasue H, Ogawa H: The relationship of left ventricular
mass to endothelium-dependent vasodilation of the brachial
artery in patients with hypertension. Cardiology 2001;
96 (1): 7-15.
Results of the current study demonstrated inverse correlation between the FMD% and the presence of microalbuminuria, whoever the correlation
not reached statistical significance (r=0.173 and
p=0.152).
4- Mancia G, De Backer G, Dominiczak A, Cifkova R,

Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen
SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A,
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Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of
Arterial Hypertension. J Hypertens 2007 Sep; 25 (9):
1751-62.
In agreement with the current study other authors evaluated the association between microalbuminuria, defined as urinary albumin excretion
between 30 and 300mg/24h, and endothelial dysfunction in essential hypertensive patients, the
5- Hashimoto M, Miyamoto Y, Matsuda Y, Akita H: New

methods to evaluate endothelial function: Non invasive
229

methods of evaluating endothelial function in humans. J
pharmacol Sci 2003; 93: 405-8.
diabetic hypertensive patients", Blood Press 2007; 5: 16.
6- Xu JZ, Zhang Y, Wu SN, Niu WQ, Zhu DL, Gao PJ:

Impaired endothelial function in hypertensive patients
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11- Taddei S, Virdis A, Mattei P, Ghiadoni L, Sudano I, Arrighi

P, Salvetti A: Lack of correlation between microalbuminuria and endothelial function in essential hypertensive
patients. J Hypertens 1995 Sep; 13 (9): 1003-8.
7- Halcox JP, Donald AE, Ellins E, Witte DR, Shipley MJ,

Brunner EJ, Marmot MG, Deanfield JE: Endothelial
function predicts progression of carotid intima-media
thickness. Circulation 2009 Feb 24; 119 (7): 1005-12.
Epub 2009 Feb 9.
12- Perticone F, Maio R, Tripepi G, Sciacqua A, Mallamaci

F, Zoccali C: "Microalbuminuria, endothelial dysfunction
and inflammation in primary hypertension", Journal of
Nephrol 2007; 20 Suppl 12.
13- Touboul PJ, Elbaz A, Koller C, Lucas C, Adrai V, Chedru
F, Amarenco P: "Common carotid artery intima-media
thickness and brain infarction", Circulation 2000; 18, 102
(3): 313-8.
8- Perticone F, Maio R, Ceravolo R, Cosco C, Cloro C,

Mattioli PL: Relationship between left ventricular mass
and endothelium-dependent vasodilation in never-treated
hypertensive patients. Circulation 1999 Apr 20; 99 (15):
1991-6.
14- Savoiu G, Dragan S, Nicola T, Fira-Mladinescu O, Gorun

C, Noveanu L, Tudor A, Muntean D, Mihalas G: Prognostic value of brachial artery flow-mediated dilation and
carotid artery intima-media thickness in hypertensive
patients. Rev Med Chir Soc Med Nat Iasi 2008 Apr-Jun;
113 (2): 331-6.
9- Palmieri V, Storto G, Arezzi E, Pellegrino T, Mancini M,

Di Minno G, Ferrara AL, Cuocolo A, Celentano A: Relations of left ventricular mass and systolic function to
endothelial function and coronary flow reserve in healthy,
new discovered hypertensive subjects. J Hum Hypertens.
2005 Dec; 19 (12): 941-50.
15- Lin JX, Yang X, Zheng XY, Chen DG: Endothelial dysfunction and target organ damage in hypertensive patients
complicating with or without metabolic syndrome. Zhonghua Xin Xue Guan Bing Za Zhi 2007 Aug; 35 (8): 7104.
10- Tsai WC, Lin CC, Huang YY, Chen JY, Chen JH: "Association of increased arterial stiffness and inflammation
with proteinuria and left ventricular hypertrophy in non-
230
Importance of Inflammatory Cytokines and Endothelial Peptides in

Predicting Hypertensive Left Ventricular Hypertrophy
OMYMA G AHMED, MD; HATEM A HELMY, MD*; OSAMA A IBRAHIEM, MD**;
MARWA A AHMED, MD; ASMA F HASSAN, MD
Background: Although it has been hypothesized that hypertension in part is an inflammatory disorder, the link between
inflammation and endothelial disorders with hypertensive complications as left ventricle hypertrophy (LVH) is still marginal.
This study was designed to investigate the role of inflammatory markers as interleukin-6 (IL-6), high sensitivity C reactive
protein (Hs-CRP), endothelial peptides as endothelin-1 (EDN-1) and nitric oxide (NO) and serum lipid profile in predicting
LVH. It also focused on the pathophysiological responsibility of inflammation and endothelial dysfunction in developing
hypertensive LVH.
Subjects and Methods: To examine these hypothesis forty hypertensive patients were enrolled and divided by using
echocardiography into hypertensive patients with normal left ventricular mass (Group I) and hypertensive patients with LVH
(Group II). Ten normotensive subjects were concerned and considered as control group . ELISA technique was used for
measuring plasma concentrations of IL-6, Hs-CRP, EDN-1 by special kits, while serum NO and lipid profile were measured
by spectrophotometer.
Results: Both hypertensive groups were relatively matched together regarding age, gender, body surface area and body
mass index (BMI), however they were significantly greater than control. Serum levels of IL-6, Hs-CRP and END-1, were
significantly higher and those of NO were significantly lower in both hypertensive groups compared to normotensive. Moreover,
these changes were obvious in hypertensive patients with LVH. Additionally, estimation of serum lipid profile showed that
levels of total cholesterol, triglycerides, and low density lipoproteins (LDL-C) were significantly elevated and that of high
density lipoproteins (HDL-C) were significantly reduced in group (II) compared to other groups. Among both hypertensive
patients, LV mass index was significantly positively correlated with serum levels of IL-6, Hs-CRP, EDN-1, cholesterol,
triglyceride, LDL-C and significantly negatively correlated with HDL-C but not with age and NO levels. However, the slope
of these relations was steeper in the hypertensive group with LVH. Besides, levels of IL-6 and EDN-1 were the most predictors
(r=0.849, p<0.0001, r=0.889, p<0.0001 respectively) for LVH.
Conclusion: The inflammatory markers are significantly increased in hypertensive patients with LVH. Increased EDN-1
and lowered NO are also concerned to a greater extent in hypertensive LVH that confirm a key pathophysiological role of
inflammation and endothelium dysfunction in developing and progression of hypertension and LVH which is vital for
recommending prophylactic and therapeutic strategies.
Key Words: Inflammatory cytokines Endothelial peptides Left ventricular hypertrophy.
Introduction
hemodynamic and nonhemodynamic factors (Angela et al, 2005). LVH is considered a fundamental
risk factor for cardiovascular events and sudden
death (Beverly et al, 2000) because it predisposes
to arrhythmias and maximizes the consequences
of acute myocardial ischaemia (Heckbert et al,
2006).
LVH is an important clinical finding that arises

from and contributes to a number of serious cardiovascular conditions. It is modified by both
The Departments of Physiology, Cardiology* and Internal
Medicine**, Faculty of Medicine, Assuit University, Egypt.
Hs-CRP has been linked to cardiovascular diseases (Ridker et al, 2002). The raised Hs-CRP and
other markers of inflammation, could point to an
active involvement of inflammatory process in the
development of the hypertensive syndrome (Fernan-
Manuscript received 5 Feb., 2010; revised 20 March, 2010;

accepted 22 March, 2010.
Address for Correspondence: Dr. Omyma G Ahmed,
The Department of Physiology, Faculty of Medicine,
Assuit University, Egypt.
231
Importance of Inflammatory Cytokines & Endothelial Peptides
dez-Real et al, 2001, Hackam & Anand, 2003 and

Danesh et al, 2004). In addition, the endothelium
system is comprised of 4 active endothelins, with
EDN-1 being the predominant isoform in the cardiovascular system (Yanagisawa et al, 1988). Increased EDN-1-may be implicated in hypertension,
congestive heart failure, and coronary artery disease
(Gary et al, 2007).
of body weight and height (to calculate body mass

index).
Biochemical measurements:
Blood samples (10ml) were obtained from healthy
controls and patients. The samples were taken
slowly from an antecubital vein and were transferred to chilled sterile disposable tubes. (5ml)
was heparinized and separated as plasma and the
rest was separated as serum after centrifugation
at 3000 r.p.m. for 20min. Serum and plasma
immediately stored at 70C until assay.
Up till now, the predictors of systemic hypertension and LVH are indefinite and our knowledge
about the possible mechanisms involved in development of hypertensive LVH is incomplete. To
solve this problem, this study was planned to prove
the predictive value of inflammatory markers (IL6, Hs-CRP), endothelial peptides (EDN-1 and NO)
and serum lipid profile in developing hypertensive
LVH. Also, the motivation behind this investigation
was to focus on their contribution in pathogenesis
of hypertension and LVH. This may be needed for
prophylactic and therapeutic purposes.
Enzyme-linked immunosorbent assays (ELISA)

were performed for measuring concentrations of
IL-6 (Cat. No. M1916), Hs-CRP (Cat. No. 7033)
and plasma EDN-1 (Cat. No. 6901) using Biosurce Europe commercial kits with monoclonal
antibodies against each substance and following
the instructions supplied with each kit. The apparatus used was Ansoth, 2000 manufactured in
Austria.
Subjects and Methods
Serum NO was determined through evaluating

its oxidation products (nitrates and nitrites) by
using Griess reagent through spectrophotometer
as described by Ding et al (1988).
Study population:
This study was carried out throughout cooperation between departments of Physiology,
Cardiology and Internal Medicine in Assiut University Faculty of Medicine. Forty outpatients with
essential hypertension were enrolled in this study.
All subjects provided their informed consent, and
the study protocol was approved by the Human
Study Ethics Committee of Assiut University.
Blood pressure was measured at the outpatient
clinic, and hypertension was defined according to
JNC-VII (2003) as systolic pressure 140mmHg,
diastolic pressure 90mmHg, or both. The patients
were echocardiographically divided into a hypertensive patients (n=20) with normal left ventricular
mass (Group I) and a hypertensive patients (n=20)
with left ventricular hypertrophy (Group II). Ten
normotensive subjects served as the normotensive
control group (C).
Fasting total cholesterol levels were measured

by quantitative enzymatic colorimetric determination using Stanbio-cholesterol Liqui Color kit
(procedure No. 1010), measured by spectrophotometer according to the method of Flegg (1973).
HDL-C levels were measured by using StanbioHDL Cholesterol kit (procedure No. 0599) according to the method described by Finley (1978).
Triglycerides levels were measured by using
Stanbio Liquicolor Trigycerides kit (procedure
No. 2100) according to the method described by
Bucolo and David (1973). The LDL was calculated by subtracting both levels of HDL and one
fifth of triglycerides from the levels of total
cholesterol (Friedewald et al, 1972).
Exclusion criteria: Cases showing clinical or

laboratory evidences of inflammation, renal failure,
secondary causes of hypertension, valvular diseases,
overt heart failure or coronary artery diseases were
excluded.
Body mass index (BMI):

Firstly, body weight and height were measured
to calculate body surface area according to Mosteller equation (1987). BMI was calculated as body
weight (Kilograms) divided by height (meters)
squared. BMI was used as an index of relative
adiposity (Lazarus et al, 2000).
All subjects were submitted to full history,

examination, ECG (to detect criteria of LVH),
detailed echocardiography (to estimate the LV wall
thickness and mass index) as well as measurements
Echocardiography:
LV mass was determined from Echocardiographic measurement of the left ventricle by stander
232
Omyma G Ahmed, et al
techniques with subjects in the supine position

using HP (Sonos 4500) (Hewlett-Bakard USA).
Studies were performed with two-dimensional
guided M-mode echocardiography with transducer
frequencies appropriate for body size. Measurement
of the left ventricular internal dimension, the posterior wall thickness and interventricular septal
thickness were made during diastole according to
the methods established by American Society of
Echocardiography (Sahn et al, 1987). Left ventricular mass index was calculated by dividing LV
mass by body surface area (Liebson et al, 1993).
The cutoff level used to define the most severe
LVH was a LV mass index >116g/m2 in men and
104g/m2 in woman (Devereux, 1996).
according to that described by Knapp and Miller

(1992). A value of p0.05 was considered statistically significant.
Results
Statistical analysis of studied parameters supported a vital role of inflammatory markers and
endothelial peptides in predicting hypertensive
LVH. Also, this study highlighted on the possible
mechanisms underlying the development of essential hypertension and LVH. A summary of these
results is shown in Figs. (1,2) and Tables (1-3).
Clinical characteristics (Table 1):
When patients were divided according to the
presence or absence of LVH, both hypertensive
patients (Group II versus Group I) were matched
together regarding age (59.151.32 versus 58.6
1.51 years), sex (male/female = 6/14), body surface
area (1.760.038 versus 1.690.03m2) and body
mass index (30.361.06 versus 27.441.08Kg/m2).
Echocardiographic records revealed significant
(p<0.0001) increase left ventricular mass and left
ventricular mass index in the hypertensive patients
with LVH (Group II) when compared with hypertensive patients with normal left ventricle mass
(Group I). Also, most of studied clinical parameters
were significantly higher in hypertensive groups
versus controls.
Statistical analysis:
Data are expressed as mean SE for all parameters. The data were analyzed by using GraphPad
Prism data analysis program (GraphPad Software,
Inc., San Diego, CA, USA). For the comparison
of statistical significance between patients and
normal subjects, Student Newman-Keuls t-test for
unpaired data was used. For multiple comparisons,
one-way analysis of variance (ONE-WAY-ANOVA)
test followed by least Significant Difference (LST)
was used. Correlations of ventricular mass index
with the other variables were assessed using Spearmans non-parametric correlation coefficient
Table 1: Clinical characteristics of normotensive subjects and hypertensive patients.

Hypertensive patients
Parameters
Normotensive
subjects
(Group C)
n=10
Normal left
ventricle mass
(Group I)
n=20
Left ventricle
mass hypertrophy
(Group II)
n=20
Male/female
7/3
6/14
6/14
Age (Years)
Range
46.101.04
58.601.51***
27%
59.151.32***
28%
Body surface area (m2)
1.660.036
1.690.03
1.8%
1.760.038
6%
Body mass index (Kg/m2)
24.121.095
27.441.08
13.7%
30.361.06***
25.8%
LV Mass (gm)
136.66.5
139.47.9
2.04%
226.27.4***
OOO
65.5%
LV Mass index
78.734.32
82.453.85
4.7%
134.16.15**
OOO
70.33%
(LVM/Body surface area)
Data are the means SE, % deviation from control, ** = p<0.01/*** = p<0.001 Vs. control group,
O O O = p<0.001 group II versus group I. Other comparisons between groups were not significant p>0.05, % increase.
233
Biochemical characteristics (Table 2 & Fig. 1):

The levels of inflammatory cytokines, IL-6 and
Hs-CRP (16.60.49 versus 12.530.4pg/ml and
12.980.67 versus 7.230.45mg/ml respectively)
were significantly (p<0.0001) higher in group II
than group I. Simultaneously, levels of endothelial
vasoconstrictor peptide, EDN-1 showed similar
pattern. They significantly (p<0.0001) increased
in group II versus group I (13.850.76 versus
9.840.77pg/ml). However, levels of NO were
insignificantly different in both groups (20.160.84
versus 23.281.33nmol/ml).
that of NO and HDL-C significantly (p<0.0001)

declined in both hypertensive groups in comparison
to normotensive subjects.
Correlations and regression analysis (Table 3 &
Fig. 2):
Within the hypertensive patients, the degree of
hypertrophy as indicated by the magnitude of LV
mass index was significantly positively correlated
with serum levels of inflammatory markers (IL-6
and Hs-CRP), EDN-1, and serum lipids (cholesterol, triglyceride and LDL-C) but significantly negatively correlated with HDL-C and insignificantly
correlated with age and levels of NO. However,
the slope of these correlations was steeper in the
hypertensive group complicated with LVH. Besides,
levels of IL-6 and EDN-1 were the most predictors
(r=0.849, p<0.0001, r=0.889, p<0.0001 respectively) for LVH.
Statistic analysis of lipid profile showed significant increase serum levels of LDL-C, cholesterol
and triglyceride but significant decrease HDL-C
in group II versus groups I. Furthermore, the levels
of IL-6, Hs-CRP, EDN-1, LDL-C, cholesterol and
triglyceride significantly (p<0.0001) increased and
Table 2: Biochemical characteristics normotensive subjects and hypertensive patients.

Hypertension patients
Parameters
Normotensive
subjects
(Group C)
IL-6 (pg/ml)
4.350.29
12.530.4***
188%
16.60.49***
OOO
281.6%
Hs-CRP (mg/ml)
4.190.38
7.230.45***
72.6%
12.980.67***
OOO
209.7%
EDN-1 (pg/ml)
5.490.27
9.840.77***
79.2%
13.850.76***
OOO
152.3%
NO (nmol/ml)
38.353.44
23.281.33***
39.3%
20.160.84***
47.43%
Normal left
ventricle mass
(Group I)
Left ventricle
mass hypertrophy
(Group II)
Data are the means SE, % deviation from control, IL-6 = Interleukin-6, Hs-CRP = High sensitivity C reactive protein,
NO = Nitric oxide. EDN-1 = Endothelin-1, *** = p<0.001 versus control group, O O O = p<0.001 group II versus group I.
Other comparisons between groups were not significant p>0.05. % decrease, % increase.
*** ***
300
Group C (normotensive subjects)
*** ***
250
mg/dl
*** ***
Group I (hypertensive patients with normal LV)

Group II (hypertensive patients with LVH)
200
Data are the means SE. *** = p<0.001 Vs. control group,
O = p<0.05, O O O = p<0.001 group I1 (the hypertensive
patients with left ventricle mass hypertrophy versus group I
(the hypertensive patients with normal left ventricular mass).
Other comparisons between groups were not significant
p>0.05. HDL-C = High density lipoprotein cholesterol, LDLC = Low density lipoprotein cholesterol.
150
100
*** ***
50
HDL-C
LDL-C
Cholesterol Triglyceride
Figure 1: Bar graph shows serum lipid profile of normotensive subjects and hypertensive patients.
234
18
10
13
8
50
60
70
80
LV mass index
90
100
100
120
140
LV mass index
160
IL-6 (pg/ml) r=0.74***
IL-6 (pg/ml) r=0.85***
Hs-CRP (mg/ml) r=0.74***
Hs-CRP (mg/ml) r=0.61***
Endothelin-1 (pg/ml) r=0.96***
Endothelin-1 (pg/ml) r=0.89***
Figure 2-A: Hypertensive patients with normal left ventricle

mass index.
180
Figure 2-B: Hypertensive patients with left ventricle hypertrophy.
Figure 2 (A,B): Significant relations and linear regression between left ventricle mass index with IL-6 (Interleukin-6), Hs-CRP
(High sensitivity C reactive protein), EDN-1 (endothelin-1) were observed in both hypertensive patients groups.
The hypertensive patients with left ventricular hypertrophy showed the steepest slope among them.
Table 3: Multiple correlations analysis in both hypertensive patients (Groups I and II) with left ventricle
mass index as a dependent variable.
Hypertensive patients
Normal left ventricle mass
(Group I) n=20
Variables
Coefficient (r)
Age
Body mass index
Left ventricle mass
IL-6
Hs-CRP
EDN - 1
NO
Cholesterol
Triglyceride
LDL-C
HDL-C
0.2044
0.3112
0.9222
0.7385
0.7428
0.9557
0.3226
0.6766
0.6429
0.6594
0.3403
IL-6
= Interleukin -6.
Hs-CRP = High sensitivity C reactive protein.
NO
= Nitric oxide.
*** = p<0.001, ** = p<0.01, * = p<0.05.
Left ventricle mass hypertrophy

(Group II) n=20
Coefficient (r)
0.3873
0.1816
p<0.0001***
0.0002***
0.0002***
p<0.0001***
0.1654
0.0011**
0.0022**
0.0016**
0.1421
0.02928
0.5725
0.7231
0.8492
0.6069
0.8890
0.1485
0.6349
0.8084
0.6246
0.7556
p
0.9053
0.0104*
0.0005***
p<0.0001***
0.0059**
p<0.0001***
0.5440
0.0035**
p<0.0005***
0.0042**
0.0002***
EDN-1 = Endothelin -1,

HDL-C = High density lipoprotein cholesterol.
LDL-C = Low density lipoprotein cholesterol.
Discussion
left ventricular hypertrophy, could be markedly

under the influence of co-existing risk factors such
as age, gender, obesity, and dyslipidaemia (Smith
and Mensah, 2003). Also, hypertension and LVH
are associated with increased risk for sudden death
while regression of LV mass is associated with
Cardiovascular disease is directly related to the

level of blood pressure, however, BP is not the
only determinant of cardiovascular damage and
the propensity to develop organ damage, including
235
reduction of cardiovascular events, thus confirming

the importance of predicting LVH (Agha et al,
1998 and Heckbert et al, 2006).
In the current investigation, both hypertensive

groups (I & II) had a significant increase of inflammatory cytokines (IL-6 increased 188% and 281.6%
respectively and Hs-CRP increased 72.6% &
209.7% respectively) when compared to control
subjects that agreed with studies of Ridker et al
(2002), Gavin et al (2003), Sesso et al (2003),
Danesh et al (2004) and Raitakari et al (2005).
They reported that CRP and blood pressure are
independent determinants of cardiovascular risk,
and their predictive value is additive. Increasing
levels of blood pressure may stimulate a proinflammatory response and that endothelial inflammation
may also precursor the changes in arterial wall that
characterize the hypertensive state (Intengan &
Schiffrin, 2001, Venugopal et al, 2002 and verma
et al, 2002a). Furthermore, Chae et al (2001),
Fernandez et al (2001) and Bermudez et al (2002)
demonstrated that levels of CRP and other markers
of inflammation, such as interleukin-6 related to
levels of blood pressure.
Despite accumulating data, the relationship

between hypertensive LVH and both vascular inflammation and endothelium dysfunction is uncertain and our knowledge about the possible pathophysiological roles of inflammation and endothelial
dysfunction in progression of hypertension and
LVH are still deficient.
This investigation hypothesized that inflammatory cytokines (IL-6, Hs-CRP), endothelial peptides
(EDN-1 and NO) and serum lipid profile may have
a role in predicting and explaining possible pathophysiological mechanisms of hypertensive LVH.
To accomplish the suggested goals, forty hypertensive patients were selected and evaluated their LV
mass index, plasma concentrations of IL-6, HsCRP, EDN-1, serum NO and lipid profile.
In this study, age incidence was significantly
higher in both hypertensive groups (I & II) comparable to controls (27% and 28% respectively),
similarly BMI was greater in both groups (13.7%
and 25.8% respectively). These findings emphasized that aging and BMI were determinants of
hypertension. These findings were in line with
study of Futoshi et al (2007). In addition, Toshio
et al (1996), Makoto et al (2002), Tuomilehto
(2004) and Lepira et al (2006) reported that aging
is powerful and independent risk factors for hypertensive LVH and impaired microvascular circulation. Furthermore, aging appears as the main clinical determinant of large artery stiffness (Benetos
et al, 2002 and Kenchaiah & Pfeffer, 2004) and it
produces a diffuse focal loss of ventricular myocytes, so burden the remaining myocytes with
stress, leading to reactive hypertrophy (Simon,
2004). Moreover, de Simone et al (1998) verified
the role of obesity in such a pathophysiology of
hypertension. Also, it acts as a strong determinant
of LVH and the adipose tissue is a recognizable
site of cytokine production, in particular interleukin6 and tumor necrosis factor.
The potential pathophysiological mechanisms

that verify association between blood pressure and
inflammatory markers are suggested by many
investigations. Increased blood pressure, pulsatile
blood flow and vascular strain may encourage
vascular inflammation through increase of soluble
intercellular adhesion molecule-1 that up regulates
monocyte chemoattractant protein-1 (Wung et al,
1996 and Chappell et al, 1998). These changes, in
turn, result in increasing monocyte adhesion to the
endothelium that triggers inflammation process
(Capers et al, 1997). Furthermore, elevated blood
pressure may lead to generation of reactive oxygen
species and increased oxidative stress (Yasunari
et al, 2002). Hypertension, inflammatory molecules
such as CRP and TNF- are increased and related
to both oxidative stress and endothelial activation
(Santina et al, 2006). Also, Rocha et al (2002)
found that angiotensin II induced hypertension in
rat models through direct inflammatory response
in smooth muscle cells by stimulation of interleukin-6 release which is a primary stimulus for CRP
synthesis in the liver that supports relationship
between interleukin-6 levels and blood pressure
(Wang et al, 2003). So, Hermann et al (2006) added
that anti-inflammatory drugs can be used as a novel
therapy of hypertension.
Besides, hypertensive groups concerned in this

work, were fairly matched together regarding age,
gender, body surface area and body mass index
that concurred with the studies of Pavlos et al
(2005) and David et al (2006). They found that
hypertensive patients with or without LV H did
not differ regarding age, sex, waist to hip ratio and
diastolic BP.
Alternatively, CRP may potentially play a more

direct role in promoting hypertension by lessening
the production of dilator NO by endothelial cells
(Verma et al, 2002a) and augment the production
236
of EDN-1, a potent endothelium-derived constrictor,

and may induce the expression of monocyte
chemoattractant protein-1 and soluble intercellular
adhesion molecule-1 via EDN-1-and interleukin6-dependent pathways (Verma et al, 2002b).
risk factors like age, hypertension, and hyperlipidemia are associated with impaired endotheliumdependent vasodilation either as a consequence of
increased inactivation of endothelium-derived
vasodilators or increased formation of endotheliumderived contracting factors (Yoshida et al, 2007).
Inflammation has also been associated with decreased endothelium-dependent relaxation, a process related to an alteration in the bioavailability
of NO. This imbalance of endothelium-derived
factors plays a role for development of hypertension, LVH and ischemic vascular diseases (Santina
et al, 2006).
In the current research, plasma levels of IL-6

and Hs-CRP in hypertensive patients with LVH
(group II) were significantly higher than group I
(hypertensive patients with normal LV mass). These
findings agreed with the supposed relation of
inflammation with the progression of hypertension
and LVH and coincided also with the results of
Pavlos et al (2005) and David et al (2006) who
reported that patients with LV H had higher CRP,
brain natriuretic peptide concentrations and higher
systolic blood pressure than those without LV
hypertrophy. Also, Gil et al (2007) added that both
systemic inflammation and endothelial damage
were associated with LVH occurrence. These findings suggest that alterations of LV mass are associated with inflammation in essential hypertensive
patients which may explain the increased cardiovascular risk associated with LVH.
Moreover, Gary et al (2007) found that EDN1-mediated vasoconstrictor tone increases with age
in healthy men but can be alleviated with regular
aerobic exercise. Also, EDN family gene polymorphisms might play an important role in the etiology
of essential hypertension (Mariko et al, 2007).
Lipid profile estimation, in this research, revealed a significant increase in LDL-C, total cholesterol and triglyceride levels while a significant
decrease in HDL-C in hypertensive patients with
LVH (group II) compared to groups I and control
subjects. These results showed significant increased
risky lipids (cholesterol, triglyceride, LDL-C)
whereas cardio-protective lipid, HDL-C significantly declined in selected patients in relation to
controls. These may support their influence on
progression of hypertension and development of
LVH. The relationship between serum lipids and
hypertensive LVH was studied by other investigators (Manninen et al, 1992; Fruckart & Duriez,
2002; Vittorio et al, 2003 and Roberto et al, 2004).
They found that left ventricular hypertrophy was
diagnosed by echocardiography, and associated
with obesity, subclinical hyperglycemia, low (HDLC) and high triglycerides that emphasized involvement of dyslipidaemia in pathophysiology of hypertension and LVH.
Plasma levels of EDN-1 in hypertensive patients

with LVH demonstrated significant increase whereas serum NO levels significantly decreased in
comparable to those patients with normal LV mass
or normotensive subjects involved in this study.
Significant alterations in endothelial peptides
(EDN-1 and NO) in both hypertensive patients
groups harmonized with other investigations (Kharbanda, et al, 2002; Jin et al, 2003; Stankevicius et
al, 2003; Angela et al, 2005; Santina et al, 2006
and Edgar et al, 2008). They reported that increased
EDN-1-mediated vasoconstrictor tone and declined
release of endothelium-derived relaxing factors
such as NO have been linked to the pathophysiology
of hypertension and LVH. Also, endothelial NO
synthase expression and activity are lower in LVH
(Yoshida et al, 2007). Treatment with antioxidant
probucol induced reduction of LVH and increased
NO bioavailability through its scavenger capacity
(Aubin et al, 2006).
In hypertensive patients, the degree of hypertrophy as indicated by the magnitude of LV mass

index (greater than 116g/m2 in men and 104g/m2
in woman) was significantly positively correlated
with serum levels of inflammatory markers (IL-6
and Hs-CRP), EDN-1, and serum lipids (cholesterol, triglyceride and LDL-C), significantly negatively correlated with HDL-C and insignificantly correlated with levels of NO. However, the slope of
these correlations was steeper in the hypertensive
group complicated with LVH.
The impending pathophysiological role of endothelium in hypertension is verified by many

studies. The endothelium regulates the underlying
smooth muscle layer and vascular tone by release
of endothelium-derived relaxing factors such as
NO and prostaglandins, as well as vasoconstricting
factors such as EDN-1, superoxide (O2), and thromboxane (Stankevicius et al, 2003). Cardiovascular
237
The correlations analysis used in this study

revealed the specifically highest correlation of both
IL-6 and EDN-1 levels (r=0.849, p<0.0001,
r=0.889, p<0.0001 respectively) for LVH. This
result highlighted the superior predictive roles of
inflammatory cytokine (IL-6) and EDN-1 for hypertensive LVH that concurred with the study of
Gil et al (2007). Also, Howard et al (2007) supported that CRP strongly associated with an increased risk of hypertension. The previous data
established involvement of innate immunity pathway down to interleukin-6 and on to CRP in the
genesis of hypertension and LVH. Bhalla et al
(2005) and Irzmanski et al (2007) found high
concentration of atrial natritic peptid (ANP) and
BNP in concentric LVH. So, in hypertensive patients LV hypertrophy can be excluded on the basis
of a single blood sample for determination of BNP
and CRP (David et al, 2006).
therapy for their prevention and management.

Because electrocardiographic criteria for LVH may
be insensitive for the detection of increased LV
mass and echocardiographic results are labor- and
time-intensive and may not be adequate in all
patients, especially in those with obesity or pulmonary disease, measurements of plasma inflammatory cytokines and endothelial peptides levels may
be useful for the detection of concentric LVH in
essential hypertensive patients.
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241
Ambulatory Arterial Stiffness Index and its Correlation with Target

Organ Damage in Patients with Essential Hypertension
MOHAMED M SAAD, MD; MOHAMMED A ABDEL WAHAB, MD
Background: Increased arterial stiffness has been shown to predict cardiovascular mortality in patients with primary
hypertension. Asymptomatic organ damage is known to precede cardiovascular events.
Aim: To detect the correlation between ambulatory arterial stiffness index (AASI) as a measure of arterial stiffness with
the early and late target organ damage.
Patients and Methods: 70 subjects were divided into 2 groups. Group 1 (includes 50 hypertensive patients) and group 2
(include 20 normo-tensive subjects).
Office and 24h systolic and diastolic blood pressure measurement was done for all groups and from it AASI was calculated.
We also assessed the intima-media thickness (IMT) of the common carotid artery, and left ventricular mass index (LVMI). Also,
detection of microalbuminuria and fundus examination was done for all subjects.
Results: AASI is significantly increased in hypertensive group compared to normotensive group (p<0.001). Furthermore,
AASI is also significantly correlated with markers of target organ damage namely, LVM (p<0.001), LVMI (p<0.001),
microalbuminuria (p=0.009), right common carotid artery IMT (p=0.002), left common carotid artery IMT (p<0.001), and mean
common carotid artery IMT (p<0.001), prevalence of carotid plaque (p=0.034) and fundus retinopathy (p<0.001) Moreover,
AASI correlates with the number of target organ damage.
Conclusion: AASI as a marker of arterial stiffness is increased in hypertensive patient. AASI not only correlates with all
subclinical target organ damage but also progressively increases with the degree of subclinical target organ damage. This may
clarify the usefulness of AASI as a marker for early detection of high risk hypertensive patients and for assessment of the
efficacy of different therapeutic modalities in prevention of target organ damage.
Key Words: Hypertension AASI Target organ damage.
Introduction
cardiographic left ventricular hypertrophy(LVH),

echocardiographic LVH, carotid wall thickening,
ankle brachial blood pressure index <0.9, slight
increase in serum creatinine, low estimated glomerular filtration rate, and microalbuminuria [1].
The occurrence of major cardiovascular events

is usually the result of long term exposure to
hypertension and other cardiovascular risk factors,
and is often preceded by the development of asymptomatic functional and structural abnormalities,
this so called subclinical organ damage phase, is
potentially reversible and in turn represent a strong
independent predictor of unfavorable outcome and
these subclinical organ damages include; electro-
Arterial stiffening plays an important role in

the development of hypertension and cardiovascular
diseases [2]. Arterial stiffness that can be detected
and treated at early stage, is a strong predictor of
cardiovascular morbidity and mortality [3].
Although several indexes of arterial stiffness
are currently used, they remain underused in routine
clinical practice for cardiovascular risk stratification, possibly because with the exception of pulse
pressure, measurement of most indexes requires
special equipment and highly trained observers [4].
The Department of Cardiology, Minya University.

Manuscript received 29 Jan., 2010; revised 2 March, 2010;
Address for Correspondence: Dr. Mohamed Abdel Kader,
Cardiology Department, El-Minya University Hospital.
243
Ambulatory Arterial Stiffness Index & its Correlation with Target Organ Damage
Ambulatory arterial stiffness index (AASI) has

been proposed as a marker of arterial stiffness,
which predicts cardiovascular mortality [5]. AASI
was significantly correlated with the pulse wave
velocity both in males and females. Also it was
significantly correlated with the peripheral and
central augmentation indexes, both before and after
adjustment of the body height and the 24-h pulse
rate [4].
cuff. The device was set to measure blood pressure

at 15-minute intervals during the daytime and at
30-minute intervals during the nighttime with the
patient instructed to hold the arm immobile at the
time of measurements preferably at the level of
the heart and to keep the daily activities and quality
of sleep for 24 hours.
Calculation of the Ambulatory Arterial Stiffness
Index (AASI):
From 24-hour recordings, we computed for
each participant the regression slope of diastolic
on systolic blood pressure, the regression line was
not forced through the origin (intercept 0), because
during diastole when flow drops to 0, such a phenomenon does not occur for blood pressure [4].
The rationale underlying this is that, for any given
increase in distending arterial pressure, systolic
and diastolic pressures tend to increase in a parallel
fashion in a compliant artery, whereas in a stiff
artery, the increase in systolic pressure is accompanied by a lesser increase, or even by a decrease,
in diastolic pressure.

This study included 70 Subjects aged from 30 to
60 years who were divided into 2 groups:
Group 1: 50 untreated hypertensive subjects, which
is proved by office blood pressure measurement and 24-hours ABPM.
Group 2: 20 normotensive subjects, proved by
office blood pressure measurement and
24-hours ABPM and used as a control
group.
Based on the investigation of target organ damage
(TOD), group 1 has been classified into the following subgroups:
Group 1a (TOD0): Includes 12 patients with no
subclinical organ damage.
Group1b (TOD1): Includes 12 patients with only
one subclinical organ damage.
Group 1c (TOD2): Includes 13 patients with two
sub-clinical organ damage.
Group 1d (TOD3): Includes 5 patients with three
Group 1e (TOD4): Includes 8 patients with four
AASI is defined as 1 minus the regression slope.

AASI increased with age, the upper boundary of
the 95% confidence band for individual prediction
was 0.53 at 20 years and 0.72 at 80 years, the AASI
remained significantly higher in women than men
[4].
Colored duplex ultrasound to measure the
Intima-media thickness (IMT): The end-diastolic
IMT of both common carotid artery was measured
From the leading edge of the 1st echogenic line to
the leading edge of the 2nd echogenic line 10mm
caudal to the bulb using Hewlett Packard Sonos
1000 system, with 7.5Hz linear array transducers,
with the patient in the supine position and the neck
in slight hyperextension. A Plaque was defined as
presence of a focal thickening greater than 1.5mm
and plaques were sought in the entire extra-cranial
carotid tree.
Exclusion criteria includes: Tobacco smoking,

previous myocardial infarction, coronary bypass
graft, cardiac valve disease, stroke, diabetes, dyslipidemia and obesity.
All the participant were subjected to: History
taking, clinical examination, Office blood pressure
measurement (Blood pressure >140/90 was considered hypertensive), measurement of body mass
index and body surface area, Laboratory investigation (Fasting and post prandial blood sugar,
lipogram, blood urea nitrogen, serum creatinine,
and assessment of micro-albuminuria).
Echocardiography evaluation of the LVMI:

Was done according to the recommendations of
the American Society of Echocardiography (ASE)
as follows:
LV mass in grams = 0.8 (1.04 [LVIDD + PWTD + IVSTD]3
[LVIDD] 3) + 0.6 g.
Ambulatory blood pressure monitoring: The

ABPM device (model: TM 2430 Space Labs Inc)
was fixed to the non-dominant arm with a suitable
And then indexing the LVM to height 2.7 and

BSA.
244
Mohamed M Saad & Mohammed A Abdel Wahab
Funduscopic retinal examination:

Subjects were graded according to Modified
Scheie Classification:
There is a statistically significant difference

between both groups as regard the office systolic
(p<0.001) and diastolic blood pressure (p<0.001)
also the mean 24 hour systolic (p<0.001) and
diastolic blood pressure (p<0.001). Also, There is
a statistically significantly increased AASI in group
1 compared to group 2 (p<0.001).
Grade 0 No changes.
Grade 1 Minimal arteriolar narrowing.
Grade 2 Obvious arteriolar narrowing with focal
irregularities.
Table 3: Office and ambulatory blood pressure data.
Grade 3 Grade 2 + retinal hemorrhages and/or

exudate.
Group 1 (n=50) Group 2 (n=20)
Grade 4 Grade 3 + swollen optic nerve (Malignant

hypertension).
Office SBP
Office DBP
Mean 24h SBP
Mean 24h DBP
AASI
Statistical method:
Data was analyzed by the Statistical Package
for the Social Sciences (SPSS), version 16 for
Window. All data were reported as mean SD. A
Student t-test was used to compare variables for
testing statistical significant difference between
two groups and the differences were considered
significant at a two-tailed p0.05 and MannWhitney Test used to study the correlations of the
non parametric variables.
Age
BMI
FBS
2 hour PP
Cholesterol
Triglycerides
LDL
HDL
SD
48.28
25.16
100.82
126.36
163.68
160.78
85.84
46.9
6.40
2.53
8.49
7.68
19.22
21.24
8.69
6.48
45.25
24.35
100.85
128.40
166.95
150.50
79.65
50.6
7.89
1.79
8.16
7.82
14.98
32.56
9.93
5.25
Gender:
Male
Female
Number
Number
31
19
62
38
15
5
75
25
127.35
77.5
123,05
92.86
.5205
5.32
6.39
6.65
8.50
.06245
Age
SBP
DBP
M 24h SBP
M 24h DBP
LVM
LVMI
MA
RCCA
LCCA
MCCA
Gender
Fundus retinopathy
Plaque
0.99
0.197
0.989
0.322
0.498
0.124
0.12
0.26
<0.001
<0.001
<0.001
<0.001
<0.001
Pearson Correlation
0.272
0.760
0.619
0.668
0.653
0.613
0.543
0.312
0.391
0.258
0.512
0.339
0.514
0.255
0.023
<0.001
0.001
<0.001
<0.001
<0.001
<0.001
0.009
0.002
<0.001
<0.001
0.004
<0.001
0.034
SBP
= Systolic blood pressure.
DBP
= Diastolic blood pressure.
M 24h SBP = Mean 24 hour systolic blood pressure.
M 24h DBP = Mean 24 hour diastolic blood pressure.
LCCA = Left common carotid artery intima media thickness.
RCCA = Right common carotid artery intima media thickness.
MCCA. = Mean common carotid artery intima media thickness.
MA
= Microalbuminuria.
LV mass = Left ventricular mass.
LVMI = Left ventricular mass index.
Table 2: Gender distribution among the study groups.

Group 2 (n=20)
15.94
10.94
15.12
6.63
.09539
p-value
p-value
BMI = Body Mass Index.

FBS = Fasting Blood Sugar.
2 hour P = 2 hour Post Prandial Blood Sugar.
LDL = Low Density Lipoprotein.
HDL = High Density Lipoprotein.
Group 1 (n=50)
168,86
97.7
149.86
74.8
.7706
Variable
Group 2 (n=20)
Mean
SD
Table 4: Correlations of AASI with the parametric and non

parametric variables.
Table 1: Patients characteristics.
SD
Mean
AASI was found to be significantly correlated

with the age (p=0.023) Fig. (1). Moreover, AASI
is significantly higher in females than males
(p=0.004). Also, AASI was positively correlated
with the office SBP (p<0.001), office DBP
(p=0.001), the Mean 24h SBP (p<0.001), Mean
24h DBP (p<0.001), Table (4).
There is no significant difference among the

study groups regarding age, gender distribution,
body mass index, blood sugar levels and lipid
profile (Tables 1,2).
Mean
SD
SBP = Systolic blood pressure.

DBP = Diastolic blood pressure.
Mean 24h SBP = Mean 24 hour Systolic Blood Pressure.
Mean 24h DBP = Mean 24 hour Diastolic Blood Pressure.
AASI = Ambulatory arterial stiffness index.
Results
Group 1 (n=50)
Mean
p-value
0.304
245
0.25
Right CCA-IMT
Furthermore, AASI is also significantly correlated with markers of target organ damage namely,
LVM (p<0.001), LVMI (p<0.001) Fig. (2), microalbuminuria (p=0.009) Fig. (3), right common carotid
artery IMT (p=0.002) Fig. (4), left common carotid
artery IMT (p<0.001) Fig. (5), and mean common
carotid artery IMT p<0.001), prevalence of carotid
plaque (p=0.034) and fundus retinopathy (p<0.001).
Moreover, AASI correlates with the number of
target organ damage Fig. (6), Table (4).
Right CCA-IMT
0.20
p=0.02
0.15
0.10
0.05
0.00
0.00
70
p=0.023
30
0.35
20
0.30
10
0
0.00
0.50
0.75
1.00
AASI
Figure 1: Shows significant positive correlation between the
AASI and age.
0.25
1.00
Left CCA-IMT
p<0.001
0.25
0.20
0.15
0.10
0.05
125
0.00
LVMI
100
0.0 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90
1.0
AASI
p<0.001
LVMI
0.75
40
Left CCA-IMT
Age
50
0.50
AASI
AASI and the right common carotid artery intima
media thickness.
Age
60
0.25

AASI and the left common carotid artery intima
media thickness (left CCA-IMT).
75
50
0.95
25
0
0.00
0.90
0.25
0.50
0.75
1.00
AASI
ambulatory arterial stiffness index (AASI) and the
left ventricular mass indexed to the height raised
to the power of 2.7 (LVMI).
AASI
0.85
0.80
0.75
0.70
250
Microalbuminuria
Microalbuminuria
200
0.65
p=0.009
100
TOD0
TOD1
TOD2
TOD3
TOD4
Figure 6: Shows the association between the ambulatory
arterial stiffness index and the degree of target
organ damage in hypertensive patients.
50
Discussion
150
Results of the current study revealed significant

positive correlation between age and the AASI
(p=0.026). In agreement with our results, other
studies found a significant positive correlation with
the age [6,7].
0
0.0 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.0
AASI
-50
ambulatory arterial stiffness index (AASI) and the
level of microalbuminuria.
246
Mohamed M Saad & Mohammed A Abdel Wahab
Results of the current study revealed a significantly higher AASI in females than males
(p=0.0086). This result is similar to those of Li et
al, 2006 and Dolan et al, 2006 who found that
AASI was significantly correlated with the subject
gender, being higher in females than males [4,8].
(AIx) as a measure of arterial stiffness and they

found the higher the level of microalbuminuria the
more increased the augmentation index [11].
Moreover, Leoncini et al, studied the association
of the AASI and target organ damage in patients
with primary hypertension, the results demonstrated
significant correlation between the AASI and microalbuminuria [7].
Results of the current study revealed a significant increase in the value of the AASI in hypertensive than normotensive group (p=0.001). In agreement with this result, previous study revealed a
significant difference between the normotensive
and hypertensive patients as regard the value of
the AASI, being higher in the hypertensive than
the normotensive subjects [4].
Also Munakata et al, considered the brachialankle pulse wave velocity as a measure of arterial
stiffness and detected that the prevalence of microalbuminuria increased with a graded increase
in brachial-ankle pulse wave velocity in nevertreated hypertensive patients (p<0.0001) [12].
Results of the current study revealed significant

positive correlation between AASI and both office
and 24 hour systolic blood pressure (p<0.001).
Several other studies revealed significant positive
correlation between AASI and systolic blood pressure, both office and 24 hour recording [7,8].
Results of the current study revealed that the

AASI significantly correlated with increased common carotid artery intima media thickness (CCAIMT) (p=0.002, p<0.001 and p<0.001) for the right
and left and mean CCA-IMT respectively and the
presence of carotid plaque (p=0.034). In agreement
with the current study Okura et al, evaluated the
association between the cardio-ankle vascular index
(CAVI) as a measure of arterial stiffness and the
common carotid artery intima media thickness
(CCA-IMT) in a group of patients with essential
hypertension. The CAVI was positively correlated
with CCA-IMT (p=0.0022) [13].
This study found also significant positive correlation with diastolic blood pressure both office
and 24 hour recording (p=0.001). In contrary to
this result, Dolan et al, demonstrated that with
increasing AASI the diastolic blood pressure fell
slightly [8].
This is probably because the subjects age in
their study was higher 54.614.6 years ranging
from 16 to 96 years where the mean age of our
patients was 48.286.40. This difference in mean
age may be the explanation as the diastolic blood
pressure, largely determined by peripheral vascular
resistance, increases until middle age and then
tends to fall. On the other hand, the systolic blood
pressure and pulse pressure are influenced more
by the stiffness of large arteries and progressively
increase with age [9].

AASI was positively correlated with increased left
ventricular mass, indexed to the height powered
to the value of 2.7 (p<0.001). The same result
obtained by the study of Leoncini et al, who studied
the association of the AASI and target organ damage in patients with primary hypertension and
found significant positive correlation with increased
left ventricular mass, indexed to the body height
raised to the power of 2.7 [7] . Also Tsai et al,
concluded that Stiffness index (SI) which is a
measure of arterial stiffness and derived from
digital volume pulse SI was higher in patients with
LVH than those without [14].

AASI was positively correlated with microalbuminuria as a sub-clinical organ damage (p=0.009).
In agreement with the current study Multe` et al,
examined the correlation of the aortic pulse wave
velocity (PWV) as a measure of arterial stiffness
in comparison with the urinary albumin excretion
in hypertensive patients, and found that the PWV
found to be higher in hypertensive patients having
albumin excretion rate higher than median, when
compared with those below the median [10].
Furthermore, the current study demonstrated

that the higher the AASI the higher the degree of
subclinical organ damage (positive graded association between the AASI and the degree of subclinical organ damage).
Similar results were obtained by [14] who studied the association between arterial stiffness and
left ventricular hypertrophy and proteinuria in 205
Also, Tsioufis et al, studied the relation of the

microalbuminuria and the augmentation index
247
Hour Ambulatory Pulse Pressure as Predictors of Mortality
in Ohasama, Japan". Stroke 2007; 38: 1161-1166.
patients with essential hypertension, Stiffness index

was gradually increased among patients without
LVH, with LVH but not proteinuria, and with LVH
and proteinuria.
7- Leoncini G, Ratto E, Viazzi f, Vaccaro V, Parodi A, Falqui

V, Conti N, Tomolillo Cinzia, Deferrari G, Pontremoli R:
Increased Ambulatory Arterial Stiffness Index is associated
with Target Organ Damage in Primary Hypertension.
Hypertension 2006; 48: 397-403.
Also, Leoncini et al, studied the association

between the AASI and target organ damage in
essential hypertensive patients, and found that the
association between ambulatory stiffness and target
organ damage seems to be graded, because patients
with more severe organ involvement are characterized by higher AASI [7].
8- Dolan E, Thijs L, Li Y, Atkins N, McCormack P, McCormack S, OBrien E, Staessen JA, Stanton AV: "Ambulatory
Arterial Stiffness Index as a Predictor of Cardiovascular
Mortality in the Dublin Outcome Study". Hypertension
2006; 47: 365-370.
9- Oliver JJ, Webb DJ: "Noninvasive Assessment of Arterial
Stiffness and Risk of Atherosclerotic Events", Arteriosclerosis and Thrombosis and Vascular Biology 2003; 23:
554-566.
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Mongivoi R, Piazza G, Nardi E, Andronica G, Cerasola
G: Relationship between albumin excretion rate and aortic
stiffness in untreated essential hypertensive patients.
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11- Tsioufis C, Tzioumis C, Marinakis N, Toutouzas K,
Tousoulis D, Kallikazaros I, Stefanadis C, Toutouzas P:
Microalbuminuria Is Closely Related to Impaired Arterial
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2- Hermeling E, Hoeks AP, Winkens MH, Waltenberger JL,

Reneman RS, Kroon AA, Reesink KD: Noninvasive
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Between Systolic and Diastolic Pressure Ranges. Hypertension 2009 Nov; 23.
12- Munakata M, Nunokawa T, Yoshinaga K, Toyota T:

Brachial ankle pulse wave velocity is an independent risk
factor for microalbuminuria in patients with essential
hypertension-a Japanese trial on the prognostic implication
of pulse wave velocity. Hypertens Res 2006; 29 (7): 51521.
3- OBrien E: Ambulatory Blood Pressure Measurement A

Troven of Hidden Gems?, Hypertension 2006; 48: 364365.
4- Li Y, Wang JG, Dolan E, Gao PJ, Guo HF, Nawrot T,
Stanton AV, Zhu DL, OBrien E, Staessen JA: "Ambulatory
Arterial Stiffness Index Derived From 24-Hour Ambulatory Blood Pressure Monitoring", Hypertension 2006; 47:
359-364.
13- Okura T, Watanabe S, Kurata M, Manabe S, Koresawa

M, Irita J, Enomoto D, Miyoshi K, Fukuoka T, Higaki J;
Relationship between cardio-ankle vascular index (CAVI)
and carotid atherosclerosis in patients with essential
hypertension. Hypertens Res 2007 Apr; 30 (4): 335-40.
5- Stergiou GS, Kollias A, Rarra VC, Roussias LG: Ambulatory Arterial Stiffness Index: Reproducibility of Different
Definitions. Am J Hypertens 2009 Nov; 19.
14- Tsai WC, Lin CC, Huang YY, Chen JY, Chen JH: "Association of increased arterial stiffness and inflammation
with proteinuria and left ventricular hypertrophy in nondiabetic hypertensive patients", Blood Press 2007; 5: 16.
6- Kikuya M, Staessen JA, Ohkubo T, Thijs L, Hoshi H,

Hashimoto J, Totsune K, Satoh H, Wang J-G, OBrien E,
Imai Y: "Ambulatory Arterial Stiffness Index and 24-
248
Relevance of Homocysteine on Brachial Flow-Mediated Vasodilation and

Carotid and Femoral Intima-Media Thickness in Siblings of
Hypertensive Patients
MOHAMED FAHMY ELNOAMANY, MD; HALA MAHFOUZ BADRAN, MD;
HESHAM HASAN EBRAHEEM, MD; AHMED ASHRAF REDA, MD;
NEVEN ABELMONEM ELSHEEKH, MSc
Background: Mild hyperhomocysteinemia, a risk factor for vascular disease, is common in the general population. Offspring
of hypertensive parents, have been reported to have endothelial dysfunction compared with the offspring of normotensive
parents. This does not occur simply as a consequence of increased blood pressure but may rather be a cause of the condition.
Carotid intima-media thickness (CIMT) is the second valid marker of generalized atherosclerosis.
Objectives: To study the relation of sonographically determined carotid and femoral intima-media wall thickness and
enothelial function to serum homocysteine (Hcy) concentrations in offspring of hypertensive parents.
Methods: Plasma homocysteine levels were measured in normotensive siblings for hypertensive patients (n=78) and
normotensive controls (n=30). All subjects were non-diabetic, had no past history of myocardial infarction, stroke or peripheral
vascular disease and had normal renal functions. Brachial artery flow-mediated (FMD) and nitroglcerine-mediated vasodilatation
(NTGMD) were measured to assess endothelial function. Also carotid and femoral intima-media thickness that reflect vascular
disease were examined.
Results: Hcy level was found to be significantly higher in normotensive siblings when compared to controls (13.74.5
versus 7.82.7 micromol/L, p<0.001). CIMT and femoral IMT were significantly increased in siblings in comparison to control
(0.720.6mm versus 0.580.6mm, p<0.01 and 0.710.07 versus 0.540.06mm, p<0.001 respectively). FMD and FMD% that
reflect endothelial dysfunction but not NTGMD & NTGMD% were significantly lower in siblings compared with control
(0.690.42mm versus 1.70.27mm and 20% versus 55% respectively, p<0.01 for each).
Conclusion: Plasma homocysteine levels are significantly elevated in normotensive siblings for parents with essential
hypertension. Increased carotid and femoral IMT in addition to endothelial dysfunction may serve as results of hyperhomocysteinemia
that create the potential cardiovascular risk.
Key Words: Homocysteine Brachial flow-mediated vasodilation Offspring of hypertensive patients.
Introduction
pertensive patients [1]. Furthermore, epidemiologic

studies have shown that healthy offspring of hypertensive patients exhibit many features of the
metabolic syndrome and risk factors for atherosclerosis, such as hyperinsulinemia, insulin resistance,
and lipid disorders [2].
Essential arterial hypertension (EH) is an important risk factor for atherosclerosis. There is
growing evidence that endothelial dysfunction is
the earliest event in atherogenesis and also precedes
morphological changes of the arterial wall in hy-
Previous researches based on plethysmographic

investigation showed that normotensive subjects
with a family history of EH had higher levels of
peripheral resistance than controls, which is probably a consequence of endothelial dysfunction of
the small vessels [3]. These findings could imply
that, in subjects with hypertensive familial trait
(FT), a functional abnormality of endothelium may
The Department of Cardiology, Faculty of Medicine,

Menoufiya University, Shebin El Kom, Egypt.
Address for Correspondence: Dr. Mohamed Fahmy
Elnoamany, 11 Yossef Street from Talaat Harb Street, Shebin
Elkom, Menoufyia, Egypt, mnoamany@hotmail.com
249
Relevance of Homocysteine on Brachial Flow-Mediated Vasodilation
appear early in life or may even be directly inherited.
(hypertensive siblings). The remaining 30 subjects,

for whom neither parent had any evidence of hypertension (defined as blood pressure >140/90
mmHg and confirmed from general practice records
or by an investigator), served as controls. 7 subjects
in the first group had a parental history of ischemic
heart disease, and 6 subjects had a family history
of type II (non-insulin-dependent) diabetes mellitus.
All the subjects included in the study, were nonsmoker, non-diabetic, had no past history of myocardial infarction, stroke or peripheral vascular
disease and had normal renal functions. The study
was approved by the Research Ethical Committee
of Menoufyia University Hospital and all subjects
gave a written informed consent. The study was
carried out from January 2007 to June 2008. None
of the subjects had receiving medication before or
during the study.
The association between plasma homocysteine

and patients with EH and their non-hypertensive
siblings is recently explored [4].
The impact of elevated plasma homocysteine
(Hcy) levels seems to be clinically relevant, since
the total cardiovascular risk of hyperhomocysteinemia is comparable to the risk associated with
hyperlipidemia or smoking. There is substantial
evidence for impairment of endothelial function
in human and animal models of atherosclerosis,
occurring even before development of overt
plaques. Interestingly endothelial dysfunction appears to be a sensitive indicator of the process of
atherosclerotic lesion development and predicts
future vascular events [5,6].
For each patient the following was done:
A fundamental question which remains unanswered is whether endothelial dysfunction in

healthy offspring of hypertensive, if indeed present,
is a genetic predisposition or consequence of the
presence of other associated risk factors like hyperhomocysteinemia.
1- Complete history taking.

2- Thorough clinical evaluation.
3- 12-lead resting ECG.
4- Conventional echocardiographic examnation:
A full echocardiographic examination was performed. All individuals underwent full M-mode,
two-dimensional, and color-Doppler examinations
with a commercially available system (ATL HDI
3000 CV Diagnostic Ultrasound System) with
2.5MHz transducer. The measurements were carried
out according to the recommendations of the American Society of Echocardiography [7]. Left ventricular end diastolic and systolic dimensions (LVEDD
& LVESD) and thicknesses of the interventricular
septum (IVST) and posterior wall (PWT) were
measured at onset of the electrocardiographic Q
wave. Left ventricular myocardial mass (LVM)
was calculated using the formula of Devereux et
al [8]. Body surface area (BSA) was determined
from height and weight as described by Du Bois
et al [9].
We hypothesized that there is relation between

endothelial function in offspring of hypertensive
patients and homocysteine level, as homocysteineinduced vascular disease might contribute to the
development and progression of atherosclerosis in
family of hypertensive parents.
Aim of the work:
The aim of the present study was to evaluate
non-invasively whether endothelial function as
assessed by flow-mediated dilation (FMD) of the
brachial artery and carotid and femoral intima
media thickness, as an early marker of atherosclerosis, are also impaired in normotensive offspring
of subjects with essential hypertension. Also, to
find whether these abnormalities, is related to
homocysteine blood level in those subjects with
hypertensive familial trait.
5- Endothelial function assessment:
Methods
The endothelial function test was performed

by high-resolution B-mode ultrasound imaging of
brachial artery using a non-invasive methodology
described by Corretti et al [10] and Celermajer et
al [11] with modifications [12]. The examination
was done by a single trained sonographer using
ultrasound imaging system (ATL, HDI 3000 CV.)
with a 7.5-MHz linear array transducer. The oper-
Subjects:
A total of 108 healthy volunteers were recruited
from hospital staff or through family practices with
which links have been established. Of those, 78
had either a maternal or a paternal history of hypertension or both parents were hypertensive, as
confirmed by hospital or general practice records
250
Mohamed F Elnoamany, et al
ator was blind to the patient laboratory, clinical

and echocardiographic data.
6- Carotid ultrasound: [14]

The same operator performed carotid artery
examination with an ECG-triggered ultrasound
imaging system (ATL, HDI 3000 CV) with a 7.5MHz linear array transducer during the whole
study. Common, internal, and external carotid
arteries and carotid bulb in both sides were studied
in longitudinal and transverse planes. A preliminary
scan verified the presence of plaques in the carotid
tree. The carotid IMT was measured as the distance
from the leading edge of the first echogenic line
to the leading edge of the second echogenic line,
as defined by Pignoli et al [15] . The first line
represented the luminal-intimal interface and the
collagen-containing upper layer of the tunica adventitia formed the second line. The distance from
the first line of the near wall to that of the far wall
was defined as luminal diameter (LD), and the
distance from the second line of the near wall to
that of the far wall was defined as interadventitial
diameter (IAD). IMT was measured on three systolic frames (taken at the T-wave of the ECG), 1cm
proximal to the bulb. Positions with plaques were
exempted from measurements. Plaques were considered the protrusions with a thickness >50% of
the thickness of the surrounding wall that were
found anywhere in the carotid system or local
thickenings of at least 1.3mm [16]. Flow velocities
were detected by the linear probe using the smallest
size of the sample volume placed in the center of
the vessel and keeping the angle between ultrasound
beam and the longitudinal vessel axis between 45
and 56. After 1 minute for stabilization, carotid
peak systolic velocity (PSV) was recorded [14].
The test consisted of four phases as follow:

Rest, after reactive hyperemia (endotheliumdependent phase or flow-mediated dilation (FMD),
again with the subject at rest, and finally, after
administration of sublingual nitrate (endotheliumindependent phase or nitroglycerine-mediated dilation (NGMD). All measurements were performed
in the same place, in longitudinal section 5-10cm
above the antecubital fossa of the right upper arm.
At the end of the first phase of resting when a
satisfactory position was found to carry on the
endothelial study, the skin was marked and the arm
remained in the same position throughout the test.
At this moment, the luminal diameter and blood
flow velocity were determined for the first phase.
To obtain an increased flow, a cuff was placed on
the right upper arm and it was inflated to 300mm
Hg, resulting in a complete interruption of blood
flow during a period of 1-5 minutes, and then the
cuff was deflated. A second and third scan were
obtained after 15 and 90 seconds after the cuff was
released (known as reactive hyperemia phenomenon) that was followed in normal subjects by a
brachial FMD. Ninety seconds after ischemia, three
measurements of the diameter of the brachial artery
were taken at the diastolic period (FMD). Ten
minutes of rest was then allowed for recovery of
the vessel and at the end of this period a sublingual
tablet of isosorbide dinitrate 5.0mg (NTG), was
given to the subjects. Five minutes after isosorbide
dinitrate administration three measurements were
obtained for brachial artery diameter and blood
flow velocity to determine nitrate induced vasodilation of the arterial wall known as (endotheliumindependent vasodilation). The mean of these
values was used in subsequent analyses. FMD
response was expressed as the change in diastolic
diameter of the brachial artery during reactive
hyperemia compared with the baseline (rest) measurement and used as a measure of endotheliumdependent vasodilation. The mean of these values
were used in subsequent analyses. For each subject
we reported baseline diameter, absolute change
and percent change in diameter during FMD and
NTG-mediated vasodilation.
7- Examination of femoral artery:

Femoral imaging is performed with the patient
lying in the supine position on an examination
table. Using a transducer with a 7.5MHz, linear
transducer for evaluation of the common femoral
artery. Common femoral artery is located at the
level of the groin. The artery lies lateral to the
common femoral vein. Imaging performed in the
longitudinal plane, and a Doppler signal obtained
from this artery at 60 angle to the vessel walls.
The FIMT and PSV were examined, as previously
described [17] in predefined segments of the common femoral arteries on both sides then the mean
value was obtained.
Previous studies have shown that, the intraand interobserver variability for repeated measurements of the same recording of the brachial artery
diameter were 2.161.7% and 2.411.9% respectively [13].
8- Laboratory examination:
All blood samples were collected by venipuncture into EDTA tubes within 2 hours of obtaining
the Ultarsonic and echocardiogrphic measurements.
251
LV mass index were significantly higher in siblings

in comparison to control (p<0.001). In contrast,
there was no significant difference between siblings
and control as regard to age, body mass index,
total Cholesterol, LDL, HDL and fasting plasma
glucose (Table 1, Figs. 1,2).
Plasma samples for measurements of fasting total

plasma homocysteine concentrations were measured by high-performance liquid chromatography
and electrochemical detection [18]. Ten mm 3 of
blood with ethylenediaminetetraacetic acid was
drawn from each subject, and the vials were put
immediately into crushed ice (to stop homocysteine
release from red blood cells). After approximately
1 hour (30 to 70 minutes), blood was centrifuged,
and the plasma was transferred to plastic vials and
stored at 20C. Storage lasted for a minimum of
1 week to a maximum of 2 months. The first step
was to reduce the disulfide bonds with trinbutylphosphine, and then trichloroacetic acid was
added; after centrifugation, derivatization was
performed with 7-fluorobenzo-2-oxa-1,3-diazole4-sulfonamide in a 0.125mol/L borate buffer at pH
8. Cysteine, cysteinyl-glycine, and homocysteine
were separated and quantified by the isocratic
elution of a reversed phase column within 4 to 5
minutes. The elution phase was done with 15%
acetonitrile. An internal standard (sulfosalicylic
acid) was added to all the samples. This method
allows the determination of homocysteine concentrations to 1 micromol/L [19].
Table 1: Baseline clinical and laboratory characteristics of

studied population.
Variable
Hypertensive
Controls
Sibling
(n=30)
(n=78)
t
Test
Age (year)
SBP (mm Hg)
DBP (mm Hg)
BMI (kg/m2)
FBG (mg/dl)
TC (mg/dl)
HDL (mg/dl)
LDL (mg/dl)
TG (mg/dl)
HCY (mol/l)
LVMI (gm/m2)
212.7
117.75.9
79.612.98
21.630.92
76.852.42
158.333.35
41.771.45
117.441.11
161.951.82
13.694.51
97.261.36
1.37
4.60
2.89
1.31
1.06
1.12
1.11
1.12
6.32
8.8
4.1
>0.05
<0.001
<0.01
>0.05
>0.05
>0.05
>0.05
>0.05
<0.001
<0.001
<0.001
201.6
101.37.7
70.174.45
20.831.18
74.731.73
142.434.58
42.171.74
113.131.5
139.472.33
7.782.65
86.131.01
*
: Values are expressed as means SD.
SBP : Systolic blood pressure. HDL : High density lipoproteins.
DBP: Diastolic blood pressure. LDL : Low density lipoproteins.
BMI: Body mass index.
TG : Triglycerides.
FBG: Fasting blood glucose. HCY : Homocycteine.
TC : Total cholesterol.
LVMI: Left ventricular mass index.
Concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, serum

creatinine, and fasting plasma glucose were measured by standard laboratory assays.
140
Siblings
Control
117.7
120
101.3
97.3
100
Data were analyzed by SPSS statistical package
version 11.0 (SPSS Inc, Chicago, IL, USA). Quantitative data expressed as mean and standard deviation (SD). Comparisons between means were
evaluated by unpaired t-test or ANOVA (with post
hoc test) for continuous variables and by chi-square
test for proportions. Pearson correlation coefficient
(r) was used to measure association between two
quantitative variables. Level of significance was
set as p-value <0.05 [20].
86.1
79.6
80
70.2
60
40
20
0
LVMI
DBP
SBP
Figure 1: Comparison of blood pressure and left ventricular
mass in studied groups.
Results
Hcy (mmol/L)
Clinical and laboratory characteristics of studied

population:
The present study included 108 normotensive
subjects, 78 of them were siblings of hypertensive
patients with mean age (212.7 years), and 30
subjects assigned as a control group with mean
age (201.6 years). The siblings had significant
higher systolic and diastolic blood pressure compared with control (p<0.001, <0.01 respectively).
Also Homocysteine level, serum triglyceride and
16
14
12
10
8
6
4
2
0
13.7
Hcy
7.8
Siblings
Control
Figure 2: Homocyctiene level in hypertensive siblings and

control (p<0.001).
252
Ultrasound measurements:
In hypertensive siblings the diameter of the
carotid artery was significantly increased in comparison to control (7.670.61mm versus 6.74
0.86mm p<0.01). Furthermore, the carotid IMT
was significantly higher in siblings (0.720.60mm)
compared with the control (0.580.60mm) p<0.01.
However, no significant difference was detected
in the peak systolic velocity of carotid flow (PSV)
between siblings and control.
Analysis of brachial artery parameters in studied

populations: (Table 3 & Fig. 4)
Although the PSV of brachial flow was significantly lower at rest (p<0.05) and during reactive hyperemia (p<0.01) in siblings than in control, there was no significant difference of PSV
between both group as regards NTG mediated
dilation.
Comparing the brachial artery diameter at rest,
there was no difference in baseline diameter of the
brachial artery between siblings and control group
(4.050.57mm versus 3.940.22mm). During reactive hyperemia the diameter of brachial artery
only in control group showed significant increase
compared to resting diameter (p<0.001). While
with NTG inhalation (endothelial independent
vasodilation) both siblings and control showed
significant increase from resting diameter
(p<0.001).
As regard to the femoral artery diameter, it was

notably larger in siblings (6.92.1mm) compared
with the control group (6.01.1mm) p<0.05. Similarly, the femoral IMT was significantly increased
in siblings (0.710.0mm) versus (0.540.06mm)
in control group, p<0.001. Besides the PSV of
femoral arterial flow was significantly higher in
siblings compared to control group (56.79
21.32cm/s) versus (41.79.68cm/s) (p<0.001) (Table 2 & Fig. 3).
Table 2: The Ultrasound characteristic of carotid and femoral
arteries.
Hypertensive
Controls
t
Sibling
(n=30) Test
(n=78)
Carotid artery
CIMT (mm)
0.720.6
IAD (mm)
7.670.61
Carotid PSV (cm/s) 47.432.52
Femoral artery:
FIMT (mm)
IAD (mm)
Femoral PSV
(cm/s)
Table 3: Brachial artery Measurements during reactive hyperemia and NTG inhalation in studied groups.
p
Brachial artery
Measurements
0.580.60 2.97 <0.01

6.740.86 5.37 <0.01
42.17.75 0.09 >0.05
0.710.07
0.540.06 2.95 <0.001
6.92.1
6.01.1
1.01 <0.05
56.7921.32 41.79.68 5.19 <0.001
*
: Values are expressed as means SD.
CIMT : Carotid Intima-Media Thickness.
IAD : Interadvential diameter.
PSV : Peak systolic velocity.
FIMT : Femoral Intima-Media Thickness.
0.8
0.72
0.7
p<0.01
0.71
p<0.001
0.58
0.6
0.54
0.5
0.4
0.3
0.2
0
FIMT
Siblings
Controls
(n=30)
Luminal diameter:
At rest
Reactive hyper.
NTG inhalation
F-test
p
4.050.57
4.650.63
6.020.35*
60.89
<0.001
3.940.22
5.710.14*
5.350.44*
65.73
<0.001
PSV:
At rest
Reactive hyperemia.
NTG inhalation
F-test
p
62.854.38
57.265.7
55.434.88
31.84
< 0.001
67.971.63
60.91.45
59.76.56
91.54
<0.001
FMD
% FMD
NTG-MD
% NTG-MD
0.690.42^
19.65.48^
1.970.71
48.64.99
1.70.27
54.57.34
1.810.28
49.87.17
PSV
: Peak systolic velocity.
FMD : Amount of change in Flow mediated-dilatation of brachial
artery.
% FMD: Percent of Flow mediated-dilatation of brachial artery.
NTG-MD : Amount of change in Nitroglycerin-Mediated dilatation.
% NTG-MD: Percent of Nitroglycerin-Mediated dilatation.
Hcy: Homocysteine.
* : Significantly higher than at rest.
: Significantly lower than at rest.
^ : p<0.01 compared to control.
0.1
CIMT
Hypertensive
Sibling
(n=78)
Control
Figure 3: Carotid and femoral IMT in hypertensive siblings

and control.
253
The velocity of brachial blood flow at baseline

significantly higher in control (67.971.63cm/s)
versus (62.854.38cm/s) in siblings, this PSV of
blood flow across brachial artery after reactive
hyperemia was significantly reduced (60.9
1.45cm/s) in control and did not change significantly (57.265.7cm/s) in siblings as shown in
Table (3) and Fig. (4). Administration of sublingual
Nitroglycerin induced significant increase in the
brachial artery diameter in both control and siblings
(5.350.44mm) and (6.020.35mm), respectively
which are significantly higher than the corresponding baseline diameters (p<0.001 for each).
6.5
6
Siblings
Comparing the PSV with flow mediated dilation

and NTG mediated dilation, no significant difference was detected between siblings and control as
regard baseline values. In hypertensive siblings,
the PSV during NTG inhalation was significantly
lower compared to baseline value. Conversely, the
PSV during reactive hyperemia did not differ significantly in comparison to baseline value. As
regard the control group PSV during flow mediated
dilation & NTG mediated dilation were significantly lower in comparison to baseline value (Table
3).
Table 4: Changes of brachial artery flow velocities during
reactive hyperemia and after Nitroglycerin inhalation
in both siblings and control.
6.02
Control
5.71
5.5
5.35
5
4.65
4.5
4.05
3.94
3.5
3
At rest
Reactive hyperemia NTG inhalation
Figure 4: Pattern of changes in flow mediated dilation and

NTG mediated dilation in siblings and control.
Siblings
1.97
Control
1.7
1.5
p<0.001
0.69
PSV:
FMD
NTG
Paired t-test
p
0.050.35
0.170.22
2.98
<0.05
7.080.61
8.274.12
0.57
>0.05
% PSV:
FMD
NTG
Paired t-test
p
0.80.65
2.740.35
4.72
<0.01
10.61.16
12.32.14
4.10
>0.05
Comparing the PSV with flow mediated dilation and NTG mediated dilation, No significant
difference was detected between siblings and control. In contrast the PSV and percent of change
in PSV during NTG inhalation was significantly
higher than that during reactive hyperemia in
hypertensive siblings only while no difference
between them in control group (Table 4).
p>0.05
Pearson correlation coefficient was used to

examine the relationship between NTG mediated
dilation and flow mediated dilation to the carotid
IMT in both groups. Despite no relationship was
detected between NTG and % NTG mediated
dilation and carotid IMT in any group, FMD and
%FMD of brachial artery diameter showed inverse
relationship to carotid IMT in hypertensive siblings
(r=0.50, p<0.001, r=0.62, p<0.001) respectively
(Table 5 & Fig. 6).
1.81
0.5
0
Flow mediated dilation
Controls
(n=30)
* Values are expressed as means SD.

PSV : Peak systolic velocity.
FMD : Flow mediated-dilatation.
NTG : Nitroglycerin mediated dilation.
Comparing the amount of changes () and

percent of change (%) in brachial artery diameter
during reactive hyperemia between siblings and
control, both FMD and %FMD in siblings during
reactive hyperemia were significantly lower in
comparison to control (p<0.01 for each). In contrast,
during NTG mediated dilation (endotheliumindependent vasodilation) there was no significant
difference between both groups (Table 3, Fig. 5).
2.5
Hypertensive
sibling
(n=78)
Brachial artery
Measurements
NTG mediated dilation
Considering the relationship between homocysteine level and carotid diameter; no significant
relationship was detected between them. Further-
Figure 4: Pattern of changes in flow mediated dilation and

NTG mediated dilation in siblings and control.
254
more, the endothelial dysfunction of brachial artery

in response to reactive hyperemia did not show
significant correlation with homocysteine level

(p>0.05) (Table 5 & Fig. 7).
Table 5: Correlation between carotid and brachial vascular function and homocysteine in hypertensive siblings.
NTG-MD
FMD
LD
Homocysteine
LD
%LD
%LD
CMIT
0.50
<0.001
0.18
>0.05
0.50
<0.001
0.62
<0.001
0.17
>0.05
IAD
0.06
>0.05
0.09
>0.05
0.06
>0.05
0.13
>0.05
0.09
>0.05
Hcy
0.05
>0.05
0.10
>0.05
0.08
>0.05
0.06
>0.05
LVMI
0.11
>0.05
0.16
>0.05
0.05
>0.05
0.18
>0.05
0.02
>0.05
CIMT : Carotid intima-media thickness.

IAD : Interadventitial diameter.
NTG-MD : Nitoglycerine-mediated dilation.
FMD : Flow-mediated dilation.

Hyc : Homocycteine.
LVMI : Left ventricular mass index
16
14
CIMT (mm)
CIMT (mm)
12
10
8
6
4
2
0
0.5
1.5
2.5
0.2
Flow mediated dilation
0.4
0.6
0.8
1.2
CIMT
Figure 6: Relationship between FMD and CIMT in siblings

of hypertensive patients (r=.50, p<0.001).
Figure 7: Relationship of CIMT to Hcy level in hypertensive

siblings (r=.17, p>0.05).
Figures 8,9: Measurement of intima-media thickness in carotid artery (0.8mm) & femoral artery (0.7mm) in one of the
hypertensive siblings.
255
Figures 10,11: Measurement of peak systolic velocity of brachial artery flow at rest (78cm/s) & flow-mediated dilation (68cm/s)
in one of the hypertensive siblings.
also between homocysteine in children and CVD

in their parents or relatives. Furthermore there is
reduction in CVD after homocysteine-lowering
intervention with B vitamins [22].
The present study was designed to evaluate the
role of genetic heritability for hypertension as an
independent risk factor that can alter endothelial
function and the prevalence of elevated homocysteine levels in siblings of hypertensive patients.
This may reveal whether endothelial dysfunction
pre-dates the development of hypertension in such
high-risk group.
In the present work, the first offspring of parents
with essential hypertension showed significant
higher systolic and diastolic blood pressure and
increased LVMI, This is in agreement with findings
reported by Zizek et al [22] who recently investigated left ventricular (LV) morphology and function
in normotensive offspring of subjects with essential
hypertension and demonstrated an increase in LV
mass and alterations in LV diastolic function in
the offspring (familial trait) which are linked to
endothelial dysfunction.
Figures 12: Measurement of peak systolic velocity of brachial

artery flow during nitroglycerine-mediated vasodilation (65cm/s) in the same sibling.
Discussion
The endothelium is both a target and a moderator of cardiovascular disease (CVD). Changes in
endothelial function occurs early in the course of
atherosclerosis before plaques exist, and certainly
before clinical detection of atherogenic lesions.
In our study we also attempted to come back

with a fundamental question which remains unanswered for long time which is, whether endothelial
dysfunction in hypertension, if indeed present, is
a cause or consequence of the condition. Whereas
studies in hypercholesterolemia have shown the
reversal of endothelial dysfunction with effective
treatment [23,24] , this has not been consistently
demonstrated in hypertension [25,26,27]. The study
of individuals who are at increased genetic risk
for hypertension, although clinically normal, offer
an alternative approach which avoids any confounding effects of treatment [1].
There is continuing discussion concerning the

presence of endothelial dysfunction in hypertension.
Studies have shown that, the endothelium is functionally abnormal in arterial hypertension and may
contribute to endothelial dysfunction in persons
with positive family history of hypertension [21].
Elevated plasma total homocysteine is an also
recent risk factor for occlusive CVD. This concept
is based on the observations of premature vascular
disease in patients with homocysteinuria. There is
a relation between homocysteine and both clinical
CVD as well as preclinical atherosclerotic disease,
256
Our study data demonstrated that when non

invasive evaluation of endothelial dysfunction was
done with high-resolution ultrasonography and
Doppler, normotensive young siblings of hypertensive patients showed increased carotid and femoral
intima-media thickness in comparison to control.
In addition, the flow-mediated dilation was considerably lesser in siblings of hypertensive patients
in comparison to control group.
free subjects with risk factors for vascular disease,

before anatomical evidence of atherosclerosis
appears. Additionally, Taddei et al [3] reported that,
normotensive offspring of hypertensive parents
had a reduced vasodilator response to acetylcholine
compared with that of normotensive offspring of
normotensive parents.
More recently, the same investigators reported
studies suggested that, the bioactivity of nitric
oxide may be reduced in normotensive offspring
of hypertensive parents and therefore they are at
increased risk of developing high blood pressure
[11].
Endothelial independant vasodilation, as assessed by NTG inhalation, was similar in both

siblings of hypertensive patients and control group,
which means intact endothelial independant vasodilatory function in siblings of hypertensive
patients. This vasodilation response to NTG, a
direct smooth muscle cell dependent vasodilator
is not affected in hypertensive siblings that point
to intact arterial contractility. Taken altogether,
these findings are consistent with the possibility
that endothelial function is the main site of alteration.
The present study demonstrates that normotensive offspring of hypertensive parents have increased LVMI and hyperhomocysteinemia. Our
study suggests that homocysteine may be associated
risk factor for increased left ventricular mass in
siblings of hypertensive patients. A number of
pathophysiologic mechanisms have been suggested
to explain this relationship. In the Framingham
Heart Study [29] the relations of plasma homocysteine to left ventricular structure and function was
studied and found to be positively correlated. This
study is suggesting that Hyperhomocysteinemia
promotes LV hypertrophy through vascular and
non-vascular mechanisms. Homocysteine has
growth-promoting and collagen productionstimulating effects on vascular smooth muscle cells
and inhibitory effects on endothelial cell growth.
Homocysteine induces oxidative stress and activates
matrix metalloproteinases causing endothelial and
structural vascular dysfunction, which ultimately
leads to atherosclerosis. In addition to the vascular
effects, homocysteine has been demonstrated to
have direct adverse effects on the myocardium in
experimental settings, affecting the extracellular
matrix more than the cardiomyocyte compartment.
Homocysteine directly promotes cardiac fibrosis
and cardiac matrix metalloproteinase activity,
resulting in ventricular dysfunction [29,30].
In the current study measurement of fasting

homocysteine showed significant increase in normotensive young siblings of hypertensive patients
in comparison to control. These findings are similar
to what reported in previous studies [4] when adult
hypertensives are compared to adult normotensive
subjects. It may convey that the decrease in arterial
compliance occurs prior to the detection of abnormal blood pressures and both siblings of hypertensive patients and their parents exposed to the similar
factors that cause early atherosclerotic changes in
siblings and cause marked atherosclerosis in their
parents when exposed to other environmental risk
factors [22].
The impairment of endothelial function in young
symptom free subjects with positive family history
of hypertension may be a possible explanation of
previous observation reported by Williams et al
[28] in epidemiological study of normotensive persons aged 20 to 49 years with at least two hypertensive first degree relatives. They followed them
for 7 years and found increased risk for developing
high blood pressure, suggesting the possible role
of endothelial dysfunction as cause and not the
result of hypertension meanwhile, this endothelial
dysfunction may initiate the first stage in atherosclerosis cascade [28].
In the present study, our analyses cannot exclude

the possibility that elevated homocysteine is a
marker of some other factor causally associated
with increased prevalence of parental CVD. For
example, low socioeconomic status is likely to be
associated both with increased risk of CVD and
elevated homocysteine. However, our study suggests that, the contribution of the family history
to the risk of premature atherosclerosis may be
attributable in part to the effects of a shared environment and shared genes on homocysteine level.
Furthermore our results are in agreement with

Celermajer et al [11] who reported that, flowmediated dilation is impaired in young symptom-
257
Several traditional risk factors are associated

with total homocysteine and may confound the
relation between homocysteine and CVD. These
results indicate that in siblings of hypertensive
patients homocysteine level is associated risk factor
for the development of functional and morphologic
lesions in arterial tree, particularly in the femoral,
carotid arteries and brachial arteries.
supplement and follow-up of endothelial dysfunction by Duplex which are needed in other following
studies.
Study limitation:
The study subjects were carefully selected to
avoid interference of any other risk factors that
may predispose to endothelial dysfunction. However, larger number of siblings and different age
groups may be required, including children. The
levels of nitric oxide and L-arginine in those siblings may have additional benefits to enforce the
underlying mechanism of endothelial dysfunction
in the studied groups. The higher levels of homocysteine in siblings in relation to control may
explain possible genetic basis for hyperhomocysteinemia in subjects with hypertensive familial
trait.
Elevated homocysteine, Endothelial dysfunction, and loss of elasticity in the arterial wall
through impairing nitric oxide mediated relaxation
of the vessels and smooth cell proliferation all
contribute to increase incidence of CVD in these
unlucky group.
Finally our results go parallel to data reported
by Jain et al [4] who reported that, Plasma homocysteine levels are significantly elevated in patients
with essential hypertension and their normotensive
siblings. Thus, plasma homocysteine may serve as
a marker for the development of essential hypertension [4].
Conclusion
Our results show that endothelial dysfunction
is present in healthy normotensive offspring of
hypertensive parents even in absence of other risk
factors. Elevated homocysteine in this population
may be among the earliest abnormalities associated
with but not correlated with impaired endothelial
function. Careful follow-up of these subjects should
offer further insights into disease pathogenesis. A
major challenge for the future is to establish whether the progression of endothelial dysfunction can
be retarded after considering other risk factor
modification, like hyperhomocysteinemia.
Our study showed no correlation among homocysteine, CIMT and FMD% at homocysteine
level 9.79 micromol/L and most studies showed
correlation at higher level and associated risk
factors e.g. aging, essential hypertension, glucose
intolerance and higher cholesterol level. So hyperhomocysteinemia as an isolated phenomenon probably confers minor risk, but it further increases the
risk when it occurs in combination with other
factors that provoke vascular lesions. Thus, hyperhomocysteinemia seems to be a particularly strong
risk factor in subjects with an underlying disease
and predicts the short-term outcome in such individuals [30].
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JJ, Mulder BJ: Increased carotid and femoral intimamedia thickness in patients after repair of aortic coarctation: Influence of early repair. Am Heart J 2006; 151:
242-7.
30- Gaetano V, Simona M, Donatella S, Francesco B, Rita P,

Matteo P, Giuseppe S, Graziana L, Elmo M: Relevance
of Homocysteine on Brachial Flow-Mediated Vasodilatation and Carotid and Femoral Intima-Media Thickness in
Patients With Hypercholesterolemia. Am J Cardiol 2004;
93: 1413-16.
18- Araki A, Sako Y: Determination of free and liquid homocysteine in human plasma by high performance liquid
chromatography with flourescence detection. J Chromatogr
1987; 422: 43-52.
31- Yasmin Rosalaba Falzone, Morris J Brown: Determinants

of arterial stiffness in offspring of families with essential
hypertension. AJH 2004; 17: 230-238.
259
Significant Value of Oxidized LDL Serum Level in Diabetic Coronary

Artery Disease Patients
IHAB MOSTAFA ABDEL-FATTAH, MD; HESHAM HASSAN, MD; WALAA FARID, MD;
MAATHER EL SHAFIE, MD; MOSTAFA HAMED, MBBCH; ABDALLAH MOSTAFA, MD
Introduction: It is suggested that Oxidized LDL (Ox-LDL) plays a key role in the atherogenesis and atherosclerotic
complications including coronary artery disease (CAD). It exerts several biological effects that may contribute to the initiation
and progression of the atherosclerotic process.
Aim of the Work: To correlate between Ox-LDL serum level and the extent of coronary artery disease in diabetic patients.
Subjects and Methods: 80 subjects were included in this study. Group A included 40 diabetic CAD patients. Group B
included 20 non-diabetic CAD patients. 20 healthy individuals were included as control group. Serum lipid profile and OxLDL levels were measured in all subjects. Coronary angiography was done for all patients in group A and group B.
Results: Ox-LDL level was significantly higher in group A (19.15mg/dl) and group B (16.74mg/dl) than control group
(10.22mg/dl) (p<0.0001). Also, Ox-LDL was significantly higher in group A than group B, (p<0.0001). The number of diseased
vessels was significantly higher in group A (2.30.7) than group B (1.80.8), (p=0.008). Also the number of diseased segments
was significantly higher in group A (4.12.2) than group B (2.91.8), (p=0.023). There was a direct correlation between the
Ox-LDL level and the number of diseased vessels (p=0.002) and the number of the diseased segments (p<0.0001). By ROC
curve, the sensitivity of Ox-LDL level to diagnose LAD artery disease was 100% versus 67.6% for LCX and 87.8% for RCA.
Conclusion: The level of Ox-LDL was higher in diabetics in comparison with non-diabetics indicating increased oxidative
stress in diabetic patients. Increased serum Ox-LDL may predict the extent of coronary artery disease in diabetic and nondiabetic patients. This increase in Ox-LDL was directly correlated to the number of diseased vessels and segments. Ox-LDL
was more sensitive for the detection of LAD artery disease than RCA and LCX artery disease.
Key Words: Oxidized LDL Coronary artery disease Diabetes mellitus.
Introduction
increased triglyceride levels, decreased HDL-C

levels, prolonged postprandial lipemia, and normal
or slightly elevated plasma total and LDL-C levels,
in addition to high free fatty acid (FFA) levels.
There is also an increase in the oxidation of LDL,
transforming it into the more atherogenic type
oxidized LDL (ox-LDL) [2].
Among risk factors for CAD, diabetes mellitus

(DM) is a major contributor, not only for the development of CAD but also for outcome following
various manifestations of the disease [1].
Diabetes mellitus causes macro-angiopathic
changes in the blood vessels which subsequently
causes ischemic heart diseases and peripheral
vascular disease, the role of DM as a risk factor
for ischemic heart disease may be partially explained by lipoprotein abnormalities including
Ox-LDL is a key mediator in atherogenesis and

a marker of coronary artery disease CAD. Oxidative
modification of lipids and proteins is a common
part of inflammatory diseases. Recently, circulating
ox-LDL have been shown to be a useful parameter
for identifying CAD and also to be a marker for
differentiating the degree of severity of acute
coronary syndromes [3].
The Department of Cardiology, Menofiya University, Egypt.

Extensively ox-LDL triggers the endothelial

production of cytokines that attract macrophage
Address for Correspondence: Dr. Ihab Mostafa Abdel-Fattah,

The Department of Cardiology, Menofiya University, Egypt.
261
and T-lymphocyte white blood cells to form atheromatous plaques by causing them to adhere to the
surface of the endothelial cell layer and facilitate
their movement across the endothelial cell to the
intimal layer of the arterial wall. In the next step,
ox-LDL which is no longer recognized by LDL
cholesterol receptors on cell surfaces, is treated as
a foreign body and picked up by the scavenger
receptors on macrophages, which absorb the LDL
and turn into foam cells. The bubbles of the ''foam"
are oxidized LDL cholesterol particles [4].
patients on dietary treatment alone, documentation

of two or more abnormal fasting blood glucose
levels or an abnormal glucose tolerance test according to World Health Organization criteria was
required for the diagnosis of diabetes.
Aim of the work:

The aim of this work is to study the correlation
between the level of serum oxidized Low Density
Lipoprotein (ox-LDL) and the extent of coronary
artery disease (CAD) in ischemic patients with or
without type 2 diabetes.
Previous cardiac interventions e.g. (PCI ,.).
Ischemic cardiac patients should have:

Typical chest pain.
ECG changes suggesting cardiac lesion.
Previous admission to hospital by CAD.
Other investigations suggesting CAD such as
+ve stress test, +ve isotope scanning.
Exclusion criteria:
Chronic alcoholism.
Gross obesity.
Hypothyroidism and other endocrinopathies.
The study was carried out on 80 subjects. Sixty

CAD diabetic and non diabetic patients underwent
coronary catheterization to detect the severity and
the extent of CAD.
Coronary lesions less than 50%.

Patients with dilated or ischemic cardiomyopathy.
Patients with valvular heart disease.
The study also included 20 subjects with normal

coronaries as detected by coronary angiography
as a control group matched for age and gender.
Pre-existing cerebrovascular disease (symptoms

of cerebrovascular insufficiency, history of stroke
or transient ischemic attack).
The selected individuals were divided into three

groups:
Patients with pre-existing hepatocellular diseases.
Group A: 40 CAD patients with type II DM.
Patients with renal insufficiency.
Group B: 20 non diabetic, CAD patients.
Ischemic patients who did not undergo coronary

angiography.
Group C: 20 normal individuals (not diabetic and

with normal coronaries) as a control
group.
Cardiac arrhythmias.
Biochemical measurements:
Lipid profile.
For inclusion in the study, type 2 diabetic patients

must have:
1- Age of onset of established diabetes >35 years.
They were measured by the auto-anlyser Synchron CX 5 (Beckman, USA).
2- Intake of oral anti-diabetics and/or diet only to

control the diabetic state for at least one year.
The Total Cholesterol, Triglyceride, LDL and

HDL were measured for all subjects.
3- Absence of history of diabetic keto-acidosis.
Oxidized LDL.
Serum oxidized LDL (Ox-LDL) levels were
measured by a competitive ELISA utilizing a
specific murine monoclonal antibody, mAb4E6.
Fasting blood sampling were collected by venipuncture before angiography in tubes, allow
to clot, and separate the serum by centrifugation. Samples were stored at 80C.
4- Presence of clinical or pre-clinical evidence of

one or more of micro-vascular and/or macrovascular diseases as a complication of DM.
Diagnostic criteria and definitions of risk factors
for DM:
Diabetes is defined if patients were under treatment with insulin or hypoglycemic agents. For
262
Ihab M Abdel-Fa ttah, et al

Table 1: Age and lipid profile among different groups.
Coronary angiography:
Diagnostic coronary artery catheterization were
done to all patients to assess the severity and the
extent of CAD.
Group A
No 40
Age
53.905.97
(years)
Coronary angiography was done to control group,

as a result of chest pain and inconclusive ETT
or thallium study in order to exclude Coronary
lesions.
10
M1
8
13
RV
16
11
AM
14
49.954.57
>0.05
HDL
48.9310.31 77.4010.80
(mg/dl)
48.355.34
LDL
157.9569.22 117.8523.13 91.7029.87
(mg/dl)
>0.05
<0.001
The level of serum ox-LDL was higher in group

A (19.1572.480mg/dl) than group B (16.745
1.618mg/dl) and group C (10.2251.178mg/dl)
(p>0.0001). These results showed that, ox-LDL is
higher in ischemic and diabetic patients rather than
ischemic group only (Fig. 2).
20
5
3
M2
Ox-LDL (mg/dl)
D1
6
15
RCA
Balanced Coronary
(LAO view)
Circulation
51.808.59
2 LAD
LACX
TG
160.3243.27 149.9564.23 112.9532.89 <0.005
(mg/dl)
The extent of CAD were assessed either by:

The number of diseased vessels (one, two or
three vessel disease).
The number of diseased segments (we divided
the coronary artery tree into 16 segments) Fig.
(1).
12
Group C
No 20
TC
235.8870.23 199.8037.65 162.3032.74 <0.001
(mg/dl)
The severity of CAD were assessed for each

lesion (Lesions less than 50% were excluded
from the study).
LMCA
1
Group B
No 20
15
D2
10
LCA
(RAO view)
Figure 1: Segments of coronary artery tree.
1- LMCA, 2- Proximal LAD, 3- Mid LAD, 4- Distal LAD,

5- 1st diagonal, 6- 2nd diagonal, 7- Proximal LCX, 8- Mid
LCX 9- Distal LCX 10- OM1, 11- OM2, 12- Proximal RCA,
13- Mid RCA, 14- Distal RCA, 15- PDA and 16- Posterolateral
(PL) branch.
Group 1
Group 2
Group 3
Figure 2: Ox-LDL level among different groups.
The number of diseased vessels was significantly higher in group A (2.30.7) than group B
(1.80.8), (p=0.008). Also the number of diseased
segments was significantly higher in group A
(4.12.2) than group B (2.91.8), (p=0.023). There
was a direct correlation between the Ox-LDL level
and the number of diseased vessels (p=0.002) and
the number of the diseased segments (p<0.0001)
(Figs. 3,4).
Results
There was no statistical significant difference
between the three groups (A, B and C) as regard
the age (53.905.97, 51.808.59 and 49.954.57
years respectively) (p>0.05).
As shown in Table (1), the total cholesterol
level and LDL level were significantly higher in
group A than group B and group C (p<0.001). Also,
the triglyceride level was higher in group A than
group B and group C (p<0.005).
The ROC curve was used to detect the sensitivity and specificity of lipid profile parameters and
Ox-LDL for the detection of coronary artery disease
(Fig. 5).
263

30
Ox-LDL showed a higher sensitivity to detect

CAD than all other lipid parameters:
Area under the ROC curve for Ox-LDL=0.944
(94.4%).
Area under the ROC curve for LDL=0.820
(82.0%).
Area under the ROC curve for total cholesterol=
0.811 (81.1%).
Area under the ROC curve for TGs=0.692
(69.2%).
Area under the ROC curve for HDL=0.601
(60.1%).
Ox-LDL showed 100% sensitivity and 83.3%
specificity in detection of LAD lesion in comparison with, 87.8% sensitivity and 66.7% specificity
for detection of RCA lesion, and 67.6% sensitivity
and 84.8% specificity for detection of LCX lesion.
(Figs. 6,7,8).
r=0.391, p=0.002**
Ox-LDL level
25
20
15
10
5
0
0
1
2
Number of diseased vessels
Figure 3: Correlation between number of diseased vessels

and Ox-LDL level.
30
r=0.508, p=0.000**
25
100
15
80
10
Sensitivity
Ox-LDL level
Ox LDL
20
60
Area under the ROC
curve = 0.94
40
0
0
4
6
8
Number of diseased vessels
10
20
Figure 4: Correlation between number of diseased segments

and Ox-LDL level.
0
0
20
100
40
60
100-Specificity
80
100
Figure 6: ROC curve of Ox-LDL detecting LAD lesions.

80
80
40
Sensitivity
Sensitivity
Ox LDL
100
60
20
0
0
20
40
60
100-Specificity
80
Ox LDL
HDL
LDL
Cholesterol
100
60
Area under the ROC

curve = 0.84
40
20
0
0
TGs
Figure 5: ROC curve of different lipids detecting CAD.
20
40
60
100-Specificity
80
100
Figure 7: ROC curve of Ox-LDL detecting RCA lesions.
264
Ihab M Abdel-Fa ttah, et al

Ox LDL
In our series Ox-LDL was more sensitive for

the detection of LAD artery disease than RCA and
LCX artery disease. These results may suggest that
circulating Ox-LDL may be a possible biochemical
risk marker of LAD artery disease especially in
diabetic patients with CAD [20].
100
Sensitivity
80
60
Area under the ROC

curve = 0.82
Conclusion
40
The level of Ox-LDL was higher in diabetics

in comparison with non-diabetics indicating increased oxidative stress in diabetic patients. Increased serum Ox-LDL may predict the extent of
coronary artery disease in diabetic and non-diabetic
patients. This increase in Ox-LDL was directly
correlated to the number of diseased vessels and
segments. Ox-LDL was more sensitive for the
detection of LAD artery disease than RCA and
LCX artery disease.
20
0
0
20
40
60
100-Specificity
80
100
Figure 8: ROC curve of OX-LDL detecting LCX lesions.
Discussion
Diabetes mellitus is a syndrome with metabolic
and vascular components which are interrelated.
The role of diabetes mellitus as a risk factor for
ischemic heart disease may be partially explained
by lipoprotein abnormalities including increased
triglyceride levels, free fatty acid levels and also
Ox-LDL levels [5,6] . Hyperinsulinemia may be
responsible for the low HDL cholesterol levels and
may contribute to increased blood pressure level
[7,8] . Formation of advanced glycosylation endproducts (AGEs) causes release of cytokines that
can affect proliferation and function of vascular
cells leading to vascular thickening and endothelial
dysfunction [9-10].
References
1-
American Diabetes Association, National Institute of

Diabetes and Digestive and Kidney Diseases: The prevention or delay of type 2 diabetes (Position Statement).
Diabetes Care 2005; 27 (Suppl. 1): 547-554.
2- Haffner SM, Goldberg RB: New strategies for the treatment

of diabetic dyslipidemia. Diabetes Care 2002; 25: 12378.
3-
Holvoet P, Mertens A, Verhamme P, Bogaerts K, Beyens

G: Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease. Arteioscler
Thromb Vasc Biol 2000; 21: 844.
4- Steinberg D, Witztum JL: Is the oxidative modification

hypothesis relevant to human atherosclerosis? Do the
antioxidant trials conducted to date refute the hypothesis?
Circulation 2002; 105: 2107-2111.
In our series, the oxidative stress was higher

in diabetic patients with CAD indicated by increased Ox-LDL level. The level of serum OxLDL was higher in the diabetic group 19.15
2.4mg/dl than non-diabetic group (16.751.6mg/dl).
This may be due to increased level of AGEs that
initiate oxidation of LDL [12,13].
5- Watkins PJ, Amiel SA, Howel SL, Turner E: Diabetes

and its management Sixth edition, Blackwell Puplishing.
Diabetes Care 2003; 9: 261-8.
6- Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part
1: Diagnosis and classification of diabetes, provisional
report of a WHO Consultation. Diabet Med 2000; 15:
539.
Over the last years the oxidative modification

of LDL in diabetic patients had gained more interest
[14,15]. Therefore measurement of circulating OxLDL may be helpful for identifiying high-risk
patients with type 2 diabetes and CAD [16,17] .
Regarding the correlation between the level of
serum Ox-LDL and the extent of CAD, we found
that there was a positive correlation between the
level of Ox-LDL and the number of diseased vessels
and segments. This correlation may be a new
reliable method of detection of the severity of CAD
in diabetic ischemic patients [18,19].
7- Gerich JE: The genetic basis of type 2 diabetes mellitus:

Impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev 1998; 19: 491.
8- Kriketos AP, Greenfield JR, Peake PW, Furler SM, Denyer
GS, Charlesworth JA, Campbell LV: Inflammation, Insulin
Resistance, and Adiposity: A study of first-degree relatives
of type 2 diabetic subjects Diabetes Care 2004; 27 (8):
2033-2040.
9- Bertoni AG, Sydah S, Brancati FL: Diabetes and the risk
of infection related mortality in USA. Diabetes Care 2001;
24: 1044-1049.
265

10- M Coutinho, HC Gerstein, Y Wang, S Yusuf: The relationship between glucose and incident cardiovascular events:
A meta regression analysis of published data from 20
studies of 95,783 individuals followed for 12.4 years.
Diabetes Care 1999; 22, pp. 233-240.
15- Amos AF, McCarty DJ, Zimmet P: The rising global

burden of diabetes and its complications: Estimates and
projections to the year 2010. Diabet Med 1997; 14 (Suppl
5): S1-85.
16- Simons LA, Simons J: Diabetes and coronary heart disease.
N Engl J Med 1998; 339: 1714-5.
11- Cho E, Rimm EB, Stampfer MJ, et al: The impact of

diabetes mellitus and prior myocardial infarction on
mortality from all causes and from coronary heart disease
in men. J Am Coll Cardiol 2002; 40: 954-60.
17- Steiner G: Treating lipid abnormalities in patients with

type 2 diabetes mellitus. Am J Cardiol 2001; 88: 37N40N.
18- Herlitz J, Wognsen GB, Emanuelsson H, Haglid M,
Karlson BW, Karlsson T, Albertsson P, Westberg S: Mortality and morbidity in diabetic and nondiabetic patients
during a 2-year period after coronary artery bypass grafting. Diabetes Care 1996.
12- Malmberg KS, Yusuf H.C. Gerstein et al: Impact of

diabetes on long-term prognosis in patients with unstable
angina and non-Q-wave myocardial infarction: Results
of the OASIS (Organization to Assess Strategies for
Ischemic Syndromes) Registry. Circulation 2000; 102,
pp. 1014-1019.
19- Imanaga Y, Sakata N, Takebayashi S, Matsunaga A, Sasaki

J, Arakawa K, Nagai R, Horiuchi S, Itabe H, Takano T:
In vivo and in vitro evidence for the glycoxidation of low
density lipoprotein in human atherosclerotic plaques.
Atherosclerosis12000; 50: 343-355.
13- GUSTO IIb Investigators, DK McGuire, H Emanuelsson,

CB Granger, et al: Influence of diabetes mellitus on
clinical outcomes across the spectrum of acute coronary
syndromes: Findings from the GUSTO IIb study. Eur
Heart J 2000; 21, pp. 1750-1758.
20- Becker A, Bos G, de Vegt F, et al: Cardiovascular events

in type 2 diabetes: Comparison with nondiabetic individuals without and with prior cardiovascular disease. 10year follow-up of the Hoorn study. Eur Heart J 2003; 24:
1406-13.
14- H King, RE Aubert, WH Herman: Global burden of

diabetes, 1995-2025. Prevalence, numerical estimates,
and projections. Diabetes Care 1998; 21, pp. 1414-1431.
266
Effect of Glucose Insulin Infusion on High Sensitivity C-Reactive

Protein and Left Ventricular Global Systolic Function in Diabetic Patients
Presenting with ST Segment Elevation Myocardial Infarction (STEMI)
OSAMA ABDEL AZIZ RIFAIE, MD; IMAN ESMAT SAYED IBRAHIM, MD;
AHMED MOHAMMED ONSY, MD; GEORGE GHALY GIRGUS, MBBCH*
Acute myocardial infarction (AMI) is the leading cause of death over the world. It is well established that diabetic patients
have worse prognosis after AMI than those without diabetes. Inflammatory markers such as CRP reflect the extent of myocardial
necrosis and correlate with cardiac outcomes following AMI. Glucose insulin infusion is a widely applicable, low-cost therapy
that has been postulated to improve outcomes in patients with ST elevation myocardial infarction (STEMI).
Objective of the Work: The present study was conducted to determine the effect of glucose insulin infusion on high sensitivity
C-reactive protein levels, left ventricular global systolic function, and cardiac adverse events in patients with ST segment
elevation myocardial infarction during the early hospitalization period.
Patients and Methods: This study included 60 patients admitted to the coronary care units of El-Sahel teaching hospital
and Ain Shams University Hospitals with STEMI. All patients in this study were either known to have DM or hyperglycaemia
on admission. All patients were candidates for thrombolytic therapy. They were divided into two groups. The glucose-insulinpotassium (GIK) group (30 patients) received glucose-insulin infusion according to a predefined protocol for 24 hours. The
control group (30 patients) received subcutaneous soluble insulin every 8 hours according to a sliding scale. All patients included
in the study were subjected to full history taking, thorough general and local examination, serial 12 lead resting ECGs, serial
CK-MB levels and echocardiography. High sensitivity C-reactive protein was measured on admission and repeated 24 hours
later.
Results: There was no significant difference between the two groups regarding the sex distribution, mean age, prevalence
of the different risk factors for coronary artery disease, duration and type of treatment of DM.
A- In-hospital adverse cardiac events: There was a significant statistical difference between the two groups regarding development
of congestive heart failure (6.67% in the GIK group versus 26.67% in the control group, p<0.05).
B- Left ventricular systolic function: Ejection fraction was significantly higher in the GIK group than in the control group I
(p<0.05). In the GIK group, the mean ejection fraction (EF %) was 57.43%8.34%, while in the control group, it was
51.17%9.26%.
C- High sensitivity C-reactive protein: There was no significant difference regarding admission CRP between the two groups
(p>0.05). After 24 hours, CRP levels were significantly lower in the GIK group (15.227.27) than that of the control group
(34.457.46), p<0.001.
Conclusion: GIK infusion in patients with ST segment elevation acute myocardial infarction showed beneficial effects as
demonstrated by better preservation of the myocardial LV systolic function, lower rate of in-hospital development of congestive
heart failure, and lower levels of C-reactive protein.
Key Words: C-reative protein ST segment elevation MI Glucose insulin infusion Echocardiography.
The Department of Cardiology, Ain Shams University and

*Al Sahel Teaching Hospital, Cairo, Egypt.
accepted 1 April, 2010.
Address for Correspondence: Dr. Osama Abdel Aziz Rifaie,
The Department of Cardiology, Ain Shams University.
267
Effect of Glucose Insulin Infusion on High Sensitivity C-Reactive Protein
Introduction
University Hospitals in the period from December

2006 to January 2008. All patients presented with
acute ST elevation myocardial infarction (STEMI).
Acute myocardial infarction (MI) is the leading

cause of death over the world. If we include patients
who die before hospital admission the overall
mortality rate is 45% but incidence and mortality
declined over the past 30 years with the advent of
the coronary care units (CCU), fibrinolytic therapy
and catheter-based reperfusion [1].
Inclusion criteria:
1- Patients known to have diabetes mellitus.
2- No previous diagnosis of diabetes mellitus but
with a plasma random blood glucose level
>200mg/dl on admission.
Acute MI triggers an inflammatory reaction

which plays an important role in myocardial injury
[2]. Inflammatory markers such as C-reactive protein (CRP) reflect the extent of myocardial necrosis
and correlate with cardiac outcomes following
AMI [3].
3- Candidates for thrombolytic therapy.

Exclusion criteria:
1- Patients with unstable angina and non-ST segment elevation myocardial infarction.
A wealth of reports indicates that a random

blood sugar on admission for an acute coronary
syndrome (ACS) is strongly correlated with the
short- and long-term outcome of these patients [4].
Higher blood sugar concentrations in persons with
diabetes, including those previously undiagnosed,
are highly predictive for poorer outcome both in
the hospital and subsequently [5].
2- Onset of chest pain of more than 12 hours.

3- Patients in cardiogenic shock.
4- Patients with diabetic ketoacidosis.
5- Presence of other conditions known to modify
the serum CRP levels such as; collagen disease,
malignant disease, infectious and inflammatory
diseases, septicemia, arthritis, patients with
history of recent surgery, patients with history
of recent major trauma.
Acute myocardial infarction causes a dramatic

increase in adrenergic tone, which stimulates lipolysis, thereby increasing the levels of free fatty
acids. Several hormonal mechanisms contribute to
a decrease in insulin sensitivity and glucose utilization during acute myocardial ischaemia. The
original promise for glucose-insulin-potassium
(GIK) therapy for AMI is the reduction of free
fatty acids by insulin [6].
The diagnosis of STEMI required fulfillment two

out of the following criteria:
Typical chest pain lasting for at least 15 minutes.
ST segment elevation of more than 0.2mv in at
least 2 contiguous precordial leads or more than
0.1mv in limb leads or new left bundle branch
clock.
GIK infusion is a widely applicable, low-cost

therapy that has been postulated to improve outcomes in patients with STEMI [7].
At least two values of serum creatine kinase MB

isoenzyme two folds or more the normal range,
10 to 16 hours after the onset of symptoms.
Aim of the work:

The present study was conducted to determine
the effect of glucose insulin infusion on high
sensitivity C-reactive protein levels, left ventricular
global systolic function, and cardiac adverse events
in patients with ST segment elevation myocardial
infarction during the early hospitalization period.
A reinfarction was defined as an event fulfilling

the criteria given for ST-elevation myocardial
infarction but appearing more than 72 hours after
the index infarction.
Diabetes mellitus:
Diabetes mellitus was considered present if a

patient was given this diagnosis and was receiving
treatment (diet, tablets or insulin). Patients with
no previous diagnosis of diabetes mellitus but with
a plasma random blood glucose level >200mg/dl
on admission were also included in the study [8].
I- Subjects:
The present study included 60 patients who
were admitted to the Coronary Care Units (CCU)
of El-Sahel Teaching Hospital and Ain Shams
268
Osama A Rifaie, et al
Patients were divided into two groups, each

group 30 patients:
Group 1:
This group included patients who received, in
addition to the standard coronary care unit therapy,
glucose-insulin infusion according to a predefined
protocol for at least 24 hours [8]:
mediately in patients who developed any kind of

clinically significant arrhythmia.
Group 2:
Patients in this group were treated according
to the standard coronary care unit practice. They
received standard insulin therapy in the form of
subcutaneous soluble insulin every 8 hours according to the following sliding scale:
1- 500ml 5% glucose with 80IU of soluble insulin

(1IU/6ml).
Less than 200mg/dl: No insulin given.
2- Start with 30ml/hr.
200-250mg/dl: 5 units of soluble insulin.
3- Check plasma blood glucose after 1h.
4- Adjust infusion rate according to the protocol

and aim for a plasma blood glucose level of
130-190mg/dl.
5- Plasma blood glucose should be checked after

1h if infusion rate has been changed, otherwise
every 2 hours.
II- Methods:
All patients included in the study were subjected
to the following:
6- If the initial decrease in plasma blood glucose

exceeds 30%, the infusion rate should be left
unchanged if plasma blood glucose is >200mg/dl
and reduced by 6ml/h if plasma blood glucose
is within the targeted range of 130-190mg/dl.
A- Full history taking:
7- If plasma blood glucose is stable and <195mg/dl

after 10 PM, reduce infusion rate by 50% during
night.
Plasma blood glucose level (mg/dl):
Detailed analysis of the current AMI as regards:

1- Onset and characteristics of chest pain, its site
and presence of any associated symptoms.
2- Presence of any cardiac symptoms.
More than 270mg/dl: Give 8IU of insulin as an

intravenous bolus injection and increase infusion
rate by 2ml/h.
B- Clinical examination:
General and local cardiac examination with
special emphasis on:
200 to 270mg/dl: Increase infusion rate by 3ml/h.
1- Pulse; for rate and rhythm.
130 to 190mg/dl: Leave infusion rate unchanged.
2- Arterial blood pressure.
70 to 125mg/dl: Decrease infusion rate by 6ml/h.
3- Cardiac auscultation for S3, S4 or any associated

murmurs.
Above 350mg/dl: 20 units of soluble insulin.
With special emphasis on the coronary risk factors

including age, sex, smoking, hypertension and
dyslipidaemia.
Less than 70mg/dl: Stop infusion for 15 minutes.

Then test blood glucose and continue testing
every 15 minutes until plasma blood glucose is
>130. In the presence of symptoms, administer
30ml of 25% glucose intravenously. The infusion
rate is restarted with an infusion rate decreased
by 6ml/h when plasma blood glucose is
>130mg/dl.
4- Chest examination for any sign of pulmonary

congestion.
C- ECG:
Electrocardiograms were recorded immediately
on admission. Serial electrocardiogram tracings
were done every 6 hours during the first 24 hours
and then daily until discharge.
The infusion was started by the nurse in charge

of the coronary care unit and under medical supervision as soon as possible after the patient arrival.
Serum potassium was measured immediately before
starting the GIK infusions and then after 6, 12, 18
and 24 hours. Serum potassium was checked im-
D- Echocardiography:
Transthoracic Echocardiography was performed
within the first five to seven days of admission
according to the patients condition. Tow dimensional images from the standard parasternal long
269
females. While in the control group (group II) the

mean age was 58.95.68 years and there were 23
males 7 females.
and short axis views as well as apical views were

obtained for the assessment of:
1- Left ventricular function with special emphasis
on the ejection fraction, which was measured
by the eye balling method & M mode.
The GIK group showed that 11 patients (36.7%)

had history of hypertension, 16 patients (53.3%)
were dyslipidaemic and 17 patients (56.7%) were
smokers. While in the control group, there were
13 patients (43.3%) had history of hypertension,
14 patients (46.7%) were dyslipidemic and 21
patients (70%) were smokers.
2- Segmental wall motion abnormality after the

acute stage. Segmental wall motion abnormality
assessment was done according to 16-segment
approach (according to the American Society
of Echocardiography). The left ventricle was
divided into 16 segments and then each segment
will be judged whether normal or abnormal
based on a scheme giving a value of 1 for a
normal segment, 2 for hypokinetic, 3 for akinetic, 4 for diskinetic and 5 for aneurysmal.
In GIK group, 22 patients (73.3%) had anterior

wall MI, 6 patients (20%) had inferior wall MI and
2 patients (6.7%) had lateral wall MI. In the control
group, 19 patients (63.3%) had anterior wall MI,
8 patients (26.7%) had inferior wall MI and 3
patients (10%) had lateral wall MI.
Left Ventricular Wall Motion Score Index was

calculated by the formula:
The sum of the scores for the individual regions
/16.
There was no statistically significant difference

between the two groups (p>0.05).
Table 1: Baseline characteristics of the two groups.
E- Laboratory investigations:
1- Cardiac enzymes:
Serial measurement of serum CPK and CKMB on admission and every 8 hours during the
first 24 hours and then daily till being normalized.
Factor
2- Lipid profile:
Lipid profile was measured including: Serum
cholesterol, Triglycerides level, HDL cholesterol
level, LDL cholesterol level.
3- High sensitivity CRP:
High sensitivity CRP levels were measured on
admission and 24 hours later.
GIK group Control group

(30 patients) (30 patients)
N
Sex distribution:
Male
Females
25
5
83.3
16.7
23
7
76.7
23.3
Age (Mean SD)

Hypertension
Smoking
Dyslipidaemia
Anterior MI
Inferior MI
Lateral MI
56.87.37
11
36.7
17
56.7
16
53.3
22
73.3
6
20.0
2
6.7
p-value
0.374
58.95.68
13
43.3
21
70
14
46.7
19
63.3
8
26.7
3
10.0
0.221
0.396
0.211
0.398
0.290
0.381
1.00
Type of diabetes treatment in the two groups:

In GIK group 19 patients (76%) were on oral
hypoglycemic drugs, 5 patients (20%) were on
insulin therapy and 6 patients were on no control.
In control group 22 patients (73.3%) were on oral
hypoglycemic drugs, 3 patients (11%) were on
insulin therapy and 5 patients (16.6%) were on no
control. The difference between the two groups
was not statistically significant (p>0.05).
SPSS package (statistical package for social
sciences) version 10.0 was used for data management. Mean and standard deviation were used to
describe quantitative data. Student-test was used
to compare means of two independent groups. The
chi-square test was used to compare the proportions
of the same variable in the two study groups. pvalue is always two tailed and significant at 0.05
levels.
Table (2) shows that there was no significant

difference between the two groups regarding the
random blood sugar levels measured on admission
and after 8 hours (p>0.05).
Results
General characteristics and demographic data,
Table (1):
In the GIK group (group I) the mean age was
56.87.37 years and there were 25 males and 5
However after 16 hours and after 24 hours the

random blood sugar was significantly lower in the
GIK group than that in the control group (p<0.05).
270
Table 3: In-hospital major adverse cardiac events of the two
groups.
80
70
60
Group I
(n=30)
Factor
50
40
Death
Post infarction angina
Recurrent infarction
CHF
Arrhythmia
30
20
10
0
Mean
SD
1
2
1
2
7
3.33
6.67
3.33
6.67
23.33
1
5
2
8
10
3.33
16.67
6.67
26.67
33.33
p-value
1.00
0.212
1.00
0.04*
0.284
Group II
Table (3) shows that there was no significant

difference between the two groups in in-hospital
mortality, recurrent infarction, post infarction
angina and arrhythmias. However development of
congestive heart failure was significantly lower in
the GIK group than in the control group.
Oral hypoglycemic
Insulin
No control
Figure 1: Type of treatment of DM in the two groups.
Table 2: Blood glucose levels at different periods in the two
groups.
Group I (GIK)
RBG
On Admission
After 2hr.
After 4hr.
After 6hr.
After 8hr.
After 10hr.
After 12hr.
After 14hr.
After 16hr.
After 18hr.
After 20hr.
After 22hr.
After 24hr.
SD
Mean
SD
306.87
306.93
305.30
285.80
272.10
263.57
252.67
238.87
226.47
223.27
216.13
214.50
210.60
42.43
42.10
46.71
48.85
47.52
49.45
44.92
42.64
50.54
46.78
43.90
36.39
31.00
317.77
68.04
350
Group I
30
Group II
Mean
35
p-value
Group II
25
20
0.459
15
276.27
56.88
10
0.759
5
249.10
32.12
0.042*
235.63
38.49
0.0074*
0
Death
p-value=0.459
p-value=0.759
Group I
N=30
p-value=0.042*
200
150
100
Gr.
50
Gr.
CHF
Arrhythmia
Table 4: Results of Echocardiographic data of the studied

patients.
300
250
Post
Recurrent
infarction infarction
angina
Figure 3: In-hospital adverse cardiac events in the two groups.
* p-value significant.
EF%
LVEDD
LDESD
WMSI
p-value=0.007*
ad
m
A issi
fte o
n
A r 2h
fte r
A r 6h
fte r
A r4
fte hr
A r
fte 8h
A r 10 r
fte h
A r 12 r
fte h
A r 14 r
fte h
A r1 r
fte 6h
A r 18 r
fte h
r
A r 20
fte
hr
r
A 22h
fte
r2 r
4h
r
* Significant at p-value <0.05.
Group I
Group II
(n=30)
Group II
N=30
Mean
SD
Mean
SD
57.43
5.12
3.39
1.35
8.34
0.61
0.73
0.21
51.17
5.38
3.89
1.46
9.26
0.67
0.68
0.32
p-value
0.007*
0.123
0.105
0.121
EDD = End Diastolic Dimension.

ESD = End Systolic Dimension.
EF = Ejection Fraction.
WMSI = Wall Motion Score Index
Group
I
Table (4) shows that there was no statistically

significant difference between the studied group
and controls regarding LVEDD, LVESD and wall
Figure 2: Blood glucose levels at the different periods in the

two groups.
271
motion score index. While there was a statistically

highly significant difference among both groups
as regard ejection fraction being higher in group I.
Discussion
Experimental and clinical evidence suggests
that metabolic or ionic support of the ischemic
myocardium may reduce mortality after myocardial
infarction [9]. Glucose-insulin-potassium (GIK)
infusion as a metabolic therapy was first advocated
for the management of acute myocardial infarction
in 1960s [10,11] . Over the subsequent decades,
enthusiasm for its use has been patchy, especially
with the availability of other effective treatments
such as reperfusion therapy for AMI. Several clinical studies in the mid-1990s revived the interest
in the glycometabolic aspects of patients with AMI.
The somewhat conflicting results of these recent
studies have generated debate over the significance
of the glycometabolic state following acute coronary occlusion and the role of insulin-based infusion
therapy. Although most of the available evidence
is in favour of an insulin-based therapy, there are
still many aspects of this therapy that require
clarification [12].
70
Group I
60
Group II
50
40
30
20
10
0
EF%
FS
Figure 4: Results of Echocardiographic (EF and FS).
Results of C-reactive protein:

The study showed that the admission C-reactive
protein level in patients blood was not significantly
different in the two groups (p>0.05). While after
24 hours the CRP level in patients blood was
significantly lower in the GIK group than that in
the control group (p<0.01).
This study is a case control analytic study that

was conducted in El-Sahel Teaching Hospital and
Ain Shams University Hospital in order to determine the effect of glucose insulin infusion on Creactive protein levels and left ventricular global
systolic function in patients with ST segment
elevation myocardial infarction.
Table 5: Results of CRP in the two groups.

Group I
N=30
Group II
N=30
Our study included 60 patients admitted to

coronary care unit with acute ST segment elevation
myocardial infarction. They were divided into two
groups; GIK group (group I) and control group
(group II).
p-value
Mean
SD
Mean
SD
CRP admission
9.09
6.84
6.81
3.47
0.108
CRP after 24 hours
15.22
7.27
29.45
7.46
0.008*
There was no significant difference between

the two groups regarding sex distribution, mean
age, prevalence of the different risk factors for
coronary artery disease, duration of diabetes
mellitus and age of onset of diabetes (p>0.05).
40
Group I
35
Group II
30
I- In-hospital adverse cardiac events:

Results of our study showed that development
of congestive heart failure was significantly lower
in patients who received GIK infusion than those
in the control group. However there was no significant difference between the two groups regarding
other in-hospital adverse cardiac events (e.g. mortality, recurrent infarction and arrhythmias).
25
20
15
10
5
0
CRP admission
GIK treatment may prevent heart failure by

reducing infarct size and by providing an additional
energy substrate that supports the non-infarcted
myocardiums ability to cope with a sudden me-
CRP after 24 hours
Figure 5: High sensitivity C-reactive protein levels of the

two groups at admission and 24 hours later.
272
chanical load [13]. In a study of aortic banding in

mice, wild-type animals had a decreased highenergy phosphate profile, developed rapid LV
failure, and had a mortality rate of 40 percent at
eight weeks. In contrast, transgenic mice with a
cardiac-specific over expression of the glucose
transporter, GLUT 1, had a markedly increased
level of glucose uptake, maintained a normal high
energy phosphate profile, normal LV function, and
had a very low mortality rate. Thus, enhanced
cellular glucose uptake appears critical for the
function and survival of acutely overloaded myocardium. By increasing glucose availability and
uptake, GIK may provide important metabolic
support to the acutely overloaded non-infarct region
[14].
caemia on admission in a randomized fashion by

means of an insulin-glucose infusion. Within 24h,
glycaemia was significantly lower in the intervention group, to be maintained at a lower level during
the next year. This difference translated into 11%
reduced mortality in absolute terms, indicating an
NNT (number needed to treat) of nine patients for
one life saved. The beneficial effect was still
apparent after 3.4 years with a relative mortality
reduction of about 30% [20,21]. The second DIGAMI Trial compared the three management protocols: acute insulin-glucose infusion followed by
insulin-based long-term glucose control; insulinglucose infusion, followed by standard glucose
control; routine metabolic management according
to local practice, in 1253 patients with type2 diabetes and suspected AMI. The DIGAMI 2 Trial
did not show that an acutely introduced, long-term
intensive insulin treatment strategy improves survival in type 2 diabetic patients following Ml and
did not demonstrate that initiating treatment with
an insulin-glucose infusion is superior to conventional management. The DIGAMI 2 Trial clearly
confirmed that glucose level is a strong, independent predictor of long-term mortality following
MI in patients with type 2 diabetes, with a 20%
increase in long-term mortality for an increase in
plasma glucose by 3mmol/L [22].
GIPS-I (Glucose-Insulin-Potassium) Study reported that GIK infusion, as an adjunctive therapy

to primary PCI in AMI, appeared to decrease mortality through preventing the development of heart
failure; 91% of the study population presented
without heart failure (Killip class 1); the subsequent
development of HF was responsible for 67% of
the deaths in the Killip class 1 patients who did
not receive GIK [15].
In an attempt to verify the results of GIPS-I
study suggesting that GIK infusion might be beneficial in patients with acute STEMI without signs
of heart failure; the GIPS-II study evaluated 889
such patients. Reperfusion via primary PCI occurred in 88 percent of the patients. The primary
end point of 30-day mortality was not significantly
reduced by GIK infusion (2.9 versus 1.8 for the
control group) [16].
A meta-analysis of several early studies on

glucose-insulin-potassium (GIK) therapy in AMI,
including 1932 predominantly non-diabetic patients, suggested a proportional acute mortality
reduction of 28% [23].
In the Estudios Cardiologicos Latinoamerica
(ECLA) Trial, involving 400 patients, there was a
trend towards a non-significant reduction in major
and minor in-hospital events in patients allocated
to GIK therapy. However, in a subgroup comprising
252 patients who also had reperfusion therapy,
there was a significant reduction in mortality in
the treated group compared with the controls [24].
However, Gwilt DJ et al, in 1984 reported that

there was no significant difference between the
conventionally treated group and GIK group in
development of CHF in patients with AMI [17].
It was found that higher blood sugar concentrations in persons with diabetes, including those
previously undiagnosed, are highly predictive for
poorer outcome both in the hospital and subsequently [18,19]. In our study, blood sugar levels
were significantly lower in the insulin group after
16 hours of GIK infusion, but this could not reflect
any statistically significant difference regarding
in-hospital mortality. These results are not concordant with those of the landmark Diabetes Insulin
Glucose and Acute Myocardial Infarction (DIGAMI) Study. The first DIGAMI Study, performed
in patients with an ACS, targeted acute hypergly-
In spite of the encouraging results of the ECLA

trial, there are a number of concerns [24]:
1- There was a relatively long gap (10 to 11 hours)
between the onset of symptoms and initiation
of GIK treatment, which might attenuate the
potential benefit of GIK.
2- The mortality rate of 15.2 percent in patients
not receiving GIK who underwent reperfusion
is more than twice as high as many major trials
of thrombolysis for STEMI.
273
3- On the other hand, the mortality rate was only

6.7 percent in the non-reperfused, non-GIK
patients. This finding of a higher mortality with
reperfusion is not consistent with numerous
randomized trials of thrombolytic therapy in
STEMI and may reflect nonrandomized allocation to thrombolytic therapy with possible use
in sicker patients.
ACS appear to be a marker of widespread underlying vascular inflammation and hyperresponsiveness of the inflammatory system to even small
stimuli and they are not the result of localized
plaque rupture alone [29].
Our results are in agreement with the study of
Chaudhuri et al, in 2004, who studied the AntiInflammatory and Profibrinolytic Effect of Insulin
in Acute ST-Segment-Elevation Myocardial Infarction. Thirty-two patients receiving reteplase were
randomly assigned infusions of either insulin at
2.5 U/h, dextrose, and potassium (GIK) or normal
saline and potassium for 48 hours. Plasma concentrations of high-sensitivity C-reactive protein (CRP)
were measured at baseline and sequentially for 48
hours. Baseline CRP was significantly increased
(2- to 4-fold) at 24 and 48 hours in each group
(p<0.01). However, in the insulin group, there was
a significant (p<0.05) attenuation of the absolute
rise in concentration of CRP from baseline. The
absolute increase of CRP was reduced by 40%
(CRP) at 24 hours compared with the control group.
They concluded that Insulin has an antiinflammatory effect in patients with acute MI. These effects
may contribute to the clinical benefits of insulin
in STEMI [30].
To evaluate the use of GIK in a large scale trial,

two trials - the Clinical Trial of Reviparin and
Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation (CREATE) and the
Estudios Cardiologicas Latin America Study Group
[ECLA] 2 GIK Full Scale Trial - were formally
merged into one trial, called the CREATE-ECLA
International GIK Study. CREATE-ECLA Trial
randomized more than 20 000 patients with acute
ST-elevation infarction, out of whom 18% had type
2 diabetes, to high dose GIK or to standard care.
This included acute reperfusion therapy in more
than 80% of the patients. The overall outcome of
this large-scale study was that GIK did not influence
mortality, cardiac arrest, or cardiogenic shock. The
lack of benefit of GIK infusion was seen in all
prespecified subgroups including those with or
without diabetes, heart failure, early presentation,
and those treated with thrombolytic therapy or
primary PCI [25].
The lower levels of CRP noticed in the GIK

group in our study may indicate the beneficial
effect of GIK infusion on the short-, intermediate,
and long-term follow-up. Some studies have found
that serum CRP levels predict the risk of a recurrent
in-hospital cardiac event, 30-day or long-term
mortality after an MI.
II- Global left ventricular systolic function:

In the present study there was a significant
difference between the two groups in ejection
fraction (EF) (p<0.05). In the GIK group the mean
EF was 57.43%8.34, while in the control group
the mean EF was 51.17%9.26.
Suleiman et al, in 2003 reported that elevated

serum CRP measured 12 to 24 hours after the onset
of symptoms in 448 patients with an acute MI (76
percent ST elevation MI) was associated with a
significant increase in 30-day mortality, larger
infarct size, and more frequent heart failure [31].
Mantle JA et al, in 1981, and Sasso FC et al,

in 2000 have concluded that the infusion of insulin
and glucose did increase the contractile force [26,27].
Salter LF et al, in 1987 reported that in acute
MI there was a significantly greater improvement
in the global ejection fraction of patients receiving
GIK (increases 0.070.04) than in those randomized
to placebo (decreases 0.080.04) (p<0.02) [28].
Study limitations:
1- Limited number of the patients.
2- No follow-up was done for the patients after
discharge from the hospital to assess the longterm morbidity and mortality.
III- Results of C-reactive protein:

Results of the current study showed that the
admission C-reactive protein was not significantly
different in the two groups (p>0.05). While after
24 hours the CRP was significantly lower in the
GIK group than that of the control group (p<0.001).
Conclusion
We concluded that glucose-insulin infusion in
patients with ST segment elevation acute myocardial infarction showed beneficial effects as demonstrated by better preservation of the myocardial
LV systolic function, lower rate of congestive heart
Liuzzo et al, in 1998 mentioned that the elevated

levels of acute phase reactants in patients with an
274
failure, and lower levels of C-reactive protein

during the early hospitalization period, however
further studies with long-term follow up and larger
number of patients may be needed to establish the
effects of lower levels of C-reactive protein in the
glucose-insulin infusion group on morbidity and
mortality and after acute ST segment elevation
myocardial infarction.
14- Liao R, Jain M, Cui L, et al: Cardiac-specific overexpression of GLUT1 prevents the development of heart failure
attributable to pressure overload in mice. Circulation
2002; 106: 2125-2134.
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276

MOHAMED FAHMY ELNOAMANY, MD; IHAB MOHAMED ABDELFATTAH, MD;
ASHRAF ABDELRAOUF DAWOOD, MD*; ABDALLA MOSTAFA KAMAL, MD;
SAMAH ABDELSAMEA ZAHRAN, MBBCH
Background: Adiponectin (ADP), an adipocyte-derived protein, seems to be a link between obesity, insulin resistance, and
atherosclerosis. ADP has protective actions against the initiation and progression of atherosclerosis through anti-inflammatory
and anti-atherogenic effects and it is suggested that, hypoadiponectinemia increases the prevalence of ischemic heart disease.
Objectives: To investigate the relationship between plasma ADP levels and the severity and extent of coronary artery lesions
in patients with coronary artery disease (CAD).
Patients and Methods: The study comprised 90 patients divided according to presence or absence of CAD (proven by
coronary angiography) & diabetes mellitus (DM) into 3 groups; Group I (n=35 patients) diabetic patients with CAD, Group II
(n=35 patients) non diabetic patients with CAD and Group III (n=20 patients) non diabetic patients with normal coronaries as
a control group. Coronary angiograms were scored according to vessel score, severity score & Gensini score. Venous blood
samples were withdrawn from each subject after 12-14 hours fasting within 2 hours before coronary angiography for estimation
of serum ADP levels & lipid profile.
Results: Serum ADP levels were significantly lower in group I than group II (2.610.19g/ml Vs. 3.400.70g/ml, p<0.001)
and was significantly lower in each group in comparison to group III (5.471.04g/ml, p<0.001). Severity score, vessel score
and Gensini score were significantly higher in group I than group II (9.23.69 Vs. 7.204.27, 2.510.67 Vs. 1.470.85,
64.3633.01 Vs. 50.337.97 respectively, p<0.05 for each). A Strong negative correlation was found between Serum ADP levels
and each of Severity score (r=.7, p<0.001), vessel score (r=.6, p<0.001), Gensini score (r=.5, p<0.01), fasting and 2 hour
postprandial blood glucose (r=.5, p<0.001 for each), serum triglycerides (r=.5, p<0.01), LDL cholesterol (r=.4, p<0.05)
& total cholesterol (r=.3, p<0.05), whereas the correlation was positive with LVEF (r=.57, p<0.05) & HDL cholesterol (r=.35,
p<0.05). In multivariate logistic regression analysis, age, DM, HDL cholesterol, triglycerides & ejection fraction were found
to be the most powerful independent predictors of serum ADP levels. Serum ADP level has a cutoff point 3.8g/ml with 98.57%
sensitivity and 90% specificity regarding its ability to predict the presence of CAD.
Conclusion: ADP is an important target with anti-diabetic, anti-inflammatory, and anti-atherogenic properties. Measurement
of plasma concentrations of ADP may be a helpful tool for assessment of CAD risk. Plasma ADP levels might also represent a
novel diagnostic tool for risk stratification of patients with CAD as regard the severity and the extent of coronary artery lesions.
ADP could become a promising target for future investigations in reducing the morbidity and mortality of atherosclerotic disease.
Key Words: Adiponectin Coronary artery disease Diabetes mellitus.
Introduction
frequent cause of cardiovascular mortality. Metabolic syndrome is one of the most important factors
that increase the incidence of CAD [1].
Cardiovascular diseases are the main cause of

death in both developed and developing countries,
and coronary artery disease (CAD) is the most
Adiponectin (Arcp 30) is a colectine-type protein, which consists of 244 amino acids and is
produced by adipocytes after stimulation of PPARs
gamma ligands [2]. It is supposed that adiponectin
(ADP) is one of the factors that influences tissue
insulin sensitivity and lipid metabolism [3,4] .
ADP can directly influence muscle and liver to
stimulate fatty acid oxidation and can reverse
insulin resistance associated with both lipoatrophy
The Departments of Cardiology and Biochemistry*, Faculty

of Medicine, Menoufiya University, Shebin El Kom, Egypt.
Manuscript received 25 Feb., 2010; revised 3 April, 2010;
accepted 5 April, 2010.
Address for Correspondence: Dr. Mohamed Fahmy Elnoamany, 11 Yossef Street from Talaat Harb Street, Shebin Elkom,
Menoufyia, Egypt, mnoamany@hotmail.com
277
and obesity [2]. However, there are also data showing no association between ADP level and the
insulin resistance in obese children [5]. ADP is also
thought to have some anti-atherogenic properties
through inhibition of tumor necrosis factor (TNF)
secretion and antagonizing its activity and by
inhibiting smooth muscle cell proliferation within
the vessel wall [2]. A significant suppression of
ADP level was observed in obese subjects with
type 2 diabetes, in subjects with ischemic heart
disease, and in young men with high normal blood
pressure [6]. Moreover, many studies [7] showed
that ADP level increases after weight reduction.
These findings indicate that, ADP seems to be an
endogenous anti-atherogenic factor, regulated by
life style.
Other investigations suggesting CAD such as,

positive exercise stress ECG, positive myocardial
perfusion scanning.
Diabetes Mellitus was diagnosed as fasting
blood glucose 126mg/dl or 2 hour postprandial
blood glucose 200mg/dl [8].
Exclusion criteria: Patients with one or more
of the following criteria, were excluded from the
study:
Chronic alcoholism.
Gross obesity, body mass index (BMI) >35Kg/m2.
Hypothyroidism and other endocrinopathies.
Patients with dilated cardiomyopathy.
Aim of the work:

To investigate the relationship between plasma
ADP levels and the severity and extent of coronary
artery lesions in patients with CAD.
Patients with valvular heart disease.

Pre-existing cerebrovascular disease (symptoms
of cerebrovascular insufficiency, history of stroke
or transient ischemic attacks).
Patients with pre-existing hepatocellular diseases.
Subjects:
A total of 90 patients were recruited from patients undergoing coronary angiography for suspected CAD. According to the presence or absence
of CAD (proven by coronary angiography) and
diabetes mellitus (DM), patients were divided into
3 groups; Group I (n=35 patients) diabetic patients
with CAD, Group II (n=35 patients) non diabetic
patients with CAD and Group III (n=20 patients)
non diabetic patients with normal coronaries as a
control group. The study was approved by the
Research Ethical Committee of Menoufiya University Hospital and all subjects gave a written informed consent. All patients were selected from
Cardiac Catheterization Laboratory of Menoufiya
University Hospitals in the period from (April
2008 to January 2009).
Patients with renal insufficiency.

For each patient the following was done:
1- Complete history taking.
2- Thorough clinical evaluation.
3- Standard 12-lead resting ECG.
4- Conventional echocardiographic examnation:
Echocardiography was performed with the patient in the left lateral decubitus position. The
equipment used was Acuson 128 XP 10 C system.
Measurements were performed according to the
recommendations of the American Society of
Echocardiography [9]. With the use of the long axis
parasternal, apical 4, 5 and 2-chamber views. All
patients underwent conventional M-mode and 2D echocardiographic examination. Visual assessment of regional wall motion was performed. End
systolic diameter (LVESD) and volume, end diastolic diameter (LVEDD) and volume (by manual
tracing of endocardial borders) and left ventricular
ejection fraction (LVEF) was calculated using
Simpson's rule [10] . Conventional (continuouswave & color) Doppler valvular flow was determined.
Inclusion criteria: Patients included in the

study are those undergoing diagnostic coronary
angiography for suspected ischemic heart disease
with one or more of the following:
Typical chest pain.
Elecrocardiographic (ECG) changes suggesting
CAD.
Previous admission to hospital by CAD.
Previous cardiac interventions e.g. percutaneous
coronary intervention (PCI), coronary artery
bypass graft (CABG).
5- Angiographic analyses:
Diagnostic coronary angiography (CA) was
carried out in all patients using Judkins technique.
278
Quantitative analysis of coronary arteries was

performed with the computer-assisted coronary
angiography analysis system. End diastolic frames
from each arteriogram were selected for analysis
[11] . The percentage diameter stenosis (DS) was
assessed in different projections and the highest
value of each lesion, was chosen. Images of the
coronary tree were obtained with the digital SIEMENS HICOR 1000 set system. Two experienced
cardiologists who had no knowledge of the patients
clinical characteristics and laboratory results, reviewed all angiographic images to assess the extent
of CAD and morphology of all coronary artery
stenoses.
Coronary angiograms were scored according

to:
1- Vessel score [13]: This was the number of
vessels with a significant stenosis (50% or greater
reduction in lumen diameter). Degree of stenosis
was defined as the greatest percentage reduction
of luminal diameter in any view compared with
the nearest normal segment and was determined
visually. Scores ranged from 0 to 3, depending on
the vessels involved. Left main coronary artery
stenosis was scored as single vessel disease [13].
The coronary tree was divided into 16 segments

as follows: [12]
The left main coronary artery (LMCA) as one
segment.
The left anterior descending (LAD) artery was
divided into: Proximal, mid and distal segments
beside two diagonals, Dl and D2.
The left circumflex artery (LCX) artery was
beside two marginal branches, OMl and OM2.
The right coronary artery (RCA) artery was
beside posterior descending artery (PDA) and
postero-lateral (PL) branch (Fig. 1).
LMCA
1
2 LAD
12
LACX
14
RCA
(LAO view)
15
5
3 D1
M2
16
RV
AM
10
13
Balanced Coronary
Circulation
11
M1
6
D2
LCA
(RAO view)
Figure 1: Coronary tree:

LMCA, left main coronary artery (1).
LAD, left anterior descending, (2) proximal LAD, (3) mid
LAD, (4) distal LAD (5) and (6) Dl, D2, the two diagonals.
LCX, left circumflex artery, (7) proximal LCX, (8) mid
LCX, (9) distal LCX (10) and (11) OM1 & OM2, the two
obtuse marginal.
RCA, right coronary artery, (12) proximal RCA, (13) mid
RCA, (14) distal RCA, (15) Posterior descending artery
(PDA) and (16) postero-lateral (PL) branch.
2- Severity score [14]: The coronary circulation

was divided into eight proximal segments. Disease
in the distal segments was not considered because
of difficulty in quantifying the severity of lesions
in these areas. The eight proximal segments scored
included the left main coronary artery, the left
anterior descending artery (LAD) up to the junction
of the middle and distal third of the vessel, the
proximal third of the major septal branch of the
LAD, the proximal third of the major diagonal
branch of the LAD, the left circumflex coronary
artery (LCX) up to the junction of the middle and
distal thirds of the vessel, the proximal third of
the major obtuse marginal branch of the LCX, the
right coronary artery (RCA) up to and including
the origin of the posterior descending coronary
artery (PDA), and the proximal third of the PDA.
In cases in which the PDA was supplied by the
LCX vessel (LCX dominance), lesions in the LCX
up to the origin of the PDA were included, as were
lesions of the RCA up to the origin of the middle
and distal thirds of the vessel. The PDA was scored
identically for RCA and LCX dominant circulations. The percentage by which each lesion in the
proximal coronary circulation narrowed the artery
was assessed according to the maximal narrowing
of the diameter of the artery in all projections. The
severity of the proximal coronary disease was
assessed by assigning points to each lesion as
follows: Less than 50% stenosis of the luminal
diameter, 1 point; 50% to 74% stenosis, 2 points;
75% to 99% stenosis, 3 points; total obstruction,
4 points. The points for each lesion in the proximal
coronary circulation were summed and a score for
severity of coronary atherosclerosis was obtained.
In previous study [14], the percentage of variation
between two angiograms analyzed several months
apart without knowledge of the previous score was
4.9%.
3- Gensini score [15]: Gensini score was calculated for each patient from the coronary arteriogram
279
and was computed by assigning a severity value

to each coronary stenosis according to the degree
of luminal narrowing and its location. Reduction
in the lumen diameter and the roentgenographic
appearance of concentric lesions and eccentric
plaques were evaluated (reductions of 25, 50, 75,
90, 99%, and complete occlusion were given Gensini scores of 1, 2, 4, 8, 16, and 32, respectively).
The score was then multiplied by a factor relative
to the importance of the lesion's location in the
coronary arterial tree: for example, 5 for left main
coronary artery; 2.5 for proximal left anterior
descending coronary artery and proximal left circumflex coronary artery (3.5 if left circumflex
coronary artery is dominant); 1.5 for mid-region
of the left anterior descending coronary artery; 1
for distal left anterior descending coronary artery,
the first diagonal, the proximal, mid-region and
distal-region of the right coronary artery, the posterior descending, the mid-region and distal-region
of the left circumflex coronary artery (2 for both
of them if left circumflex coronary artery is dominant), and the obtuse marginal branch; and 0.5 for
the second diagonal and the postero-lateral branch.
The Gensini score was expressed as the sum of the
scores for all the coronary arteries. The intraobserver and interobserver variability were 0.96 and
0.94, respectively.
culture supernatants and urine. This assay employs

antibody specific for human ADP coated on 96well plate. Standard and samples are taken by
pipette into wells and ADP present in sample is
bound to wells by immobilized antibody. The wells
are washed and biotynylated anti-human ADP
antibody is added, after washing away unbound
biotylinated antibody, HRP-conjugated streptavidin
is taken by pipette to the wells. Wells are washed
again and TMB substrate solution was added to
wells and color develops in proportion to amount
of ADP bound [6].
Concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, serum
creatinine, and fasting and 2 hour postprandial
plasma glucose were measured by standard laboratory assays.
Data were analyzed by SPSS statistical package
version 11.0 (SPSS Inc, Chicago, IL, USA). Quantitative data were expressed as mean and standard
deviation (SD). Comparisons between means were
evaluated by unpaired t-test or ANOVA (F) test
(with post hoc test) for continuous variables with
determination of the least significant difference
(LSD) by pair wise comparison between group
means, and by chi-square test for proportions.
Pearson correlation coefficient (r) was used to
measure association between two quantitative
variables. Level of significance was set as p-value
<0.05 [16].
6- Laboratory examination:
All samples were collected by venipuncture
just before coronary angiography. Seven ml of
venous blood were withdrawn from each subject
after 12-14 hour fasting and divided as follows:
Results
Three ml blood was added to sodium fluoride

tube for assay of fasting blood sugar. Within 30
minutes, blood was centrifuged, serum was separated and fasting glucose was determined.
Clinical and laboratory characteristics of studied population: The study comprised 90 patients
who were divided according to the presence or
absence of CAD and DM into 3 groups; Group I
(n=35 patients) diabetic patients with CAD, Group
II (n=35 patients) non diabetic patients with CAD
and Group III (n=20 patients) non diabetic patients
with normal coronaries as a control group (Table
1).
Four ml blood was collected on a dry vacutainer

for the performance of the laboratory assay; blood
sample was left to clot, and then centrifuged at
3000/r.p.m for 10 minutes. Serum was separated
in to two separate aliquots. The first aliquot was
used for laboratory analysis of lipid profile, the
second aliquot was immediately frozen at 70c
for analysis of ADP. Serum ADP was quantitatively estimated by Enzyme-linked
immunosorbent technique using Human Adiponectin ELISA Kit, Germany [6].
Group I: Included 35 patients who are diabetic

with CAD with a mean age of 54.115.59 years,
20 (57.1%) patients were males and 15 (42.9%)
patients were females, 29 (82.9%) patients were
hypertensive, 13 (37.1%) patients were smoker
and 5 (14.3%) patients had positive family history
of CAD (Table 1).
Principle:
It is an in vitro ELIZA for quantitative measurement of human ADP in serum, plasma, cell
Group II: Included 35 patients who are non

diabetic and have CAD with a mean age 53.698.31
280
years, 30 (85.7%) patients were males and 5

(14.3%) patients were females, 22 (62.9%) patients
were hypertensive, 24 (68.6%) patients were smokers (Table 1).
Vs. 147.432.14mg/dl, p<0.05 respectively) and

in group I in comparison to group III (243.9
60.55mg/dl Vs. 191.533.38mg/dl, p<0.01, 160.8
37.77mg/dl Vs. 115.132.24mg/dl, p<0.001,
172.654.87mg/dl Vs. 127.943.88mg/dl, p<0.01
respectively) (Table 2).
Group III: Included 20 patients who have

neither diabetes nor CAD as a control group with
a mean age 51.805.95 years, 6 (30%) patients
were males and 14 (70%) patients were females,
18 (90%) patients were hypertensive, 6 (30%)
patients were smoker and 1 (5%) patient had positive family history of CAD (Table 1).
Serum ADP levels were significantly lower in

group I than group II (2.610.19g/ml Vs. 3.40
0.70g/ml, p<0.001) and was significantly lower
in each group in comparison to group III (5.47
1.04g/ml, p<0.001).
Total cholesterol, Triglycerides and LDL cholesterol levels were significantly higher in group
I compared to group II (243.960.55mg/dl Vs.
199.252.83mg/dl, p<0.01, 160.837.77mg/dl Vs.
121.540.66mg/dl, p<0.001, 172.654.87mg/dl
Levels of HDL cholesterol did not differ significantly among the three groups, p>0.05. As
regard the echocardiographic parameters, LVEDD,
LVESD and LVEF did not differ significantly
among the three groups, p>0.05 (Table 2).
Table 1: Baseline demographic and clinical characteristics of studied groups.

Group I
DM/CAD n=35
Group II
CAD n=35
Group III
Control n=20
t-Test
Age (years)
54.115.59
53.698.31
51.805.95
0.69
>0.05
Male
20 (57.1%)
30 (85.7%)
6 (30%)
0.69
<0.001
Female
15 (42.9%)
5 (14.3%)
14 (70%)
17.43
<0.001
Hypertension
29 (82.9%)
22 (62.9%)
18 (90%)
6.46
<0.05
Smoking
13 (37.1%)
24 (68.6%)
6 (30%)
10.18
<0.01
Family history
5 (14.3%)
0 (0%)
1 (5%)
5.85
<0.05
Items
Table 2: Laboratory and Echocardiographic data of the studied populations.

Group I
DM/CAD n=35
Group II
CAD n=35
Group III
Control n=20
F-Test
Total cholesterol (mg/dl)
243.960.55
199.252.83
191.533.38
Triglycerides (mg/dl)
160.837.77
121.540.66
HDL (mg/dl)
34.4810.77
LDL (mg/dl)
Items
Post-hoc p
8.85
<0.001
p1 <0.01
p2 <0.01
p3 >0.05
115.132.24
13.09
<0.001
p1 <0.001
p2 <0.001
p3 >0.05
32.921.74
36.8511.67
1.29
>0.05
172.654.87
147.432.14
127.943.88
6.79
<0.01
p1 <0.05
p2 <0.01
p3 >0.05
Adiponectin (g/ml)
2.610.19
3.400.70
5.471.04
117.26
<0.001
LVEDD (cm)
LVESD (cm)
LVEF (%)
5.040.62
3.210.62
61.579.23
5.120.67
3.410.75
59.3410.52
4.690.84
3.040.52
63.904.02
2.59
2.11
1.68
>0.05
>0.05
>0.05
p1 <0.001
p2 <0.001
p3 <0.001
p1 between DM/CAD & CAD.

p2 between DM/CAD & Controls.
p3 between CAD & Controls.
HDL: High density lipoproteins.

LDL : Low density lipoproteins.
281
LVEDD : Left ventricular end diastolic dimension.

LVESD : Left ventricular end systolic dimension.
LVEF : Left ventricular ejection fraction.
Severity score, vessel score and Gensini score

were significantly higher in group I than group II
(9.23.69 Vs. 7.204.27, 2.510.67 Vs. 1.470.85,
64.3633.01 Vs. 50.337.97 respectively, p<0.05
for each) (Table 3). In view of vessel score, ADP
levels were significantly higher in patients with
vessel score 0 (group III) when compared with
patients with vessel score 1, 2 and 3, p<0.001 for
each. ADP levels were significantly higher in
patients with vessel score 1 (3.420.98g/ml) in
comparison to those with vessel score 2 (2.83
0.39g/ml, p<0.05) and 3 (2.900.46g/ml,
p<0.01), while ADP levels did not did not differ
significantly between patients with vessel score 2

(2.830.39g/ml) and 3 (2.900.46g/ml), p>0.05.
(Table 4).
Table 3: Coronary angiographic data of the studied populations.
Group I
DM/CAD
n=35
Items
MannGroup II
Whitney
CAD n=35
U-test
Severity score 9.23.69
7.204.27
2.33
<0.05
Vessel score
2.510.67
1.470.85
1.71
<0.05
Gensini score
64.3633.01 50.337.97
1.20
<0.05
Table 4: Adiponectin levels in the studied populations in relation to vessel score.

Vessel score
Adiponectin
g/ml
Mean SD
0
n=20
1
n=17
2
n=26
3
n=27
F-test
5.471.04
3.420.98
2.830.39
2.900.46
61.59
<0.001
p1 between vessel score 0 & vessel score 1.

p5 between vessel score1 & vessel score 3.
Age
Fasting blood sugar
Postprandial blood sugar
Total cholesterol
Triglycerides
HDL
LDL
LVESD
IVS
LVPW
FS
LVEF
Severity score
Vessel score
Gensini score
No. of diseased segments
No. of diseased vessels
p1 <0.001
p2 <0.001
p3 <0.001
p4 <0.05
p5 <0.01
p6 >0.05

Table 5: Correlation between adiponectin level and some

studied parameters in coronary artery disease patients.
Variables
Post-hoc
p
Table 6: Multivariate regression analysis of predicators of

Adiponectin level among CAD patients.
95% Confidence
Interval for B
Adiponectin in CAD patients

(n=70)
r
0.049
0.457
0.501
0.289
0.531
0.35
0.4
0.067
0.061
0.014
0.43
0.57
0.73
0.62
0.530
0.179
0.183
>0.05
<0.001
<0.001
<0.05
<0.01
<0.05
<0.05
>0.05
>0.05
>0.05
<0.05
<0.05
<0.001
<0.001
<0.01
>0.05
>0.05
Variables
282
Lower Upper
Bound Bound
Age
0.33
3.99 <0.001
0.02
1.19
Male sex
0.21
0.97 >0.05
0.22
0.65
Smoking
0.15
0.79 >0.05
0.24
0.55
Hypertension
0.10
0.59 >0.05
0.45
0.64
DM
0.68
3.93 <.001
0.03
1.37
Total Cholesterol 0.001
0.18 >0.05
0.004
0.005
Triglycerides
0.15
0.51 <.01
0.04
1.11
HDL
0.17
0.71 <.01
0.03
0.9
LDL
0.001
0.51 >0.05
0.004
0.007
LVEF
0.11
2.87 <0.01
0.04
0.77
HDL
LDL
LVEF
DM
HDL : High density lipoproteins.

LDL : Low density lipoproteins.
LVESD : Left ventricular end systolic dimension.
IVS
: Interventricular septum.
LVPW : Left ventricular posterior wall.
FS
: Fractional shortening.
LVEF : Left ventricular ejection fraction.
: High density lipoproteins.

: Low density lipoproteins.
: Left ventricular ejection fraction.
: Diabetes mellitus.
400
300
2 hour PP
250
fbs
300
150
100
300
200
100
R Sq Linear = 0.209
R Sq Linear = 0.251
50
2.00
3.00
4.00
5.00
6.00
7.00
2.00
3.00
Adiponectin
5.00
6.00
7.00
Adiponectin
Figure 2: Correlation between Adiponectin fasting blood

sugar (r=.46, p<0.001).
Figure 3: Correlation between Adiponectin & 2 hour postprandial blood sugar (r=.5, p<0.001).
400
250
300
200
Triglycerides
T.Cholesterol
4.00
200
100
150
R Sq Linear = 0.14
100
R Sq Linear = 0.083
0
50
2.00
3.00
4.00
5.00
6.00
7.00
2.00
3.00
Adiponectin
5.00
6.00
7.00
Adiponectin
Figure 4: Correlation between Adiponectin & total cholesterol

(r=.3, p<0.05).
Figure 5: Correlation between Adiponectin & Triglycerides

(r=.5, p<0.01).
15
Severity score
2.5
Vessel score
4.00
2
R Sq Linear = 0.078
1.5
10
R Sq Linear = 0.077
0
2.00
3.00
4.00
5.00
6.00
7.00
2.00
Adiponectin
3.00
4.00
5.00
6.00
7.00
Adiponectin
Figure 6: Correlation between Adiponectin & vessel score

(r=.6, p<0.001).
Figure 7: Correlation between Adiponectin & severity score

(r=.7, p<0.001).
283
predicting the severity of coronary artery stenosis

without the need for invasive tests, are urgently
needed to establish new approaches for protection
against CAD.
140
Gensini score
120
100
80
The current study was carried out to investigate

the possible inter-relationship between serum levels
of ADP and the severity and extent of CAD. The
study was conducted on 35 diabetic patients with
proved coronary artery lesions, a second group of
35 non diabetic coronary artery diseased patients,
and 20 individuals non diabetic with normal coronaries as a control group.
60
R Sq Linear = 0.053
40
20
0
2.00
3.00
4.00
5.00
Adiponectin
6.00
7.00
In our study it was found that, serum ADP level

was significantly lower in diabetic coronary artery
disease patients (group I) than non diabetic CAD
patients (group II) and the two groups have a lower
ADP serum level than control group (group III).
Serum ADP level has a cutoff point 3.8g/ml with
98.57% sensitivity and 90% specificity regarding
its ability to predict the presence of CAD.
Figure 8: Correlation between Adiponectin & Gensini score

(r=.5, p<0.01).
A Strong negative correlation was found between Serum ADP levels and each of Severity
score (r=.7, p<0.001), vessel score (r=.6,
p<0.001), Gensini score (r=.5, p<0.01), fasting
and 2 hour postprandial blood glucose (r=.5,
p<0.001 for each), serum triglycerides (r=.5,
p<0.01), LDL cholesterol (r=.4, p<0.05) & total
cholesterol (r=.3, p<0.05), whereas, the correlation
was positive with LVEF (r=.57, p<0.05) and HDL
cholesterol (r=.35, p<0.05) (Table 5).
These finding are in agreement with the findings

of Kumada et al [21] who found plasma ADP levels
in CAD patients were significantly lower than
those in control subjects also, they reported that,
plasma ADP level was decreased in obesity and
type 2 diabetes as ADP itself may affect glucose
metabolism. They also reported that, ADP acts as
a protective factor in CAD and modulates the
inflammatory response in the vascular wall. Plasma
ADP rapidly accumulates in the subendothelial
space of the injured human artery and recombinant
ADP was found to inhibit monocyte adhesion to
endothelial cells and the transformation of macrophage to foam cell as well as vascular smooth
muscle cell proliferation. Because these steps are
believed to be crucial in the development of atherosclerosis, so hypoadiponectinemia may cause
excessive inflammatory response in the coronary
artery [21].
In multivariate logistic regression analysis,

age, DM, HDL cholesterol, triglycerides and
LVEF were found to be the most powerful independent predictors of serum ADP levels (Table
6). Serum ADP level has a cutoff point 3.8g/ml
with 98.57% sensitivity and 90% specificity
regarding its ability to predict the presence of
CAD.
Discussion
Adiponectin (ADP) is a hormone secreted by
adipocytes [17] that has an ameliorating effect on
the phenotype of metabolic syndrome, including
insulin resistance, hyperglycemia, and dyslipidemia
in obese diabetic subjects [18]. Low plasma ADP
levels have been associated with obesity, diabetes,
and CAD [19]. ADP also has protective activity
against atherosclerosis and inflammation [17].
Furthermore, the data of our study were found

parallel to those reported by Eynatten et al [22]
who found that, ADP levels and the extent of CAD
show a significant correlation in men and Patel et
al [23] who reported that, levels of ADP decreased
with CAD severity, without impact from systolic
dysfunction, but levels may be moderated through
established CAD risk factors such as smoking and
triglycerides.
Subjects with high plasma ADP concentrations

proved to have a significantly lower risk of myocardial infarction, independent of traditional cardiovascular risk factors such as hyperlipidemia,
diabetes, and hypertension [20] . Cardiovascular
diseases are major causes of shortened life span
especially in diabetic patients, and methods for
In terms of angiographic analysis, CAD atherosclerotic burden was quantified with coronary
284
angiography by means of one of the most accurate

available methods for scoring CAD that takes into
consideration both the degree and the site of stenosis. Thus, the relationship between CAD and plasma
ADP levels could be established with unprecedented accuracy. In the current study, a statistically
significant inverse relationship between plasma
ADP levels and the CAD atherosclerotic burden
was observed where, a strong negative and significant correlation between ADP levels and each of
severity, vessel and Gensini scores in patients with
coronary artery disease was detected, so the lower
serum ADP levels, the higher the vessel and the
severity scores. It is unlikely, in our view, that this
association was due to an acute phase response,
because plasma ADP levels did not differ between
patients with and without acute coronary syndromes.
glucose also ADP concentrations were significantly

lower in diabetics than non diabetic patients with
CAD. Many studies [5,6,29,30] confirmed the relationship between hypoadiponectinaemia and insulin-resistance syndrome and atherogenic lipid profile.
Moreover, Dunajska et al [2] proved the existence of negative correlation of ADP concentration
with total cholesterol and triglycerides and positive
correlation with HDL cholesterol concentration,
which suggests that, a relationship of ADP with
lipid metabolism may be through the hyperinsulinemia and insulin resistance. This fact, in addition
to previously described relations of ADP to insulin
resistance, indicates the important connection of
this peptide with disturbances, leading to the metabolic syndrome [4] . This mechanism was confirmed recently by Ohashi et al [31], who showed,
that, ADP gene mutation is associated with the
metabolic syndrome and CAD.
Similarly, Gksoy et al [24] and Cesari et al [25]

reported decreased serum ADP levels in CAD
patients compared to controls. This decrease is
more prominent with increasing levels of CAD
severity, which may be a helpful clue in predicting
multivessel disease. Moreover, Liang et al [26]
used a modified Gensini scoring system to define
angiographic coronary artery progression between
the index and follow-up angiograms in patients
with angina pectoris where they found that a decreased circulating level of ADP is associated with
angiographic CAD progression.
In multivariate logistic regression analysis, age,

DM, HDL cholesterol, triglycerides and LVEF
were found to be the most powerful independent
predictors of serum ADP levels. In accord with
these observational findings, Cesari et al [25] found
that age, gender, body mass index (BMI), HDL
cholesterol and triglycerides were significant predictors of plasma ADP levels. Also of interest, they
were able to identify for the first time LVEF as a
predictor of plasma ADP levels. Although the
mechanisms of this novel direct relationship cannot
be clearly clarified, it can be partially explained
by a protective effect of ADP against cardiac myocyte hypertrophy and LV dysfunction, as ADP
inhibits hypertrophic signals via AMP-activated
protein kinase [32]. Moreover, this relation could
be, at least in part, mediated by the insulin resistance, that has recently been reported to be significantly and independently related to cardiac function in non diabetic hypertensive patients [33].
In our study, there was no significant relationship between number of diseased vessels or the
number of diseased segments and serum ADP level
and this was in agreement with finding of Lim et
al [27].
On the other hand, recent reports [28] postulated
that, once CAD is established ADP levels is no
longer inversely related to systemic inflammation
and has found to be positively related to plasma
concentration of N-terminal pro brain natriuretic
peptide.
Study limitation:
In the present study, there were positive and
negative correlation between plasma concentrations
of ADP and some of the studied parameters however, although they generated significant p values,
the correlation coefficients themselves are rather
weak for some parameters. The reason may be the
relatively small numbers of participants in the
study population. Also, in this study, plasma concentrations of ADP were measured with solid phase
ELISA Kit, Germany. This assay cannot distinguish
between the lower weight trimer-dimer forms of
As regard the lipid profile, our results showed

significant negative correlation between serum
ADP levels and each of total cholesterol, serum
triglycerides, and LDL cholesterol, while the correlation was positive with HDL cholesterol. Accordingly, differences in ADP levels in men with
CAD and controls were accompanied by proatherosclerotic lipid profile. Furthermore, a strong
negative correlation was found between serum
ADP levels and both fasting and postprandial blood
285

echocardiography. J Am Soc Echocardiogr 1989; 2: 35867.
ADP and the high molecular weight complexes,

one of the factors associated with sex difference.
Therefore, further investigations involving a larger
number of patients distinguishing between men
and women are required to confirm the validity of
these results.
10- Yvorchuk KJ, Davies RA, Chang KL: Measurement of

left ventricular ejection fraction by acoustic quantification
and comparison with radionuclide angiography. AM J
Cardiol 1994; 74: 1052-1056.
11- Reiber JH, Serruys PW, Kooijman CJ, Wijns W, Slager
CJ, Gerbrands JJ, Schuurbiers JC, den Boer A, Hugenholtz
PG: Assessment of short, medium, and long-term variations
in arterial dimensions from computer-assisted quantitation
of coronary cineangiograms. Circulation 1985; 71: 2808.
Conclusion
ADP is an important target with anti-diabetic,
anti-inflammatory, and anti-atherogenic properties.
Measurement of plasma concentrations of ADP
may be a helpful tool for assessment of CAD risk.
Plasma ADP levels might also represent a novel
diagnostic tool for risk stratification of patients
with CAD as regard the severity and the extent of
coronary artery lesions. ADP could become a promising target for future investigations in reducing
the morbidity and mortality of atherosclerotic
disease.
12- Murk M Levinson: Leaning Center for coronary angiography. The heart surgery forum. Cardiothoracic multimedia
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Body mass index: A risk factor for unstable angina and
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108: 2206-11.
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287
Clinical Implications of Adipocytokine, Serum Resisten in Diabetics with

Coronary Artery Disease
MAHMOUD SOLIMAN, MD*; WALEED FATHEY, MD**; ADEL ABDEL ELGHANY, MSc;
AMIRA ABD EL KADER, MD**; GEHAN KAMAL, MD**
Background: Diabetic patients with coronary heart disease have an unfavorable outcome even after PCI or CABG. So,
investigations of novel atherogenesis markers such as adipocytokine, resisten may have a potential role in early assessment of
cardiovascular risk in patients with type 2 diabetes mellitus.
Aim of the Work: To assess serum resisten levels in diabetic patients with: Stable coronary artery disease (CAD), acute
coronary syndromes and to compare these levels with those in diabetics without coronary artery disease and healthy control.
Subjects and Methods: The present study enrolled 52 subjects: 20 patients with coronary artery disease (12 patients with
stable CAD, group IA and 8 patients with ACS, group IB), 20 patients with type 2 diabetes without coronary artery disease as
proved by coronary angiography or negative stress test, group II and 12 healthy subjects as control group III.
All subjects underwent:
History taking and thorough clinical examinations. Twelve leads ECG.
Echocardiography.
Laboratory investigations:
FBS &PPS.
HBa1c.
S. creatinine Lipid profile.
Hs CRP.
Serum resisten.
Patients with infections, inflammations, neoplasms, hepatic or renal dysfunction were excluded from the study.
Results: There was no significant difference between the three groups as regards age and sex.
Diabetic patients (group I & II) when compared with healthy control (group III) showed: Significantly higher BMI, glycated
HB, total cholesterol, LDL, Triglycerids, hs CRP & serum resisten, significantly lower HDL cholesterol & were more hypertesives.
Diabetic patients with CAD (group I) when compared with diabetics without CAD (group II) there was no significant
difference as regards BMI, the percentage of hypertensives total cholesterol, triglycerides, HDL & LDL cholesterol but group
I had significantly higher HsCRP & serum resisten.
Diabetic patients with stable CAD (group IA) when compared with diabetics with ACS (group IB) showed significantly
higher age, HB A1c and significantly lower hsCRP & serum resisten.
Serum resisten correlated significantly with BMI, glycated HB, cholesterol, TG, HDL, LDL & hs CR Pin diabetic patients.
Conclusion: Diabetic patients with CAD have significantly higher serum resisten than diabetics without CAD and healthy
control. Also, diabetic patients with ACS have significantly higher serum resisten than diabetics with stable CAD. Serum resisten
may severe as a biomarker of increased atherogenic risk in patients with type 2 diabetes.
Key Words: Diabetes Coronary artery disease Resisten.
The Departments of Cardiology* and Clinical Pathology**,

Faculty of Medicine Menofiya University.
Manuscript received 5 Jan., 2010; revised 10 Feb., 2010
accepted 11 Feb., 2010.
Address for Correspondence: Dr. Mahmoud Soliman,
Menofiya University, msoliman303@yahoo.com.
289
Clinical Implications of Adipocytokine, Serum Resisten in Diabetics
Introduction
All subjects underwent:

Full history taking & through clinical examination.
Diabetic patients are known to have 2-4 fold

increased cardiovascular risk than nondiabetics.
Also, diabetic patients with CAD have an unfavourable outcome even after PCI & CABG [1,2]. So,
investigations of novel atherogenesis biomarkers
may have a potential role in the assessment of
cardiovascular risk in diabetic patients.
Twelve leads ECG.

Echocardiogrophy.
Coronary angiography using Judking technique
(control group were excluded by ethical committee).
Laboratory investigations:
o FBS & PPS.
o HBa1c.
o S. creatinine.
o Lipid profile.
o Hs CRP.
o Serum resisten.
The adipose tissue had been recognized as an

endocrine organ which secretes numerous proteins
known as adipocytokines such as resisten, adiponectin and leptin [3]. Resisten was heavily investigated since its initial description in 2001 [4].
Several studies investigated the role of resisten
in obesity, type 2 diabetes, inflammations and
inflammation related diseases. However, the relationship between serum resisten and CAD in patients with type 2 diabetes showed marked conflicting results and needed to be investigated.
Exclusion criteria: Patients with infections

inflammations, neoplasms, hepatic or renal dysfunction, patients on thiazolidinediones were exuded from the study.
The data collected were tabulated and analyzed
by SPSS (statistical pakage for the social science
software) version II on IBM compatible computer.
Aim of the work:

To assess serum resisten levels in diabetic
patients with: Stable coronary artery disease, acute
coronary syndromes and to compare these levels
with that in diabetics without coronary artery
disease and healthy control.
Quantitative data were expressed as mean &

standard deviation (XSD) and analyzed by applying t-test for comparison of two groups of normally
distributed variables, Mann Whiteny test, U-test
for non normally distributed ones and Kruskal
Wallis test for comparison between more than two
groups of non normally distributed variables.

The present study included 52 subjects, divided
into three groups:
Group I: Included 20 patients with type 2 diabetes
mellitus with coronary artery disease. This group
was furtherly subdivided into:
Qualitative data were expressed as number &

percentage and analyzed applying Chi-square test.
All tests were used as test of significant at
p<0.05.
Group IA: 12 patients with type 2 diabetes and

stable CAD from those referred to Menofiya
University Hospital Catheterization Laboratory.
Results
the three groups as regards age & sex (p-value
>0.05) Table (1).
Group IB: 8 patients with type 2 diabetes &

acute coronary syndromes either with UA/
NSTEMI or STEMI in Menofiya University
Hospital Coronary Care Unit.
Diabetic patients (group I & II) when compared

with healthy control (group III) showed significantly higher BMI, glycated hemoglobin, total
cholesterol, LDL, triglycerides, hs CRP & serum
resisten but significantly lower HDL cholesterol
& were more hypertensive (p-value <0.001) Table
(2).
Group II: Included 20 patients with type 2 diabetes

without CAD confirmed by normal coronary
angiography or negative stress ECG.
Group III: Included 12 apparently healthy individuals and serve as control group.
290
Mahmoud Soliman, et al
Table 1: Comparison between the three studied groups as regards age and sex.
Studied groups
Kruskal
Wallis test
p-value
Group I N=20
Group II N=20
GroupIII (Control) N=12
Age:
X SD
Median
Range
52.709.12
55.0
64-38
48.056.10
47.5
57-34
46.506.37
48.0
54-32
4.85
>0.05
Sex:
Male
Female
No.
13
7
No.
14
6
No.
6
6
X2
1.32
>0.05
%
65.0
35.0
%
70.0
30.0
%
50.0
50.0
Table 2: Clinical and laboratory parameters in both diabetic groups and control group.
Studied groups
Mann
Whitney U
p-value
21.581.66
21.75
24.0-19.0
5.12
<0.001
No.
0
12
X2
24.96
<0.001
Diabetics (Group I,II) N=40
Group III (Control) N=12
BMI:
X SD
Median
Range
30.783.40
30.0
38.0-22.0
Hypertension:
Positive
Negative
No.
32
8
%
80.0
20.0
%
0.0
100
Fasting blood sugar:

X SD
Median
Range
106.3745.99
104.50
173-85
84.418.01
81.0
99-75
4.31
<0.001
2 hours post prandial

blood sugar:
X SD
Median
Range
212.2546.42
215.50
280-126
116.339.82
115.0
132-100
5.17
<0.001
Glycated Hb:
X SD
Median
Range
10.051.65
9.5
13.5-8.0
4.710.63
4.75
5.6-3.8
5.24
<0.001
Triglyceride:
X SD
Median
Range
239.6748.27
225.0
349-177
119.6611.36
120
140-102
5.21
<0.001
Cholesterol:
X SD
Median
Range
254.5744.31
250
334-182
171.1614.31
169
190-144
4.91
<0.001
HDL:
X SD
Median
Range
36.176.67
36.5
47-25
70.087.57
73
81-60
5.21
<0.001
LDL:
X SD
Median
Range
168.4241.58
170.0
237-96
78.7515.86
78
99-58
5.10
<0.001
Serum hs CRP:
X SD
Median
Range
2.671.41
3.15
4.6-0.6
0.500.26
0.45
1.0-0.2
4.72
<0.001
Resistin:
X SD
Median
Range
30.644.88
29.0
45-25
10.791.30
10.50
13-9
5.22
<0.001
291
Diabetic patients with CAD (group I) when

compared with those without CAD (group II), there
was no significant difference as regards, BMI, the
percentage of hypertensives, total cholesterol, LDL,

HDL & triglycerides but group I had significantly
higher hs CRP and serum resisten Tables (3).
Table 3: Comparison between group I and group II.

Studied groups
t-test
p-value
29.523.36
29.25
36.0-22.0
2.35
<0.05
No.
14
6
X2
2.5
>0.05
Group I
N=20
Group II
N=20
BMI:
X SD
Median
Range
32.023.03
32.0
38.0-26.0
Hypertension:
Positive
Negative
No.
18
2
%
90.0
10.0
%
70.0
30.0

X SD
Median
Range
112.8518.73
112.50
173-85
99.909.27
102.50
117-85
2.77
<0.01

blood sugar:
X SD
Median
Range
228.3043.06
227
280-145
196.2045.01
201.50
255-126
2.24
<0.05
Glycated Hb:
X SD
Median
Range
10.701.77
10.25
13.5-8.5
9.401.27
9.0
13.0-8.0
2.66
<0.05
Triglyceride:
X SD
Median
Range
251.1552.90
234.0
349-177
228.2041.32
223.0
349-177
1.52
>0.05
Cholesterol:
X SD
Median
Range
259.9547.76
262.5
334-182
249.2041.09
247
315-182
0.76
>0.05
HDL:
X SD
Median
Range
35.57.36
36.5
47-25
36.856.02
36.5
47-26
0.63
>0.05
LDL:
X SD
Median
Range
171.844.89
171.0
237-96
165.0538.87
170.0
234-96
0.50
>0.05
Serum hs CRP:
X SD
Median
Range
3.810.57
3.85
4.6-2.3
1.521.01
1.15
4.2-0.6
Mann
Whitney U
4.94
<0.001
Resistin:
X SD
Median
Range
33.305.58
32.50
45-26
27.981.69
27.75
31-25
t-test
4.08
<0.001
292
Diabetic patients with stable CAD, (group IA)

when compared with diabetics with ACS (group IB)
showed significantly higher age, HBA1c and significantly lower hs CRP & serum resisten Table (4).
Serum resisten correlated significantly with

BMI, glycated HB, total cholesterol, LDL, HDL,
triglycerides & hs CRP in diabetic patients Table
(5).
Table 4: Comparison between group IA and group IB.

Studied groups
t-test
p-value
47.757.74
45.5
60-38
2.04
<0.05
32.752.83
33.0
38.0-29.0
31.03.2
31.0
36.0-26.0
1.08
>0.05
No.
12
0
No.
6
2
%
75.0
25.0
X2
3.33
>0.05
Group IA N=12
Group IB N=8
Age:
X SD
Median
Range
56.08.71
59.5
64-40
BMI:
X SD
Median
Range
Hypertension:
Positive
Negative
%
100
0.0

X SD
Median
Range
118.7520.63
116.50
173-95
104.0 11.61
106.50
117 85
1.73
>0.05

blood sugar:
X SD
Median
Range
233.3346.55
245
280-147
220.7538.97
218.0
267-145
0.88
>0.05
Glycated Hb:
X SD
Median
Range
11.751.5
11.75
13.5- 9.0
9.120.51
9.0
10.0-8.5
3.34
<0.01
Triglyceride:
X SD
Median
Range
263.2548.85
245.5
349-213
233.056.73
223.0
325-177
1.54
>0.05
Cholesterol:
X SD
Median
Range
267.6844.99
253.5
334-214
248.5052.53
269
309-182
0.92
>0.05
HDL:
X SD
Median
Range
33.336.25
33
43-25
38.75 8.10
40.50
47 26
1.66
>0.05
LDL:
X SD
Median
Range
180.8341.83
171.0
237-123
158.2548.69
167.0
218-96
1.15
>0.05
Serum hs CRP:
X SD
Median
Range
3.460.44
3.5
3.9-2.3
4.330.27
4.40
4.6-4.0
3.72
<0.001
Resistin:
X SD
Median
Range
30.504.46
30.0
42-26
37.514.43
36.05
45-33
3.01
<0.01
293

Table 5: Correlation between resistin and various parameters.
Discussion
Resistin
MeanSD
Age
BMI
Fasting blood glucose
HbA1c%
Triglyceride
Cholesterol
HDL
LDL
Serum hs CRP
30.783.40
106.3745.99
212.2546.42
10.051.65
239.6748.27
254.5744.31
36.176.67
168.4241.58
2.671.41
Diabetes mellitus affects more than 9.3% of

Egyptians, and the number of new cases is increasing locally and worldwide [5]. This epidemic of
type 2 diabetes reflects the epidemic of over weight,
obesity, metabolic syndrome and sedentary life [6].
Correlation
p
coefficient
value
(r)
+0.048
+0.719
+0. 526
+0.678
+0.732
+0.736
+0.653
0.827
+0.685
+0.733
>0.05
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
The adipose tissue has been recognized as an

endocrine organ which secretes numerous proteins
known as adipocytokines such as resisten, adiponectin and leptin.
Several studies investigated the role of resisten
in obesity, type 2 diabetes, inflammations and
inflammation related diseases.
A cut off point of 29.5, serum resisten has

sensitivity of 75%, specificity of 80% +ve predictive value of 78.9%, ve value of 76.2 and accuracy
of 77.5% Fig. (1), Table (6).
However, the relationship between serum resisten and atherosclerotic coronary artery disease
in type 2 diabetic patients remains poorly understood and needed to be investigated.
Sensitivity
ROC Curve
1.00
In the present study, 52 subjects were enrolled

and divided into three groups:
0.75
Group I: 20 patients with type 2 diabetes and

CAD this group was subdivided into:
Group IA: Diabetics with stable CAD (12 pts).
0.50
Group IB: Diabetics with ACS (8 pts).

Group II: 20 patients with type 2 diabetes without
CAD.
0.25
Group III: 12 apperantly healthy subjects.

0.00
0.00
0.25
0.50
0.75

the three groups as regards age & sex.
1.00
1-Specificity
Diagonal segments are produced by ties
Patients with type 2 diabetes (group I & II)

when compared with healthy control showed significantly higher BMI, glycated HB, total cholesterol, LDL, TG, Hs CRP & serum resisten.
Figure 1: Area under the curve = 0.816.

At a cut off point of 29.
Table 6.
Groups
Level of
resisten
On the other hand, when diabetic patients with

CAD (group I).
Total
DM with CAD DM without CAD

No.
No.
No.
29.5
<29.5
15
5
75.0
25.0
4
16
20.0
80.0
19
21
47.5
52.5
Total
20
100
20
100
40
100
Compared with diabetics without CAD (group

II), the former showed significantly higher BMI,
glycated HB, HSCRP & serum resisten but no
significant differences of lipid profile.
Also, when diabetics with stable CAD compared
with diabetics with ACS, the former were significantly older in age & had significantly higher
glycated HB, but significantly lower Hs CRP &
serum resisten.
Sensitivity = 75.0%.
Specificity = 80.0%.
Positive predictive value = 78.9%.
Negative predictive value = 76.2%.
Accuracy of the test = 77.5%.
294
Similar results were recorded by Keun Young,

et al [7], who measured serum resisten in 45 diabetic
patients with CAD & 47 diabetes without CAD &
found higher serum resisten in the first group and
the difference was significant and persistent regardless age or body mass index.
In the second study, the design was prospective

among healthy middle aged men.
Hence, diabetes mullets was not a target at the
beginning of the study.
Limitations of the study: First, the small number
of patients in each group represents the major
limitation of this study.
Also, AL-Daghri, et al [8] found higher serum

resisten in 35 patients with type 2 diabetes & 22
patients with diabetes & CAD compared with
healthy control in Saudi Arabia.
Second, serum resisten was not correlated with

the extent and severity of CAD in the first group.
In Conclusion
Xiao-Zhi Qiao, et al [9] in 2007 measured serum

resisten in 65 patients with CAD & 26 healthy
control and found that serum resisten levels were
4 folds higher in AMI patients, 2.43 folds higher
in unstable angina patients and 1.12 folds in stable
angina patients than healthy control.
Diabetic patients with CAD have significantly

higher serum resisten than diabetics without CAD
and healthy control. Also, diabetics with ACS have
significantly higher serum resisten than diabetics
with stale CAD.
Also, similar findings were reported by Lubos

E., et al [10] in 2009 in a very large study in which
they found that resisten levels were elevated in
patients with unstable angina, NSTEMI & STEMI
and these levels may be predictive of future cardiovascular events.
Serum resisten may serve as a biomarker of

increased atherogenic risk in patients with type 2
diabetes.
References
1- Flaberty JD, David CJ: Diabetes and coronary revascularization. JAMA 2005; 293: 1501.
Wiikert C, et al [11] in 2008 found that high

serum resisten levels were associated with the risk
of MI but not with ischaemic stroke in a prospective
study after multivariable adjustment for established
cardiovascular risk factors.
2- Kipke A, Alderman AL, et al: Differential influence of

diabetes mellitus on increased Jeopardized myocardium
after initial angioplasty or bypass surgery: Bypass Angioplasty Revascularization Investigations. Circulation 2002;
105: 1914.
3- Kawashima L, Lazar MA, et al; An inflammatory cascade
leading to hyperesistenemria in humans PLOS Med 2004;
161-168.
Contradictory results were reported by Hoefle

Guenter, et al [12] who measured serum resisten is
547 patients undergoing coronary angiography for
the evaluation of stable CAD.
4- Stepan CM, Bai Ley ST, et al: The hormone resisten links
obesity to diabetes, Nature 2001; 409: 292-293.
They found that serum resisten is neither associated with the presence of significant coronary
stenosis nor with the incidence of future vascular
events but in this study, They did not differentiate
between those with diabetes and those without.
5- Herman W, Ali M, et al: Diabetes mellitus in egypt: Risk

factors, prevalence and future burden. Eastern Mediterranean Health Journal 1997; Volume 3, Issue I, 144-148.
Despite of that, serum resisten was also correlated with Hs CRP among coronary patients as in
our study.
7- Keun Y, Park H, Hyon H, et al: Serum resisten as a

biological marker for coronary artery disease and restenosis
In Type 2 Diabetic patients. Cir J 2007; 71: 868-873.
6- Rodbard H, Jollinger P, et al: Consensus Panel on Type

2 Diabetes Mellitus:An algorithms for glycemic control,
Endocr Pract 2009; 15 No. (6).
8- Al-Daghri N, Chetty R, Al Rubean K, et al: Serum resisten

is associated with C-reactive protein and LDL-cholesterol
in Type 2 diabetes and coronary artery disease in a Saudi
population. Cardiovascular Diabetology 2005; 4: 10.
Another negative results were also reported in

two large angiographic trials in 2007 & 2010
respectively, the LURIC & PRIME [13,14]. In the
first study they correlated serum resisten with the
presence of diabetes only and not with glycated
HB as in our study.
9- XiaoZhi Qiao, YunMoi Young, et al: Relationship

between resisten level in serum and acute coronary syndrome or stable angina pectoris. Journal of Zhejiang
University 2007; Volume 8, Number 12; 875-880.
295

10- Lubos E, Messow C, Schnab El R, et al: Resisten, acute
coronary syndrome and prognosis results from The atherogenesis study. Atherosclerosis 2009; Volume 193, Issue
1: 121-128.
disease Clinic Chimica Acta 2007; Volume 386 Issues 12: Pages 1-6.
13- Pilz St, Weihrauch G, et al: Implications of resisten plasma
levels in subjects undergoing coronary angiography. The
Ludwig Shafen Risk and Cardiovascular Health (LURIC)
Study, Clinical Endocrinology 2007; Volume 66 Issue
(3): Pages 380-386.
11- Weikert C, Westphal S, Berger K, et al: Plasma resisten

levels and risk of myocardial Infarction and ischemic
stroke. Journal of Clinical Endocrinology and Metabolism
2007; Volume 93 No. (7) Pages: 2647-2653.
14- Luc G, Empana J, Morange P, et al: A dipo Cytokines and

the risk of coronary heart disease in healthy middle aged
men: The P R I M E Study. International Journal of Obesity
2010; 34: 118-126.
12- Hoefle G, Saley C, Risch L, et al: Relationship between

the adipose tissue hormone resisten and coronary artery
296
Pacing Induced Cardiomyopathy, Diagnosis and Prevalence

AMR EL-HADIDY, MD*; KHALED FAROUK, MD*; HAMDY SABER, MD**;
AHMED EL-SHERIEF, MD*
Background: There is accumulating evidence that artificial stimulation from the right ventricular apex results in abnormal
ventricular activation which has major influences on left ventricular systolic and diastolic function [1,2]. The altered sequence
of ventricular activation may induce a transseptal pressure gradient affecting, end diastolic volumes and cardiac performance
[3,4] . In addition, left ventricular isovolvmic contraction time is prolonged (3) while there is a relative shortening of left
ventricular diastolic time [6]. Finally, delayed mitral valve closure, as seen in patients with left bundle branch block, may induce
mitral regurgitation. Limited reports have focused on the immediate effects of cardiac pacing on the coronary circulation with
respect to myocardial ischaemia but no data were presented on associated left ventricular dysfunction [7,8].
Objectives: This study is retrospective and prospective assessment of the prevalence of pacing-induced cardiomyopathy
clinically by symptoms, signs and NYHA stratification of the studied population, echocardiographically as reflected on LV
dilatation, LV asymmetrical hypertrophy, Nuclear imaging (radio-isotope scanning) for assessment of LV dilatation and function
and to correlate between the echocardiographic and nuclear findings post-pacemaker implantation.
Methods: The study included 40 patients (21 males, 19 females), mean age 58.5510.37 yrs, referred to the Critical Care
Department, Cairo University Hospitals from April 2005 to April 2007 who underwent pacemaker insertion to variable indications
(34 with CHB, 6 non CHB).
Excluding cardiomyopathy all patients who underwent pacemaker insertion for any cause of bradyarrhythmia, at least 6
months before the study were included; while pts with infection, acute coronary syndrome, recent cardiac surgery and those
less than 18 years old who are unable to give written informed concent were excluded.
Results and Conclusion: After completion of the statistical analysis of our study we have concluded that right ventricular
pacing affect diastolic function LV function in the short term follow-up and could be assessed by echocardiography. Regarding
the deterioration in ventricular functions we found that the diastolic dysfunction of LV and RV pacing is usually preceding
systolic dysfunction. Also RV dysfunction always precede LV dysfunction after RV pacing. The systolic dysfunction of LV is
higher with higher rates of pacing and lower in lower rates. Taking in consideration that MUGA is the gold standard technique
for assessment of LVEF, Echocardiography is overestimating for LVEF and simple 1st pass is underestimating.
Key Words: Pacing induced cardiomyopathy.
Introduction
model for the condition that has since been used

for many further studies regarding this entity [3].
Tachycardia-induced cardiomyopathy can be defined as a condition characterized by atrial or
ventricular myocardial dysfunction resulting solely
from increased atrial or ventricular rates. The most
common presentation is a dilated cardiomyopathy
with or without the causative tachycardia. It is
extremely important to recognize this condition,
as it is a potentially reversible cause of heart failure.
Gossage et al first described tachycardiainduced cardiomyopathy in 1913 in a patient with

atrial fibrillation [1]. In 1937, Brill et al reported
another case of atrial fibrillation and heart failure
that reversed following restoration of sinus rhythm
[2]. Whipple et al established the first experimental
The Department of Critical Care Medicine,
Cairo University* and National Heart Institute**.
Chronic ventricular pacing from single-chamber

devices is comparable to VT and dual chamber to
SVT with 1:1 conduction. The ventricular rate
therefore is the major determinant of onset and
Manuscript received 15 Dec., 2008; revised 4 Jan., 2009;

accepted 5 Jan., 2009.
Address for Correspondence: Dr. Khaled Farouk,
The Department of Critical Care Medicine, Cairo University.
297
Pacing Induced Cardiomyopathy, Diagnosis & Prevalence
progression of tachycardia-induced cardiomyopathy. Chronic stimulation of the ventricular myocardium results in increased LV area, mitral regurgitation (MR), elevated LV end-diastolic pressure,
and decreased LV wall thickness and ejection
fraction [4].
After taking a written informed consent from

the included pts; they were subjected to: 1) Full
medical history, base line data of past clinical
examination, 2) ECG before and after implantation
to define the cause and type of pacing (VVI, DDD,
.), 3) Baseline data of pacemaker settings including (sensing, threshold, impedance of ventricular
atrial lead), 4) Pre-implantation transthoracic
echocardiography, 5) Post implantation transthoracic echocardiography was done with the patient
examined in the left lateral recumbent position
according to the recommendations of the American
Society of Echocardiography.
Ventricular dysfunction sets in early after the

onset of the high ventricular rates and is more
marked in chronic VT than in chronic SVT [5] .
This has been observed in patients with long-term
pacing as well; patients with single-chamber (ventricular) pacing do worse than those with sequential
dual-chamber pacing (atrial paced) [6].
A- Two dimensional (2-D) echocardiography:

The standard views obtained for each patient
were the parasternal long, and short axis views at
different levels, and apical 4 and 2-chamber views.
Pacing is now indicated in various situations

of cardiac dysfunctions and bradyarrhythmias so
that we intended in this study to overview the
drawback of pacing and effect on the heart as a
pump.
B- M-mode and 2D:

Under guidance of 2D-echocardiography using
the parasternal long axis view, the M-mode cursor
was positioned at the level of the mitral valve
leaflet tips to measure the LV dimensions and LV
ejection fraction. Left ventricular end-diastolic and
end-systolic volumes were calculated using Simpson's rule to obtain LV ejection fraction (LVEF%)
in some patients especially ischemic ones.
Aim of this study: Is retrospective and prospective assessment of the prevalence of pacing-induced
cardiomyopathy Clinically by symptomatology,
clinical signs and NYHA stratification of the studied
population, Echocardiographically as reflected on
L.V. dilatation, L.V. asymmetrical hypertrophy and
correlation between echocardiographic and nuclear
findings post pacemaker implantation.
C- The Doppler study:

Pulsed wave Doppler echocardiography was
performed to assess LV filling pattern for diastolic
function assessment to detect:
Study Population
Our study group included 40 patients (21 Males
& 19 Females) admitted to the critical care department from the period of April 2005 to April 2007
with different pacing modalities.
1- Peak early diastolic inflow velocity (E-wave

velocity) (cm/sec): Measured by drawing a
perpendicular line from the summit of the Ewave to the baseline.
Included in the study were pts who underwent

pacemaker insertion for any cause of bradyarrhythmia at least 6 months before the study, while pts
with cardiomyopathy, infection, ischemic heart
disease (IHD), recent cardiac surgery and those
less than 18 years old who are unable to give
written informed consent were excluded.
2- Peak late diastolic inflow velocity (A-wave

velocity) (cm/sec): Measured by drawing a
perpendicular line from the summit of the Awave to the baseline.
3- E/A ratio: The ratio between the peak E-wave
velocity and A-wave peak velocity. It is a measure of the relative left ventricular filling.
Study population:
Methodology:
4- E-Wave deceleration time (ms): Measured from

the peak E-wave to the point where the deceleration slope hits the baseline.
Study protocol:
The study is a retrospective and prospective
for assessment of the prevalence of pacing-induced
cardiomyopathy. In retrospective cases, data were
collected from the filling system in the pacemaker
follow-up clinic.
5- Total filling duration (ms): Measured from the

beginning of the E-wave to the end of the A
wave as shown in Fig. (1).
298
Amr El-Hadidy, et al
P
Left ventricular systolic function (assessed by

echocardiography):
Echocardiographically assessed LV systolic
function showed no statistically significant difference after pacing (63.556.9) compared to (64.38
6.4) before pacing (p=0.58).
ECG
E
A
0.5
The fraction shortening (FS) of LV (assessed by

echocardiography):
The LVFS before and after pacing were assessed
by echocardiography and were not significantly
different 32.94.15 Vs 34.15.7, respectively (pvalue 0.27).
m/s
AT DT
Figure 1: Showing the relationship between the electrocardiogram ECG and pulsed Doppler recording transmitral valve flow velocity, E = E-wave of early
filling, A = A-wave of atrial filling, AT = Acceleration time and DT = Deceleration time.
Deceleration Time (DT):

There was a significant prolongation of the DT
after pacemaker implantation compared to that
before implantation (The two-tailed p-value is
<0.0001, considered extremely significant using
t-test), Table (2).
6- Post implantation, the MUGA scan (Multiple

Gated Acquisition Scan) was done for assessment of LV function (ejection fraction), and to
be compared with that obtained by echo.
Results will be shown as average values, percentages, and means with standard deviations.
Statistical inference will be performed using the
Chi square or Fisher's exact test for qualitative
variables, while Student's t-test will be used for
quantitative variables. To explore the behavior of
risk factors, relative risks and 95% confidence
intervals will be estimated. All p-values lower than
0.05 will be considered statistically significant.
Table 2: Showing DT before and after pacing.
DT
p-value
0.98
0.87
0.0001
As shown in Table (3) the mean of EF of group

A estimated by echocardiography before pacing
was 62.725.61 compared to 62.567.29 after
pacing. A difference that was statistically not
significant (p-value is 0.9416).
The DT before pacing (DT1) was 145.357.87
and after pacing (DT2) was 182.720.26 sec. and
the difference was extremely significant. (The pvalue was <0.0001) Table (3).
Table 3: Showing the EF and DT before and after pacing in
group A.
Table 1: Showing EDD and ESD before and after pacing.

After pacing
181.4519.24 ms
Group B: 22 patients (55%) with ventricular rate

below 70bpm.
Left ventricular diameters:

As shown in Table (1) there was no statistically
significant difference between the end diastolic
diameter before (EDD1) and after (EDD2) pacing
(5.150.48 Vs 5.160.44) or between the ESD 2
and ESD2 (3.30.43 Vs 3.320.34 cm) respectively.
5.160.44 cm
3.320.34 cm
145.776.93 ms
Group A: 18 patients (45%) with ventricular rate

70bpm.
Indications for pacing:

Thirty four pts (85%) had CHB and 6 (15%)
pts were paced for other causes of bradyarrhythmia
including sick sinus syndrome (SSS) and slow AF.
5.150.48 cm
3.30.43 cm
p-value
Pacemaker settings:
The studied pts were divided into two groups
according to the set rate of pacemaker.
The study comprised 40 patients, 21 males and

19 females with a mean age of 58.610.4 years.
Hypertension was found in 16 of them.
Before pacing
After (DT2)
p-value below 0.05 is considered significant.
Results
EDD
ESD
Before (DT1)
Before
EF
DT
p-value below 0.05 is considered significant.
299
62.725.61
145.357.87
After
p-value
62.567.29
182.720.26
0.94
<0.0001

Table 4: Showing the EF and DT before and after pacing in
group B.
Again the mean EF of group B estimated by

echocardiography before pacing was 65.736.8
compared to 64.366.62 after pacing. A difference
that was statistically not significant. (p-value was
0.5) Table (4).
Before
EF
DT
Also the DT1 was 146.096.29 sec and DT2

was 180.4518.78 sec. A difference that was statistically highly significant (p-value <0.0001).
After
65.736.8
146.096.29
64.366.62
180.4518.78
p-value
0.5
<0.0001
Table 5: Showing comparison between group A and group

B.
Group A
Comparing EF of group A to that of group B;

only LVEF estimated by MUGA and 1st pass were
lower in group A than B (p-value was <0.0001 and
0.0321 respectively). The other settings as the
ventricular threshold, sensing and impedence were
matched between the two groups and there were
no significant difference as shown in Table (5) and
Fig. (2).
V threshold
V sense
V impedence
EF by Muga
EF by echo
EF by 1st pass
RV EF
60
Group A
54
Group A
58
Group B
53
Group B
0.680.143
10.331.93
620.8112.8
50.444.49
62.57.29
49.225.77
50.398.97
** p-value significant.
56
52
54
51
52
50
50
49
48
48
46
Group B
p-value
0.730.15
10.551.92
612.7118.3
58.053.64
64.366.62
53.365.92
50.457.92
0.2854
0.4302
0.6252
0.0001***
0.4187
0.0321**
0.9822
*** p-value is highly significant.
47
EF of LV of group A Vs B measured by 1st pass
EF of LV of A Vs B measured by MUGA
Figure 2: Showing the EF in group A and B measured by MUGA (left) and 1st pass (right).
Classification of patients according to the period

between the implantation and post implantation
cardiac functional assessment: The patients were
divided into two groups (Group I) including 23
patient who have been subjected to cardiac function
assessment (9 months or less) post implantation
of the device and (Group II) including 17 patients
who have their assessment after more than 9 months
Table (7).
Type of pacemaker:
Out of the 30 pts studied 17 (42.5%) received
VVI pacemaker and 23 (57.5%) were implanted
non VVI devices (VDD or DDD or DDDR). The
next table shows a comparison of the initial cardiac
functional assessment in both groups using different
methods.
Table 6: No significant difference between the two groups
regarding cardiac functional assessment.
VVI
EF by Muga
EF by echo
EF by 1st pass
RV EF
EDD2
ESD2
DT2
Time from
implant to test
53.885.58
63.067.32
52.635.39
48.258.42
5.010.44
3.250.38
184.2519.34ms
11.315.18
months
Non VVI
p-value
54.745.68
63.76.73
50.436.56
51.488.23
5.250.43
3.360.33
180.2219.5ms
9.833.68
months
0.6362
0.7759
0.2662
0.2318
0.0921
0.3346
0.5206
0.2969
Comparison between methods of assessment of

LV systolic function:
Assessment of the LVEF was significantly
different between MUGA, echocardiography and
1st pass means. The p-value was <0.001, considered
extremely significant. Variation among their means
was significantly greater than expected by chance
using One-way Analysis of Variance (ANOVA)
Table (8).
300
MUGA is the gold standard method for the

assessment of EF, but first pass shows a non significant under estimation, and echocardiography
shows a significant over estimation of LVEF.
a progressive decline in ejection fraction and other

indices of LV functional competence [7].
In order to assess the LV function after pacing,
the RV was studied 40 in pts (17 VVI, 23 non VVI)
and we tried to compare the function before pacing
using echocardiography and after pacing using
echocardiography, MUGA and 1st pass.
Table 7: Showing comparison of cardiac function in those

assessed before to that after 9 months in the study
population.
Group I
Number
VVI%
DDD%
% of patients
with rate over
70 bpm
% of patients
with rate
below 70 bpm
EF by Muga
EF2 by echo
EF1 before
pacing
EF by 1st pass
RV EF
EDD2
ESD2
DT2
Group II
23
17
9/23 (39.1%) 8/17 (47%)
14/23 (60.9%) 9/17 (53%)
8/23 (34.8%) 9/17 (53%)
p-value
Our results revealed that the EDD and ESD

didn't change significantly before pacing and that
was proved by echocardiographic assessment and
this was in agreement with Michelle L. Bridenbaker
et al in St. Jude medical centre who have studied,
retrospectively, long-term right ventricular (RV)
pacing following atrioventricular node (AVN)
ablation for chronic atrial fibrillation (AF) in
patients with normal left ventricular (LV) function
in 2007 [8] . They have found that RV-pacinginduced LV dyssynchrony was associated with
deterioration in heart failure symptoms, systolic
LV function, and LV dilatation in 49% of the studied
population. After long-term RV pacing (mean
follow-up 3.8 years), LV dyssynchrony was evident
in 27 patients (49%) and was not present in 51%
of cases.
0.7492*
0.3368*
15/23 (65.2%) 8/17 (47%)

56.043.81
62.046.87
61.705.56
52.716.86
65.596.56
68.006.43
0.0570**
0.1083
0.0020***
51.225.91
50.876.71
5.200.44
3.390.36
168.1310.25
51.886.28
50.8710.03
5.120.47
3.230.35
199.4713.61
0.7339
0.6948
0.5709
0.1745
0.0001***
* Fisher's Exact Test.

** The two-tailed p-value is 0.0570, considered not quite significant.
*** Extremely significant.
In the group of patients without dyssynchrony

at long-term follow-up, NYHA class improved
from baseline and there were no changes in ejection
fraction (EF) or LV diameter. In contrast, patients
who developed dyssynchrony following long-term
RV pacing had deteriorating NYHA class, worsening EF, and significant increases in LV volumes
and LV diameter [8].
Table 8: Showing comparison between the three methods of

functional cardiac assessment.
MeansSD
Difference
p-value
MUGA
ECHO
1st Pass
54.65.57
63.556.9
51.56.14
Echo Vs
MUGA
Echo Vs
1st pass
MUGA Vs
1st pass
8.925
p<0.001
12.050
p<0.001
3.125
ns p>0.05
This conclusion is partially agrees with our

study in the part of LV dysfunction but differs as
49% has shown to develop LV dilatation because
the mean follow-up duration in our study was
shorter period (10.34.3 months) that did not give
time to deleterious effects of RV pacing on tissue
and cellular levels to take place. In our study we
didn't evaluate the LV dyssynchrony that might
occur in a small percentage of our population and
so LV dilatation was not evident. Their study was
done retrospectively on VVI pace maker without
dual mode pacing so that LV dilatation could be
more evident.
Discussion
Dyssynchrony imposed on ventricular function
by right ventricular (RV) apical pacing may lead
in some cases to worsening or appearance of heart
failure (HF) symptoms. This is a result of an altered
pattern of activation, leading to several histological
and functional adjustments of the left ventricle,
including inhomogeneous thickening of the ventricular myocardium and myofibrillar disarray,
fibrosis, disturbances in ion-handling protein expression, myocardial perfusion defects, alterations
in sympathetic tone and mitral regurgitation. Studies
of mid- and long-term effects of RV apical pacing
on left ventricular (LV) function have demonstrated
In other studies it has been also demonstrated

in humans that even as short as 2 hrs of RV pacing
causes a significant and persistent LVEF reduction
[9]. Prolongation of pacing for 1 week further reduces LVEF and it is not restored before 32h after
301
cessation of pacing have elapsed [9]. Another contributing factor to the unfavourable effect of RV
pacing on LV haemodynamics is the diminution
of LV relaxation and filling times, i.e. a diastolic
dysfunction which further impairs LV haemodynamic efficiency [10,11,12].
peared to be higher in the ventricular group than

in the atrial group, but statistically, there was no
significant change in LVEDD from pacemaker
implantation to last follow-up in either the atrial
or the ventricular groups. The limitation of our
study to elucidate the increase of EDD and ESD
of LV is mainly due to the relatively short duration
of follow-up.
In 2004, Maher El Nahlawi et al [9] have studied

left ventricular function during and after right
ventricular pacing in Northwestern University,
Chicago, Illinois, USA. They have studied 12 pts
with transvenous dual-chamber pacemakers, and
normal left ventricular function. Left ventricular
EF was measured at a fixed rate after at least 1
week of atrial pacing only (baseline), during shortterm (2 hr) and mid-term (1 week) AV sequential
pacing with a short AV delay, and after short- and
mid-term AV pacing and they have found that:
first: All subjects had a normal baseline left ventricular EF (>55%). Short-term ventricular pacing
(STVP) for 2h resulted in a significant decrease
in left ventricular EF. Immediately after discontinuing DDD pacing, there was no significant
change in left ventricular EF compared with STVP.
Second: after one week of VP, there was a significant decline in left ventricular function compared
with baseline. Furthermore, the left ventricular EF
during mid-term ventricular pacing (MTVP) was
significantly lower than the left ventricular EF
during STVP.
It has been studied that diastolic asynchrony is

more frequent than systolic asynchrony in dilated
cardiomyopathy and could be worsened by RV
pacing and even less improved by cardiac resynchronization therapy (CRT) [14].
In our study we have obtained the same results
as deceleration time was more significantly prolonged after pacing denoting more and earlier
diastolic dysfunction in all types of pacing.
Several echocardiographic studies demonstrated
that LBBB, induced by RV pacing, causes marked
diastolic function impairment both in CHF patients
[15,16] and in patients with normal systolic function
[17,18] Main diastolic abnormalities caused by
LBBB included reduced LV filling time, prolonged
isovolumic contraction and relaxation times, altered
transmitral filling patterns, and prolonged duration
of mitral regurgitation in patients with LV dysfunction. Morris-Thurgood et al found diastolic filling
abnormalities to be of crucial importance in CRT
patients and proposed that part of the benefit of
CRT was probably related to better LV filling rather
than ventricular systolic resynchronization [19].
In contrast to our study, this study has shown

that the short and long term DDD pacing have
decreased significantly the LVEF but one limitation
of this study is the small number of the studied
population (12 pts). In addition, this study utilized
a very short AV delay to guarantee 100% VP. It is
possible that some of the noted abnormalities could
be related to this "nonphysiologic" AV delay.
Other studies explained that LV diastolic dysfunction was due to ventricular interaction in
diastole that plays a potential role in CHF patients.
Atherton et al documented that LV filling was
impeded in one-half of CHF patients by ventricular
interaction in diastole from the raised RV diastolic
pressure and by external constraint from the pericardium, especially in patients with increased LV
filling pressure. This diastolic interaction could
explain the delayed onset of mechanical diastolic
motion in the LV (measured by tissue Doppler
imaging), even in patients without systolic interventricular asynchrony.
In a large randomized study comparing atrial

to RV pacing in SSS, RV pacing was associated
with a higher incidence of congestive heart failure
and consumption of diuretics than atrial pacing.
This is accompanied by a decrease in left ventricular
fractional shortening and an increased dilatation
of the left atrium in the ventricular paced patients
over long term follow-up (mean Follow-up was
over 5.5 years) [13].
Very few data exist concerning diastolic asynchrony itself [21,22]. However, it has been shown
for a long time that LBBB caused both systolic
and diastolic asynchronies [23].
The LVESD appeared to increase more in the

ventricular group than in the atrial group compared
with pre implantation values, the increase was
significant in the ventricular group but not in the
atrial group. On the other hand the LVEDD ap-
More recently, in their study of 112 CHF patients, Yu et al [21] found the incidence of systolic
302
and diastolic asynchrony to be 51% and 46%,

respectively, in patients with narrow QRS, and
73% and 69%, respectively, in patients with wide
QRS. In this study, diastolic delays were significantly longer than systolic delays. In a majority of
CHF patients, diastolic and systolic asynchronies
are both present. This may be explained by the
fact that diastole and systole are closely linked: A
delayed contraction of a segment will result in a
delayed relaxation in this segment. However, the
main result of our study and the previous studies
of Yu et al [21] is that diastolic asynchrony was
more frequently observed than systolic asynchrony.
The reasons why diastolic is more frequent than
systolic asynchrony are not clear. The length of
diastole, which includes both isovolumic relaxation
and contraction times, may make diastolic study
more sensitive than systolic and allow an earlier
identification of a delayed segment, before systolic
asynchrony occurs. This was illustrated by the fact
that diastolic asynchrony was observed alone in
more than one-third of CHF patients in our study
[21].
Cardiac dysfunction after right ventricular (RV)

apical pacing is well known but its extent, time
frame of appearance and individual effect on left
ventricular (LV), RV systolic and diastolic parameters has not been evaluated in a systematic fashion.
We have observed that RV function measured
by the 1st pass is not significantly lower than LV
EF measured by the same technique (50.4258.3,
51.56.14, respectively, p-value 0.5) but taking in
consideration that MUGA is the gold standard
technique for measuring the LV EF, the latter was
significantly higher than that of RV post pacing
(50.4258.3, 54.635.57, respectively, p-value
0.0009).
A recent Indian study that was done by SK
Dwivedi et al, in 2006. Forty eight consecutive
patients implanted a VVI pacemaker were enrolled
in this study. The first significant change to appear
in cardiac function after VVI pacing was in diastolic
properties of RV as shown by increase in RV
isovolumic relaxation time (IVRT) at 1 week and
RV deceleration time (DT) at 1 month. Increase in
RV internal dimension was also noticed at 1 week.
The LV diastolic parameters were significantly
altered after 1 month with increase in LV-IVRT
and increase in LV DT. This was followed by LV
systolic abnormality which appeared at 6 months
[25].
The lack of correlation between parameters of

diastolic asynchrony and conventional Doppler
parameters of diastolic function (E/A ratio, deceleration time, and LV diastolic filling time) may be
explained by the fact that the latter parameters are
highly dependent on LV filling pressure (which
may vary widely in patients with CHF) and do not
reflect only the diastolic coordination between LV
walls.
Their findings were similar to our study in that

it suggests that the RV affection by pacing precedes
LV and the diastolic properties were affected before
systolic properties in both ventricles. Changes in
cardiac haemodynamics start appearing as early
as one-week after VVI pacing, which are subtle
and are limited to right ventricle only. Left ventricular dysfunction occurs later and this follows RV
dysfunction, as reported in previous studies
[26,27,28]. Also, diastolic abnormalities are first to
appear which are followed by appearance of systolic
abnormalities of the respective ventricles. Their
study was unique in highlighting the sequence in
change in the LV and RV diastolic and systolic
function in a serial fashion in VVI paced patients.
In our study we have divided the population

according to the set rate of the pacemaker into
group A (18 patients (45%) with ventricular rate
70bpm) and group B (22 patients (55%) with
ventricular rate below 70bpm).
Comparing group A EF to that of group B;
LVEF estimated by MUGA and 1st pass were lower
in group A than B (p-value was <0.0001 and 0.0321
respectively). The other settings as the ventricular
threshold, sensing and impedence were matched
between the two groups and there were no significant difference, and this was in agreement with
Harvard medical school study that was done in
2004 by Kyoko Soejima, who reported that, in
patients who underwent AV node ablation for
persistent multiple atrial tachycardias, and who
then had a non-mode-switching pacemaker implanted, left ventricular dysfunction was developed after
6 years. This was resolved after programming the
pacemaker to VVI at 70bpm [24].
Faerestrand et al [29] found an increase in end

diastolic volume in VVI paced patients after 3
months. Likewise, Fehrsson et al found greater
resting LV volumes and lesser EF in patients paced
on VVI rather than with physiological pacing mode.
In most of these studies, stress has been on systolic
function of LV after long term pacing while few
have looked into the serial follow-up of these
303

patients with pacing-induced heart failure: Can resynchronization do the trick?; Europace 2006; 8 (5): 352-357.
patients. Data regarding the diastolic function is

conflicting. LeClercq et al [30] in a study of 11
patients found that filling rates improved with AAI
pacing as compared to DDD pacing, and similar
Doppler data was provided in another report by
Rosenqvist et al [31]. However data from Vardas
et al [32] found no difference in the the diastolic
Doppler indices between AAI and DDD modes of
pacing. Moreover, the systolic functions of right
ventricle as well as diastolic functions of both
ventricles have not been studied comprehensively.
8- Michelle L: Bridenbaker, RN, BSN, CPhT, Documenting

LV Dyssynchrony Induced by RV Pacing Following
Atrioventricular Node Ablation for Atrial Fibrillation,
advances in arrhythmic heart failure 2007; Vol 11.
9- Nahlawi M, Waligora M, Spies SM, Bonow RO, Kadish
AH, Goldberger JJ: Left ventricular function during and
after right ventricular pacing. J Am Coll Cardiol 2004;
44: 1883-8.
10- Stojnic B, Stojanov P, Angelkov L, Pavlovic S, Radjen
G, Velimirovic D: Evaluation of asynchronous left ventricular relaxation by Doppler echocardiography during
ventricular pacing with AV synchrony (VDD): Comparison
with atrial pacing (AAI). Pacing Clin Electrophysiol 1996;
19: 940-4.
Conclusions
After completition of the statistical analysis of
our study we have concluded that right ventricular
pacing could affect diastolic LV function in the
short term follow-up and could be assessed by
echocardiography. Regarding the deterioration in
ventricular functions we found that the diastolic
dysfunction of LV after RV pacing is usually preceding systolic dysfunction. Also RV dysfunction
always precedes LV dysfunction after RV pacing.
The systolic dysfunction of LV is higher with
higher rates of pacing and lower in lower rates.
Taking in consideration that MUGA is the gold
standard technique for assessment of LVEF,
Echocardiography is overestimating for LVEF and
simple 1st pass is underestimating it.
11- Zile MR, Blaustein AS, Shimizu G, Gaasch WH: Right

ventricular pacing reduces the rate of left ventricular
relaxation and filling. J Am Coll Cardiol 1987; 10: 7029.
12- Bedotto JB, Grayburn PB, Black WH, et al: Alterations
in left ventricular relaxation during atrioventricular pacing
in humans. J Am Coll Cardiol 1990; 15: 658-64.
13- Jens Cosedis Nielsen, MD; Henning Rud Andersen, MD,
DMSc; Poul Erik Bloch Thomsen, MD et al: Heart Failure
and Echocardiographic Changes During Long-term Follow-up of Patients With Sick Sinus Syndrome Randomized
to Single-Chamber Atrial or Ventricular Pacing; Circulation
1998; 97: 987-995.
1- Gossage AM, Braxton Hicks JA: On auricular fibrillation.

QJM 1913; 6: 435-440.
14- Iris Schuster, MD*, Gilbert Habib, MD, FACC*,*, Christophe Jego, MD*, et al: Diastolic Asynchrony Is More
Frequent Than Systolic Asynchrony in Dilated Cardiomyopathy and Is Less Improved by Cardiac Resynchronization Therapy: Am Coll Cardiol 2005; 46: 2250-2257,
doi:10.1016/j.jacc.2005.02.096.
2- Brill IC: Auricular fibrillation with congestive failure and

no other evidence of organic heart disease. Am Heart J
1937; 13: 175-182.
15- Xiao HB, Lee CH, Gibson DG: Effect of left bundle
branch block on diastolic function in dilated cardiomyopathy Br Heart J 1991; 66: 443-447.
3- Whipple GH, Sheffield LT, Woodman EG, Theophilis C,

Friedman S: Reversible congestive heart failure due to
chronic rapid stimulation of the normal heart. Proc N
Engl Cardiovasc Soc 1962; 20: 39-40.
16- Ozdemir K, Altunkeser BB, Korkut B, et al: Effect of left

bundle branch block on systolic and diastolic function of
left ventricle in heart failure Angiology 2004; 55: 63-71.
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305
Multigated Radionuclide Study of Systolic Function after Cardiac

Resynchronization Therapy
AHMED ABD EL-AZIZ, MD; ASHRAF W ANDRAOS, MD
Background: Haemodynamic deterioration in patients (pts) with congestive heart failure (CHF) and left bundle branch
block (LBBB) is thought to be due to dys-synchronous left ventricular (LV) contraction, typically seen as paradoxical septal
wall motion toward the right ventricle induced by late LV free wall contraction. Cardiac resynchronization therapy (CRT) has
emerged as a promising technique to treat pts with CHF through premature stimulation of the lateral LV wall which resynchronizes
the contractions of the septal and lateral segments of LV.
Objective: Our aim is to evaluate short term effects of CRT [either by left ventricular pacing (LVP) alone or by biventricular
pacing (BVP)] on global and regional systolic function.
Patients and Methods: Fifteen pts (9 males and 6 females) with a mean age 49.6021 yrs with severe HF and ventricular
dyssynchrony as evidenced by QRS duration 150ms and/or intraventricular mechanical delay (IVMD) 60ms by tissue Doppler
(TDI) were subjected to baseline clinical and radionuclide ventriculography assessment using multiple gated acquisition technique
(MUGA) in vivo method for scintigraphic measurement of the global LV ejection fraction (EF%) and the regional EF% in 6
segment scoring system of standard MUGA in high-lateral, mid-lateral, infero-lateral, infero-apical, lower septum and upper
septum segments. After implantation of multisite pacing devices, all patients were randomized into two phases (3 months each)
of LVP and BVP and at the end of each phase clinical and scintigraphic assessment were repeated.
Results: Although BVP alone resulted in significant shortening in the QRS width from 16731ms to 14323ms (p=0.016),
yet both modes of pacing induced significant reduction in IVMD from 11567ms at baseline to 5633ms (p<0.001) and 4932ms
(p<0.001) for LVP and BVP respectively. Both pacing modes caused similar significant improvement in global EF% from
25.13.6% at baseline to 34.94.25% (p<0.001) and 36.37% (p<0.001) for LVP and BVP respectively. Our data showed
variable increase in the regional EF% after CRT. The mid-lateral, infero-lateral and infero-apical segments showed insignificant
increased contractility after both modes of pacing. The high-lateral segment showed significant increased contractility after
CRT from 40.410% at baseline to 46.711.7% (p=0.013) and 53.214.6% (p=0.001) for LVP and BVP respectively. The striking
observation is that the septum, lower and high, showed highly significant improvement in contractility after CRT, the lower
septum increased from 9.817.8% at baseline to 34.913.4% (p<0.001) and 37.3615.6% (p<0.001) for LVP and BVP respectively
and the high septum increased from 23.312.7% at baseline to 43.413.7% (p<0.001) and 47.217.8% (p<0.001) for LVP and
BVP respectively.
The favorable scintigraphic effects obtained by both LVP and BVP were paralleled by symptomatic improvement expressed
by significant improvement in NYHA functional class from 3.30.5 at baseline to 2.20.7 (p<0.001) and 1.90.7 (p<0.001)
for LVP and BVP respectively, 6 minute walk test from 294.589m at baseline to 381.9102m (p<0.001) and 386.5105m
(p<0.001) for LVP and BVP respectively and quality of life score from 6711 at baseline to 34.417 (p<0.001) and 33.316
(p<0.001) for LVP and BVP respectively.
Conclusion: Our data clearly show that, cardiac resynchronization achieved by either LVP or BVP improve objective and
subjective parameters in pts with advanced HF. Restoration of the septal mechanical synchrony and abolishing its deleterious
effect on EF% is the cornerstone in the improved systolic function after CRT.
Key Words: Multigated radionuclide study Systolic function Cardiac resynchronization therapy.

Manuscript received 5 April, 2010; revised 15 May, 2010;
accepted 16 May, 2010.
Address for Correspondence: Dr. Ahmed Abd El-Aziz,
307
Introduction
Methods:
The studied patients were subjected to baseline
assessment including full history taking and clinical
examination, assessment of the NYHA class, twelve
lead ECG, chest X-ray and full lab investigation,
quality of life questionnaire "Minnesota questionnaire", exercise test, i.e. 6-minute walk test,
echocardiographic examination including TDI to
assess LV dyssynchrony and Gated radionuclide
ventriculography to assess LVEF. Then the patients
were randomized into two phases with cross over:
Newer non-pharmacological therapies for heart

failure are being evaluated for patients of congestive
heart failure (CHF) refractory to drug therapy.
Mechanical support with left ventricular (LV) assist
devices and heart transplantation are reserved for
a minority of patients who have severely decompensated heart failure [1].
Implanted devices, such as pacemakers and
cardioverter-defibrillators, can also be beneficial.
In particular, the recognition that ventricular dyssynchrony can be deleterious to ventricular function
has led to the development of pacemakers capable
of resynchronizing the left and right ventricles [2].
1- Biventricular pacing (BVP) phase for 3 months.

2- Left ventricular pacing (LVP) phase for 3
months.
Cardiac resynchronization therapy (CRT) has

emerged as a promising technique to treat pts with
CHF through premature stimulation of the lateral
LV wall which resynchronizes the contractions of
the septal and lateral segments of LV.
During the first phase 8 patients underwent

BVP while 7 patients underwent LVP.
At the end of each phase follow-up was done
including clinical evaluation (NYHA classification,
QOL questionnaire and exercise test), echocardiographic examination and Gated radionuclide ventriculography to assess LV global and segmental
EF.
Aim of the work:

Our aim is to evaluate short term effects of
CRT [either by left ventricular pacing (LVP) alone
or biventricular pacing (BVP)] on global and regional systolic function.
How is the MUGA scan performed?

In our study the MUGA scan was performed
with the in-vivo method in which pyrophosphate
is injected intravenously first. This accumulates
inside red blood cells. About 20 minutes later a
radioactive substance, technetium99, was injected.

Patients:
Fifteen patients with advanced heart failure
(NYHA class III or IV) were studied. They included
9 males and 6 females, with a mean age of 49.6021
yrs. All patients were admitted to the Critical Care
Unit, Cairo University for biventricular pacemaker
or triple chamber ICD implantation. At the time
of the study all patients (pts) were in sinus rhythm.
They were indicated to resynchronization therapy
on the basis of the following inclusion criteria:
Advanced heart failure of any etiology (idiopathic
in 12 and ischemic in 3 pts) on optimal drug therapy, NYHA class III or IV, LVEF 35%, LVEDD
55mm and ventricular dyssynchrony as evidenced
by QRS or TDI: QRS duration 150ms, and/or by
TDI difference between any 4 LV segments in time
to start of systolic contraction 60ms.
The pyrophosphate dilutes the radioactive substance and keeps it from seeping back out of the
red blood cells. The patient is then placed under
a special detector (Siemens, Multispect 3 system,
triple detector Gamma Camera) (Fig. 1) which is
able to detect the low-level radiation being given
off by the technetium-labeled red cells. Since the
red blood cells (including those that are radiolabeled) fill the cardiac chambers, the image produced by the gamma camera is essentially an outline
of those chambers. With some fancy computer
manipulation, the final product is a movie of the
heart beating.
We excluded from the study pts with uncorrected valvular disease or dysfunctional prosthetic
valve, recent ischemic episodes or correctable
coronary heart disease, severe primary pulmonary
disease, renal or hepatic disease, frequent atrial
and/or ventricular premature beats and suboptimal
echocardiographic window with poor image quality.
How is cardiac function measured by the MUGA?

The gamma camera can separate the left ventricle from the right ventricle by using a certain
view (left anterior oblique view) and by outlining
the LV in end diastole and in end systole, the global
and regional EF is obtained automatically.
308
Ahmed Abd El-Aziz & Ashraf W Andraos
class was NYHA III in 10 pts and IV in 5 pts. The

underlying rhythm was sinus in all pts.
The results of follow-up will be expressed in terms
of the effect of LV and BV pacing on:
I-
Global and regional EF (MUGA).
II- Cardiac resynchronization indices (ECG and

echocardiography criteria).
III- Clinical data (Exercise test, NYHA class and
QOL Score).
I- Assessment of the EF% with MUGA Scan:
Global EF% (Fig. 5):
Figure 1: Gamma Camera.
As compared to baseline the global EF%

showed significant increase with LV pacing (from
25.13.6% to 34.94.5%, p<0.001) and BV pacing
(from 25.13.6% to 36.37%, p<0.001) but no
significant change when the 2 pacing modes were
compared together (p=0.331).
The regional EF includes 6 cardiac regions

(high-lateral, mid-lateral, Infero-lateral, inferoapical, lower-septum and upper-septum) (Fig. 2).
Highseptum
Highlateral
Lowerseptum
Regional EF% (Table 1, Figs. 3,4):

We traced the regional EF% in 6 cardiac regions
(high lateral, mid-lateral, infero lateral, inferoapical, lower and upper-septum) and it was increased after both modes of pacing with no significant change between the two pacing modes
(p>0.05) for all regions.
Midlateral
When we trace the absolute change in the mean

values of the regional EF% we can notice that the
septum (lower & upper) is the main sharer in
increase the global EF% after pacing.
Inferolateral
Inferoapical
Figure 2: The six cardiac regions in which EF can be measured

using the MUGA.
Table 1: The mean values of the regional EF% measured by
MUGA.
Implantation technique:
Fourteen patients had implanted biventricular
pacemaker. One patient had received biventricular
ICD. Epicardial LV pacing was obtained via the
coronary sinus in all patients. The coronary sinus
lead was positioned in the Posterolateral branch
in 8 pts. and in the Anterolateral branch in 7 pts.
Cardiac
region
Baseline
High-lateral 40.410
Mid-lateral
LV
Pacing
p
value
BV
Pacing
p
value
46.711.7 0.013 53.214.6 0.001
24.911.6 33.512.9 0.069 32.510.1 0.073
Infero-lateral 24.012.6 25.311.4 0.723 25.514.1 0.664

Infero-apical 25.511.1 36.912.5 0.012 33.113.3 0.104
Results
Fifteen patients were eligible for the study
included 9 males, 6 females, with a mean age of
49.6021 yrs and a mean EF% of 25.13.6%. The
underlying cardiac pathology was idiopathic in 12
patients and ischemic in 3 patients. The functional
Lowerseptum
9.817.8 34.913.4 <0.001 37.315.6 <0.001
Upperseptum
23.312.7 43.413.7 <0.001 47.217.8 <0.001
p-value is compared to baseline.
309

50
II- Effect on cardiac resynchronization indices:

ECG Criteria (Fig. 6):
Compared to baseline, the QRS width did not
have any significant reduction after LVP (from
16731ms to 16529ms, p=0.724) but showed
significant reduction after BVP (16731ms to
14323ms (p=0.016).
40
EF%
30
20
10
Baseline
LV pacing
High-lateral
Lower-septum
Inferio-apical
Infero-lateral
Mid-lateral
Upper-septum
167
165
160
p=0.724
msec
180
143
140
p=0.016
120
Figure 3: Change in the mean values of the regional EF%

after LV pacing.
100
60
Baseline
50
LVP
BVP
Figure 6: Effect of both pacing modes on QRS duration.
EF%
40
Tissue Doppler criteria (Fig. 7):

Both modes of pacing induced significant reduction of IVMD as assessed by TDI from 115
67ms at baseline to 5633ms (p<0.001) and 49
32ms (p<0.001) for LVP and BVP respectively.
30
20
10
0
115
LV pacing
120
High-lateral
Lower-septum
100
Inferio-apical
Infero-lateral
Mid-lateral
Upper-septum
80
56
msec
Baseline
Figure 4: Change in the mean values of the regional EF%

after BV pacing.
60
49
40
p<0.001
20
40
30
0
25.1
Baseline
p=0.331
EF%
p<0.001
36.3
34.9
LVP
BVP
Figure 7: Effect of both pacing modes on IVMD by TDI.
20
p<0.001
10
III- Effect on clinical data (Table 2):

Both modes of pacing resulted in almost the
same degree of improvement in clinical data: NYHA functional class from 3.30.5 at baseline to
2.20.7 (p<0.001) and 1.90.7 (p<0.001) for LVP
and BVP respectively, 6 minute walk test from
294.589m at baseline to 381.9102m (p<0.001)
p<0.001
0
Baseline
LVP
BVP
Figure 5: Global EF% measured by MUGA in the two pacing

modes.
310
and 386.5105m (p<0.001) for LVP and BVP

respectively and quality of life score from 6711
at baseline to 34.417 (p<0.001) and 33.316

(p<0.001) for LVP and BVP respectively.
Table 2: Clinical data after pacing compared to baseline.

Variable
6 MWT (m)*
QOL score*
NYHA class**
Baseline
MeanSD
LV pacing
MeanSD
p
value
BV pacing
MeanSD
p
value
29489
6711
3.30.5
381.9102
34.417
2.20.7
<0.001
<0.001
<0.001
386105
33.316
1.90.6
<0.001
<0.001
<0.001
p-value is compared to baseline.

* p-value LVP Vs BVP = NS.
** p-value LVP Vs BVP = 0.05
Discussion
Different studies used different methods to

assess the effect of CRT on LV function. Acute
studies usually utilize hemodynamic variables like
pulmonary capillary wedge pressure, cardiac output
and systolic blood pressure to assess the effect of
CRT [8-11]. In other studies echocardiography was
the method of assessment. Follow-up patients with
CRT was usually done using one or more of the
following: Echocardiography, radionuclide imaging, determination of the functional NYHA class,
QOL score and the 6 minute walking test (6 MWT).
Progression of congestive heart failure, although

somewhat slowed by recent therapeutic developments, continues to be a growing problem. It affects
2-4 million people in the United States and nearly
15 million people worldwide. Recent therapeutic
advances, such as the use of ACE inhibitors, beta
blockers, hydralazine in combination with nitrates
and spironolactone, have resulted in decreased
mortality rates in patients with CHF [3-6]. Despite
these pharmacological advances, the true impact
of newer innovations in device-based therapy
remains to be determined. The overall long-term
prognosis and quality of life are still limited in
patients with moderate to severe heart failure.
Therefore, device-based therapy has been considered in the treatment equation.
In our study we used radionuclide ventriculography (MUGA) for accurate measuring of EF%
but it is more expensive than echocardiography
and require injection of radioactive material and
also more uncomfortable for the patients but has
the advantage that the regional EF% can also be
measured. Clinical assessment was done at followup using the functional NYHA class, QOL score
and the 6 WMT.
Haemodynamic deterioration in patients (pts)

with congestive heart failure (CHF) and left bundle
branch block (LBBB) is thought to be due dyssynchronous left ventricular (LV) contraction, typically
seen as paradoxical septal wall motion toward the
right ventricle induced by late LV free wall contraction. Cardiac resynchronization therapy (CRT)
has emerged as promising technique to treat pts
with CHF through premature stimulation of the
lateral LV wall which resynchronize the contractions of the septal and lateral segments of LV.
Effect on systolic function:

When we used radionuclide ventriculography
"MUGA" for accurate measurement of the LVEF%
we found its result in accordance with data obtained
from echocardiography with significant increase
in EF% with LV pacing (from 25.13.6% to
34.94.5%, p<0.001) and BV pacing (from 25.1
3.6% to 36.37%, p<0.001) with no any significant
change when EF% compared between LV and BV
pacing (p=0.331).
Patient selection and post CRT assessment:

Like most studies the inclusion criteria comprised patients suffering from dilated cardiomyopathy with EF <35% and evidence of ventricular
dyssynchrony defined by QRS duration 150ms
and/or intra VD 60ms by TDI in thesis work done
by one of our colleague [7] the cut off 60ms in
the intra VD where used to identify pts who are
likely to respond to CRT.
The interesting thing in the regional EF% obtained by MUGA is that the low values of the septal
EF% especially the lower septum before pacing
showed a very significant increase after pacing
(baseline: 9.817.8%, LV pacing 34.913.4%, BV
pacing 37.315.6%, p<0.001) which can be explained by the presence of paradoxical movement
311
of the septum before pacing which is improved by

CRT.
Our result about cardiac resynchronization

indices were in agreement with that of many recent
trials which showed that mechanical resynchronization can be achieved without achieving electrical
synchrony as LVP induced prolonged QRS duration
(Electrical Asynchrony) and significant IVMD
reduction (Mechanical Synchrony).
Our data were also in agreement with that of

Garrigue et al, 2003 [12] who used radionuclide
ventriculography to assess LV EF% and compared
2 active periods (2 months each) of LV and BV
pacing to baseline with cross over design in patients
with AF and he reported a similar significant increase in the LVEF% with each mode of pacing
(baseline: 258%, LV pacing 2910%, BV pacing
3011%, p<0.05) with no superiority of any pacing
mode over the other (p=NS) (Table 3).
Effect on clinical outcome and exercise tolerance:

Our result showed that both LV and BV pacing
resulted in significant improvement in 6 minute
walk distance, QOL score and NYHA class when
compared to baseline (p<0.001). These observed
clinical data were in accordance with that of the
Path CHF study [15] which compared to active
period (4 week each) of uni LV and BV pacing to
baseline in a crossover design. In this study Aurrichio et al, reported similar improvement in functional class, QOL score and exercise tolerance in
the 2 pacing modes [15].
Table 3: EF measured by MUGA (comparison with another

study).
EF%
Study
No.
Design
Baseline
Garrigue 13 Cross over 258

et al.
2 months
each phase
Present
study
LV
pacing
BV
p
pacing value
2910
3011
NS
Conclusion
Our data clearly show that, cardiac resynchronization achieved by either LVP or BVP improves
objective and subjective parameters in pts with
advanced HF. Restoration of the septal mechanical
synchrony and abolishing its deleterious effect on
EF% is the cornerstone in the improved systolic
function after CRT.
15 Cross over 25.13.6 34.94.5 36.37 NS

3 months
each phase
p-value LV Vs BV pacing.
Effect on cardiac resynchronization indices:

Although BVP only resulted in significant shortening in the QRS width, yet both modes of pacing
induced significant reduction of IVMD. In our
study the IVMD was detected by TDI as the difference between the latest and the earliest LV walls
(septum, lateral, anterior and inferior) to be activated.
References
1- Rose EA, Gelijns AC, Moskawitz AJ, et al: Long-term
mechanical left ventricular assistance for end-stage heart
failure. N Engl J Med 2001; 345: 1435-43.
2- Leclercq C, Kass DA: Retiming the failing heart: Principles
and current clinical status of cardiac resynchronization.
J Am Coll Cardiol 2002; 39: 194-201.
Data obtained from Bordachar et al, in 2004

also showed a significant reduction in IVMD with
LV and BV pacing [13]. Almost similar data where
obtained from the BELIEVE study which showed
a significant reduction in IVMD with LV and BV
pacing [14].
3- SOLVD Investigators; The effect of Enalapril on mortality

and the development of heart failure in symptomatic
patients with reduced left ventricular ejection fraction. N
Engl J Med 1992; 327: 685-91.
4- Ranade V, Molnar J, Khokher T, et al: Effect of angiotensinconverting enzyme therapy on QT interval dispersion.
Am J Ther 1999; 6: 257-261.
We have also shown that CRT improves LV

synchronicity not only by the early stimulation of
the delayed walls, but also by homogenously delaying those walls with early systolic contraction,
causing all walls to contract simultaneously irrespective of the regional delay in relation to QRS
onset. These regional changes could be achieved
as soon as CRT starts and so the regression in the
IVMD can be a good predictor of the subsequent
clinical improvement.
5- Packer M, Coats AJ, Fowler MB, et al: Carvedilol Prospective Randomized Cumulative Survival Study Group.
Effect of carvedilol on survival in severe chronic heart
failure. N Engl J Med 2001; 344: 1651-1658.
6- Elkayam U: Nitrates in the treatment of congestive heart
failure. Am J Cardiol 1996; 77: 41C-51C.
7- Gaber A, Hamed G, Hammouda M, et al: Multisite biventricular pacing therapy in patients with advanced heart
failure: Acute effects and short term follow-up. Critical
Care Medicine Department 2004; (thesis).
312

8- Cazeau S, Ritter P, Lazarus A, et al: Multisite pacing for
end-stage heart failure: Early experience. Pacing Clin
Electrophysiol 1996; 19: 1748-57.
prospective haemodynamic study. J Cardiac Electrophysiol

Review 2003; 7 (4): 315-324.
13- Bordachar P, Lafitte S, Reuter S, et al: Biventricular
pacing and left ventricular pacing in heart failure: Similar
hemodynamic improvement despite marked electromechanical di fferences. J Cardiovasc electrophysiol 2004;
15 (12): 1432-1347.
9- Blanc JJ, Etienne Y, Gilard M, et al: Evaluation of different

ventricular pacing sites in patients: with severe heart
failure: Results of an acute hemodynamic study. Circulation 1997; 96: 3273-7327.
10- Leclercq C, Faris O, Tunin R, et al: Systolic improvement
and mechanical resynchronization does not require electrical synchrony in the dilated failing heart with left
bundle-branch block. Circulation 2002; 106: 1760-1763.
14- Gasparini M, Bocchiardo M, Lenati M: Comparison of

1-year effects of left ventricular and biventricular pacing
in patients with heart failure who have ventricular arrhythmia and LBBB: final results from the BELIEVE multicenter randomized study. Am Heart J 2006; 152 (1): 155el155e7.
11- Turner MS, Bleasdale RA, Mumford CE, et al: Left

ventricular pacing improves haemodynamic variables in
patients with heart failure with a normal QRS duration.
Heart 2004; 90: 502-505.
15- Auricchio A, Ding J, Spinelli JC, et al: Cardiac resynchronization therapy restores optimal atrioventricular mechanical timing in heart failure patients with ventricular
conduction delay. J Am Coll Cardiol 2002; 39: 11631169.
12- Garrigue S, Bordachar P, Reuter S, et al: Comparison of

permanent left ventricular and biventricular pacing in
patents with heart failure and chronic atrial fibrillation:
313
Cobalt Chromium Coronary Stents and Drug-Eluting Stents in

Real Practice
ALI A YOUSSEF, MD1; HANAN M KAMAL, MD1; HON-KAN YIP, MD2;
CHENG-HSU YANG, MD2; CHI-LING HANG, MD2; YUAN-KAI HSIEH, MD2;
CHIH-YUAN FANG, MD2; CHIUNG-JEN WU, MD2
Background: Cobalt chromium stents (CCS) are unusually compared to drug-eluting stents (DES) for coronary intervention.
We evaluated the daily usage patterns of CCS compared to DES unconstrained by eligibility criteria.
Methods and Results: Consecutive patients (n=303) with de novo lesions treated exclusively with a CCS were compared
to 432 patients treated exclusively with a DES. Patients in the CCS group were older; frequently had heart failure, renal failure,
prior coronary balloon angioplasty, prior stroke, more co-morbidities and more multivessel disease than the DES group. The
DES group had longer, more type C and left anterior descending lesions. The in-hospital major adverse cardiac events [MACE;
death, myocardial infarction, stroke and target lesion revascularization (TLR)] were similar. At 6 months, the cumulative rate
of MACE was 12.9% in the CCS group and 5.6% in the DES group (p<0.001), this was driven by TLR. Rates of stent thrombosis
were similar among CCS (0.9%), and DES (1.0%) patients.
Conclusion: The CCSs were used in clinically higher risk patients, while DES in more severely diseased coronaries. Drugeluting stents use resulted in lower rates of clinically driven repeat revascularization with similar rates of death, MI, stroke and
stent thrombosis.
Key Words: Stents Cobalt chromium Drug-eluting Restenosis.
Introduction
associated with DES have come to light, suggesting

that the indiscriminate use of DES is actually not
advisable [7-9] . Moreover, there is controversy
regarding the advantage of using DES over BMS
in terms of clinical outcome for short lesions and
relatively large vessels (3.0mm) [6]. Also, exploring how physicians decide which stent category
for different uncontrolled clinical and angiographic
varieties, and how this impacts clinical outcomes
in real practice represents an actual live demonstration. And finally, in the majority of the randomized DES trials, the BMS used were not the most
up-to-date in terms of stent design and technology.
A study involving last-generation BMS, essentially
the cobalt chromium stents (CCS) showed lower
revascularization rates, this famous randomized
trial showed that the use of DES compared to CCS
in all patients has no clinical benefit including no
significant difference of restenosis related target
vessel revascularization [10]. However, data regarding such comparison and the usage patterns in real
world is limited in the available literatures.
While rates of restenosis and major adverse

cardiac events (MACE) have both been demonstrated to be significantly reduced with the use of
drug eluting stents (DES) compared with baremetal stents (BMS) in a broad variety of studies
and trials, [1-6] the same trials could not demonstrate
any difference in mortality or acute myocardial
infarction (AMI) rates. Therefore, the reported
clinical benefit of DES is entirely due to the highly
significant reduction in the need for repeated interventions. However, concerns about late events
The Departments of Cardiology, Suez Canal University,
Ismailia, Egypt1 and Division of Cardiology, Chang Gung
Memorial Hospital, Kaohsiung Medical Center, Chang Gung
University, Kaohsiung, Taiwan, R.O.C.2
Manuscript received 25 Jan., 2010; revised 28 Feb., 2010;
Address for Correspondence: Dr. Ali A Youssef,
The Department of Cardiology, Suez Canal University, Round
Road, Ismailia, Egypt, draliyoussef@gmail.com
315
Cobalt Chromium Coronary Stents & Drug-Eluting Stents in Real Practice
Methods
stroke, target lesion revascularization (TLR), within

6 and 12 months of the procedure and stent thrombosis. Secondary end points were acute success;
in-hospital MACE, and binary restenosis at 6 and
12 months.
Study design and patients population:

This is a single-center registry included patients
with clinical angina or a positive functional study,
with native, single treatable, coronary artery de
novo, or post balloon angioplasty (PTCA) restenosis lesions. During the period from June 2006 to
July 2007; totally 1343 patients had an elective
PCI procedure, among them 544 patients had DESs
and 799 patients had BMSs. After inclusion and
exclusion criteria, final analysis included 432
patients treated exclusively with a DES (302 Paclitaxel eluting-stents and 130 Sirolimus elutingstents) and 303 patients treated with CCS (145
Driver stent, Medtronic) and 145 Vision stent,
Abbot). Patients with multi-vessel disease were
permitted provided that only a single lesion/patient
needed intervention (other stenoses <70%), and
target vessel reference diameter (site determined)
between 2.5mm and <4.0mm. The target stenosis
severity was 70%. Exclusion criteria included
patients in whom anti-platelet therapy was not
used, patients judged to have a lesion that prevents
complete inflation of an angioplasty balloon, patients with recently (within 6 months) deployed
different types of stents, patients with culprit as
in-stent restenosis. We also exclude patients with
allergy to cobalt or chromium, contrast agents,
sirolimus, or paclitaxel; and patients presented
with acute myocardial infarction, cardiogenic shock
or terminal illness.
Multiple views were routinely obtained to avoid

foreshortening or vessels overlapping. The baseline
and follow-up angiograms were analyzed to determine the vessels with lesions and lesions baseline
findings, angiographic success, angiographic adverse events, and thrombolysis in myocardial infarction (TIMI) flow. Angiographic follow-up was
performed as clinically driven study or according
to physician practice.
Cardiac enzymes (Troponin, creatine kinase
and creatine kinase- MB) were routinely measured
at intervals of 8 and 12 hours, with further measurement at 18, 24 hours and followed-up accordingly if there are symptoms or signs suggestive of
acute coronary syndrome event and/or the procedure was complicated and/or routine enzymes
measurements were found to be increasing. An
electrocardiogram was routinely obtained at presentation and 16 to 24 hours after the procedure
or before discharge. Myocardial infarction during
follow-up was diagnosed according to standard
criteria (elevated cardiac enzyme levels >3 times
the upper reference value of normal, associated
with any elevation above the upper reference value
of normal in creatine kinase-MB levels or increased
levels of troponin or creatine kinase-MB fraction
in association with chest pain and/or ischemic
electrocardiographic changes). Target lesion revascularization was defined as any re-intervention
(surgical or percutaneous) to treat a luminal stenosis, including the 5-mm distal or proximal segments
adjacent to the index stent. Online quantitative
coronary analysis (QCA) was routinely done by
the attending physician or his assistant.
Procedures and post intervention medications:

All interventions were performed according to
current standard guidelines [11] and the final interventional strategy, including type and size of stent
was entirely left to the discretion of the operator.
Angiographic success was defined as residual
stenosis <30% by visual analysis in the presence
of grade TIMI 3 flow. Periprocedural glycoprotein
IIb/IIIa inhibitors, heparin and oral antiplatelets
were used according to current standard guidelines
[11]. Long term use of other medications including
statins was left to the operators decision. Drugeluting stents were available in diameters of 2.25
to 3.5mm and in lengths of 8 to 33mm. Cobalt
Chromium stents were available in diameters of
2.25 to 3.50mm and in lengths of 8 to 32mm.
Stent thrombosis was considered acute (0 to 24

hours), subacute (24 hours to 30 days), or late
(31 days). Stent thrombosis was defined as either
definite or probable stent thrombosis. Definite
stent thrombosis was defined as the presence of
angiographic thrombus in a stent that previously
had been successfully deployed accompanied by
an acute coronary syndrome. Probable stent thrombosis is defined as unexplained sudden cardiac
death or Q-wave MI in the distribution of the
stented artery.
Study end points and analysis:

The primary composite end point was the rate
of MACE, in the form of cardiovascular death,
non-fatal myocardial infarction, cerebrovascular
316
Ali A Youssef, et al
Clinical follow-up was performed in hospital,

during office visits at 30 days, 6 and 12 month
after the procedure and during routine office visits
every one or two months and via telephone if the
patient missed hospital follow-up.
tially old age group, with prevalent diabetes mellitus

(39.8% for CCS group and 39.3% for DES group,
p=0.93), high incidence of hypertension (70.7%
for CCS group and 69.3% for DES group, p=0.74)
and renal failure (28.5% for CCS group and 21.3%
for DES group, p=0.076). The CCS group had
older age, higher rates of clinical heart failure,
poorer left ventricular systolic function, more prior
percutaneous coronary intervention (PCI), and had
more prior stroke and more prevalent comorbidities. The occurrence of multi-vessel disease was
more prevalent in the CCS group; however, the
DES group had longer lesions, more type C and
left anterior descending (LAD) lesions.
Angiographic success was defined as attainment

of <30% residual stenosis of the target lesion with
TIMI 3 flow. Procedural success was considered
if angiographic success was achieved without the
occurrence of in-hospital MACE. Information about
the in-hospital outcomes was obtained from hospital
records for all patients (there was no included cases
of referral to other hospitals).
Post discharge follow-up was routinely done
at out-patient basis after 1-2 week post discharge
then every 1-2 months. All repeat interventions
(surgical and percutaneous) and rehospitalizations
were retrospectively collected during the followup. Follow-up coronary angiography was essentially obtained as clinically indicated by symptoms.
Because of the well-known effect of angiographic
reevaluation in increasing the incidence of repeat
revascularization; [12] clinically driven repeat
revascularization was defined as any intervention
motivated by a significant luminal stenosis (70%
diameter stenosis) or 50% in the presence of
genuine anginal symptoms and/or proven myocardial ischemia in the target vessel territory by noninvasive testing. In asymptomatic patients (i.e. preoperative assessment or caring physician preference), if there is lesions 50% and <70% and
reintervention was recommended, this was calculated as binary restenosis but not included in the
definition of the study TLR.
Procedure outcome:
The number of stents implanted per patient and
the mean stent length were similar between both
groups (Table 3). The mean stent diameter was
smaller in the DES group. Stent deployment in the
CCS group needed less frequent predilatation
(73.3% versus 98.8%, p<0.0001) with smaller final
maximum balloon-to-vessel ratio (1.050.18 for
CCS group and 1.120.19 for DE group S,
p<0.001). Importantly, less frequent post-stenting
expansion with high pressure balloon was used in
the CCS group (35.6% versus 77.5%, p<0.0001),
also lesser final maximum high pressure post dilatation compared to the DES group (16.64.3 versus
19.14.5 p<0.0001). The initial angiographic and
procedural success rates were similar in the two
cohorts. There were two reported cases of acute
closure in the CCS group (one case of stent thrombosis and the other due to stent edge dissection)
and 3 cases in the DES group (two cases of acute
stent thrombosis and one case of stent edge dissection).
Statistical analysis was performed using SPSS
11.5 for Windows (SPSS, Inc., IL, USA). Numerical
values are expressed as mean SD. Continuous
variables are compared using the Student unpaired
t-test. The chi-square test is used to compare frequency ratios between groups. The result are considered statistically significant when p<0.05. All
major clinical end points were analyzed on the
basis of intent-to-treat. The authors were not blinded
to the data and they take responsibility for its
integrity.
Clinical outcome:
The in-hospital MACE rates for both groups
(Table 4) showed no significant difference (1.9%
for CCS versus 1.8% for DES, p=0.76), two patients
(0.6%) in the CCS group and 3 patients (0.7%) in
the DES group needed revascularization, all by
PCI. Revascularization was needed for a patient
in each group who had acute stent thrombosis, also
for 2 more patients in the DES group for limited
flow due to stent edge dissection, one of them also
got nonfatal MI. Complete follow-up information
was available for 98% of patients in both groups
and the majority of those who missed clinical
follow up were contacted by telephone, the mean
follow-up period for 14.7 months for the CCS
group and 16.5 months for the DES group.
Results
Patient and lesion characteristics:
Baseline and procedure characteristics are
shown in Tables (1,2). The study cohort is essen-
317
At 6 months, the MACE rate was significantly

higher in the CCS group than the DES group
(12.5% versus 5.6%, p=0.001) the cumulative
incidence of death (cardiac) and myocardial infarction was similar between both groups (Table
5). Rates for stent thrombosis were low (<1%) for
both groups and not significantly different.
significantly more TLR at 6 months than patients

in the DES group (8.9% versus 4.3%, respectively;
p=0.004).
Multi-variate regression analysis of 6 month
clinical outcome in the studied population showed
baseline left ventricular systolic function and procedure success as predictors of death. History of
prior bypass graft surgery, use of CCS and the need
for predilatation were independent predictors of
restenosis (Table 6).
In the CCS group 36.6% had (within 6 months)

an angiographic follow up study versus 59.7% for
the DES group (p<0.0001), (Table 5). The 6 month
minimal lumen diameter (2.00.75mm versus
2.370.8mm, p=0.001), late loss (1.510.9mm
versus 0.780.73mm, p<0.0001) and loss index
(0.570.35 versus 0.220.31, p<0.0001) were
higher in the CCS group compared to the DES
group. The CCS group had more 6 month binary
restenosis rate compared to the DES (12.5% versus
6.0%, p<0.0001). Patients treated with CCS had
The 1-year MACE rate (Table 7) was higher in

the CCS (13.5% versus 7.2%. p=0.001), driven by
more rates of TLR in the CCS group (9.6% versus
4.2%, p=0.003), with no significant difference in
death, MI or stroke rates. Rates for stent thrombosis
were low (<1.0%) for both groups and not significantly different.
Table 1: Baseline patient characteristics.

Patient characteristics
CCS (N=303)
DES (N=432)
p-value
Age (mean SD) (yrs)

Men
HTN (mm Hg)
DM
Current Smoking
T. cholesterol (mean SD) (mg/dl)
Triglycerides (mean SD) (mg/dl)
Prior MI
Heart failure
Prior PCI
Prior CABG
Stroke
PAD
Body weight (mean SD) (kg)
S. Creatinine (mean SD) (mg/dl)
Cr clearance sex corrected (ml/hr)
Renal failure/impairment*
Hemoglobin (mg/dl)
Ejection Fraction (mean SD)
Co-morbidities#
65.8911.58
222 (73.3)
208 (70.7)
117 (39.8)
86 (29.0)
187.148.87
182.1197.9
82 (28.4)
53 (17.9)
119 (39.3)
21 (6.9)
38 (13.2)
30 (10.0)
66.3613.86
1.882.28
60.744.38
85 (28.5)
12.632.16
61.5815.9
107 (35.3)
63.6810.47
325 (75.2)
298 (69.3)
169 (39.3)
154 (35.6)
188.744.3
164.3122.9
111 (25.7)
27 (6.6)
125 (28.9)
21 (4.9)
27 (6.3)
27 (6.3)
67.8211.82
1.511.78
65.738.1
91 (21.3)
12.951.92
65.7414.56
104 (24.1)
0.007
0.54
0.74
0.93
0.065
.72
.142
0.32
0.0001
0.004
0.234
0.002
0.68
0.13
0.016
0.13
0.076
0.52
0.002
0.001
Number of diseased vessels:

1
2
3
56 (18.5)
88 (29.0)
159 (51.1)
82 (19.0)
198 (45.8)
152 (48.9)
0.0001
*Defined as S. creatinine >1.4 mg/dl

HTN: Hypertension, DM: Diabetes Mellitus, MI: Myocardial infarction, CHF: Congestive heart
failure, PCI: Percutaneous coronary intervention, CABG: Coronary artery bypass graft, PAD: Peripheral
arterial disease.
#Co-morbidity includes medically significant non-cardiovascular, non-procedure related clinical
disorders, including history of upper gastrointestinal bleeding, respiratory failure, sepsis, pneumonias,
treated cancers and others.
318
Table 2: Baseline angiographic data.
Lesion characteristics
Preprocedure RVD (mm)
Preprocedure MLD (mm)
Preprocedure diameter
stenosis %
Lesion length (mm)
CCS
(N=303)
Table 4: In-hospital adverse events.

DES
(N=432)
CCS (N=303) DES (N=432) p-value
p
value
Total
Death
MI
Revascularization
Stroke
Stent thrombosis
3.10.66 2.980.52 0.06

0.610.36 0.560.32 0.0001
81.269.52 80.8510.6 0.59
16.766.74 19.738.2 0.001
6 (1.9)
3 (1.0)
1 (0.3)
2 (0.6)
0
1 (0.3)
8 (1.8)
2 (0.5)
1 (0.2)
3 (0.7)
1 (0.2)
2 (0.5)
MI: Myocardial infarction.
Target vessel:
LAD
LCX
RCA
112 (36.9) 245 (56.7)

94 (31.1) 78 (18.1) <0.0001
97 (32.2) 109 (25.2)
Table 5: Six-month clinical and angiographic data.
AHA lesion class:

A
B1
B2
C
4 (1.3)
41 (13.5)
166 (54.8)
92 (30.4)
3 (0.7)
28 (6.5)
211 (48.8) <0.0001
190 (44.0)
Pre procedure TIMI flow:

0
1
2
3
30 (9.9)
16 (5.3)
75 (24.8)
182 (60.1)
36 (8.3)
30 (6.9) 0.61
117 (27.1)
249 (57.6)
RVD
MLD
LAD
LCX
RCA
AHA
TIMI
: Reference vessel diameter.

: Minimal lumen diameter.
: Left anterior descending.
: Left circumflex.
: Right coronary artery.
: American heart association.
: Thrombolysis in myocardial infarction.
Table 3: Procedure related characteristics and outcome.

CCS
(N=303)
Predilataion (%)
Post (high pressure)
dilatation (%)
Max. balloon size ( SD)
Max. balloon-to-vessel
ratio ( SD)
Max balloon pressure
( SD)
Number of stents used
( SD)
Stent diameter ( SD)
Stent length ( SD)
Final residual stenosis
( SD)
Acute lumen gain ( SD)
Post procedure TIMI
flow (%):
2
3
Angiographic success
(%)
Procedure success (%)
0.76
DES
(N=432)
CCS
(N=303)
DES
(N=432)
p
value
Statins use
Aspirin
Clopidogrel
T. Cholesterol
Triglycerides
Angiographic
follow-up
MLD
Late loss
Loss Index
157 (57.1)
205 (73.7)
138 (49.8)
182.639.5
176.7143.2
111 (36.6)
263 (66.1)
326 (81.9)
244 (61.3)
174.244.1
162.8107.3
258 (59.7)
0.018
0.01
0.003
0.08
0.28
<0.0001
2.00.75
1.510.9
0.570.35
2.370.8
0.780.73
0.220.31
0.001
<0.0001
<0.0001
Total major events:

Death
MI
Stroke
Stent thrombosis
TLR
38 (12.5)
9 (3.0)
1 (0.3)
1 (0.3)
2 (0.6)
27 (8.9)
24 (5.6)
8 (1.9)
3 (0.7)
1 (0.2)
3 (0.7)
18 (4.3)
0.001
0.14
0.52
0.83
0.64
0.004
Binary restenosis
(50%)
38 (12.5)
26 (6.0)
<0.0001
MLD: Minimal lumen diameter.

MI : Myocardial infarction.
TLR : Target lesion revascularization.
p
value
222 (73.3) 388 (98.8) <0.0001

108 (35.6) 335 (77.5) <0.0001
Table 6: Multi-variate analysis of 6-mon outcome for CCS

Vs. DES.
3.260.4
1.050.18
3.260.36
1.120.19
0.92
0.001
Factor
16.64.3
19.14.5
<0.0001
1.10.3
1.090.5
0.18
3.220.38
23.355.4
11.227.8
3.120.31
27.015.6
11.179.1
0.05
0.71
0.94
Death:
Procedure success
LVEF (>40% Vs <40%)
2.54.66
2.49.61
0.32
Table 7: 12 months MACE.
Odds
ratio
95% CI
p
value
Stent restenosis:
Stent type (DES Vs CCS) .558 0.303-0.819 0.001
CABG history
3.945 1.56-9.979 0.004
Predilatation Vs direct
4.0
1.19-14.29 0.01
stenting
0.09
0.036 0.008-0.162 <0.0001

0.155 0.03-0.795 0.025
CCS (N=303) DES (N=432) p-value

Total major events:
Death
MI
Stroke
Stent thrombosis
TLR
5 (1.7) 2 (0.5)
298 (98.3) 430 (99.5)
295 (97.4) 421 (97.5) 0.87
289 (95.4) 413 (95.6) 0.51
MI: Myocardial infarction.
319
41 (13.5)
10 (3.3)
1 (0.3)
1 (0.3)
2 (0.6)
29 (9.6)
31 (7.2)
10 (2.3)
3 (0.7)
1 (0.2)
4 (0.9)
18 (4.2)
0.001
0.28
0.003
TLR: Target lesion revascularization.
Discussion
CCS. There was an imbalance of baseline clinical

and procedural factors that could potentially influence the likelihood of repeat revascularization;
however, superiority of DES in reducing the TLR
was confirmed after statistical adjustment. This is
an important observation because the efficacy of
DES for reducing the incidence of restenosis, in a
single treatable lesion, has been unequivocally
demonstrated only in highly selected patients in
the early DES trials [23,24]. Studies showed significant impact of stent design on restenosis rates [2528], and patterns of neointimal hyperplasia [29,30].
One important observation is the lower rates of
TLR and binary restenosis in both groups including
much lower rate among CCS compared to impression of huge difference between DES and BMS in
the randomized trials. This finding was reported
by some studies [6] , still one study showed no
significant clinical difference, even in revascularization between DES and CCS [10]. A registry from
Japan for daily practice use of Sirolimus-eluting
stents reported 17.7% MACE rate and 14.0% insegment binary restenosis rate [31]. The current
study included patients with lesions that were
treated by a single stent rather complex coronary
lesion. Also there are reports suggesting favorable
outcome of CCS platform-compared to other BMSwith less strut thickness and better deliverability
[13,32,33]. Predilataion to pave the way for stents
was an independent predictor of restenosis in this
study, and was significantly more frequently needed
in patients treated by DES; this reflects the effect
of better deliverability of the CCS [33] . From a
safety standpoint, there was certainly no significant
or excess of death, MI, or stent thrombosis among
either group of patients over the 1-year follow-up
period. Observational registries from Europe have
reported 1-year rates of death ranging from 1.4%
to 5.3%, with combined death and MI rates ranging
from 2.7% to 8.8% when DES were used [5-7] .
Differences in completeness of follow-up and
possibly in the types of patients treated and
interventional techniques used may explain the
variation in these rates. Certainly, the results from
our study compare favorably with those reported
earlier. In terms of adjudicated stent thrombosis,
we observed that rates between CCS and DES were
similar and low.
This registry has several unique features that

distinguish it from other published registry reports
characterizing the outcomes of patients treated
with BMS and DES in routine clinical practice.
First, this comes from an Asian center, where
patients represent a major, relatively homogenous,
race among the world population, also that practice
patterns probably differ according to region. Second, this study compared DES to the up-to-date
bare metal stent platform, the CCS, which are
increasingly recommended as better than stainless
steel as stent platform [13]. Third, this nonrandomized study reflects the physicians' attitude for
choosing and managing such different stents at
different clinical scenarios.
Significant differences were noted in the manner
in which physicians selected patients for CCS
compared with DES. Physicians favored CCS for
older patients, more with history of prior PCI,
history of stroke, renal impairment, clinical heart
failure, poorer left ventricular systolic function
and other co morbidities. On the other hand, DESs
were chosen for patients with better overall clinical
profile, yet for longer lesions, smaller vessels, and
more frequently for LAD stenting.
This practice pattern probably was based on
the belief that the DES would be effective in the
treatment of relatively more difficult lesions subsets
[14-16] . The presence of poor clinical conditions
and shorter life expectancy might have impacted
the choice of stent type, favoring the use of the
fully reimbursed CCS rather than DES. The recommendations of longer use of clopidogrel for
patients treated with DES, [17-18] and the possible
higher bleeding risk as in patients with renal failure
or renal impairment, and other comorbidities associated with bleeding tendency might have influenced the physicians' choice of stent, again favoring
CCS in such clinically worse patients. Unadjusted
event rates showed a trend of more death among
CCS-treated patients at the 6-month follow-up.
This difference was not statistically significant
even with higher prevalence of high-risk features.
Both subsets of stents had similarly high procedure
success. Left ventricular systolic function and
procedure success, but not stent type, impacted
the rates of death at 6-month according to the
multi-variate analysis. Several studies support the
superiority of DES over BMS in reducing revascularization [19-22]. This study supports the effectiveness of DES for reducing TLR compared with
Study limitations:
As an observational study, we fully expected
a selection bias between CCS and DES-treated
patients because our primary goal was to describe
usage patterns unconstrained by eligibility criteria.
320
8-
Furthermore, we can't extrapolate our practice and

study results to all centers in the country. Additionally, the potential exists that we did not capture all
adverse events, but we achieved high rates of
clinical follow-up and had stent thrombosis events
adjudicated as much as we could. Our mean followup interval was 14.7 month for CCS and 16.5
month for DES; there would be considerable value
in more extended follow-up. We are not very sure
about some of the 6-month and one-year deaths as
cardiac, noncardiac, or unknown. Outcome beyond
1 year would be quite desirable, given recent
awareness of very late DES thrombosis.
Pinto Slottow TL, Waksman R: Overview of the 2006

Food and Drug Administration circulatory systems device
panel meeting on drug-eluting stent thrombosis. Catheter
Cardiovasc Interv 2007; 69: 1064-74.
9- Curfman GD, Morrissey S, Jarcho JA, Drazen JM: Drugeluting coronary stents-promise and uncertainty. N Engl
J Med 2007; 356: 1059-60.
10- Kaiser C, Brunner-La Rocca HP, Buser PT, Bonetti PO,
Osswald S, Linka A, et al, for the BASKET Investigators:
Incremental cost-effectiveness of drug-eluting stents
compared with a third-generation bare-metal stent in a
realworld setting: Randomised Basel Stent Kosten Effektivitats Trial (BASKET). Lancet 2005; 366: 921-29.
11- Smith SC Jr, Feldman TE, Jacobs AK, Morrison DA,
Hirshfeld JW Jr, O' Neill WW, et al: ACC/AHA guidelines
of percutaneous coronary interventions ACC/AHA/SCAI
2005 Guideline Update for Percutaneous Coronary Intervention A Report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the
2001 Guidelines for Percutaneous Coronary Intervention).
Available at: http://www.scai.org/pdf/PCIguideline.pdf.
Conclusions
This single center registry provides considerable
information regarding PCI as performed in the era
of DES. It reflects the manner of physicians in
choosing stent type according to the clinical and
lesions characteristics. This study showed superiority of DES in reducing TLR, with significant,
but not that huge gap, compared to CCS. Both
types of stents were similar regarding death, MI,
Stroke and stent thrombosis rates.
12- Ruygrok PN, Melkert R, Morel MA, Ormiston JA, Br

FW, Fernandez-Avils F, et al: Does angiography six
months after coronary intervention influence management
and outcome? Benestent II Investigators. J Am Coll
Cardiol 1999; 34: 1507-1511.
13- Kereiakes DJ, Cox DA, Hermiller JB, Midei MG, Bachinsky WB, Nukta ED, et al: Guidant Multi-Link Vision
Stent Registry Investigators: Usefulness of a cobalt chromium coronary stent alloy. Am J Cardiol 2003, 92: 4636.
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322
Immediate Versus Next Day Coronary Angioplasty in Non-ST Segment

Elevation Acute Coronary Syndrome Patients
WALID MAAMOUN, MD
Background: Two invasive strategies have emerged for managing patients with NSTE-ACS; these are immediate or deferred
intervention. The optimal timing of such intervention has not been well established. This trial was designed to determine the
influence of timing of PCI in patients with NSTE-ACS assuming that cardiac events are reduced by immediate PCI as compared
with a deferred approach with PCI in the next day, both under triple anti-platelet therapy protection.
Methods: The subjects, 116 Patients (93men and 23 women) who were presented as a case of Non ST-segment elevation
acute coronary syndrome eligible for PCI; They were randomly assigned to receive either an immediate invasive strategy (treated
with PCI directly after the diagnostic coronary angiography) or an invasive intervention scheduled on the next working day
(the patients transferred to the coronary care unit after diagnostic coronary angiography for medical stabilization then after 1236 hrs they underwent PCI in an elective fashion). The combined incidence of all-cause death, nonfatal myocardial infarction
(MI) and re-hospitalization for angina during the 30 days after randomization was investigated. Safety end points were the inhospital occurrence of major bleeding.
Results: The baseline characteristics were well balanced between treatment groups with the angiographic data showed no
significant difference. The study end point combining death, MI, or readmission because of recurrent ischemia at 1-month
follow-up occurred in 31.6% of patients with the immediate strategy and 23.2% of patients with the next day strategy (p=0.3).
No significant difference was found in major bleeding between the two groups.
Conclusion: An immediate intervention strategy for patients with NSTE-ACS did not improve the cardiac events in
comparison to catheterization scheduled on the next working day, supporting that the immediate approach is feasible but not
superior.
Key Words: Angioplasty Non-ST elevation.
Introduction
patients with NSTE-ACS; these are immediate or

deferred intervention [3,4,5]. The optimal timing of
such intervention has not been well established.6
Early intervention might prevent ischemic events
that could occur while the patient is awaiting a
delayed procedure. Alternatively, by treating a
patient with intensive antithrombotic therapy and
delaying intervention for several days, procedurerelated complications might be avoided with intervention on a more stable plaque [7,8]. Thus, the
question of when to intervene in patients with
NSTE-ACS has not been definitively answered.
In patients with myocardial infarction with STsegment elevation, it is well established that the
earlier primary percutaneous coronary intervention
(PCI) can be performed, the lower the mortality
[1,2].
Randomized trials have also shown that a policy
of routine invasive strategy is beneficial and improves outcome in patients with NSTE-ACS. Two
invasive strategies have emerged for managing
Ain Shams University.
This trial was designed to determine the influence of timing of PCI in patients with NSTE-ACS,
whether the cardiac events will differ by an immediate PCI as compared with a deferred PCI approach
in the next day, both under triple anti-platelet
therapy protection.
Manuscript received 5 Jan., 2010; revised 10 Feb., 2010

Address for Correspondence: Dr. Walid Maamoun,
Ain Shams University.
323
repeated in case of recurrent ischemic episode

during hospitalization.
Study design:
This study was a randomized, prospective trial
in patients presented with NSTE-ACS eligible for
PCI.
Coronary angiography and angioplasty:

Patients randomized to immediate PCI were
treated with PCI directly after the diagnostic coronary angiography. The patients randomized to
next day PCI were transferred to the coronary care
unit after diagnostic coronary angiography and
stabilized medically. After 12-36 hrs the patients
underwent PCI in an elective fashion. The protocol
required all interventional procedures to be performed with the use of tirofiban infusion. All
patients were followed-up from randomization to
hospital discharge. An outpatient visit was conducted at 30 days after discharge.
Patients:
A total of 116 patients with NSTE-ACS were
enrolled from February 2007 through march 2009
at USTH in Yemen. They were randomly assigned
to receive either an immediate invasive strategy
or an invasive intervention scheduled on the next
working day (between 12 and 36 hours after enrollment). Non-ST-segment elevation ACS was
defined by the presence of at least 2 of the following
criteria: (1) symptoms of myocardial ischemia, (2)
electrocardiographic ST-segment abnormalities
(transient elevation or significant depression of
>1mm in 2 contiguous leads, or (3) an elevated
cardiac troponin T value (>0.01ng/l). Patients were
not randomized when there was any contraindication to PCI or angiography did not demonstrate
significant coronary stenosis amenable for PCI,
when coronary artery bypass grafting (CABG) was
judged to be the preferred treatment.
Study end points:

The study end point was the combined incidence
of all-cause death, nonfatal myocardial infarction
(MI) and re-hospitalization for angina during the
30 days after randomization in the trial. Safety end
points were the in-hospital occurrence of major
bleeding.
Descriptive statistics and patient data listings
were used to summarize the data collected on the
case report form. Continuous variables were summarized using means and standard deviations Categorical variables were described using frequencies
and percentages. Continuous variables were compared with the use of the Student t-test or the
Mann-Whitney U test for skewed data. Comparison
between groups for categorical variables was performed using 2 or Fisher exact test, when appropriate. A p-value of 0.05 (two sided) was used to
indicate significance.
Clinical exclusion criteria for the study were

acute ST elevation myocardial infarction, previous
revascularization, refractory ischemia, major arrhythmias, or hemodynamic instability requiring
immediate catheterization; any contraindication
for the use of anti platelets including glycoprotein
IIb-IIIa receptor antagonist.
All patients gave written informed consent
before proceeding to the catheterization laboratory.
In-hospital medical treatment and follow-up:
At admission, a bolus dose of 300mg aspirin
and 600mg clopidogrel was given followed by
respectively 81-100mg and 75mg by mouth daily.
Aspirin was given indefinitely and clopidogrel for
6-12 months according to the type of stent (s). In
addition, patients were treated with low molecular
weight heparin according to the current guidelines.
-Blockers, statins, and angiotensin-converting
enzyme inhibitors were strongly recommended as
concomitant treatments. Patients underwent 12lead electrocardiography before and after revascularization. Blood samples were taken every 6 hours
before and after intervention (up to 24 hours after
intervention) for measurement of troponin and
creatine kinase MB values. Blood sampling was
Results
One hundred sixteen patients were randomly
assigned to undergo immediate or next day intervention at university of science and technology
hospital in Yemen. Baseline characteristics were
well balanced between treatment groups (Table 1).
As expected from the enrollment criteria, many
patients presented with co morbid conditions
[43.3% in Group I and 53.6% in group II] with
diabetes, [35% in group I and 41.1% in group II]
with hypertension. The patients received optimal
medical therapy, which was similar in the 2 study
groups, including statins (95% VS 92.8%), blockers (91.7% VS 89.3%), angiotensin-converting
324
Walid Maamoun
Table 2: Comparison of procedure characteristics among
study patients.
enzyme inhibitors (86.6% VS 82.1%), and intense

anti-platelet therapy as shown by high doses of
clopidogrel and tirofiban in 116 patients (100%).
Low-molecular-weight heparin was the only anticoagulation prescribed. One-month follow-up was
obtained in all patients.
Immediate
PCI
Group I
(n.60)
Table 1: Comparison of baseline clinical variables for study

patients.
Immediate
PCI
Group I
(60 pts)
Next day
PCI
Group II
(56 pts)
p
value
Age (years)
55.4010.1
56.8814.1
.06
Male n (%)
52 (86.7%)
41 (73.2%)
0.1
BMI Kg/m2
21.93.3
22.53.7
0.5
Smoking n (%)
27 (45%)
21 (37.5%)
0.4
Hypertension n (%)
21 (35%)
23 (41.1%)
0.5
Diabetes mellitus n (%) 26 (43.3%)
30 (53.6%)
0.3
Dyslipidemia n (%)
34 (56.7%)
24 (42.9%)
0.1
EF (%)
52.5%6.3% 52.2%6.9%
Medical Treatment
100%
100%
Clopidogrel
100%
100%
B blockers
91.7%
89.3%
Statins
95%
92.8%
Clinical variables
82.1%
LMWH
100%
100%
Tirofiban
100%
100%
p
value
No. of DES stents (%) (54/86) 62.8% (51/85) 60%
No. of BMS stents (%) (32/86) 37.2% (34/85) 40%
0.5
No. of stent/patient
1.480.6
0.9
Diameter of stent (mean) 3.040.3
3.040.3
0.07
Length of stent (mean) 23.874.83
22.885.49
0.06
Single vessel disease % (33/60) 55%
(32/56) 57%
0.9
Two vessel disease %
(21/56) 37.5% 0.6
1.510.65
(mean)
(24/60) 40%
Three vessel disease % (3/60) 5%
(3/56) 5.4%
No. of vessel/patient
1.470.6
0.9
1.500.6
Study end points:

The study end point combining death, MI, or
readmission because of recurrent ischemia at 1month follow-up occurred in 31.6% of patients
with the immediate strategy and 23.2% of patients
with the next day strategy (p=0.3) (Fig. 1).
0.4
Aspirin
ACE inhibitors/ARBS 86.6%
Next day
PCI
Group II
(n.56)
The incidence of the 3 components taken individually through 30 days was not significantly
different between the two groups. Recurrent ischemia was slightly higher with the immediate
strategy than with the delayed approach (25% VS
21.4%, respectively; p=0.6), and there were only
three mortality cases ,all of them in the immediate
strategy group, while there were no MI in any of
the groups (Fig. 1).
NS
Procedure characteristics:
Median time from randomization to angioplasty
was 160 minutes in the immediate intervention
group, compared with 21 hours in the delayed
intervention group, confirming that intervention
in this group was most often performed on the day
following randomization vascular access was femoral in all patients. the angiographic data showed
non significant difference between both groups of
patients, no. of vessel/patient was (1.500.6 in
group I VS 1.470.6 in group II, p=0.9), and the
mean length of stents was (23.874.83 VS 22.88
5.49 in group I and II respectively; p=0.06) while
the mean diameter of stents was (3.040.3 in group
I VS 3.040.3 in group II, p=0.07). Patients undergoing PCI received (1.510.65 stents in group I
of which 62.8% were drug eluting stents and
1.480.6 stents in group II of which 60% were
drug-eluting stents, p=0.9) (Table 2).
40
Group I
Group II
30
20
10
0
MI
Death
Read- Composite Bleeding

mission endpoint
Figure 1: Study end points and safety outcome.
325
Safety outcomes:
AS there was no significant difference between
both groups regarding the composite end point,
there was no difference in major bleeding (5% in
group I VS 10.7% in group II; p=0.3) (Fig. 1). The
most frequent overt bleeding complications were
gastrointestinal tract (4 patients) and puncturerelated (4 patients, three groin hematomas and one
retroperitoneal) bleeding; and intracranial hemorrhage (one patient).
in the next day is feasible but does not reduce the

risk of MI and is not associated with significant
differences in other efficacy or safety outcomes,
and does not benefit a particular subgroup of patients. But it does shorten hospital stay significantly.
among the results of that trial The primary end
point did not differ between the 2 strategies (median
troponin I value, 2.1ng/mL VS 1.7ng/mL in the
immediate and delayed intervention groups, respectively; p=0.70). The key secondary end point was
observed in 13.7% of the group assigned to receive
immediate intervention and 10.2% of the group
assigned to receive delayed intervention (p=0.31).
The other end points, as well as major bleeding,
did not differ between the 2 strategies while the
only significant difference came in length of hospital stay, which was a median of 55 hours with
the early strategy group Vs. 77 hours with the
delayed group (p<0.001) [19].
Discussion
Although meta-analysis of previous randomized
trials that compared an invasive strategy with a
conservative strategy in patients with acute coronary syndromes have shown a benefit for an invasive strategy [9,10]. The timing of angiography in
the invasive strategy group of these previous studies
ranged from as early as 19 hours after randomization in one large trial 11 to as late as 96 hours in
another large trial [12]. Given this wide variation
in the timing, there remains substantial uncertainty
regarding the optimal timing for intervention in
such patients [9]. Small randomized trials comparing
early intervention with delayed intervention have
generated conflicting results [13,14]. Although some
observational analysis have suggested that earlier
intervention, as compared with delayed intervention, may reduce events [15,16]. Others have suggested that outcomes appear to be similar between
the two approaches [17] . Also, there has been a
suggestion of a hazard associated with routine
early intervention [9,11,12,18].
The ICTUS investigators assigned 604 patients

to early invasive strategy and 596 to selectively
invasive strategy between July 2001 and August
2003. This study was powered to detect a 25%
difference in the primary endpoint, which was a
composite of death, nonfatal myocardial infarction,
or re-hospitalization for angina within a year of
randomization. There were no difference in the
cumulative rate of primary endpoint which was
22.7% in the early invasive management group
and 21.2% among patients randomized to selectively invasive strategy; Re-hospitalization rate in
the early invasive group was 7.4% versus 10.9%
(p=0.04); One-year mortality in both groups was
2.5%. So the conclusion was that a strategy of
selective invasive management is as effective as
routine early invasive treatment with no additional
benefit of the early invasive approach [11].
The principal findings of our study are that in

patients with acute coronary syndromes without
ST-segment elevation, an immediate intervention
strategy (median time to angiography was 160
minutes) was not superior to a next day intervention
strategy (median time to angiography was 21 hrs)
for the prevention of death, myocardial infarction,
or recurrent ischemia. On the contrary, the incidence
of the study end points were higher in the immediate
invasive strategy group (31.6%) VS (23.2%) in the
group assigned to a next day invasive strategy but
this difference was not statistically significant
(p=0.3), even in the individual components of the
end points and the safety outcome (major bleeding
was 5% in group I and 10.7% in group II, p=0.3).
The benefit of early intervention in NSTE-ACS

has been observed in ISAR-COOL study (The
Intracoronary Stenting with Antithrombotic Regimen COOLing-off), which randomized patients to
receive either 3 to 5 days (median time 86 hours)
of prolonged antithrombotic therapy followed by
coronary angiography (''cooling off'' strategy) or
an expedited coronary angiography strategy (within
6 hours, median time 2.4 hours).The trial showed
that a significant benefit in rates of 30-day death/MI
was derived from the use of an expedited angiography strategy (11.6% versus 5.9%) [15].
The result of our study was concordant with

the ABOARD trial; Dr. Montalescot and his colleagues concluded that the primary PCI strategy
for NSTE ACS compared with a rapid intervention
Discordant with this study; a recent randomized

prospective multicentre trial showed that the incidence of MI was significantly higher among the
326
Walid Maamoun
patients treated with immediate PCI. This trial was

performed in 251 patients admitted with NSTEACS, eligible for percutaneous coronary intervention (PCI). The incidence at 30 days of the primary
end point (death, MI and unplanned revascularization) was 60% in the group receiving immediate
PCI and 39% in the group receiving deferred PCI
(p=0.004). No deaths occurred in either group. MI
was significantly more common in the group receiving immediate PCI (60% VS 38%, p=0.005).
Unplanned re-vascularization was similar in both
groups. The observed difference was preserved
over 6-months follow-up. The results suggest that
PCI for high-risk patients with non-refractory
NSTE-ACS should be delayed for at least 24h after
hospital admission [14].
NSTE-ACS eligible for CABG were excluded

which may affect the prevalence of clinical outcomes.
References
1- Cannon CP, Gibson CM, Lambrew CT, et al: Relationship
of symptom-onset-to-balloon time and door-to-balloon
time with mortality in patients undergoing angioplasty
for acute myocardial infarction. JAMA 2000; 283: 29412947.
2- Antman EM, Hand M, Armstrong PW, et al: 2007 Focused
Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. Circulation 2008; 117: 296-329.
3- Keeley EC, Boura JA, Grines CL: Primary angioplasty
versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised
trials. Lancet 2003; 361: 13-20.
Accordingly, the up-to-date data failed to provide answers on the optimal timing of intervention
in NSTE-ACS patients but our study and most of
recent studies proved the lack of significant difference in the rate of death, myocardial infarction, or
safety outcome between these two invasive strategies suggesting that most patients with NSTE-ACS
can be treated safely with either early intervention
or delayed intervention with the use of contemporary medical therapy that included low-molecularweight heparin, glycoprotein IIb/IIIa inhibition at
the time of percutaneous procedures, clopidogrel,
and intensive lipid-lowering therapy aiming to
prevent the hazard seen in the early invasive strategy and putting in mind the time-event relationship;
sufficient time is needed to allow pharmacological
stabilization, but postponement of intervention
may lead to an increase of new spontaneous events.
Future larger trials are awaited to provide answers
on the optimal delay to PCI in patients with NSTEACS.
4- Cannon CP, Weintraub WS, Demopoulos LA, et al: TACTICS (Treat Angina with Aggrastat and Determine Cost
of Therapy with an Invasive or Conservative Strategy)
Thrombolysis in Myocardial Infarction 18 Investigators.
Comparison of early invasive and conservative strategies
in patients with unstable coronary syndromes treated with
the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med
2001; 344: 1879-1887.
5- Morrow DA, Cannon CP, Rifai N, et al: TACTICS-TIMI
18 Investigators. Ability of minor elevations of troponins
I and T to predict benefit from an early invasive strategy
in patients with unstable angina and non-STelevation
myocardial infarction: Results from a randomized trial.
JAMA 2001; 286: 2405-2412.
6- Yusuf S, Flather M, Pogue J, et al: Variations between
countries in invasive cardiac procedures and outcomes
in patients with suspected unstable angina or myocardial
infarction without initial ST elevation. OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) Registry Investigators. Lancet 1998; 352: 507-14.
7- E Ronner, E Boersma, KM Akkerhuis, et al: Patients with
acute coronary syndromes without persistent ST elevation
undergoing percutaneous coronary intervention benefit
most from early intervention with protection by a glycoprotein IIb/IIIa receptor blocker. Eur Heart J 2002; 23:
239-246.
Conclusion
The data from this study demonstrated that the
immediate intervention strategy for patients with
NSTE-ACS did not improve the cardiac events in
comparison to catheterization scheduled on the
next working day, supporting that the immediate
strategy is feasible but not superior.
8- Fox K, Poole-Wilson P, Clayton T, et al: Five-year outcome

of an interventional strategy in non-ST-elevation acute
coronary syndrome: The British Heart Foundation RITA
3 randomized trial. Lancet 2005; 366: 914-920.
Study Limitations:
Limitations of our study include first, the small
sample size. Second, we were only able to compare
in-hospital outcomes and It is unknown whether
the long-term mortality and morbidity will differ
or not. Third, the study included only the NSTEACS patients who were eligible for PCI, while the
9- Mehta SR, Cannon CP, Fox KA, et al: Routine VS selective

invasive strategies in patients with acute coronary syndromes: A collaborative meta-analysis of randomized
trials. JAMA 2005; 293: 2908-2917.
10- Bavry AA, Kumbhani DJ, Rassi AN, et al: Benefit of
early invasive therapy in acute coronary syndromes: A
meta-analysis of contemporary randomized clinical trials.
J Am Coll Cardiol 2006; 48: 1319-1325.
327

11- de Winter RJ, Windhausen F, Cornel JH, et al: Early
invasive versus selectively invasive management for acute
coronary syndromes. N Engl J Med 2005; 353: 10951104.
dromes: Results from the SYNERGY trial. Circulation

2007; 116: 2669-2677.
16- Swanson N, Montalescot G, Eagle KA, et al: Delay to
angiography and outcomes following presentation with
high-risk, non-ST-elevation acute coronary syndromes:
Results from the Global Registry of Acute Coronary
Events. Heart 2009; 95: 211-215.
12- FRagmin and Fast Revascularisation during In Stability

in Coronary artery disease Investigators. Invasive compared with non-invasive treatment in unstable coronaryartery disease: FRISC II prospective randomized multicentre study. Lancet 1999; 354: 708-15.
17- Ryan JW, Peterson ED, Chen AY, et al: Optimal timing
of intervention in non-ST-segment elevation acute coronary
syndromes: Insights from the CRUSADE (Can Rapid risk
stratification of Unstable angina patients Suppress ADverse
outcomes with Early implementation of the ACC/AHA
guidelines) Registry. Circulation 2005; 112: 3049-3057.
13- Neumann FJ, Kastrati A, Pogatsa-Murray G, et al: Evaluation of prolonged antithrombotic pretreatment ("coolingoff" strategy) before intervention in patients with unstable
coronary syndromes: A randomized controlled trial. JAMA
2003; 290: 1593-1599.
14- Riezebos RK, Ronner E, Ter Bals E, et al: Immediate
versus deferred coronary angioplasty in non-ST-elevation
acute coronary syndromes. Heart 2009; 95: 807-812.
18- Boden WE, O'Rourke RA, Crawford MH, et al: Outcomes

in patients with acute non-Q-wave myocardial infarction
randomly assigned to an invasive as compared with a
conservative management strategy. N Engl J Med 1998;
338: 1785-1792.
15- Tricoci P, Lokhnygina Y, Berdan LG, et al: Time to

coronary angiography and outcomes among patients with
high-risk non ST-segment elevation acute coronary syn-
19- Gilles Montalescot, Guillaume Cayla, Jean-Philippe Collet,

et al: Immediate VS Delayed Intervention for Acute
Coronary Syndromes. JAMA 2009; 302 (9): 947-954.
328
Association between Transforming Growth Factor-1 Gene C-509T and

T869C Polymorphisms and the Rheumatic Heart Disease in Egypt
HANAN M KAMAL, MD1; GEHAN HUSSEIN, MD2; HOWAYDA HASSOBA, MD3;
NESRIN MOSAD, MD4; MOSLEH A ISMAIL, MD5; AMAL A GAD, MD6
Introduction: Rheumatic heart disease (RHD) is a major public health problem in developing countries. Transforming
growth factor beta 1 (TGF-1) is a cytokine that plays a critical role in matrix remodeling and in enhancing collagen synthesis
and tissue fibrosis. A suggested role of TGF-1 as a cause of the typical fibrosis and valvular deformity in RHD was proposed.
Moreover, a possible role for TGF-1 gene polymorphism in determining the risk/protection of RHD has been suggested. We
investigated the possible relationship between the TGF-1 gene C-509T and T869C polymorphisms and RHD, as well as their
relation to the number and severity of valvular affection.
Patients and Methods: Seventy-three patients with RHD diagnosed by echocardiography (mean age 31.714.7 yrs, male:
female 20:53) and, age, sex-matched unrelated healthy volunteers (n=55) (control group) were included. Patients were classified
according to age into children group (n=24, mean age 14.43.1 yrs, and adult group (n=49, mean age 40.29.9 yrs). Twentyeight (38%) patients had mitral valve disease (MVD) while, 45 (62%) patients had combined valvular disease (CVD).
Methods: TGF- genomic DNA was extracted and amplified using primers specific for C-509T, T869C polymorphisms.
Genotyping were performed by restriction fragment length polymorphism analysis (RFLP) using the restriction enzymes Eco81I
and PvuII for C-509T and T869C respectively. The C-509T polymorphism was categorized according to the size of the digested
products; the homozygous C allele showed two bands (223 and 183bp) while, the homozygous T allele showed a non-digested
band with 406bp. The homozygous C allele of the TGF-1 gene T869C polymorphism appeared as a single 248bp band, while,
the T allele showed 230 and 18bp bands.
Results: T869C TT genotype was significantly more frequent in RHD (total population) and in children with RHD compared
to control [OR: 3.27; (95% CI: 1.13-9.46); p=0.02], [OR: 6.0; (95% CI: 1.74-20.65) ; p=0.002] respectively. The frequency of
T869 allele was significantly higher in adults and children groups compared to control, [OR: 1.89 (95% CI: 1.07-3.33); p=0.02],
[OR: 2.32; (95% CI: 1.16-4.66); p=0.01] respectively. C-509T genotypes distributions were not different between RHD and
controls. However, the -509T allele seems to confer susceptibility to RHD [OR: 1.78; (95% CI: 1.02-3.11); p=0.03]. Both adults
and children showed no significant difference in the genotypes distribution and allelic frequencies of TGF-1 C-509T polymorphism
compared to control. In addition, genotype distribution and allelic frequencies of C-509T or T869C did not differ between MVD
and CVD and did not have any relation with the severity of valvular affection.
Conclusion: TGF-1 T869C TT genotype is a risk factor for RHD especially in children, T869 allele is a risk factor in
adults and children. In addition, 509T allele could be a risk factor for RHD. These results support a role for the TGF-1 gene
C-509T and T869C polymorphisms in determining the risk/protection of RHD in Egyptian patients.
Key Words: Rheumatic heart disease Transforming growth factor beta 1 TGF-1 gene polymorphism.
Introduction
almost half of the 2.4 million children affected by

RHD globally, live in Africa [1]. The disease has
the potential to undermine national productivity
since it affects the most productive part of the
population. According to the World Health Organization (WHO), rheumatic fever (RF)/RHD affects
about 15.6 million people worldwide, with 282
000 new cases and 233 000 deaths each year [2].
Rheumatic heart disease (RHD) is a major

public health problem in developing countries with
The Departments of Cardiology1, Biochemistry2, Clinical
Pathology3, Pediatric4, Family Medicine5 and Internal
Medicine6, Faculty of Medicine, Suez Canal University, Egypt.
The hallmark of RHD pathogenesis is the organization of the acute inflammation induced by
rheumatic fever. This results in fibrotic valvular
deformity with subsequent thickening and retraction
Address for Correspondence: Dr. Hanan Mohamed Kamal,

MD; Cardiology Department, Faculty of Medicine, Suez Canal
University, Ismailia, Egypt, hananmkamal@yahoo.com
329
Association between Transforming Growth Factor-1 Gene C-509T & T869C
of valvular leaflets, and secondary damage from

turbulent flow because of this valvular dysfunction
[7,8].
A previous study showed that Chinese patients

with RHD had a lower frequency of TGF-1 C509T CC genotype and a higher frequency of
T869C T allele compared to control, which supported a possible role for the TGF-1 gene C-509T
and T869C polymorphisms in determining the
risk/protection of RHD [18]. Five polymorphisms
were found in the TGF-1 gene, including 988C/
A, 800G/A, 509C/T, 869T/C (Leu10/Pro10; T29>C) and 915G/C [19,20] . Those polymorphisms
were not distributed similarly among different
populations or diseases [21]. The pattern of TGF1 polymorphisms and the distribution of different
genotypes among Egyptians are unknown. Thus,
we chose the two polymorphisms, 509C/T and
869T/C, known previously to be related to RHD
in other populations, to explore the relationship
between these polymorphisms and RHD among
Egyptian patients as well as their relation to the
severity of valvular affection.
Lymphocytes of RHD patients exhibit T helper

2 (Th2) type cytokine responses [9]. The Th2 immune response is known to promote fibrotic process
by activating fibroblast proliferation, myofibroblast
differentiation, extracellular matrix deposition, and
transforming growth factor-beta 1 production [10,11].
Transforming growth factor beta 1 (TGF-1)
is a polypeptide member of the transforming growth
factor beta superfamily of cytokines. It performs
many cellular functions, which include the control
of cell growth, cell proliferation, cell differentiation,
and apoptosis. In addition, TGF-1 plays a critical
role in matrix remodeling and in enhancing collagen
synthesis [12]. With repeated injury, the increase
in TGF-1 production is sustained, leading to tissue
fibrosis [13].
The association between TGF-1 expression

and diseased heart valves had been the focus of
previous studies which indicated that TGF-1 was
markedly expressed within calcific aortic stenosis
cusps. Moreover, TGF-1 mediated the calcification
of aortic valve interstitial cells in cell culture via
apoptosis [14].
Patients:
This case-controlled study was approved by
the institutional review board (IRB) of Suez Canal
University. The study included 73 patients with
echocardiographically diagnosed RHD (mean age
31.714.7 yrs (range 7-63), male: female 20:53).
Fifty-five age and sex-matched unrelated healthy
volunteers with normal echocardiographic results,
no autoimmune diseases, or a family history of
RHD served as a control group.
Recently, TGF-1 expression was significantly

higher in rheumatic mitral valves, compared to
control valves. Additionally, high TGF-1 expression positively correlated with the proliferation of
myofibroblasts, valvular fibrosis, inflammatory
cell infiltration, neovascularization and calcification
in the valvular leaflets. These results support the
hypothesis that TGF-1 expression might play
som;e role in the prolonged fibrosis and severe
valvular deformity typical of RHD [15].
In the period from June 2008 to June 2009,

patients were recruited from the outpatient clinics
of the Cardiology, Pediatrics, and Internal Medicine
departments of Suez Canal University Hospital
and from Family Practice Centers affiliated to
Faculty of Medicine, Suez Canal University Patients were classified according to age into: Children group (n=24, mean age 14.43.1 yrs (range
7-18) and, adult group (n=49, mean age 40.29.9
yrs (range 26-63).
The possibility that TGF-1 gene polymorphism

might play a role in determining the susceptibility
to RHD was suggested. A polymorphism in the
TGF-1 gene, +869T/C in the region encoding the
signal peptide that results in a Leu to Pro substitution at amino acid position 10 was investigated.
The C allele (Pro) of this polymorphism showed
a 2.8-fold higher secretion of TGF-1 than the T
allele (Leu) [16], and the C allele was associated
with high serum concentrations of TGF-1 [17].
This difference in serum concentration was more
apparent in the CC homozygote than in the CT and
TT heterozygotes [18].
RHD patients were further classified based on

the echocardiograhic findings into: Patients with
mitral valve disease (MVD) (n=28, 38%), and
patients with combined valvular disease (CVD)
(n=45, 62%). The CVD category consisted of MVD
plus aortic stenosis or aortic regurge or both, MVD
plus tricuspid stenosis, or MVD plus all. Patients
with predominant mitral regurgitation or patients
with aortic or tricuspid valvular disease alone were
excluded from this study. The severity of valvular
330
Hanan M Kamal, et al
lesions was graded according to echocardiographic

findings as mild (n=6, 8.2%), moderate (n=26,
35.6%), or severe (n=41, 56.2%).
with a final extension at 72C for 10min. Amplified

products were visualized by electrophoresis in 2%
agarose gel stained with ethidium bromide. Then,
10l of amplified products were digested at 37C
overnight with 3U Eco81I and 5U PvuII restriction
enzymes (Fermentas Inc, USA) for C-509T and
T869C polymorphisms, respectively. The digestion
products were visualized on 3% agarose gel stained
with ethidium bromide. C-509T polymorphism on
the promoter region of TGF-1 gene was categorized according to the digestion products into:
individuals homozygous for the C allele showing
two bands (223 and 183bp) while, homozygous
for the T allele had a non-digested band at 406bp
(Fig. 1A). The homozygous C allele of the TGF1 gene T869C polymorphism appeared as a single
248bp band, while, the T allele was digested by
PvuII restriction enzyme and showed 230 and 18bp
bands (Fig. 1B).
Methods:
Echocardiography was performed in the
echocardiography laboratory of Suez Canal University Hospital using Vivid-7 Dimension echocardiographic unite (GE Vingmend Ultrasound,
Horten, Norway) with a multi-frequency probe
ranging between 1.7 and 3.4MHz. M-mode, TwoDimensional and Doppler echocardiographic measurements with color flow imaging were made by
independent observers. Rheumatic heart disease
was defined by the presence of any definite evidence of mitral- or aortic-valve regurgitation seen
in two planes by Doppler echocardiography, accompanied by at least two of the following three
morphologic abnormalities of the regurgitant valve:
restricted leaflet mobility, focal or generalized
valvular thickening, and abnormal subvalvular
thickening. For a definite diagnosis of rheumatic
heart disease, these features had to be identified
concordantly by each of the echocardiographers,
all of whom were experienced in the diagnosis of
rheumatic heart disease. All cardiac dimensions
and functions as well as the severity of valvular
affection were calculated [22,23].
Statistical analysis: Data was analyzed using

SPSS program. Data were presented as mean
SD, percentages as appropriate. Comparison of
allelic and genotypes frequencies, and association
of polymorphisms with rheumatic heart disease
were examined for statistical significance using
standard Pearson chi-square test (2) or Fishers
exact test as appropriate. Odds ratios (ORs) with
95% confidence intervals (CIs) were calculated to
assess the relative disease risk conferred by a
specific allele. A p-value <0.05 was considered
statistically significant.
Genotyping of the C-509T and T869C polymorphisms of TGF-1 gene: Genomic DNA was
extracted from peripheral blood leukocytes using
the Wizard Genomic DNA Purification Kit
(Promega, Madison WI), and stored at 20C. C509T and T869C genotyping were performed by
restriction fragment length polymorphism analysis.
Polymerase chain reactions (PCRs) were carried
out in a total volume of 25l with 250ng of genomic
DNA, 2.5U Taq polymerase in 1X Taq polymerase
buffer (Promega, Madison
WI), 1.5mmol MgCl2,
~
2mM of each dNTP 1pmol of each primer. Primers
for C-509T polymorphism were 5-CCGCTTCTGT
CCTTTCTAGG (forward) and 5-AAAGCGGGTG
ATCCAGATG (reverse) [24] generating a PCR
product of 406bp while, primers for T869C polymorphism were 5`-TCCGGGCTGCGGCTGCA
GC-3` (forward) and 5-TCGCGGGTGC TGTTGTACA-3` (reverse) [18,25] generating a PCR product
of 248bp. PCR amplifications were performed
using Robocycler gradient 96 thermocycler (Stratagene, USA) according to the following cycling
conditions: Initial denaturation at 94C for 5min,
followed by 35 cycles at 94C for 30sec, 56C (C509T)/58C (T869C) for 30sec, and 72C for 30sec,
Results
Study population characteristics:
The echocardiographic characteristics of the
study population was shown in Table (1), pulmonary artery pressure was found to be normal in
(17%) patient , mildly elevated in (19%) patients,
moderately elevated in (16%), and severely elevated
in (46%) patient. Left ventricular ejection fraction
was estimated to be normal in (80%) patients,
mildly depressed in (12.3%) patients, and severely
depressed in only (6.8%) patients. Left ventricular
dilatation was reported in 22% of patients, however
left atrial dilatation were reported in 74% of patients.
TGF-1 genotypes and alleles frequencies in the
study population:
The frequencies of the C-509T and T869C
single nucleotide polymorphisms (SNP) of the
TGF-1 gene were examined in rheumatic heart
disease (RHD) patients and healthy controls. Both
331
SNPs were in accordance with the Hardy-Weinberg

equilibrium in cases and controls. Genotype and
allele frequencies of both polymorphisms are shown
in (Table 2). The -509T allele seems to confer
susceptibility to (RHD) with an odds ratio (OR)
of 1.78 [95% confidence interval (CI) 1.02-3.11;
p=0.04]. However, the C-509T genotypes distribution were not different among RHD patients and
healthy controls (p=0.1).
1.84 [(95% CI: 0.93-3.6); p=0.07]. In addition,

there were no statistically significant association
between either TGF-1 C-509T or T869C polymorphism and the severity of RHD (Table 6).
(A)
406
223
183
Comparison of the genotypes distribution of

TGF-1 T869C SNP between patients and controls
showed that the TT genotype was significantly
more frequent in RHD patients [OR: 3.27 (95%
CI: 1.13-9.46); p=0.02, Table 2], suggesting a
possible protective effect of the TGF-1 T869C
CC genotype. The frequency of the T allele was
higher in patients with RHD than in control however, the difference did not reach the statistically
significant levels [OR: 2.02 (95% CI: 1.21-3.39);
p=0.06].
(B)
248
230
Figure 1: Detection of transforming growth factor-1

gene C-509T and T869C Polymorphisms. The figure shows
electrophoresis patterns of digested PCR products of the C509T and T869C polymorphisms in 2.5% agarose gel. A) The
digestion of the PCR products of the C-509T polymorphism;
Lane 1: molecular weight marker (200bp 1kb and 1.5kb);
lanes 2, 3 and 5: homozygote (CC) genotype (223 and 183
bp); lane 6: Homozygote (TT) genotype showing a 406 bp
fragment of undigested PCR product; lane 4 and 7: heterozygote (CT) genotype (406, 223 and 183bp). B) The digestion
of the PCR products of the T869C polymorphism; Lane 1:
molecular weight marker (200-600bp); lane 2: homozygote
(TT) genotype (230 and 18bp); lanes 3, 7 and 8: Homozygote
(CC) genotype showing a 248bp fragment of undigested PCR
product; lanes 4-6: heterozygote (TC) genotype (248, 230
and 18bp).
TGF-1 genotypes and alleles frequencies in the

different patients' subgroups:
RHD patients were sub-grouped according to
their age group into children (24/73, 32.8%) and
adults (49/73, 67.2%); the genotype and allele
frequencies of TGF-1 C-509T and T869C SNPs
in both subgroups were compared to control subjects (Tables 3,4, respectively). The distribution
of the TT genotype of TGF-1 T869C SNP in
children with RHD was significantly higher compared to controls [OR: 6.0 (95% CI: 1.74-20.65);
p=0.002, Table 3], confirming that this genotype
increases the risk to RHD. The OR for the comparison between adult patients with RHD and controls
also showed a similar trend for the TGF-1 T869C
but with no statistically significant difference of
genotype distribution compared to controls (Table
4). The frequency of T869 allele was significantly
higher in adults and children groups compared to
control, [OR: 1.89 (95% CI: 1.07-3.33); p=0.02],
[OR: 2.32; (95% CI: 1.16-4.66); p=0.01] respectively Both children and adults subgroups showed
no significant difference in the genotypes distribution and allelic frequencies of TGF-1 C-509T
polymorphism in comparison to control subjects
(Tables 3,4).
Table 1: The echocardiographic characteristics of the study

population.
Echocardiographic
variable
End diastolic diameter
(mm)
End systolic diameter
(mm)
Posterior wall thickness
(mm)
Septal thickness (mm)
Left atrium dimension
(mm)
Aortic root diameter
(mm)
Right ventricle
dimension (mm)
Peak systolic aortic
gradient (m/sec)
Mean systolic aortic
gradient (m/sec)
Ejection fraction (%)
Fractional shortening
(%)
Pulmonary artery
pressure (mmHg)

between MVD and CVD regarding genotype distribution and allelic frequencies of TGF-1 C-509T
or T869C SNPs (Table 5). However, the T allele
frequency of the T869C SNP was higher in patients
with CVD than those with MVD with an OD of
332
Minimum Maximum Mean SD

30
78
51.1110.09
17
61
33.849.34
13
9.161.59
6
20
13
87
9.041.70
48.0312.39
18
37
25.113.85
14
57
29.906.71
112
22.0422.20
69
11.0614.57
35
15
77
46
60.678.83
32.846.10
10
120
48.6324.37
Table 2: TGF-1 genotypes distribution and allele frequencies
in patients with rheumatic heart disease versus
healthy controls.

in adult patients with rheumatic heart disease versus
healthy controls.
RHD
TGF-1
patients
polymorN=73
phisme
n (%)
Adult
TGF-1
patients
polymorN=49
phisme
n (%)
Control
N=55
n (%)
2
(p-value)
OR (95% CI)
Control
2
N=55
(p-value)*
n (%)
OR (95% CI)
C-509T:
CC 31 (42.5) 32 (58.2)
CT 32 (43.8) 20 (36.4)
TT 10 (13.7) 3 (5.4) 4.1 (0.12)* 2.25 (0.71-10.5)
C-509T:
CC 21 (42.8) 32 (58.2)
CT 22 (44.8) 20 (36.4)
TT 6 (12.4) 3 (5.4) 1.5 (0.21)
Allele:
C
T
94 (64.4) 84 (76.4)
52 (35.6) 26 (23.6) 4.25 (0.04) 1.78 (1.02-3.11)
Allele:
C
T
T869C:
TT
TC
CC
18 (24.7) 5 (9.0)
7.18 (0.02) 3.27 (1.13-9.46)
35 (47.9) 25 (45.5)
20 (27.4) 25 (45.5)
T869C:
TT 9 (18.4) 5 (9.0) 1.91 (0.166) 2.25 (0.69-7.24)
TC 28 (57.1) 25 (45.5)
CC 12 (24.5) 25 (45.5)
Allele:
T
C
71 (48.6) 35 (31.8) 7.31 (0.06) 2.02 (1.21-3.39)

75 (51.4) 75 (68.2)
Allele:
T
C
2.41 (0.57-10.24)
64 (65.3) 84 (76.4)
34 (34.7) 26 (23.6) 3.09 (0.07) 1.71 (0.93-3.14)
46 (46.9) 35 (31.8) 4.98 (0.02) 1.89 (1.08-3.33)

52 (53.1) 75 (68.2)
Abbreviations and symbols:

RHD = Rheumatic heart disease.
OR = Odds ratio.
CI = Confidence interval.
*Fishers exact test.

OR = Odds ratio.
Table 3: TGF-b1 genotypes distribution and allele frequencies

in children with rheumatic heart disease versus
healthy control.

in patients with mitral valve disease versus combined
valvular disease.
Children
Gene
Controls
patients
2
polymorN=55
N=24
(p-value)
phisme
n (%)
n (%)
MVD
CVD
Gene
patients patients
2
polymorOR (95% CI)
N=28
N=45 (p-value)*
phisme
n (%)
n (%)
OR (95% CI)
C-509T:
CC
CT
TT
10 (41.7) 32 (58.2)
10 (41.7) 20 (36.4)
4 (16.6) 3 (5.4) 2.6 (0.1)*
C-509T:
CC 10 (35.7) 21 (46.7)
CT 15 (53.6) 17 (37.8)
TT 3 (10.7) 7 (15.5) 1.77 (0.4)* 1.53 (0.36-6.5)
Allele:
C
T
30 (62.5) 84 (76.4)
18 (37.5) 26 (23.6) 3.2 (0.073) 1.93 (0.93-4.28)
Allele:
C
T
35 (62.5) 59 (65.6)
21 (37.5) 31 (43.6) 0.14 (0.7)
T869C:
TT
TC
CC
9 (37.5) 5 (9.0) 9.25 (0.002) 6.0 (1.74-20.65)

7 (29.2) 25 (45.5)
8 (33.3) 25 (45.5)
T869C:
TT
TC
CC
5 (17.8) 13 (28.9) 3.4 (0.17)

12 (42.9) 23 (51.1)
11 (39.3) 9 (20.0)
Allele:
T
C
25 (52.1) 35 (31.8) 5.8 (0.015) 2.32 (1.16-4.66)

23 (47.9) 75 (68.2)
Allele:
T
C
22 (39.3) 49 (54.4) 3.18 (0.07) 1.84 (0.93-3.6)

34 (60.7) 41 (45.6)
3.46 (0.71-16.88)

OR = Odds ratio.

MVD = Mitral valve disease.
CVD = Combined valvular disease.
OR = Odds ratio.
CI
= Confidence interval.
333
1.787 (1.025-3.11)
1.86 (0.58-5.97)

Table 6: TGF-1 allele frequencies and severity of rheumatic
heart disease.
RHD
Severity
Mild
Moderate
Severe
p-value
C-509T Polymorphism
T869C Polymorphism
n (%)
Allele (C)
Allele (T)
Allele (T)
Allele (C)
N=94
n (%)
N=52
n (%)
N=71
n (%)
N=75
n (%)
8 (8.5)
34 (36.2)
52 (55.3)
4 (7.7)
18 (34.6)
30 (57.7)
0.7
4 (5.6)
25 (35.2)
42 (59.2)
lesions [37]. Previously, an increased expression

of TGF-1 in rheumatic mitral valves that was
associated with valvular fibrosis, inflammatory
cell infiltration was demonstrated [15]. In addition,
the same study confirmed that ongoing inflammation (mainly composed of T-lymphocytes) was
present in the apparently resting valves of advanced
chronic RHD (CRHD).
8 (10.7)
27 (36.0)
40 (53.3)
In addition to the proposed role of TGF-1

overproduction in the pathogenesis of RHD an
association between TGF-1 gene polymorphisms
and valvular disease was suggested [18]. Currently,
efforts are made to effectively attenuate fibrosis
and hypertrophy in cardiovascular disease suchas post-ischemic fibrosis, and dilated and hypertrophic cardiomyopathies-by targeting the TGF1 [38].
0.5

Discussion
Chronic rheumatic heart disease demonstrates
severe fibrosis and distortion of valvular leaflets
[8,26]. The factors leading to continued fibrosis and
subsequent valvular disease remain incompletely
defined. RHD is a disorder with autoimmune features, and its pathophysiology is not completely
understood. Although no specific "RF gene" has
been identified, several studies have suggested that
genetic susceptibility to RF and RHD is linked to
HLA class II alleles/haplotypes (HLADR2 in African Americans, HLA-DR4 in American whites,
HLA-DQA1 in Chinese southern Hans, and HLADR7 and HLA-DRw53 in Brazilians) [27-29].
Regarding TGF-1 T869C polymorphism, we

have demonstrated that T869C TT genotype was
significantly more frequent in RHD patients compared to normal control. This significance was
manifested primarily in the children, suggesting
that TGF-1 T869C TT genotype is a possible risk
factor for RHD especially in children (with a
possible protective effect of the TGF-1 T869C
CC genotype). Previously, 869T TT genotype was
significantly higher in patients with severe
Hashimoto's disease [39] . Also, TGF-1 T869C
polymorphism was associated with disease progression of other fibrotic conditions i.e. idiopathic
pulmonary fibrosis [40]. Accordingly, T869C polymorphism might explain partially the pathogenesis
of the progression of valvular fibrosis and calcification in RHD.
TGF-1 is a multifunctional cytokine that controls the proliferation and differentiation of many
cell types [30]. This cytokine is also involved in
the production and degradation of the extracellular
matrix. TGF-1 activates gene transcription, thereby increasing synthesis and secretion of collagen
and other matrix proteins [31] . Furthermore, it
decreases the synthesis of proteolytic enzymes
such as collagenase, which degrade matrix proteins,
and increases the synthesis of protease inhibitors
such as plasminogen activator inhibitor, which
block the activity of the proteolytic enzymes [32].
Consequently, this cytokine is thought to play a
critical role in fibrotic conditions.
The polymorphism 869T/C gives rise to a

LeuPro polymorphism at amino acid residue 10
in the signal peptide, which allows export of the
newly synthesized protein across the membranes
of the endoplasmic reticulum [41]. In several previous studies, 869T allele or 869TT genotype has
been reported to be associated with reduced production of TGF-1 protein [19,42]. The reduction
in protein production may be a result of the lower
export efficiency influenced by 869T allele. According to our study, the frequency of T869 allele
was higher in patients with RHD than in control
however, this difference did not reach statistically
significant levels. In the mean time, the frequency
of T869 allele was significantly higher in each of
children and adults groups compared to control.
Previously, high frequency of allele 869T was
Accordingly, considerable evidences indicated

that TGF-1 overproduction had a role in fibrosis
and dysfunction of heart valves [14,33,34]. TGF-1
induces the differentiation of cardiac fibroblasts
to myofibroblasts [35], which can produce up to
twice as much collagen as their fibroblast precursors
[36]. The emergence of these cells had been closely
correlated with valvular fibrosis and degenerative
334
reported in patients with rheumatic heart disease,

rheumatoid arthritis (RA) and severe forms
Hashimoto's disease [18,43,44]. These results suggest
that T869 allele may be another risk factor for
RHD as reported previously [18]. The frequency
rates of TGF-1 T869C polymorphism CC genotype and the C allele in control Egyptian subjects
were relatively concordant to those reported by
others [45].
Since TGF-1 gene polymorphisms were hypothesized to be associated with the severity of
RHD, we studied the distribution of the C-509T
and T869C polymorphisms in the MVD and CVD
subgroups. The T allele frequency of the T869C
SNP was higher in patients with CVD than those
with MVD suggesting that this allele may increase
the risk of mutivalvular affection in RHD patients.
Our results showed no significant evidence of an
association between either TGF-1 C-509T or
T869C polymorphism and number of valve affected or the severity of RHD as reported previously
[18].
Since we have no TGF-1 levels to show the

association between the TGF-1 levels and RHD,
the interpretation for our results is limited. We
explored the associations between the polymorphism 509C/T and RHD by genotype analysis.
No significant difference was found in C-509T
genotypes distribution between RHD patients and
healthy controls as reported previously [46] . In
addition, both adults and children showed no significant difference in the either genotype distribution or allelic frequencies of TGF-1 C-509T
polymorphism compared to control. However,
509T allele seems to confer susceptibility to RHD.
Finally, only the proportions of genotypes or

allelic frequency at polymorphisms 869T/C in
TGF-1 gene was found to show significant association with RHD in our study while, polymorphism
C-509T did not show the same significant association.
Conclusions
TGF-1 T869C TT genotype is a risk factor for
RHD especially in children while, T869 allele is
a risk factor in adults and children. In addition,
509T allele could be a risk factor for RHD. These
results support a role for the TGF-1 gene C-509T
and T869C polymorphisms in determining the
risk/protection of RHD in Egyptian patients. However, the absence of an association between TGF1 gene polymorphism and both number of affected
valves and severity of RHD indicates that complex
as well as multi-factorial mechanisms are involved.
Future studies on larger population are warranted.
Some studies showed that patients with rheumatic heart disease or RA have a lower frequency
of genotype CC at polymorphism C-509T [18,44].
Previously, C-509T polymorphism was significantly
associated with the plasma concentration of TGF1, explaining 8.2% of the additive genetic variance
of TGF-1 concentration [47], the association between -509-T allele and high TGF-1 concentration
was pronounced in individuals homozygous for
this allele than in heterozygous patients, suggesting
a dose response effect of the T allele on circulating
concentration of TGF-1. In addition, the TGF-1
concentration was estimated to be approximately
twice as high in patients who are TT homozygotes
compared with patients who are CC homozygotes
(CC) [47]. This may explain why the TGF-1 C509T CC genotype may confer protection from
RHD. The difference in our results from others
can be partially explained by the difference in
ethnic background, sample size, and detection
methods.
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337
The Association of PvuII Lipoprotein Lipase Gene Polymorphism with

Coronary Artery Disease in Egyptian Southern Territory
HANAN M AHMED, MD1; DOAA A FOUAD, MD2; OMAR HERDAN, MD1,
HALA K ELSHEREEF, MD1; LUBENA M TAG, MD3; EBTSAM FAROUK, MD3;
MADLEEN A ATIA, MD3; HEBAT ALLA G RASHED, MD3;
WAFFAA TOHAMY EL-SHERIF, MD3; EMAN MOSAAD, MD4
Background: Lipoprotein lipase (LPL) plays a major role in lipoprotein metabolism. It has been demonstrated that
polymorphisms in the LPL gene were associated with increased risk of coronary artery disease (CAD). However, controversy
is found about PvuII restriction fragment length polymorphism (RFLP) sites and its relation to CAD.
Aim: This study aimed to investigate the frequency of pvuII RFLP among a group of southern Egyptian CAD patients and
to assess the effect of different PvuII LPL genotypes on both lipid profile, and the clinical and angiographic presentation of
CAD in the southern Egyptian territory.
Patients and Methods: The study included 35 CAD patients, 12 presented with a history of MI and 23 with unstable angina,
and 20 controls. The mean age of the patient group was 394.5. Twenty six of them (74.3%) were males and 9 (25.7%) were
females. The severity of angina pectoris was assessed according to NYHA classification from class I-IV. Coronary angiography
was performed to both patients and controls. Serum lipogram was assayed on BME Hitachi 911 autoanalyzer, while Apo
lipoprotein A (Apo-A) and apo lipoprotein B (Apo-B) were assayed by radial immune-diffusion (RID) plates. PvuII LPL
genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-REFLP).
Results: Within the CAD patients, the PvuII -/- genotype was found in 7 individuals (35%), the +/ genotype in 18 individuals
(51.4%), and the +/+ genotype in 10 individuals (28.6%). The frequency of the +/ allele showed statistically significant increase
in CAD patients when compared to controls (p<0.001). Serum cholesterol, triglycerides and LDL-C showed statistically
significant increase in patients with genotype +/+ when compared to those with genotype / (P<0.001 for each). Using coronary
angiography; 19 patients (54.2%) had single vessel CAD, and 16 (45.7%) had multi-vessel CAD. The frequency of genotype
+/+ among diabetic patients showed statistically significant increase when compared to non-diabetic patients while the frequency
of genotype / in diabetic patients showed statistically significant decrease when compared to non-diabetic patients (p<0.001
for each). The genotype +/+ was also associated with significantly higher number and % of patients having a history of MI and
worse NYHA class (p<0.05 for each), together with an insignificant increase in the frequency of multi vessel coronary artery
disease (MVCAD) than single vessel coronary artery disease (SVCAD) compared to / and /+ patients.
Conclusion: The presence of P+ allele of PvuII polymorphism of LPL gene triggers susceptibility to the development of
dyslipidemia and vascular atherogenesis which in turn promotes the occurrence of CAD diseases and can act as a marker for
the analysis of this genetic defect. In the southern Egyptian CAD patients, the +/+ genotype can be associated with more
aggressive clinical and angiographic presentation.
Key Words: PvuII lipoprotein lipase gene Polymorphism Coronary artery disease.
Introduction
The Departments of Internal Medicine1, Cardiology2,
Clinical Pathology3 and Clinical Pathology4, South Egypt
Cancer Institute, Faculty of Medicine, Assiut University.
Plasma triglyceride (TG) levels, a marker for

TG-rich lipoproteins, are considered an established
risk factor for coronary artery disease (CAD)
independent of other lipoproteins [1,2]. Elevated
TG-rich lipoprotein levels may not only promote
a more rapid progression of atherosclerosis but
could also lead directly to myocardial ischemia,

Address for Correspondence: Dr. Hanan M Ahmed,
The Department of Internal Medicine, South Egypt
Cancer Institute, Faculty of Medicine, Assiut University.
339
The Association of PvuII Lipoprotein Lipase Gene Polymorphism
particularly in subjects with the high-TG/low-HDL

trait, which is frequently present in CAD patients
and is an important marker for TG-rich lipoproteins
[3].
beneficial genetic variant with respect to lipoprotein

metabolism [9].
PvuII restriction fragment length polymorphism
sites, located on introns 6, of the LPL gene are the
most common, and various reports have associated
them with CAD [7,10]. PvuII polymorphism is also
associated with elevated triglyceride levels and
the severity of CAD and with type II diabetes in
CAD patients [9]. However, some investigators did
not show an association of the PvuII polymorphism
genotype with adverse lipid levels or coronary
artery disease [11]. To our knowledge no studies
have previously examined the clinical significance
of these polymorphism with CAD. So, this study
aimed to investigate the frequency of pvuII RFLP
polymorphism among southern Egyptian CAD
patients and to assess the effect of different PvuII
LPL genotypes on lipid profile and the severity of
coronary artery disease.
Lipoprotein lipase (LPL) plays a major role in

lipoprotein metabolism by hydrolyzing core triglycerides of circulating chylomicrons and very
low-density lipoprotein (VLDL). The action of
lipoprotein lipase on triglyceride-rich lipoproteins
promotes the exchange of lipids and apolipoproteins
between lipoproteins. LPL also plays a noncatalytic
bridging role as a ligand in lipoprotein-cell surface
interactions and receptor-mediated uptake of lipoproteins with its ability to bind simultaneously to
both lipoproteins and cell surface receptors [4].
Therefore, LPL is indirectly involved in the maturation of the majority of plasma lipoproteins [5].
As LPL has a contributory role in the manifestations
of many pathological conditions related to the
metabolism of triglyceride-rich lipoproteins and
dysfunction, the deficiency of LPL activity has
been associated with the pathogenesis of various
dyslipoproteinemias and production of atherogenic
particles, such as intermediate-density lipoproteins
(IDL) and low-density lipoproteins (LDL) [4].

This study included thirty five CAD patients
and twenty controls with matched age and sex. All
studied patients and controls were subjected to
thorough medical history taking and clinical examination including, history of hypertension, diabetes,
chest pain, smoking and medication. Body mass
index (BMI) was estimated as weight in kg divided
by height in meters Squared. Informed consent
was obtained from all patients and controls. The
institutional ethical committee approved the study
design. Patients were included in the study in the
period between January and April, 2009.
It has been demonstrated that polymorphisms

in the LPL gene were associated with increased
risk of coronary artery disease (CAD), implicating
their roles in the development of atherothrombotic
disease. Only a small percentage of CAD patients
have recognized monogenetic disease due to dysfunctional mutations in lipoproteins or lipoproteinrelated genes (e.g., receptors, catabolic enzymes).
Thus, as much as one half of risk remains unexplained [6]. The LPL gene is located on chromosome
8p22, it contains 10 exons and encodes a 448amino acid mature protein [7]. Several DNA variants
of the LPL gene have been found and reported to
underlie changes in plasma lipoprotein levels. For
examples, HINDIII polymorphism of interon 8 of
this gene is associated with elevated triglyceride
levels and low levels of high density lipoproteins
(HDL) which were associated with premature
coronary artery disease (CAD) [8]. On the other
hand, the risk of CAD is decreased by Ser447Stop
polymorphism, the Ser447Stop mutation has been
identified just 635bp downstream from HINDIII
polymorphism. This mutation is a consequence of
a C to G transversion at nucleotide 1595 in exon
9, which converts the serine 447 codon (TCA) to
a premature termination codon (TGA), which underlies increased HDL cholesterol levels and decreased triglyceride levels, and is considered as a
Study patients and controls were selected from

consecutive patients presenting for coronary angiography at the cardiology and internal medicine
departments of Assiut University Hospital complaining of suspected CAD, previous myocardial
infarction (MI), or valvular heart disease requiring
angiographic evaluation. Within the patient group,
the severity of angina pectoris was assessed using
the Rose questionnaire according to NYHA classification from class I-IV [12]. Of the 35 CAD patients, 12 presented for angiography with a history
of MI, 23 with unstable angina. Patients had angiographically documented CAD (>50% stenosis
of 1 vessel). Of the 20 control subjects with normal
coronary arteries, 6 presented for angiography with
chest pain syndromes without CAD and 14 with
valvular disease. All controls had no history of
hypertension or diabetes. Patients who had unstable
angina or who suffered a myocardial infarction
340
Hanan M Ahmed, et al
within the preceding 6 months were excluded from

the study. Also patients who had <50% stenosis of
CA vessels were excluded.
used Philips Integris H 5000 system with triple

mode image intensifier magnification [13,18,23].
The video signal of the magnified region of interest
was subsequently digitized at a matrix size of
512x512x8 bits.
Sample handling and investigations:

Blood samples were collected at the morning
of coronary angiography. Six ml venous blood was
collected after 12-16 hours fasting and was divided:
3ml in tube containing EDTA (ethylene diamine
tetra-acetic acid) for complete blood count, ESR
and DNA isolation and the remaining 3ml were
collected in plain tubes. The samples were centrifuged within 30 minutes at 3000rpm for 10 minutes
and the serum samples then collected and divided
into aliquots and stored at 70C for further analysis.
For QCA, the coronary tree was divided into

15 segments, according to the American Heart
Association classification [14]. For calibration, the
boundaries of a non-tapering part of the catheter
were determined automatically over a length of
approximately 2cm. To determine the contours of
the vessel, the user only had to indicate the beginning and end of the coronary segment to be analyzed, after which a path line was computed connecting these two points. Obstructions within these
segments were coded and analyzed separately so
that the maximal stenosis in each of 15 coronaryartery segments was assessed. CAD was defined
when at least one coronary artery had 50% luminal
diameter occlusion. Coronary artery disease was
quantified as single vessel, or multi-vessel disease,
defined as a stenosis of more than 50% of the
luminal diameter in one, or more than one coronary
artery or their major branches.
Serum lipogram (total cholesterol, triglyceride

and HDL-C) was assayed on BME Hitachi 911
autoanalyzer. Apolipoprotein A(Apo-A) and apolipoprotein B (Apo-B) were performed by radial
immuno diffusion (RID) by kit supplied by Immuno
AG (Vienna, Austria).
Lipoprotein Lipase genotyping was performed
by polymerase chain reaction and restriction fragment length polymorphism (PCR-REFLP), DNA
isolation was performed by QIAamp DNA mini
kit. Lipoprotein Lipase gene detection was performed by PCR using the primer sequence as follow
5-ATG GCACCC ATG TGT AAG GTG-3, and
5-GTG AAC TTC TGA TAA CAA TCT C-3 and
puReTaqTMReady-To GoTMPolymerase Chain
supplied by (GE Health care kit) lot number (279557-01). The amplification profile was as follow
(1min at 95C, 1min at 55C and 7min at 72C for
30 cycles and 5min at 72C for one cycle). Genotyping was performed by incubation of the amplified product with Pvu II restriction enzyme (7.3ul
of free water 2ul multi-core 10x buffer, 0.2ul of
acetylated BSA, 0.5ul PvuII enzyme and 10ul of
amplified DNA) and incubated at 37C for 1 hour.
The digested products were detected by 2% agarose
gel electrophoresis. The 430bp-long products will
be digested to 320 and 110bp-long products if there
was a Pvu II restriction site.
The cardiologist who performed the angiographies was uninformed to LPL genotypes. Patients
were designated as having significant CAD if they
had 50% stenosis of at least one coronary artery
or major branch and no CAD if no stenosis was
present. Patients with minor CAD (50% stenosis)
were designated as having an "indeterminate" CAD
status and were excluded from the study. Single
vessel CAD was found in 19 patients (54.2%),
multi-vessel CAD was found in 16 patients (45.7%).
All data were expressed as mean standard
error of Mean (SD). Either the Student's t or ChiSquare test was used to compare means or frequencies using statistical package SPSS.
Results
The study included 35 CAD patients and 20
controls. The mean age of the patient group was
394.5 (33-53 years). Twenty six of them (74.3%)
were males and 9 (25.7%) were females. Twenty
one patients (60%) were smokers, 19 (55%) were
diabetics and 18 (51.4%) were hypertensive. Table
(1) shows the demographic data and the lipid profile
in patients and controls. Serum cholesterol, triglyceride, LDL-C, cholesterol/HDL-C and Apolipoprotein B showed statistically significant increase
PCR-REFLP analysis, using PvuII restriction

enzyme analysis by agarose gel electrophoresis:
430bp (-/-), 430bp, 320bp and 110bp (+/-) and
320bp and 110bp (+/+).
Quantitative Coronary Angiography (QCA):
Coronary angiographies were performed according to the standard Judkins technique [13]. We
341
in CAD patients compared to control group

(p<0.0001, <0.001, <0.001, <0.001 and <0.0001
respectively).
showed statistically significant increase in CAD

patients when compared to controls (p<0.001). No
significant difference in the distribution of PvuII
genotypes of -/- and +/+ between CAD patients
and controls (Fig. 2).
Table 1: Demographic data, Lipid profile, Apolipoprotein A

and Apolipoprotein-B in patient and control groups.
Table 2: Lipoprotein Lipase genotypes by pvuII REFLP

analysis in patients and control group.
Patients
Mean SD
(35)
Controls
Mean SD
(20)
Age (Years)
394.5
375.3
N.S
Sex:
Male
Female
26 (74.3)
9 (25.7%)
13 (65%)
7 (35%)
N.S
BMI
29.021.5
28.631.84
NS
** p<0.001
Smoking %:
Non-smoker
Smoker
14 (40%)
21 (60%)
12 (60%)
8 (40)
NS
DM:
Non-diabetic
Diabetic
16 (45%)
19 (55%)
20
0
Hypertension:
Without HT
With HT
17 (48.5%)
18 (51.4%)
20
0
PCR-REFLP analysis using PvuII restriction

enzyme analysis:
Fig. (1) shows PCR-REFLP analysis, using
PvuII restriction enzyme analysis by agarose gel
electrophoresis in 9 of our patients representing
the 3 genotypes of LPL.
Serum Cholesterol
mg/dl
Serum Triglyceride
mg/dl
HDL-C mg/dl
LDL-C mg/dl
Chol/HDL-C
Apoliporotein A
Apoliporotein B
Genotype
254.5118.0 169.923.8
<0.001
210.7118.1 128.840.5
<0.001
45.814.0
164.299.5
5.72.6
856.2329.5
1477.387.3
N.S
<0.001
<0.001
<0.05
<0.0001
DM = Diabetes mellitus.
BMI = Body mass index.
50.59.0
96.321.2
3.60.8
997.0125.3
1130.8161.5
/+
+/+
Patients
7 (20%)
18 (51.4%)**
10 (28.6%)
Control
8 (40%)
7 (35%)
5 (25%)
500
400
300
200
100
50
HT = Hypertension.
N.S = Non significant.
PvuII polymorphism and CAD:

Table (2) shows the results of Lipoprotein
Lipase genotypes by pvuII REFLP analysis in
patients and control group: The PvuII genotypes
were determined by PCR and digestion using the
PvuII restriction enzyme. When present, the PvuII
site produces a 430-bp fragment after digestion, it
was referred to the polymorphic allele displaying
the restriction site with a plus sign (+) and the
allele without the site with a minus sign (-). Within
the control group (n=20), 8 individuals (40%)
carried the -/- genotype, 7 (35%) carried the +/genotype, and 5 individuals (25%) carried the +/+
genotype. Within the CAD group (n=35), the -/genotype was found in 7 individuals (35%), the
+/- genotype in 18 individuals (51.4%), and the
+/+ genotype in 10 individuals (28.6%). For the
PvuII genotypes, the frequency of the +/- allele
Figure 1: PCR-REFLP analysis, using PvuII restriction enzyme

analysis by agarose gel electrophoresis: 430bp (/),
430bp, 320bp and 110bp (+/-) and 320bp and 110bp
(+/+). Patient number 8 showed: No restriction,
genotype /; 1, 2, 5, 6,7 and 9: Genotype +/; 3
and 4: genotype +/+; M: 50bp marker.
PvuII polymorphism and clinical variables:

The association between Lipoprotein lipase
pvuII REFLP genotypes and different clinical
variables is presented in Table (3). The frequency
of genotype +/+ among diabetic patients showed
statistically significant increase when compared
to non-diabetic patients while the frequency of
genotype -/- in diabetic patients showed statistically
significant decrease when compared to non-diabetic
patients (p<0.001 for each).
342
Table 3: Lipoprotein lipase pvuII REFLP genotypes and
different clinical variables.
PvuII polymorphism and CAD presentation:

We found that the No. of CAD patients was
significantly higher in the -/+ genotype compared
to controls (p<0.001) (Table 2). Out of the 35 CAD
patients, 18 (51.4%) were proved to carry the -/+
genotype Vs 10 (28.6%) carrying the +/+ genotype,
and 7 (20%) carrying the -/-genotype (Table 2).
Genotype
Clinical variables
/ (7)
/+ (18)
+/+ (10)
Smoking%:
Non-smoker
Smoker
3 (42.8%)
4 (57.1%)
7 (38.8%)
11 (61.1%)
4 (40%)
6 (60%)
DM (%):
Non-diabetic
Diabetic
5 (71.5%)
2 (28.5%)**
8 (44.4%)
10 (55.5%)
3 (30%)
7 (70%)**
Clinical
variables
6 (60%)
4 (40%)
Clinical
presentation:
MI (12)
UA (23)
1 (14.28%) 6 (33.33%) 5 (50%) <0.05

6 (85.72%) 12 (66.66%) 5 (50%)
Angina class:
Class I
Class II
Class III
Class IV
1 (14.28%)
3 (42.85%)
3 (42.85%)
Hypertension%:
Without HT
With HT
3 (42.8%)
4 (57.1%)
8 (44.4%)
10 (55.5%)
Table 5: CAD Presentation According to LPL pvuII genotypes.
DM = Diabetes mellitus.
HT = Hypertension.
**p<0.001
PvuII polymorphism and lipid profile:

Table (4) shows Lipid profile, Apolipoprotein
A and Apolipoprotein B in patients group according
to Lipoprotein lipase genotypes: Serum cholesterol,
triglycerides and LDL-C showed statistically significant increase in patients with genotype +/+
when compared to those with genotype -/- (p<0.001
for each). Serum triglycerides and Cholesterol/
HDL-C showed statistically significant increase
in patients with genotype +/+ when compared to
those with genotype +/- (p<0.001 for both).
/ (7)
/+ (18)
CAD = Coronary artery disease.

UA = Unstable angina
70
57.1
1 (5.5%)
5 (27.77%)
10(55.55%)
2 (11.11%)
p
+/+ (10) value
2 (20%) <0.05
4 (40%)
4 (40%)
MI = Myocardial infarction.
61.11
60
60
% of cases
50
40
42.85 38.9
40
30
20
10
Table 4: Lipid profile, Apolipoprotein A and Apolipoprotein

B in patients group according to pvuII Lipoprotein
lipase genotypes.
0
SVCAD
MVCAD
Geno type /
Genotype
Lipid profile
/ (7)
/+ (18)
+/+ (10)
210.776.1
239.286.9
312.2169.6a
179.184.4
Serum
Triglyceride
mg/dl
174.979.4
297.2156.0ab
HDL-C mg/dl 44.515.9
47.815.0
43.011.6
LDL -C mg/dl 129.060.0
157.975.8
200.3125.9a
Chol/HDL-C 5.52.5
5.02
7.23.1ab
Apoliporotein 630.8421.3
A
965.9248.1 816.6332.0
Serum
Cholesterol
mg/dl
Genotype (No. and % of patients)
Geno type /+
Geno type +/+
Figure 2: The extent of CAD in different genotypes.
CAD = Coronary artery disease, SVCAD = Single vessel coronary
artery disease, MVCAD = Multivessel coronary artery disease.
In the present study, the severity of CAD was

clinically assessed using both clinical presentation
with either myocardial infarction or angina pectoris,
and the NYHA classification of angina pectoris
(Table 5). Of the 35 CAD patients, 12 presented
with a history of MI and 23 with unstable angina.
We found that the number and % of patients having
a history of MI in the +/+ genotype [5 out of 10
(50%)] was significantly higher than MI patients
of both -/+ genotype [6 out of 18 (33.33%)] and
the -/- genotype (1 out of 7 (14.28%) (p<0.05).
Apoliporotein 1465.4332.1 1392.0411.9 1639.2359.0

B
a p<0.001 +/+ vs. / PvuII lipoprotein lipase mutation.
ab p<0.001 +/+ vs. /+ PvuII lipoprotein lipase mutation.
343
Moreover, NYHA classification for angina pectoris

was significantly different between LPL genotypes.
Patients in the highest NYHA class were more
often of the +/+ genotype, followed by -/+, and
lastly the -/- genotype (p<0.05).
On the other hand, the extent of CAD judged

by No. of occluded vessels assessed by angiographic measurements was insignificantly more pronounced in the +/+ genotype compared to both /
and /+ genotypes (Tables 5,6 & Fig. 2).
Table 6: The extent of CAD by coronary angiography and angina class at different LPL pvuII genotypes.
Genotype
Clinical variables
/ (7)
/+ (18)
+/+ (10)
Coronary angiography
SVCAD
MVCAD
SVCAD
MVCAD
SVCAD
MVCAD
No. and % of patients
4 (57.2%)
3 (42.8%)
11 (61.2%)
7 (38.8%)
4 (40%)
6 (60%)
Angina class [No., (%)]:

Class I
Class II
Class III
Class IV
1 (14.3%)
2 (28.6%)
1 (14.3%)
1 (14.3%)
2 (28.6%)
1 (5.6%)
4 (22.2%)
6 (33.3%)
1 (5.6%)
4 (22.2%)
2 (11.1%)
1 (10%)
2 (20%)
1 (10%)
1 (10%)
2 (20%)
3 (30%)
CAD
= Coronary artery disease.
SVCAD = Single vessel coronary artery disease.
MVCAD = Multivessel coronary artery disease.
Discussion
latter authors however reported that LPL-PvuII

polymorphism cannot be used as an independent
genetic risk factor for CAD.
Molecular cardiology has changed our concepts

of cardiovascular development, disease etiology,
pathophysiology and therapy at a rapid pace. New
developments in molecular biology have directed
research of human disease etiology towards its
genetic basis [15] . Cardiovascular disease, as a
result of the atherosclerotic process, can serve as
a model for disease management. It is estimated
that more than 400 genes are involved in the regulation of processes such as endothelial function,
coagulation, inflammation and carbohydrate and
amino acid metabolism. Of these, lipoprotein metabolism is probably best understood [16]. Lipoprotein lipase (LPL) is a key enzyme in lipoprotein
metabolism and a major candidate gene for coronary heart disease [4] . In the current study, we
investigated the influence of PvuII RFLP polymorphism of LPL gene on lipid parameters as well as
its impact as a risk factor on CAD.
Never less, we recorded a significant increase

in the No. of patients having history of MI in
comparison to UA patients in the +/+ genotype.
This was associated with significantly higher NYHA class in both MI and UA patients among the
+/+ genotype patients, followed by the /+, and
lastly the / genotype. Meanwhile, we detected
a non significant increase of the frequency of multivessel to single vessel CAD in +/+ genotype patients compared to / and +/ genotypes. These
findings are in agreement with others who found
that LPL PvuII (+/+) genotype was strongly associated with severe myocardial infarction by promoting more severe atherogenesis of coronary
arteries [19] . A significant relationship between
LPL mass and activity and the severity of ischemia
(as defined by angina class and ambulatory ECG)
was also recorded [20]. Others have also reported
that homozygous genotype (PvuII +/+) was more
prevalent in the CAD group in comparison with
the control group [4].
We found that the frequency of the LPL-PvuII

+/ allele showed statistically significant increased
in CAD patients when compared to controls. These
findings are in agreement with others [17] who
reported that the most frequent genotype among
CAD patients was (+/). On the other hand, we
found no significant difference in the frequency
of LPL PvuII (+/+) genotype in the CAD group
compared to the control group in this study population. These findings are similar to those reported
by Abu-Amero et al [10] and Cagatay et al [18]. The
In the present study, we also investigated the

relationship between PvuII polymorphism genotypes and the lipid profile, there was a statistically
significant increase in serum cholesterol and LDLC, Cholesterol/HDL and triglycerides in patients
with genotype +/+ when compared to those with
genotype /. These laboratory findings can actually
344
explain the worse clinical presentation and the

higher percentage of MVCAD in the +/+ compared
to +/ and / genotypes. The strong association
between the genotype +/+ and both DM, dyslipidemia, and the more severe CAD presentation that
we detected in this group of patients is of great
importance.
Apo A-I and apo B have been reported to yield

different results [27]. Long-term studies of apo AI concentrations in numerous LPL mutation carriers
showed no significant difference in Austrian [28],
US American [29], Dutch, English, Swedish, and
Scottish population [30], which is consistent with
our findings. In contrast, some authors reported a
significantly lower concentration of apo A-I in the
French-Canadian population [31]. Theoretically,
this can be possible because triglyceride containing
HDL are better substrates for hepatic lipase, so the
lipid-poor apo A-I is more rapidly cleared from
the circulation [32]. Kinetic studies showed the apo
B production rates to be increased in familial
combined hyperlipoproteinemia in FrenchCanadians [33].
These findings are also in agreement with the

others [3,21,22] who attributed increased triglycerides, cholesterol, and LDL levels to dysfunction
and deficiency of LPL activity which has been
associated with the pathogenesis of various dyslipoproteinemias, and production of atherogenic
particles, such as intermediate-density lipoproteins
and LDL. The latter authors have also reported
that LPL polymorphism at PvuII polymorphic site
had a pivotal role of LPL in triglyceride hydrolysis
in plasma lipoproteins. This process initiates the
conversion of chylomicrons and VLDLs to their
remnant particles, and also has a major modulating
effect on the levels of lipid composition of HDLs
and LDLs.
Goodarzi et al [34] , reported that there were

several genetic relationships between the region
harboring LPL gene on chromosome 8 (8p22) or
its polymorphisms, respectively, and insulin resistance syndrome components (dyslipidemia, obesity,
hypertension, microalbuminuria) or surrogate indices of insulin sensitivity/resistance. A compelling
evidence of both linkage and association of haplotypes of LPL gene with a direct index of insulin
sensitivity has been provided [35], these findings
were proved in our study by the increased frequency
of /+ and +/+ genotypes in diabetic CAD patients
when compared to non-diabetic patients.
The mentioned data supports the findings which

suggest a novel function of PvuII p+ allele, in both
PvuII +/+ and +/ genotypes, as a useful genetic
marker associating many atherosclerotic vascular
diseases [9,17,23] . Moreover, Georgiev et al [4]
reported that the PvuII polymorphism in the LPL
gene is a frequent variant and it increases triglyceride levels and the risk of the appearance of
coronary artery disease.
Conclusion
The presence of P+ allele of PvuII polymorphism of LPL gene triggers susceptibility to the
development of dyslipidemia and vascular atherogenesis which in turn promotes the occurrence of
CAD diseases and can act as a marker for the
analysis of this genetic defect. In the southern
Egyptian CAD patients, the +/+ genotype can be
associated with more aggressive clinical and angiographic presentation.
Controversy continues regarding the mechanism

of occurrence of atherosclerotic CAD and its associations to LPL gene polymorphism. It is well
known that LPL is one of the most appalling candidate genes that might explain the abnormalities
of lipids and lipoproteins seen in atherosclerotic
CAD since a functional mutation in LPL gene
causes a decreased LPL activity [24]. The exact
mechanism, by which a mutation in LPL should
result in remnant accumulation, is not clear. Reduced HDL-cholesterol may result in reduced
reverse cholesterol transport, indirectly promoting
atherosclerosis [25]. Also, mutations in LPL resulting in increased triglyceride levels could promote
atherosclerosis by their association with small,
dense LDL particles, by an influence on haemostasis or by promoting post-prandial triglyceride-rich
lipoproteins [26]. Besides linkages disequilibrium
with other causative mutations nearby cannot be
excluded.
Limitations:
The small sample volume of the study population is the main limitation of the present study.
This is attributed to the high coast of gene analysis.
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347
A Wolf in a Sheeps Skin Atrial Flutter with 1:1 Nodo-Ventricular

Conduction Secondary to Sympathomimetic Inhalant (Salbutamol)
in a Young Patient with Acute Bronchial Asthma.
A Case Report with Literature Review
MOHAMMED FAKHRY ABDULMOHSEN, MD, MESC, FACC
Introduction: Atrial flutter is less common arrhythmia than atrial fibrillation and its incidence in United States of America
is 200,000 persons per year. Atrial flutter as atrial fibrillation can be induced by good number of drugs e.g. cardiac stimulants
such as dopamine, dobutamine and arbutamine, antiarrhythmic drugs with proarrhythmic potential, especially class I-antiarrhythmic
drugs, and cholinergic drugs. Sympathomimetic inhalants such as albuterol using a spacer device may induce atrial fibrillation
even in young individual, but there were no reported cases of atrial flutter induced by sympathomimetic inhalants. Here we
are reporting an interesting case of atrial flutter with 1:1 nodo-ventricular conduction induced by sympathomimetic inhalant
drug-salbutamol (ventolin) in a young patient presented with acute bronchial asthma.
Case Presentation: A 21-year-old Saudi patient who presented to emergency department (ED) with acute attack of bronchial
asthma and acute follicular tonsillitis. Upon the use of salbutamol (ventolin) inhalation therapy, he developed atrial flutter with
1:1 nodo-ventricular conduction and a very high ventricular rate (VR = 270b/m). Patient was significantly hemodynamically
unstable; with hypotension, pallor, sweating and agitation till the atrial flutter was electrically cardioverted to sinus rhythm.
Conclusion: It appears that sympathomimetic inhalants can induce atrial flutter with a very high ventricular response; which
might be a life threatening arrhythmia if not treated promptly and timely with DC cardioversion.
Key Words: Wolf Acute bronchial asthma Salbutamol.
Introduction
rhythm, and frequently degenerates into atrial

fibrillation. Atrial flutter is less common than atrial
fibrillation. Its incidence in the general population
in United States of America (USA) is relatively
low (37/100.000 person-year). From 1985-1990,
of patients admitted to US hospitals with a diagnosis
of supra-ventricular tachycardia, 77% had atrial
fibrillation, 10% had atrial flutter, and the incidence
of atrial flutter was 200,000 cases per year [3] .
The incidence increases with age, and it is more
than twice in men compared with women [3]. It
occurs more in patients with: Coronary artery
disease (CAD) especially postoperatively, hypertensive heart disease, atrial dilatation, mitral and
tricuspid valve stenosis and regurgitation, pulmonary embolism, alcoholism, and chronic ventricular
failure. It can also occur due to thyrotoxicosis,
pericarditis, chronic obstructive pulmonary disease,
hypoxia, diabetes mellitus and surgery for congenital heart disease [3]. It can be congenital or even
occur in utero [4]. Atrial flutter occurs also in about
30% of cases of atrial fibrillation, and rarely occurs
Atrial flutter was first described in 1911 [1] and

was first identified as independent medical problem
in 1920 by the British physician Sir Thomas Lewis
and colleagues [2]. In its typical presentation, it
occurs due to a macro-reentrant circuit in the right
atrium, so it falls in the category of supraventricular tachycardia. Its first occurrence Its first
occurrence is usually associated with a fast heart
rate (230-380b/m). It is typically an unstable
The Department of Internal Medicine, College of Medicine,

King Faisal University, Dammam, Saudi Arabia and King
Fahd Hospital of the University, Al-Khobar, Saudi Arabia.
Manuscript received 25 March, 2010; revised 29 April, 2010;
Address for Correspondence: Dr. Mohammed Fakhry,
Consultant Internist/Cardiologist Department of Internal
Medicine, King Fahd Hospital of the University, Saudi Arabia,
fakhri_fakhria@yahoo.com
349
without any underlying heart disease [4]. The main

pathophysiologic mechanism of typical (classical)
atrial flutter (type I) is a macro-reentrant circuit
in the right atrium initiated by a premature electrical
impulse. The reentrant loop circles the right atrium,
passing through the ismuth-a body of fibrous tissue
in the lower atrium between the inferior vena cava
and the tricuspid valve. Type I of atrial flutter is
further divided into subtypes, known as counterclockwise atrial flutter and clockwise atrial flutter
depending on the direction of the current passing
through the loop. The counterclockwise atrial flutter
(known as cephalad directed atrial flutter) is more
commonly seen. The flutter waves in this rhythm
are inverted in ECG leads II, III, and aVF. In
clockwise atrial flutter, the reentry loop cycles in
opposite direction, thus the flutter waves are upright
in II, III, and aVF [5-8]. Type II atrial flutter (atypical) follows a significantly different reentry pathway to type I flutter, and is typically faster, usually
340-350b/m. However type II flutter is less extensively studied and electroanatomically characterized. It may originate from right atrium (surgical
scar [i.e. incisional reentry]), or from left atrium
(pulmonary vein [i.e. focal reentry]), or mitral
annulus [9]. Here, we present an interesting case
report of a young Saudi male who developed atrial
flutter with 1:1 nodo-ventricular conduction at a
rate 270b/m as a complication of sympathomimetic
inhalant therapy salbutamol, used to treat a patient
with acute attack of bronchial asthma.
utamol neubulization therapy 2.5mg within 10

minutes from his arrival, oral amoxicillin and
oxygen therapy. Ten minutes later he had a very
severe episode of fast palpitation associated with
dyspnea, dizziness, and profuse sweating. The
ECG monitoring showed very fast and regular
narrow QRS supraventriclar tachycardia at a rate
of 270b/m. At this stage, the patient was managed
by the emergency physician with verapamil 10mg
intravenously, but had no response. Then, a dose
of 6mg adenosine was repeated twice at an interval
of 20 minutes (cumulative doses of adenosine was
24mg) with no effect. After the failure of this
antiarrhythmic drugs' to terminate this supraventricular tachycardia (approximately after 90
minutes from the onset of the arrhythmia) we were
called to evaluate this patient's condition. The 12
lead electrocardiogram showed typical (type 1)
atrial flutter with 1:1 AV conduction at a rate of
270b/m (Fig. 1). Carotid sinus massage failed to
terminate this arrhythmia or even to slow down
the AV conduction for better documentation of
atrial flutter. However clear flutter waves were
seen in his jugular veins, and he was hemodynamically unstable, hypotensive (BP 80/40), profusely
sweating and agitated and his HR was still 270bpm.
Patient was given 5mg valium intravenously as
sedative, and a synchronized DC cardioversion
with 50 Joules had successfully converted the atrial
flutter into sinus tachycardia at a rate of 112/m
(Fig. 2). The patient became hemodynamically
stable within 1-2 minutes, with BP 102/70, normal
JVP, and pulse oxymetry showed O2 saturation of
95%. Chest examination revealed prolonged expiration with expiratory rhonchi, the cardiovascular
system, abdomen and CNS examination was unremarkable. He was admitted to the regular medical
ward and managed as a case of upper respiratory
tract infection and follicular tonsillitis with antibiotic therapy (oral amoxicillin). He was discharged
home on the second day in a very good condition
on verapamil 40mg TID and PRN bronchodilator
inhalation therapy, and to be followed-up in OPD
on regular basis. His investigations revealed the
following: Echocardiogram and echo-Doppler study
was Normal, CBC: WBCs=19.2x103, neutrophyls=
77%, bands=2%, lymphocytes=12%, monocytes
=9%, and platelets=132x103, random blood sugar
was 133mg/dl, hyroid function tests and serum
electrolytes were within normal limits. The verapamil was discontinued after 6 months when he
remained free of any recurrence of cardiac arrhythmia.
Case Presentation
A 21-year old Saudi gentleman, known case of
bronchial asthma (BA) since childhood had infrequent presentations to emergency department (ED)
with no hospital admission. On June 25, 2008 he
reported to the ED of King Fahd Hospital of the
University, Eastern Saudi Arabia with acute attack
of bronchial asthma and was managed with a single
dose of 2.5mg salbutamol neubulization therapy
and was sent home in a better condition. He presented again to the ED on June 26, 2008 (within
<24 hours), at 10:00 am complaining of severe
breathing difficulty, cough and wheezing. His
condition was diagnosed again as an acute exacerbation of bronchial asthma and acute follicular
tonsillitis. The respiratory rate was 26 per minute,
his cardiac rhythm was sinus tachycardia at heart
rate of 110b/m, blood pressure 105/70 with no
pulsus pardoxicus, and his temperature was 38.7C.
The pulse oxymetry Showed that his O2 saturation
was 95%. He was treated accordingly with salb-
350
Mohammed F Abdulmohsen
Figure 1: A 12 lead electrocardiogram showing narrow QRS supraventricular tachycardia probably Atrial Flutter with 1:1 AV
conduction. Note the saw tooth appearance of the P waves in the inferior leads and note also that these waves are
mainly with negative polarity, which may indicate typical (Type 1) atrial flutter.
Figure 2: A 12 lead ECG performed after termination of atrial flutter with DC shock showing sinus tachycardia with HR of
112 bpm.
Discussion
filling and subsequently the cardiac output (CO)

will be severely diminished in such cases, and the
patient usually suffers of the clinical manifestations
of low cardiac output. In patients with atrial flutter
or atrial fibrillation, the accessory pathway is not
a requisite part of the tachycardia mechanism, and
the flutter or fibrillation occurs in the atrium unrelated to accessory pathway. The propagation to the
ventricle during atrial flutter or atrial fibrillation
can occur through the normal AV node-His bundle
or accessory pathway. At a very rapid rate, the
refractory period of the accessory fascicle can
shorten significantly and permit a very rapid ven-
Some arrhythmias are serious regardless of the

clinical setting such as sustained ventricular tachycardia (VT) and ventricular fibrillation (VF). Some
others may be serious because of the clinical setting
(e.g. rapidly conducted atrial fibrillation in a patient
with severe CAD, severe mitral stenosis, or hypertrophic obstructive cardiomyopathy). Atrial flutter
may become serious arrhythmia if it occurs with
very fast AV conduction, especially 1:1 conduction
with rapid ventricular response (VR) similar to
what happened with our patient. The left ventricular
351
tricular rate during atrial flutter or atrial fibrillation

[4] . This very rapid ventricular rate may exceed
the ability of the ventricle to follow an organized
manner; it can result in fragmentation and disorganization of ventricular activation and degenerate
into ventricular fibrillation [2]. Therefore, atrial
flutter with 1:1 AV conduction and very high ventricular response are considered to be a wolf in
sheep's skin, and DC cardioversion should be
directly considered as the initial treatment strategy
without unnecessary delay.
secondary to sympathomimetic inhalants in patients

with acute attacks of bronchial asthma. This extremely high HR may not be tolerated by the organized activation system of the ventricle and may
degenerate into ventricular fibrillation. Therefore
DC cardioversion should be considered as the
initial therapeutic strategy and should be applied
without delay to terminate such serious cardiac
arrhythmia.
Atrial fibrillation has been recognized to be

induced by several drug groups [10] e.g. cardiac
stimulants such as dobutamine, dopamine, and
arbutamine [11-13] antiarrhythmic drugs with proarrhythmic potential [14-19] especially class Iantiarrhythmic drugs [14] and cholinergic drugs
[20]. Sympathomimetic inhalants such as albuterol
using a spacer device may induce atrial fibrillation
even in young individual [21]. However, after an
ample English literature search through Pub
Med/Medline database, we were able to cite good
number of references to show that atrial flutter can
be similarly induced by some drugs, but the number
of those references is much less than what was
found in relation to atrial fibrillation. The most
important group of drugs found to induce atrial
flutter with 1:1 conduction is class I-C antiarrhythmic drugs; propafenone and flecainide [2224] . In an epidemiological study [3] it has been
found that 4 of 181 (2.2%) patients with initial
diagnosis of atrial flutter were receiving also antiarrhythmic drugs. In another French study, 7 cases
of atrial flutter with 1:1 conduction were observed
between 1996 and 2001 in patients receiving oral
amoidarone [25] . Notably, we failed to cite any
report to show if there is any link between atrial
flutter and sympathomimetic inhalants. Therefore,
we feel that this case report might be of significant
importance to shed some light on adverse effects
of high doses of sympathomimetic inhalants, especially when used in acute stressful situation such
as acute bronchial asthma. It also emphasizes the
great importance of continuous medical education
(CME) for emergency physicians regarding the
adverse effects and contraindications of commonly
used drugs in emergency department such as adenosine which is contraindicated in cases of asthma
[26].
1-
Jolly WA, Ritchie WJ: Auricular Flutter and fibrillation.

Heart 1911; 2: 177-221.
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Lewis T, Feil HS, Stroud WD: "Observation upon flutter,

fibrillation, II: The nature of auricular flutter". Heart
1921; 7: 191.
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Conclusion
Atrial flutter with 1:1 nodo-ventricular conduction and a very high heart rate (HR) may occur
352
Mohammed F Abdulmohsen
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R, Wellen HJ: Class I antiarrhythmic drug induced atrial
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Nadeau R: Effect of intravenous and oral calcium antagonists (diltiazem and verapamil) on sustenance of atrial
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RB, Tilley SL: Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells.
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Hayashi Y, Uraoka T: Clinical characteristics and possible
mechanism of paroxysmal atrial fibrillation induced by
353
The Predictive Value of E/E' Ratio and Left Atrial Appendage

Function for Atrial Fibrillation Recurrence after Successful Cardioversion
KHALID M ABD EL SALAM, MD
Background: Maintenance of sinus rhythm (SR) is the remote goal of therapy after successful cardioversion for atrial
fibrillation (AF) therefore several clinical, electrocardiographic, biochemical and echocardiogrphic parameters have been
proposed for prediction of AF recurrence yet with variable sensitivity and specificity.
Objective: To assess the value of the ratio of early diastolic mitral inflow velocity to early diastolic tissue Doppler mitral
annular velocity (E/E') and that of the left atrial appendage function for prediction of atrial fibrillation (AF) recurrence after
successful cardioversion.
Patients and Methods: The study included 35 patients with non valvular atrial fibrillation who underwent transthoracic
(TTE) and transesophageal echocardiography (TEE) before electrical cardioversion. Left atrial dimension and area, left ventricular
dimensions and ejection fraction (EF), mitral flow E wave velocity and TDI mitral annular E' were measured from TTE with
calculation of the E/E' ratio. At TEE, the LAA function including LAA emptying flow velocity, LAA area and LAA ejection
fraction, were measured.
Results: After 6 months follow-up SR was preserved in 21 patients (60%) and AF recurred in 14 patients (40%). The E/E'
was significantly lower (7.755.0 Vs 16.678.2, p=0.014) and the mean LAA peak emptying flow velocity was significantly
higher in patients who maintained SR than in those who showed recurrence of AF (3813 Vs 1910cm/sec; p=0.013. (Receiver
operating characteristic (ROC) analysis showed that E/E' ratio of 12 or more predicted recurrence of AF with a sensitivity of
68% and a specificity of 62% while LAA emptying velocity of 22cm/sec or less predicted AF recurrence with a sensitivity of
61% and a specificity of 55%.
Conclusion: Both E/E' ratio and LAA emptying velocity may predict AF recurrence after successful cardioversion with
higher sensitivity for E/E' ratio. This findings might be of help in planning the strategy of treatment and choice of therapeutic
options in patients with AF.
Key Words: E/E' ratio Left atrial appendage function Atrial fibrillation.
Introduction
However the benefit of an aggressive conversion

strategy compared to pharmacologic heart rate
control is still controversial [3,4], and atrial fibrillation is a heterogeneous disease. So identification
of patients at risk for recurrence with the use of
simple and objective parameters may be helpful
in tailoring the treatment.
Atrial fibrillation (AF) is the most common

sustained cardiac arrhythmia especially in the
elderly [1,2]. Elective electrical cardioversion (CV)
represents an important therapeutic option in patients with persistent AF to attempt sinus rhythm
(SR) restoration. However, AF recurrences are
frequent after successful cardioversion approximately 50% at one year [3].
Several predictors have been identified including age, history of AF, left ventricular intra-cavitary
pressure, left atrial (LA) dilatation, LA appendage
functions, and hyperthyroidism have been associated with increased recurrence rates of AF [5-9].

Zagazig University.
Manuscript received 2 February, 2010; revised 17 March,
2010; accepted 18 March, 2010.
The early diastolic velocity of the mitral valve

annulus (E') reflects the rate of myocardial relaxation. When combined with measurement of the
early transmitral flow velocity (E), the resultant
Address for Correspondence: Dr. Khalid M Abd El Salam,

Zagazig University.
355
The Predictive Value of E/E' Ratio & Left Atrial Appendage Function
ratio (E/E') correlates well with mean LVDP and

It was propose that the E/E' ratio be used as the
initial measurement for estimation of LV filling
pressures, particularly in those patients with preserved systolic function [10].
volume at the leaflet tips. The peak early diastolic

velocity E was measured [14].
By switching to TDI mode tissue Doppler imaging of the mitral annulus was obtained from the
apical four-chamber view, using a 1- to 2-mm
sample volume placed in the septal and lateral
sides of the mitral valve annulus. The TDI mitral
annular velocities were measured including the
early diastolic velocity (E') [15] TDI velocities are
taken as an average between septal and lateral
readings.
Several studies have suggested that atrial appendage (LAA) function reflect left atrial contractile function, However the role of left atrial appendage (LAA) function, for prediction of
cardioversion outcome remains unclear [11,12] and
no data is available about the role of E/E' ratio in
this regard.
The E/E':
It measured by dividing peak E wave velocity
(measured by transmitral pulsed Doppler) by peak
E' wave velocity (measured by tissue Doppler
imaging at the septal and lateral mitral annulus).
This ratio is taken as an indicator of LV filling
pressure [16].
Patient population:
This study included thirty-five patients (25
males and 10 females age range of 56-76 years)
who were presented to the CCU of Cardiology
Department, Zagazig University for elective cardioversion of non valvular AF. All patients gave
their informed consent. The study was approved
by the ethics committee of our hospital. Patients
with valvular HD, unsuccessful cardioversion, and
patients demonstrating intracardiac thrombus during
TEE were excluded from the study.
Following the TTE and after a 6-h fasting period, all patients underwent TEE examination.
During the TEE, images were analyzed on-line
for the presence of intracardiac thrombus. To view
the maximal size and to obtain the highest resolution of the LAA. The gain was continuously adjusted to ensure the best possible visualization and
to avoid noise artifact. The maximal and minimal
LAA area were measured and the LAA EF was
calculated as follows LAA EF equals LAAmax
area-LAA min area/LAA max area x 100 [17,18].
Echocardiography:
Transthoracic (TTE) and transeosophegial
echocardiography (TEE) were performed 24h before the CV attempt with system (Hewlett-Packard
Sonos 5500 using the 2.5MHz transducer. The TEE
was performed with multiplane probes with a 7MHz transducer) according to the recommendations
of the American Society of Echocardiography [13]:
The following TTE measurements were taken by
parasternal long-axis view from two-dimensional
targeted M-mode tracings LA diameter, LV enddiastolic and end-systolic diameter, LV septal and
posterior end-diastolic wall thickness were all
measured and with calculation of ejection fraction
and fraction shortening. Left atrial area was taken
by 2-D mode apical 4 chamber view using arealength method.
The LAA velocity profiles were obtained by

pulsed-wave Doppler interrogation 1cm within the
orifice of the LAA and the LAA peak emptying
velocity was measured [17,18].
The present study aimed to assess the role of

E/E' ratio and left atrial appendage (LAA) function
for prediction of AF recurrence after successful
cardioversion in patients with non valvular AF.
All the measured velocities taken as a mean of

five cardiac cycles.
A thrombus was considered to be present when
a well-circumscribed, echodense intracavitary mass
that was acoustically distinct from the underlying
endocardium was detected [19]. And Spontaneous
echocardiographic contrast was defined as an intra
cavitary swirling smoke like echo within the left
atrium or LAA [20].
Cardioversion:
Synchronized cardioversion was performed
during deep sedation delivering a stepwise sequence
of biphasic shocks as follows: First discharge 100J;
in case of failure a second discharge was delivered
at 150J; in case of failure a third discharge was
delivered a 200J; in case of failure of a 200J bi-
Mitral inflow was assessed in the apical fourchamber view, using pulsed-wave Doppler
echocardiography, with the Doppler beam aligned
parallel to the direction of flow and the sample
356
ratio was significantly higher in patients with AF

recurrence than in those who maintained SR at 6
months (16.675.2 Vs 7.755.0, p=0.007) (Fig. 1)
while the transmitral early diastolic velocity (E
wave velocity) showed no significant difference
between both groups (Table 3).
phasic shock, attempts were terminated and the

electrical cardioversion classified as ineffective.
Follow-up:
After elective cardioversion, patients were
followed monthly for 6 months. Additional followup visits were performed at patient's request in the
case of symptom recurrence.
TEE parameters of LAA function are shown in

Table (4). Patients with AF recurrence showed a
significantly lower LAA emptying velocity than
in those who maintained SR (1910 Vs 3813cm/s,
p=0.04), (Fig. 2) they also showed a larger LAA
area (6.83.3 Vs 5.51.7cm2, p=0.04) and a lower
LAA EF yet the difference between groups was
statistically not significant.
The statistical analysis was performed using
SPSS software (version 12.1; SPSS, Inc, Chicago,
IL). Continuous variables are expressed as mean
standard deviation. The unpaired Student t-test
was used to compare continuous variables, and
categorical data were analyzed using the 2 test.
Correlation between variables was done using
correlation coefficient (r) to detect if changes in
one variable accompanied by change in other variable. Variables found to be significantly related
with AF recurrence were entered into a stepwise
regression analysis to investigate the independent
effect on AF recurrence. A cut of value was detected
by ROC analysis [21] Statistical significance was
set at the 0.05 level.
Receiver operating characteristic (ROC) analysis showed that age 70 years or greater predicted
recurrence of AF with a sensitivity of 63% and a
specificity of 55%; left atrium diameter 38mm or
greater predicted AF recurrence with a sensitivity
of 41% and a specificity of 52%; left atrium area
13cm2 or greater predicted AF recurrence with a
sensitivity of 54% and a specificity of 61%; and
LAA emptying velocity of 22cm/s or less predicted
AF recurrence with a sensitivity of 61% and a
specificity of 55%, finally, an E/E' of 12 or more
predicted recurrence of AF with a sensitivity of
68% and a specificity of 62% (Fig. 3).
Results
This study included 35 patients with persistent
AF who showed SR after successful cardioversion.
They were 25 males and 10 females with age range
of 56-76 years. After 6 months follow-up SR was
maintained in 21 patients (Group I) while 14 patients showed recurrence of AF (Group II).
There were a significant positive correlation

between E/E' ratio and both LAD & LAA flow
(Figs. 4,5). Also the relation between LAD ad LAA
flow was significantly positive correlation (Fig.
6).
Demographic and clinical characteristics of the

study patients are listed in Table (1). Patients who
showed recurrence of AF after 6 months were
significantly older than those patients who maintained SR (mean age 715 Vs 648 years; p=0.006)
while no significant difference was observed between both groups regarding HR, SBP, DBP.
Table 1: Demographic and clinical characteristics of the study

population.
Pre-cardioversion transthoracic echocardiographic parameters are shown in Table (2). Patients

with AF recurrence showed a significantly larger
left atrium diameter (394 Vs 354mm, p=0.045),
and larger left atrium area (13.43.5 Vs 11.5
2.4cm2, p=0.007), left ventricular EDD was higher
and EF was lower in patients with AF recurrence
however the difference between both groups was
statistically not significant.
Characteristics
Group I
Group II
Age (years)
Male/Female
HR bpm
SBP mmHg
DBP mmHg
Hypertension (n)
COPD (n)
Diabetes (n)
648
15/6
9911
14023
7014
7 (33.3%)
5 (23.8%)
14 (66.6%)
715
10/4
10013
14125
7513
7 (50%)
6 (42.8%)
6 (42.8%)
<0.05
>0.05
>0.05
>0.05
>0.05
>0.05
>0.05
>0.05
AF
= Atrial fibrillation.
COPD = Chronic obstructive pulmonary disease.
p>0.05 Non Significant, p<0.05 Significant.
Table 2: Conventional TTE data of the study groups before

cardioversion.
The E' mean velocities was significantly lower

(5.11.10 Vs 8.92.7cm/s, p=0.04) and the E/E'
357
Characteristics
Group I
Group II
LVEDD (mm)
LVEF (%)
LAD (mm)
LA area (cm2)
532
0.560.12
354
11.52.4
543
0.540.1
394
13.43.5
>0.05
>0.05
<0.05
<0.05
Table 3: Transmitral early diastolic flow (E), TDI mitral
annular early diastolic velocity (E') and E/E' in both
groups.
Group I
Group II
E velocity cm/s
E' mean velocity cm/s
E/E' mean
6919.2
8.92.7
7.755.0
8522.2
5.11.10
16.675.2
>0.05
<0.05
<0.05
r2 = 0.84
50
40
LAF Flow
Variable
60
Table 4: TEE parameters of LAA function in both groups.

Parameters
Group I
Group II
30
20
LAA Emptying Velocity cm/s 3813

1910
<0.05
LAA Area cm2
5.51.7
6.83.3
<0.05
LAA Ejection Fraction
47.413.7 48.314.8 >0.05
10
0
0
10
20
30
E/E
20
Figure 4: Correlation between E/E' and LAA emptying.
25
10
r2 = 0.2944
20
0
Group II
Group I
Figure 1: The LAA flow in Group I and II patients.
15
10
40
5
30
20
0
30
35
10
0
70
45
Figure 5: Correlation between E/E' and LAD.

Group II
Group I
Figure 2: The E/E' ratio in Group I and II patients.
68
44
r2 = 0.2224
62
61
42
55
60
40
40
38
LAD
50
30
20
36
10
34
40
LAD
Sensitivity
Specificity
32
LAA emptying velocity 22cm/s
30
E/E 12
Figure 3: The sensitivity and specificity of the LAA emptying

velocity and the E/E ratio in predicting AF recurrence
after cardioversion.
20
40
60
LAA Flow
Figure 6: Correlation between LAD and LAA emptying.
358
Figure 7-A: (Beofre cardioversion) PWD of mitral flow

(upper left) and TDI of the septal (upper right)
and lateral (lower right) mitral annular walls of
a patient who showed no AF recurrence with
E/E' of 4.3.
Figure 7-B: (6 months after successful cardioversion) PWD

of mitral flow (upper left) and TDI of the septal
(upper right) and lateral (lower right) mitral
annular walls of a patient who showed no AF
recurrence with E/E' of 4.8.
Discussion
of patients at risk for recurrence with the use of

simple and objective parameters may be helpful
in tailoring the treatment [3,4].
Atrial fibrillation (AF) is the most common

sustained cardiac arrhythmia especially in the
elderly. As the benefit of an aggressive conversion
strategy compared to pharmacologic heart rate
control is still controversial [3,4], and since atrial
fibrillation is a heterogeneous disease, identification
The association between AF recurrence and LV

diastolic dysfunction was previously well established [10,16]. Combining transmitral flow velocity
with annular velocity (E/E') has been proposed as
359
a tool for assessing LV filling pressures that combines the influence of transmitral driving pressure
and myocardial relaxation. However, no data was
published assessing the role of E/E in predicting
AF recurrence after cardioversion.
function. These findings may make measurement

of these parameters a useful noninvasive tool in
selecting which patients should undergo elective
DC cardioversion for persistent AF.
Clinical implications:
The findings of this study have relevant clinical
implications as they identify E/E' ratio and LAA
emptying velocity measurements as an important
tool to estimate the probability of AF recurrence
in the population of patients referred for electrical
cardioversion. A low probability of sinus rhythm
maintenance, is expected in those patients who
have high E/E' >12 ratios and low LAA <22cm/s
emptying velocity. Cut off levels suggesting inefficacy of cardioversion attempts have been proposed, which need to be confirmed by further
investigations.
The LAA flow velocity represents left atrial

contractile function, it is highly variable in patients
with AF ranging from preserved contraction to
absence of movement of appendage [10].
The aim of this study was to assess the role of
the E/E' ratio and left atrial appendage (LAA)
function for prediction of cardioversion outcome
in patients with non valvular AF.
In this study the E/E' ratio was significantly
higher in patients with AF recurrence and it could
predict those patients who failed to maintained SR
at 6 months. This could be explained by the fact
that increased E/E' reflects LV diastolic dysfunction
and increased LV diastolic pressure a factor which
may play a role in AF recurrence. This is in agreement with those investigators who found a close
association between the E/E' and the LVEDP [15,16]
and others who found that E/E' correlated with
biochemical markers of LV diastolic dysfunction
[22]. This study was also in agreement with those
who found that patients with overt congestion,
significant atrial dilatation, and high atrial pressures
have a higher incidence of relapse after electrical
cardioversion for AF [23,24].
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may be related also to volume overload of the
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ratio and reduced LAA emptying velocity before
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Tenekecioglu E, et al: Evaluation of left atrial appendage
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361
Intermediate-Term Follow-up Results of Pulmonary Balloon Valvuloplasty;

Insights from Doppler Tissue Imaging; Mansoura Experience
MOHAMED MATTER, MD*; HALA ALMARSAFAWY, MD*; MONA HAFEZ, MD*;
MOHAMED MAGDY ABOU ELKHIER, MD*; MOHAMED ELTAHAN, MD**
Background: Percutaneous pulmonary Balloon valvuloplasty (PBV) has established itself as the primary alternative to
surgery for the treatment of isolated pulmonary valve stenosis. Tricuspid annular velocities derived from Doppler tissue imaging
(DTI) provide information about RV long-axis function and can solve the limitation of the conventional methods. The purpose
of this study was to evaluate the results of intermediate term follow-up of PBV in children and adolescents in our institution
and evaluation of right ventricular function "both systolic and diastolic" using DTI.
Methods: We conducted a prospective study on fifty three patients with ages ranges from 6 months to 8 years (4.252.95)
with isolated VPS. All patients performed complete conventional 2-dimensional Doppler echocardiography and DTI at lateral
tricuspid annulus, using the apical four-chamber view before PBV and during intermediate term follow-up of 3 years.
Results: Tricuspid systolic annular velocity (Sm) increased from 9.692.14cm/s to 12.062.21cm/s (p<0.0001), early
diastolic annular velocity from (Em) from 10.663.22cm/s to 14.262.71cm/s (p<0.0001), and the ratio of Em/Am from 0.990.38
to 1.450.24 (p<0.0001), while late diastolic annular velocity (Am) decreased from 11.162.35cm/s to 10.032.54cm/s. RV
Tei index significantly reduced from to 0.570.26 before PBV to 0.320.064 during the follow-up period. Transvalvular
instantaneous pressure gradient correlated negatively with tricuspid annular systolic velocity (r 0.33, p0.01), tricuspid annular
Em/Am ratio (r 0.58, p<0.0001) and positively with RV Tei index (r 0.63, p<0.0001).
Conclusion: Our experience indicates that PBV is a safe and effective management of patients with congenital VPS. DTI
is valuable in the detection of early myocardial dysfunction and can solve the limitation of conventional methods. DTI could
detect the improvement in the RV systolic and diastolic dysfunction during the follow-up period.
Key Words: Doppler tissue imaging Pulmonary stenosis Pulmonary balloon valvuloplasty.
Introduction
namics, which regresses after correction of valvular

stenosis [5,6]. Similarly, cyanosis can occur with
right-to-left atrial shunting through a patent foramen
ovale due to severe VPS and decreased right ventricular chamber compliance.
Pulmonary valve stenosis, usually due to domeshaped valve apparatus, resulting from commissural
fusion, comprises approximately 10% of all congenital heart diseases [1,2] including 10-15% dysplastic valves [3,4] which are due to markedly
thickened immobile cusps with variably reduced
mobility. In moderate-to-severe valvular pulmonary
stenosis (VPS), subvalvular hypertrophy can cause
infundibular narrowing and obstructive hemody-
Kan et al [7] introduced percutaneous pulmonary

balloon valvuloplasty (PBV) in 1982, and since
then this has become the treatment of choice for
both children and adults. The short and long-term
results of PBV are excellent and comparable to
surgery [8,9].
The Departments of Pediatrics Pediatric Cardiology Unit*

and Anaesthesia**, Childrens Hospital, Mansoura University,
Egypt.
Abnormalities of the diastolic filling of the

right ventricle (RV) in patients with right ventricular
hypertrophy, although not documented as extensively as left ventricular filling abnormalities in
patients with left ventricular hypertrophy, are not
unexpected finding [10]. It is postulated that children
with valvular pulmonary stenosis have right ven-

Address for Correspondence: Dr. Mohamed Matter, M.D.,
Pediatric Cardiology Unit, Mansoura University Children`s
Hospital, Mansoura City, Egypt, mkmatter72@yahoo.com
363
Intermediate-Term Follow-up Results of Pulmonary Balloon Valvuloplasty
tricular diastolic filling abnormalities that may be

due to either right ventricular hypertrophy or right
ventricular outflow tract obstruction [11].
severe VPS with transvalvular instantaneous pressure gradient 50mmHg, were selected for PBV.
However, cyanosed patients with right-to-left atrial
shunt through patent foramen ovale due to severe
VPS and right ventricular compliance failure were
also included. Patients must be in sinus rhythm.
Patients with Predominant infundibular or supravalvular stenosis or other associated cardiac anomaly were excluded from the study.
Doppler tissue imaging (DTI) was introduced

as a new non-invasive simple echocardiographic
method for assessment of the ventricular systolic
and diastolic functions that can solve the limitation
of the conventional methods [12]. The myocardial
early diastolic velocities, combined to Doppler
standard tricuspid inflow measurements, represent
reliable indices of right chamber hemodynamics,
the ratio between the Doppler tricuspid E velocity
and the DTI-derived early diastolic velocity of the
lateral tricuspid annulus being positively related
to the mean right atrial pressure after heart transplantation. The assessment of RV regional time
intervals may have clinical implications. In particular the relaxation time of the lateral tricuspid
annulus, very short or even absent in healthy subjects, increases progressively with the pulmonary
systolic artery pressure and its length is strongly
influenced also by the increasing RV wall thickness
in septal hypertrophic cardiomyopathy and in
hypertensive left ventricular hypertrophy. Longitudinal follow-up of RV DTI patterns will be useful
to evaluate the progression from early RV wall
dysfunction until the development of global RV
failure and the possible beneficial effect of cardiac
drugs on RV function as determined by DTI evaluation.
Methods:
Standard echocardiography:
Every patient underwent a detailed standard
echo Doppler cardiographic study. Echocardiograms were obtained using a SONOS 5500 (Hewlett
Packard, Andover, Mass, U.S.A.), and images were
obtained according to guidelines of the American
Society of Echocardiography using 8MHz phasedarray transducer [13]. Peak pressure gradient across
the pulmonary valve was derived from continuous
wave Doppler recordings at parasternal short axis
view. Two D-echocardiographic measurements of
the pulmonary annulus in parasternal short axis
view. RV diameter at end diastole (RVDd) and RV
anterior wall thickness (RVAWT) were measured
from M-mode recordings of the RV cavity in the
parasternal short-axis view. RV ejection fractions
(RVEF) were measured using Simpson volume
estimates. RV filling indices were obtained by
placing a 2-mm PW Doppler sample volume at the
tip of the tricuspid valve leaflets to record transtricuspid Doppler velocities from an apical 4chamber view. Peak early RV filling velocity (E),
peak late atrial filling velocity (A), E/A ratio were
measured. All measurements for diastolic indices
were obtained in three consecutive cardiac cycles
at end-expiration and averaged.
The purpose of this study was to evaluate the

results of intermediate term follow-up of balloon
dilatation of the stenotic pulmonary valve in children and adolescents in our institution and evaluation of right ventricular function "both systolic
and diastolic" using DTI.
Doppler tissue imaging studies:

Right ventricular DTI study was assessed by
recording long-axis motions at lateral tricuspid
annular site with Pulsed wave DTI techniques [14].
Pulsed wave DTI was performed using a special
software package available on the Sonos 5500.
Pulsed wave DTI was performed by adjusting the
spectral pulsed Doppler signal filters to obtain a
Nyquist limit of 15 to 20cm/s and high-frame-rate
(>150 frames/s) images and using the minimal
optimal gain to assure clear and well-defined pulsed
wave DTI wave borders. Care was taken to obtain
an ultrasound beam parallel to the direction of the
annular motion. In the apical 4 chambers view, the
pulsed Doppler DTI sample volume was placed at
Study population:
A total of 53 patients (35 boys; 18 girls) with
noncorrected, isolated congenital valvar pulmonary
stenosis visiting our outpatient clinic at the Mansoura University Childrens hospital, Egypt were
enrolled in this study. At the time of PBV, their
ages range from 6 months to 8 years (4.252.95),
mean body weight (17.519.34) Kg and BSA
(0.560.23) m2. All children were examined according to a strict protocol, as described in the
Methods section. The children and their parents
gave informed consent. This protocol had institutional review board approval. Patients, with clinical
and echocardiographic evidence of moderate to
364
Mohamed Ma tter, et al
the lateral margin of the tricuspid annulus. The

systolic velocity (Sm), the early diastolic myocardial velocity (Em), the late diastolic myocardial
velocity (Am) at the time of atrial contraction, and
the ratio of Em/Am were determined. All recordings
were made using a sweep speed of 100mm/s, with
an electrocardiogram (lead II). The intervals (a)
between the end of the late diastolic annular velocity (Am) and the onset of the early diastolic annular
velocity (Em) were equal to the sum of the isovolumetric contraction time (ICT), isovolumetric
relaxation time (IRT), and ejection time (ET). The
ET (b) was measured as the duration of the systolic
annular velocity (Sm). The sum of the ICT and
IRT was obtained by subtracting (b) from (a). Then,
RV Tei index was calculated as (a b)/b. The IRT
was measured from the pulsed wave DTI recordings
as the time interval from the end of the systolic
annular velocity (Sm) to the onset of the early
diastolic annular velocity and the ICT was obtained
by subtracting the IRT from (a b). All parameters
were measured during end expiration and three
consecutive cardiac cycles were measured and
averaged for each measurement.
the two observations and Pearsons correlation

coefficients are calculated as well.
Results
Our studies included 53 patients (35 boys; 18
girls), their ages range from 6 months to 8 years
(4.252.95), mean body weight (17.519.34) Kg
and BSA (0.560.23) m 2 . Forty three (81.1%)
patients had typical PVS with a domed stenotic
pulmonary valve. Pulmonary valve dysplasia, which
was defined as the presence of markedly thick,
immobile valve leaflets with nodular hyperplasia,
was present in 10 patients (18.9%). Three patients
had Noonans syndrome. Four patients had cyanosis
from right-to-left atrial shunting across a patent
foramen ovale. No patient had evident pulmonic
annular hypoplasia. The period of follow-up was
3 years ending January 2009. A single balloon
technique was used in 47 patients and a doubleballoon technique was required in 6 patients. The
pulmonary annulus was (11.421.31) mm, the size
of the balloon was (15.561.95) mm and balloon
annulus ratio was 1.340.07. The peak to peak
systolic gradient across the pulmonary valve reduced markedly from 71.66 12.88 mmHg before
the procedure to 21.007.90mmHg immediately
after the dilatation (p<0.0001) and continued reduction on intermediate term follow-up to 20.01
6.96mmHg (p<0.0001). Re-intervention was done
in 5 patients (9%).
Balloon pulmonary valvuloplasty:

The technique of PBV was described in detail
elsewhere [7], after initial hemodynamic assessment,
right ventricular angiography was performed and
maximal internal diameter of the pulmonary valve
(annulus) from the hinge point to hinge point during
systole measured from lateral projection of the
right ventricular angiogram by digital subtraction
angiography and corrected for magnification. The
suitable balloon size was chosen according to
annular diameter.
The right ventricular anterior wall thickness

(RVAWT) reduced from 9.301.56 to 7.831.28mm
(p<0.0001). RV diameter at end diastole (RVDd)
decreased from 12.392.09 to 11.102.62mm
(p<0.006). The pulmonary annulus increased from
11.851.85mm to 15.501.19mm (p<0.0001).
There was no change in RVEF before or after PBV
at follow-up. There is marked reduction in the
frequency of tricuspid regurgitation from 88.7%
(47) before PBV to 22.6% (12) on intermediate
term follow-up. There was a gradual increase in
the number of patients with pulmonary insufficiency such that 96.2% of patients had pulmonary
insufficiency at late follow-up. There was mild
pulmonary insufficiency in 75.4% of the patients,
moderate degree in 15.1% and severe degree in
5.7%. No pulmonary insufficiency in 3.8% of the
patients. However, the pulmonary insufficiency
was not severe in that none of the patients had
right ventricular dilatation or paradoxical septal
motion. Also, none of the children required surgical
intervention for treatment of pulmonary insufficiency (Table 1).
Data were analyzed Statistical Package for
Social Science program (SPSS version 15.0 for
Windows, Chicago, IL); normally distributed data
are presented as mean and standard deviation. The
paired sample t-test was used to compare data
before and after PBV. The level of statistical significance was set at p<0.05. Spearmans correlation
coefficient was used to test the relationship between
various parameters. To assess interobserver variability, DTI data from video recordings of 25
randomly selected patients were analyzed twice
by the two observers within a period of time,
approximately two weeks, between the two observations before PBV and another two observations
during the follow-up period. Interobserver variability is expressed as mean difference SD between
365

Table 1: 2D, M-mode and colored Doppler echocardiography
in the studied patients.
Before PBV Follow-up
RVAWT (mm)
RVDd (mm)
Pulmonary annulus
(mm)
RVEF %
9.301.56
11.10 2.62
11.851.85
7.831.28
<0.0001
12.392.09 0.006
15.501.19 <0.0001
39.774.08
40.322.56 0.411
90.6% (48)
9.6% (5)
0%
75.5% (40)
15.1% (8)
5.7% (3)
Frequency of TR (%) 88.7% (47)
22.6% (12)
Severity of PR (%):
Mild PR
Moderate PR
Severe PR
RVAWT
RVDd
RVEF
PR
TR
(Fig. 3). No significant correlation (r 0.13, p 0.32)

was found between tricuspid annular systolic velocity and RV anterior wall thickness (Fig. 4).
Interobserver variability:
The interobserver variability for measurements
of Tricuspid systolic annular velocity (Sm), RV
Tei index and is summarized in (Table 3). Interobserver variability shows high correlation coefficients and low variability (r=0.94 for tricuspid
systolic annular velocity (Sm), r=0.97 for RV Tei
index) when tested before PBV and (r=0.98 for
tricuspid Sm velocity, r=0.96 for RV Tei index)
when tested during the follow-up period.
: RV anterior wall thickness.

: RV diameter at end diastole.
: RV ejection fraction.
: Pulmonary regurgitation.
: Tricuspid regurgitation.
Table 2: Conventional and Doppler tissue imaging parameters

in the studied patients.
Before PBV Follow-up
The right ventricular filling indices showed

significant increase in RV early diastolic filling
(E) velocity from 0.560.14m/s to 0.870.14 m/s
(p<0.0001), E/A ratio from 0.770.19 to 1.310.22
(p<0.0001) and tricuspid deceleration time (DT)
from 89.215.88 msec to 121.0209.47msec while
there was significant reduction in RV late diastolic
(A) filling velocity from 0.730.11m/s to 0.67
0.12m/s (p<0.02) during the follow-up period.
Tricuspid E velocity 0.560.14

(m/s)
0.870.14
<0.0001
Tricuspid A velocity 0.730.11

(m/s)
0.670.12
0.02
0.770.19
1.310.22
<0.0001
Tricuspid E/A ratio
Tricuspid DT (msec) 89.215.88
121.0209.47 <0.0001
Tricuspid Sm
velocity (cm/s)
9.692.14
12.062.21
<0.0001
Tricuspid Em
velocity (cm/s)
10.663.22
14.262.71
<0.0001
DTI studies of the tricuspid annular velocities

revealed significant increase in the tricuspid systolic
annular velocity (Sm) from 9.692.14cm/s to
12.062.21cm/s (p<0.0001), early diastolic annular
velocity (Em) from 10.663.22cm/s to 14.26
2.71cm/s (p<0.0001), and the ratio of early to late
tricuspid annular velocities (Em/Am) from 0.99
0.38 to 1.450.24 (p<0.0001). while late diastolic
annular velocity (Am) decreased from 11.16
2.35cm/s to 10.032.54cm/s (p<0.02) and tricuspid
IRT from 68.4214.76 msec before PBV to 58.40
7.11msec (p<0.0001) during the follow up period.
RV myocardial performance index (Tei index) in
our patients showed good improvement in the
global RV function as it was significantly decreased
from 0.570.26 before PBV to 0.320.06 during
the follow-up period (Table 2).
Tricuspid Am
velocity (cm/s)
11.162.35
10.032.54
0.02
Tricuspid Em/Am
0.990.38
1.450.24
<0.0001
Transvalvular instantaneous pressure gradient

correlated negatively with tricuspid systolic annular
velocity (r 0.33, p=0.01) (Fig. 1), tricuspid annular
Em/Am ratio (r 0.58, p<0.0001) (Fig. 2), and
positively with RV Tei index (r 0.63, p<0.0001)
Tricuspid systolic 0.0550.16

(Sm) velocity
Tricuspid IRT (msec) 68.4214.76 58.407.11

RV Tei index
0.570.26
0.320.064
<0.0001
<0.0001
DT: Deceleration time.

IRT: Isovolumeteric relaxation time.
Table 3: Interobserver variability before PBV and during the

follow-up period.
During the
follow-up
Before PBV
r*
Mean
difference
SD
RV Tei index
0.0020.01
*Pearson correlation coefficient.
366
r*
Mean
difference
SD
0.94
0.0100.11
0.98
0.97
0.0070.01
0.96
r 0.33, p 0.01
2.00
r 0.58, p<0.0001
Tricuspid Em/Am ratio
Tricuspid Sm velocity
15.00
12.50
10.00
7.50
1.50
1.00
0.50
5.00
0.00
0
20
40
60
80
Instantaneous pressure gradient
100
Figure 1: Correlation between transpulmonic instantaneous

pressure gradient and tricuspid Sm velocity.
20
40
60
80

pressure gradient and tricuspid Em/Am ratio.
r=0.63, p<000.1
r 0.13, p 0.32
15.00
Tricuspid Sm velocity
1.25
RV Tei index
100
1.00
0.75
0.50
0.25
12.50
10.00
7.50
5.00
20
40
60
80
100
8
9
10
11
RV anterior wall thickness
12

pressure gradient and RV Tei index.
Figure 4: Correlation between RV anterior wall thickness

and tricuspid Sm velocity.
Discussion
6.96mmHg. These results was similar to previous

studies [17,18,19].
Balloon valvuloplasty is currently the preferred

therapeutic alternative to surgical valvotomy in
selected patients with isolated congenital pulmonary
stenosis [15] . The rational for intervention has
included prevention and relief of symptoms, prevention of changes in the right ventricle and pulmonary artery, and the prevention of progression
to more severe degree of stenosis [16].
The acute results of PBV were satisfactory in

all patients with isolated pulmonary valve stenosis.
Five patients developed restenosis one year after
the initial procedure and were subjected to repeat
PBV with successful relief of the pressure gradient.
It has been reported that initial PBV performed in
patients under 2 years of age is associated with an
increased incidence of restenosis [8]. This fact is
consistent with the finding that children less than
2 years of age with pulmonary valve stenosis show
evidence of progression of pressure gradient during
long term follow-up. Therefore, it may be better
to perform PBV after 2 years of age, taking the
natural history of the disease into consideration.
The present study demonstrates that PBV affords both acute and intermediate-term relief of
valvular obstruction in patients with isolated pulmonary valve stenosis. Transpulmonary systolic
pressure gradient was reduced from 71.6612.88
mmHg before the procedure to 21.007.90mmHg
immediately after the dilatation and continued
reduction on intermediate term follow-up to 20.01
Previous reports have demonstrated that the

most significant factor affecting the acute results
367
of PBV is the selection of balloon diameter [20,2,21].

In our study the balloon annulus ratio was approximately 130%. The use of oversized balloons was
earlier recommended [22] however; recent studies
have suggested that a balloon size equal to annulus
size is optimal in terms of obtaining excellent acute
and long term results [8]. Oversize balloons more
than 150% of annulus diameter may increase the
risk of valve disruption, outflow damage to the
right ventricle and femoral vein damage. We suggest that balloon/annulus diameter ratio of 130%
was the proper choice in our study group.
filling velocity from 0.560.14m/s to 0.870.14m/s

(p<0.0001), while there is significant reduction in
RV late diastolic filling velocity from 0.730.11m/s
to 0.670.12 m/s (p<0.02). The E/A ratio increased
from 0.770.19 to 1.310.22 (p<0.0001) at intermediate term follow up. There is increase in tricuspid deceleration time from 89.215.88msec to
121.0209.47msec. This is in agreement with the
results previously [26] reported that in the longterm follow-up, all right ventricular diastolic filling
indices in successfully treated pulmonary stenosis
patients improved compared with untreated patients
and approached values found in normal subjects.
Another study [11] demonstrated that Children with
valvular pulmonary stenosis have right ventricular
diastolic filling abnormalities that may be due to
either right ventricular hypertrophy or right ventricular outflow obstruction and these diastolic
filling indices did not improve immediately after
PBV in the first day but significant improvement
was observed when re-examined by the sixth
month. These data suggest that RV diastolic filling
abnormalities are more likely a result of right
ventricular hypertrophy than of right ventricular
outflow obstruction. This clearly indicates that RV
diastolic dysfunction, present in patients with
valvular pulmonary stenosis, starts to improve
gradually after the relief of obstruction and return
to normal pattern after sometimes needed for the
hypertrophied myocardium to regress.
In our study, the pulmonary annulus increased

in diameter in follow-up as a result of increased
pulmonary flow after dilatation from 11.85
1.85mm to 15.501.19mm and this is in agreement
with the previous studies [23,24].
Double-balloon technique was required in 6
patients with annulus diameter more than 20mm
and satisfactory acute and intermediate term result
were obtained. This technique appears to be suitable
in adult with larger size annuli because a single
large balloon may cause vascular damage. In our
study we found that the prevalence and degree of
pulmonary insufficiency increased at intermediateterm follow-up such that 96.2% of patients had
pulmonary insufficiency, although none of them
developed right ventricular volume overload nor
required surgery. This was similar to the previous
reports [25].
Measurement of tricuspid annular motion from

the apical view has been suggested as a method of
estimating right ventricular function. However,
there are few reports on the analysis of tricuspid
annular motion in right ventricular disease. Descent
of the right ventricular base is both sensitive and
specific for the identification of patients with
hemodynamic significant right ventricular dysfunction, and the most powerful predictor of adverse
outcome in patients with myocarditis [30]. Hoffmann, et al and Alam, et al [31,32] reported that,
the use of tricuspid annular motion for analysis of
right ventricular function is the logical consequence
of recent findings on tricuspid annular motion. A
systolic velocity, even greater than that of the
mitral annulus has been demonstrated for the tricuspid annulus in healthy subjects, indicating that
longitudinal shortening plays an important role in
right ventricular function. In the present study, we
used tricuspid systolic annular velocity (Sm) as an
index of right ventricular systolic function. We
found significant improvement in tricuspid systolic
annular velocity (Sm) from 9.692.14 cm/s before
The right ventricular anterior wall thickness

(RVAWT) was reduced on the intermediate term
follow-up from 9.301.56 to 7.831.28mm also
RVDd decreased from 12.392.09 to 11.102.62
mm which in agreement to the previous studies
[16,26] that documented regression of RV hypertrophy but in contrast to other study [27] that demonstrated, even after successful relief of the outflow
tract obstruction, regression of the right ventricular
hypertrophy may not occur for a time, if it occurs
at all.
We report in the present study that global right
ventricular systolic function as evaluated by RVEF
was not changed at follow-up. It was reported
[28,29] that the majority of patients with pulmonary
stenosis have normal right ventricular function as
evidenced by normal right ventricular stroke volume and ejection fraction.
We found improvement of the RV diastolic
dysfunction at intermediate term follow-up as
evident by significant increase in RV early diastolic
368
PBV to 12.062.21cm/s (p<0.0001) during the

follow-up period. Moreover we also reported a
significant negative correlation between transvalvular pressure gradient and tricuspid annular systolic velocity (r 0.33, p 0.01). In addition, no
significant correlation (r 0.13, p 0.32) was found
between tricuspid systolic annular velocity and RV
anterior wall thickness. Hoffmann, et al [31] demonstrated that, a negative correlation was found
between right ventricular systolic pressure and
systolic tricuspid annular motion. Thus, a significantly elevated right ventricular pressure may
mimic depressed right ventricular function. Meluzin
et al. [33] documented that a low peak systolic
tricuspid annular velocity proved to have a high
predictive accuracy for right ventricular dysfunction
determined by radionuclide ventriculography.
Therefore, we can clearly demonstrate that although
a global systolic function seems to be normal when
evaluated by conventional method, but DTI can
detect early myocardial systolic dysfunction at
different myocardial sites.
right ventricular pressure in patients with congenital

heart disease.
In the present study, using DTI-derived myocardial performance index (Tei index) to evaluate
the global right ventricular function, we found
improvement in RV Tei index from 0.570.26
before PBV to 0.320.064 at follow-up. Also significant positive correlation was found between
the transvalvular pressure gradient and RV Tei
index (r 0.63, p<0.0001). Recent studies have
shown that the RV Tei index is useful for serial
evaluation of patients with congenital heart disease
and represents a simple method of assessing RV
myocardial performance. Moreover, it has the
advantage of simultaneous recording of systolic
and diastolic velocity patterns, suggesting that the
DTI-derived Tei index is a feasible approach to
assess global RV function in children [37] . The
myocardial performance index has been shown to
be a much better predictor of outcome than other
conventional measures of ventricular performance
[38].
Evaluating RV diastolic function using DTI in

our patients before PBV and during the follow-up,
we found improvement in right ventricular diastolic
dysfunction as evident by significant increased
tricuspid early diastolic annular velocity (Em) from
10.663.22cm/s to 14.262.71cm/s (p<0.0001),
and the ratio of early to late tricuspid annular
velocities (Em/Am) from 0.990.38 to 1.450.24
(p<0.0001) while significant decreased tricuspid
late diastolic annular velocity (Am) from 11.16
2.35cm/s to 10.03 2.54 cm/s (p<0.02) and tricuspid
annular IRT from 68.4214.76 msec to 58.40
7.11msec at (p<0.0001). Significant negative correlation was observed between the transvalvular
pressure gradient and tricuspid annular Em/Am
ratio (r 0.58, p<0.0001). Therefore, we can demonstrate improvement in the right ventricular diastolic dysfunction after relief of right ventricular
obstruction. Frommelt, et al [34] suggested that
early diastolic tricuspid annular velocity (Em) may
also provide insight into RV relaxation, and tricuspid annular DTI patterns consistent with delayed
relaxation, characterized by decreased early diastolic annular velocities and prolonged isovolumic
relaxation time. Other studies [35,36] concluded
that, hypertrophic changes in the right ventricle
lead to an alteration in compliance and characterized by a shift in ventricular filling from early to
late diastole. Em/Am ratio, derived from tricuspid
annular velocities as measured by DTI, is a valuable, noninvasive tool for detecting an elevated
Conclusion
Our experience indicates that PBV is a safe and
effective management of patients with congenital
valvular pulmonary stenosis with good acute and
intermediate term results. DTI is valuable in the
detection of early myocardial dysfunction not
detected by conventional methods. DTI could detect
the improvement in the RV systolic and diastolic
dysfunction during the follow-up period.
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370
Assessment of NT-pro-BNP Levels in Patients with Atrial Fibrillation

before and after Cardioversion and their Relation to Left Atrial Function
ISLAM A EL-SHERBINY, MD; TAMER M MOSTAFA, MD; MAHMOUD H SHAH, MD;
ISMAIL M IBRAHIM, MSc
Atrial fibrillation (AF) has a progressive nature and tends to become sustained over time and more resistant to cardioversion
(DCC). Assassment of mechanical and neurohormonal remodeling in patients with AF is extremely important and enhances
treatment strategies in these patients.
Aim of the Work: To assess the value of alterations in plasma amino terminal fragment of the brain natriuretic peptide
prohormone (NT-pro-BNP) in predicting AF recurrence after DCC and its relation to left atrial function.
Patients and Methods: 30 patients with first episode of AF and normal LV function subjected to clinical, ECG, echocardiographic
evaluation of LA size and function, measurement of NT-pro-BNP (before, 3 days and at 3 months after DCC) and Direct-current
cardioversion (DCC). After 3 months follow-up patients were divided into; Group I; patients with maintained sinus rhythm after
DCC, Group II; patients with AF recurrence after DCC.
Results: Baseline NT-pro-BNP is elevated in AF patients and its level decreases after successful cardioversion and reelevation
denotes AF recurrence.A cut-off value of baseline NT-pro-BNP 850pg/ml predict AF recurrence with a sensitivity of 94.7%
and a specificity of 90.9%. Doppler transmitral A wave & mitral annular A velocities are predictors of AF recurrence. By
multivariate analysis the baseline and percentage reduction in NT-pro-BNP, LA maximum volume & interatrial conduction time
(IACT) are independent predictors of AF recurrence after DCC.
Conclusion: Baseline NT-pro-BNP and echocardiographic parameters of LA size and function can be used as predictors
of AF recurrence and provides an objective tool for choosing management strategy for AF.
Key Words: Atrial Fibrillation NT-pro-BNP Echocardiography.
Introduction
& may be responsible for recurrence of AF after

restoration of sinus rhythm(SR) (AF begets AF
while SR does not beget SR) (Casaclang-Versoza
et al, 2008).
Atrial fibrillation (AF) is the most frequently

seen sustained arrhythmia in clinical practice. It
is closely associated with an increased cardiovascular morbidity and mortality as well as reduction
of patient's functional capacity. Electrical and
structural remodeling starts shortly after the onset
of AF (Kaya et al, 2008). This remodeling represents a spectrum of pathophysiological changes
include alterations at the levels of ionic channels,
cellular energy balance, neurohormonal expression,
inflammatory response, and physiologic adaptations
Successful cardioversion of AF usually results

in Left atrial (LA) stunning which is the transient
impairment of LA mechanical function was shown
to favor recurrence of AF after successful cardioversion (Mattioli et al, 2008).
Because of heterogenity of AF, the treatment
modality should be individualised for every patient.
Objective prediction of immediate, short-term and
long-term success of rhythm control strategy is
cornerstone in AF management (Wilber, 2009).
The Department of Cardiology, Zagazig University.

N-terminal pro-brain natriuretic peptide (NTpro-BNP) plasma levels were found to be elevated
Address for Correspondence: Dr. Islam A El-Sherbiny,

The Department of Cardiology, Zagazig University.
371
in AF even with normal left ventricular (LV) function. After successful DCC, its level decreases
when a persistent sinus rhythm can be restored
(Shin et al, 2005). Baseline level before cardioversion was shown to predict recurrence of AF. The
percentage reduction in NT-pro-BNP level is also
predictive of the success of cardioversion. This
percentage reduction may give objective basis for
determining further management of AF such as
repeat cardioversion (Thejus and Francis, 2009).
according to presenting patient's rhythm after 3

months:
Group I: Including 19 patients who had initially
successful cardioversion and maintained the sinus
rhythm after 3 months.
Group II: Including 11 patients who had initially
successful cardioversion but AF recurred at 3
months post-cardioversion.
Group III: Ten control patients in sinus rhythm
and normal left ventricular function (ejection
fraction >50%) defined as.
Impaired left atrial function after cardioversion

is a predictor of AF recurrence. This also can
determine further management options for AF
(Leung et al, 2008).
Exclusion criteria: Left ventricular ejection

fraction <50%, Valvular stenosis or regurgitation
> mild, New York Heart Association (NYHA)
functional class > II, Presence of left atrial thrombus
in initial echocardiography, cardiac surgery within
3 months, reversible causes of AF such as abnormal
plasma potassium level (i.e. <3.5 or >5.5mEq/L),
acute infections, pericarditis, excessive use of
adrenergic stimulants or thyroid dysfunction, Patients with creatinine level >1.5 mg/dl (males) and
>1.4mg/dl (females) and Patients with contraindications to long-term amiodarone use.
The aim of this work is to assess the ability of

baseline plasma levels of NT-pro-BNP and echocardiographic parameters of LA function to predict
recurrence of AF after successful direct current
cardioversion (DCC) to determine further management options and risk stratification for AF.
This study was carried out in Cardiology Department, Faculty of Medicine, Zagazig University
during the period from April 2009 to October
2009.
Methods: Patients were subjected to the following; Full history taking: with special emphasis on
age of patient, duration of atrial fibrillation, past
history of hypertension, ischemia or diabetes and
drug history clinical examination.
The study included 30 consecutive patients who

presented with acute onset atrial fibrillation (AF)
and underwent electrical cardioversion.
Resting 12-lead surface electrocardiography

(ECG): To detect rhythm, rate and the possible
underlying cause.
All the following inclusion criteria must be fulfilled:
Echocardiography: Trans-thoracic echocardiographic examination was done using HewelettPakard 5500 Sonos machine imaging system
equipped with a 4MHz transducer. Every patient
is examined 3 times: before cardioversion, shortly
after cardioversion (average 3 days) and 3 months
after cardioversion. All measurements are taken
according to the recommendations of the American
Society of Echocardiography. A simultaneous electrocardiogram was recorded in all subjects. The
following measurements were obtained: Assessmant
of left ventricular (LV) function: By using Tiech
technique LV dimensions are measured and Using
modified Simpson's rule (Lang et al, 2006), Transmitral pulsed-Doppler pattern: During the state of
AF, the peak E wave velocity can only be measured.
However, in the state of the sinus rhythm, both
peak E wave and A wave velocities are measured.
The transmitral flow velocity recordings are aver-
1- Atrial fibrillation documented by 12-lead sufface

ECG and rhythm strip. The index episode must
be the first detected one.
2- Preserved left ventricular function defined as
ejection fraction >50%.
3- Successful electrical cardioversion defined as
maintained sinus rhythm for at least 24 hours
post-cardioversion.
4- Patients must be eligible to be given long term
amiodarone for maintenance of sinus rhythm
at doses of 800mg in the first 14 days, 600mg
in the next 14 days and 400mg therafter.
Contraindications to amiodarone use must be
absent. The patients were discharged in sinus
rhythm and followed-up for 3 months for AF recurrence. Patients were subdivided into two groups
372
Islam A El-Sherbiny, et al
aged from 3 cardiac cycles then the average of E

& A wave velocities. Absence or peak A wave
velocity less than 50msec is taken as a cutoff value
denoting atrial stunning after cardioversion (Climent et al, 2006).
Blood sampling: Every patient was sampled

immediately before cardioversion, 3 days after
cardioversion and 3 months after cardioversion.
In each time, 5 milliliters of venous blood were
collected with the patient lying supine using chilled
syringe in chilled polypropylene tubes each containing lithium heparin. Since ethylenediamine
tetra acetic acid (EDTA) causes a decrease in the
values measured, tubes containing EDTA should
not be used. The tubes were gently rocked several
times immediately after collection of blood. Then,
samples were centrifuged for 10 minutes and plasma was collected in eppendorf tubes and kept at
70C till analysis.
Assessment of left atrial (LA) size and function: M-mode echocardiography and 2-dimensional
echocardiography: by obtaining a standard apical
4-chamber view, LA volume is measured by applying Simpson's method. A horizontal line is drawn
across the mitral annular plane, and LA area does
not include the funnel of the mitral valve leaflets.
The largest left atrial volume (Vmax.) is measured
at the beginning of the diastole at the opening of
mitral valve. The smallest LA volume (Vmin.) is
measured at ventricular end-diastole coinciding
with R wave on the recoded ECG. LA emptying
fraction is calculated from the following equation:
LAEF % = (Vmax. Vmin.) / Vmax. (Leung et
al, 2008).
Principle of the method (package insert of

VIDAS NT-proBNP kits):
The assay principle combines a one-step immunoassay sandwich method with a final fluorescent
detection (enzyme-linked fluorescent assay). The
sample is transferred into the well containing antiNT-proBNP antibody (conjugate) labeled with
alkaline phosphatase. The sample/conjugate mixture
is cycled in and out of the solid phase receptacle
(SPR) several times and so enables the antigen to
bind with the immunoglobulins fixed to the interior
wall of the SPR. Two detection steps are performed
successively. During each step, the substrate (4Methyl-umbelliferyl phosphate) is cycled in and
out of the SPR and then conjugate enzyme catalyzes
the hydrolysis of this substrate into a fluorescent
product (4-Methyl-umbelliferone), the fluorescence
of which is measured at 450nm. The intensity of
the fluorescence is proportional to the concentration
of antigen present in the sample. At the end, results
are automatically calculated by the instrument in
relation to two calibration curves corresponding
to the two detection steps. A fluorescence threshold
value determines the calibration curve to be used
for each sample.
Peak atrial systolic mitral annular velocities

during atrial contraction (A'): They are measured
from the apical 4-chamber view with the pulsed
wave sample volume placed at septal and lateral
mitral annular tissues. At least three consecutive
traces recorded and averaged, E/E': It is measured
by dividing peak E wave velocity (measured by
transmitral pulsed Doppler) by peak E' wave velocity (measured by pulsed Doppler tissue imaging
at the septal mitral annulus). This ratio is taken as
an indicator of LV filling prassure (Dokainish et
al, 2005).
Segmental LA function: From the apical 4chamber view, we put the pulsed sample volume
at the LA mid-free wall, the right atrial mid-free
wall and the inter-atrial mid-septum and record
the S', E' and A' at every site. These measures were
taken to show segmental atrial contractions.
Performance: Studies performed using

VIDAS NT-proBNP kits gave the following results: The VIDAS NT-proBNP measurement range
is 20-25000pg/mL, The analytical detection limit,
defined as the lowest concentration of NT-proBNP
that can be distinguished from the zero concentration with a probability of 95%, is <20pg/mL &
functional sensitivity; defined as the lowest concentration of NT-proBNP that can be measured
with an inter-assay coefficient of variation of 20%,
is <50pg/mL. No hook effect was found up to NTproBNP concentrations of 500000pg/mL.
Inter-atrial conduction time (IACT): It is

measured from the onset of P wave in ECG to the
onset of A' wave at both lateral and medial aspects
of mitral annulus. These measures were averaged
and taken as an indicator of atrial electromechanical
coupling (Cui et al, 2008).
Measurement of plasma level of N-terminal
pro-BNP: This was done using VIDAS NTproBNP kits which are used on the VIDAS instruments and apply Enzyme-Linked Fluorescent Assay
technique (ELFA).
373
Direct Current Cardioversion (DCC): Synchronized cardioversion was performed during deep
sedation with intravenous midazolam delivering a
stepwise sequence of biphasic shocks as follows:
first attempt at 100 Joules; in case of failure a
second attempt was delivered at 150 Joules; in
case of failure a third attempt was delivered a 200
Joules; in case of failure of a final attempt at 200
Joules. With failure of the fourth attempt, cardioversion was terminated and classified as unsuccessful. Patients who were cardioverted are maintained on amiodarone at a dose of 800mg for the
first 14 days, 600mg for the next 14 days and
400mg thereafter.
lated using Pearson's formula. Degree of significance is calculated from p-value where p>0.05
indicates non-significance, p<0.05 indicates significance and p<0.01 indicates high significance.
Statistical analysis was performed with SPSS software program (Swinscow, 1994).
Results
between groups as regards demographic and clinical
characteristics Table (1).
NT-pro-BNP data: Baseline NT-pro-BNP level
was elevated in all 30 patients with persistent AF
(848.3742.1 Vs 101.380.7 p<0.001) compared
to the healthy control group and the difference was
statistically highly significant (p<0.001) (Fig. 1).
Statistical analysis: Normal distribution of data

was verified with Kolmogorov-Smirnov test. Data
showing a normal distribution are presented as
mean standard deviation. Comparisons between
non-Gaussian variables were performed with MannWhitney or Wilcoxon signed-rank test, as appropriate. Comparisons of proportions between groups
were performed with chi-square test or Fisher's
exact test, as appropriate. Univariate analysis was
performed exploring the effect of different parameters as predictors of AF recurrence. Multivariate
analysis was performed by scatter analysis on those
variables significantly affecting AF recurrence at
univariate analysis. A receiver operating characteristic curve (ROC) analysis has been planned to
identify possible cut-offs to predict AF recurrence
at 3 months. Correlation coefficient (r) was calcu-
3500
p<0.001
NT-pro BNP pg/ml
3000
2500
2000
1500
1000
500
0
Figure 1: NT-pro BNP in control & patients with AF.
Table 1: Demographic and clinical characteristics of the studied groups.

Group I
Group II
Group III
Significance
Age (years)
X SD
39.311.5
47.38.6
40.69.6
p=0.11
Gender N (%):
Male
Female
8 (42.1)
11 (57.9)
7 (63.6)
4 (36.4)
4 (40.0)
6 (60.0)
p=0.45
BMI (kg/m2) disease:

CAD
HTN
DM
Depression
Post-operative
27.63.8
4 (21.1)
8 (42.1)
4 (21.1)
1 (5.3)
2 (10.5)
28.56.01
4 (36.4)
6 (54.4)
4 (36.4)
0 (0.00)
0 (0.00)
27.34.2
p=0.40
p=0.629
p=0.51
p=0.62
p=0.77
p=0.72
AF duration (hrs):
X SD
Range
26.8715.8
4-48
28.411.7
16-48
t=0.26,
p=0.79
Medications:
ACE inhibitors
Beta-blockers
8 (42.1)
4 (21.1)
6 (54.5)
4 (36.4)
p=0.50
p=0.62
Control.
AF patients.
374
Table 2: Comparison of NT-pro-BNP level in the 3 groups.
NT-Pro-BNP
pg/ml
At baseline
3 days after DCC
At 3 months after DCC

Group III
Group I
Group II
Group I
Group II
Group I
Group II
X SD
409.6243.0 1606.1702.0* 173157.7$ 920.2375.8**,# 48.937.7
972.2325***,## 101.380.7
Range
39-912
784-3520
20-588
475-1614
20-140
610-1613
20-250
Median
412
1501
178
761
32
902
77
* : Group II at baseline versus group I at baseline (p<0.001).

** : Group II 3 days after DCC versus group I 3 days after DCC (p<0.001).
***: Group II at 3 months post-DCC versus group I at 3 months post-DCC (p<0.001).
$ : Group I 3 days after DCC versus group I at baseline (p<0.001).
#
##
: Group I at 3 months post-DCC versus group I at baseline (p<0.001).

: Group II 3 days after DCC versus group II at baseline (p<0.001).
: Group II at 3 months post-DCC versus group II at baseline (p<0.05).
: Group III versus group I at baseline (p<0.001) and group II at baseline (p<0.001).
The baseline NT-pro-BNP level was significantly lower in group I than in group II (p<0.001). It
was also found that follow-up NT-pro-BNP levels
(both 3 days after cardioversion and at 3 months
post-cardioversion) were significantly lower in
group I than in group II (p<0.001).
BNP level above 850pg/ml had a specificity of

90.9%, a sensitivity 94.7% and accuracy of 93.3%
by using receiver operating curve (ROC) analysis
for prediction of AF recurrence at 3 months(Area
under curve AUC = 0.9280.054. 95% confidence
interval CI = (0.812-1.0). Percentage reduction =
NT-pro-BNP/baseline NT-pro-BNP.
In group I: There was a decrease in median

NT-pro-BNP levels 3 days after cardioversion
(p<0.001) with further decrease at 3 months postcardioversion (p<0.001).
The percentage reduction of NT-pro-BNP 3

days after cardioversion was significantly greater
in group I than in group II (58.3% Vs. 40.7%
p=0.01). A receiver operating curve (ROC) analysis
of AF recurrence by 3 months as a function of
Percentage reduction in NT-pro-BNP level has
been performed. A percentage of 54.5% was found
to have 80% sensetivity and 86% specificity for
AF recurrence. Percentage reduction = NT-proBNP/ baseline NT-pro-BNP. AUC = 0.8650.054.
95% CI = (0.812-1.0).
In group II: There was a decrease in median

NT-pro-BNP levels 3 days after cardioversion
(p<0.001). However, at 3 months post-cardioversion
the median NT-pro-BNP levels showed no further
decrease.
Validity of NT-pro-BNP in prediction of AF
recurrence: A cut-off value of baseline NT-proMedian NT-pro-BNP
Median NT-pro-BNP
450
1600
400
1400
350
1200
1000
250
Pg/ml
Pg/ml
300
200
800
600
150
100
400
50
200
0
GI
baseline
GI
GI
3 day after CV 3 month after CV
G II
baseline
G II
G II
3 day after CV 3 month after CV
Figure 2: NT-pro-BNP at baseline, 3 days after cardioversion & 3 months post-cardioversoin for group I & group II.
375
1.0
1.00
(A)
0.75
Sensitivity
Sensitivity
0.8
(B)
0.6
0.4
0.50
0.25
0.2
0.0
0.00
0.0
0.2
0.4
0.6
0.8
1.0
0.00
Specificity
0.20
0.50
0.75
1.00
Specificity
Figure 3: ROC analysis of baseline NT-pro-BNP (A) & Percentage reduction in NT-pro-BNP 3 days after cardioversion (B)
as a predictor of AF recurrence.
significant difference when compared to control

group.
As regards left atrial diameter (LAD), LA Vmax

& LA Vmin: The difference between the two groups
was statistically highly significant (p=0.001).
As regards LAEF: When LA EF for each group

was compared to that for control group, the difference was statistically significant (p<0.05).
All patients were examined by conventional

and tissue Doppler echocardiography 3 days and
3 months after cardioversion. The obtained data
are illustrated in (Table 5).
Our study proved that the region with highest

contractility in the atria are the lateral part of the
mitral annulus followed by the medial part of the
mitral annulus, the right atrial mid-free wall, the
left atrial mid-free wall and, lastly, the inter-atrial
mid-septum. Also, we proved that contractility of
medial parts of the mitral annulus remained significantly lower 3 months after DCC when compared
to control group. Despite improvement of global
LA function after DCC. A' at lateral mitral annulus
was significantly lower 3 days after DCC when
compared to control group (p<0.05). At 3 months
postcardioversion, A' at lateral and medial mitral
annulus in group I showed significant recovery
when compared to values measured at 3 days
(p<0.05).
Comparison between echocardiographic data

for group I and II 3 days after cardioversion reveals:
The difference between the two groups as regards
A wave velocity, number of stunned cases and
inter-atrial conduction time (IACT) at medial mitral
annulus were statistically significant (p=0.04, 0.04
& 0.02 respectively). As regards A' velocity at
lateral mitral annulus the difference was statistically
borderline significant (p=0.05).
Global and Segmental atrial function:
Global left atrial function was assessed using
peak A wave velocity and LA emptying fraction
(LA EF). Segmental atrial function was assessed
by measuring A' velocity at 5 regions in both atria:
lateral mitral annulus, medial mitral annulus, left
atrial mid-free wall, right atrial mid-free wall and
interatrial mid-septum. All parameters were assessed 3 days and 3 months after cardioverion.
Results are shown in Table (5).
Table 3: Baseline echocardiographic data of group I & II.
EF (%)
LAD (mm)
LA Vmax (ml)
LA Vmin (ml)
E (cm/sec)
E/E'
LA EF (%)
As regards A wave velocity: Three days after

DCC A wave velocity for each group was compared
to that for control group, the difference was statistically significant (p<0.05). 3 months after DCC,
A wave velocity for group I had no statistically
376
Group I
(N=19)
Group II
(N=11)
p-value
53.65.6
27.85.4
447.9
29.44.0
78.66.0
6.91.0
55.84.9
52.72.1
45.14.6
72.37.2
32.03.97
76.17.5
6.70.9
55.52.8
0.62
0.001
0.001
0.25
0.15
0.10
0.85
Table 4: Follow-up echocardiographic data of group I and group II.
Parameter
3 days
after DCC
3 months
after DCC
Group II
3 days after DCC
Group III
(control)
A (cm/sec)
50.412.0
58.47.1
43.28.8
57.412.1#
E/A
1.540.37
1.40.14
1.660.72
1.40.27
Stunned cases N (%)
5 (26.3%)
7 (63.6%)*
LA EF (%)
4516
598
4715
5810#
E/E'
6.681.26
6.521.2
6.851.1
5.941.2
A' (lat mit ann) (cm/sec)
8.53.3
9.62.17
6.13.1*
9.41.8#
IACT (lat mit ann) (millisec)
93.719.1
84.812.7
107.422.4
81.511.3
A' (med mit ann) (cm/sec)
8.02.8
8.51.6##
6.13.2
9.21.4#,$
IACT (med mit ann) (millisec)
91.616.7
87.711.6
106.518.5*
83.211.0
A' (LA mid-free wall) (cm/sec)
8.63.3
8.53.5
8.42.9
8.72.9
A' (RA mid-free wall) (cm/sec)
8.23.5
8.83.3
8.72.8
8.63.4
A' (IA mid-septum) (cm/sec)
8.12.9
8.33.0
7.83.3
8.52.8
* : Group II 3 days after DCC versus group I 3 days after DCC (p<0.05).
$ : Group III versus group I 3 months after DCC (p<0.05).
# : Group III versus group I 3 days after DCC (p<0.05) and group II 3 days afetr DCC.
##: Group I at 3 months post-DCC versus group I 3 days after DCC (p<0.05).
Table 5: Multivariate analysis for prediction of AF recurrence.
Comparison between the group I and group II

as regards clinical data, NT-pro-BNP data and
echocardiographic data revealed that only 8 parameters were significantly different between the two
groups:
Baseline NT-pro-BNP
B SE
0.430.118
<0.001
Percentage reduction in NT-pro-BNP 0.0310.017 <0.05
Presence of coronary artery disease.

Baseline NT-pro-BNP.
LA Vmax
0.0150.008 <0.05
IACT (med mit ann)
0.0090.005 <0.05
Percentage reduction in NT-pro-BNP.

B: Beta.
SE: Standard error.
Left atrial diameter before DCC.

Table 6: Correlation between baseline NT-pro-BNP and
percentage reduction in NT-pro-BNP with the various echocardiographic parameters.
Left atial maximum volume before DCC.

Peak A wave, velocity & stunning 3 days after
DCC.
Correlation
p
coefficient
value
(r)
Correlation
p
coefficient
value
(r)
A' measured at lateral mitral annulus 3 days after

DCC.
Parameter
IACT measurd at medial mitral annulus 3 days

after DCC.
AF duration
0.01
>0.05
0.47
>0.05
LA diameter
0.63
<0.001
0.40
>0.05
Multivariate analysis using scatter analysis of

these 8 parameters revealed that only 4 of them
remained significant as independent predictors of
AF recurrence: Baseline NT-pro-BNP, Percentage
reduction in NT-pro-BNP, Left atial maximum
volume before cardioversion, inter-atrial conduction
time measurd at medial mitral annulus 3 days after
cardioversion. As shown in Table (6).
LA Vmax
0.66
<0.001
0.38
>0.05
LA Vmin
0.64
<0.001
0.37
>0.05
E/E'
0. 4
<0. 01
0.14
>0.05
LA EF %
0.07
>0.05
0.09
>0.05
A' (lat mit ann)
0.13
>0.05
0.35
>0.05
A' (med mit ann)
0.05
>0.05
0.31
>0.05
IACT (lat mit ann)
0.19
>0.05
0.18
>0.05
377

90
60
80
50
70
LA max vol.
LAD
40
30
20
60
50
40
30
20
10
10
r=0.63, p<0.001
r=0.66, p<0.001
0
0
500
1000
1500
2000
2500
3000
Baseline NT-pro-BNP
500
1000
1500
2000
2500
3000
Baseline NT-pro-BNP
Figure 4: Correlation between baseline NT-pro-BNP and LA D & LA max vol.
Discussion
little acute fluctuations over different hemodynamic

profiles. Baseline NT-pro-BNP was significantly
higher in patients with AF when compared to an
age-matched control group. This explained by the
different factors: (1) Elevated atrial pressure due
to loss of atrial contraction; (2) Increasing LV end
diastolic pressure; (3) Atrio-ventricular uncoupling;
(4) The tachycardia itself since it has been proved
that patients with tachycardia (paroxysmal supraventricular tachycardia and AF) had higher
levels of BNP during tachycardia (Corell et al,
2007). (5) Irregularity of ventricular rhythm may
cause a decrease in cardiac output The main source
of natriuretic peptides in AF is the atria. Inoue et
al (2000). Our finding agrees with different studies:
Shin et al (2005), Corell et al (2007), Jug et al
(2009) and Kallergis et al (2010) found that patients
with AF had higher median NT-pro BNP levels
than patients with sinus rhythm (SR) with p-value
<0.001. Compared to aforementioned studies, the
median value of NT-pro-BNP in AF patients in our
study was relatively smaller. This may be attributed
to the fine selection of patients in our study where
all patients had EF >50%, none of them had diastolic dysfunction or elevated creatinine level more
than 1.4 mg/dl. Our patients had a relatively higher
BMI which is known to be inversely correlated
with NT-pro-BNP. The relatively smaller number
of the studied group may be another factor contributing to this difference.
AF is a major cause of morbidity and mortality.

There is still no agreement about AF management.
The question of rate control versus rhythm control
strategy is still frequently investigated. Rhythm
control provides cure from the arrhythmia, better
quality of life, higher exercise tolerence, shorter
duration of anticoagulation and lesser mortality.
Unfortunately, a big number of clinical trials e.g
AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management), RACE (Rate Control
Vs. Electrical Cardioversion), PIAF (Pharmacologic
Intervention in Atrial Fibrillation), and STAF (Strategies of Treatment of Atrial Fibrillation) failed to
demonstrate these anticipated benefits of rhythmcontrol strategies. The explanation may be the
delayed onset of rhythm control and suboptimal
risk-benefit profile of current anti-arrhythmic drugs
(Wilber, 2009). It is reasonable to estimate whether
the potential hazards and cost of available rhythm
control methods are justified in every indiviual
patient with persistent AF (Sanna et al, 2009).
Although advanced age, enlarged atrium, depressed
ejection fraction, and numerous previous recurrences are predictors of unsuccessful cardioversion.
No risk stratification system is currently available
to select patients before rhythm control (Kirchhof
et al, 2009).
The present study investigated short-term and
mid-term prediction of AF recurrence after electrical cardioversion using NT-pro-BNP and some
echocardiographic left atrial size and function.
In our study, we found that NT-pro-BNP levels

decreased significantly after successful electrical
cardioversion of AF. NT-pro-BNP level measured
3 days after cardioversion to give time for clearance
of AF-induced elevation of NT-pro-BNP, stabiliza-
The study depended upon NT-pro-BNP level

because it is more stable than BNP so that it shows
378
tion of patient's hemodynamics and normalization

of the neuro-hormonal surge associated with AF
(which affects natriuretic peptide production and
neutral endopeptidase activity). Decrease in NTpro-BNP after cardioversion is explained by regular
sinus rhythm which will result in a more efficient
ventricular performance. Danicek V, et al (2008)
and Kallergis et al (2010) revealed a similar result.
Also in accordance with our result is that NT-proBNP level is shown to decrease after other modalities of AF cardioversion. Hwang et al (2009)
described a significant decrease after radiofrequency ablation and Albage et al (2003) documented
the same result after Maze procedure.
On the other hand, other studies fail to demonestrate the predictive value of NT-pro-BNp. Shin
et al (2005) found that baseline NT-proBNP was
higher (1570.5pg/ml Vs 973.6pg/ml) in patients
who eventually developed a recurrence of AF, but
this difference did not achieve statistical significance. Danicek et al (2008), Tveit et al (2009)
found that baseline NT-proBNP did not predict
whether patients would maintain SR after cardioversion of AF. Tveit et al (2009) The possible
explanation of this contradiction is: that recurrence
of AF in the aforementioned studies was more
frequent than in our study. The baseline characteristics of patients included in their study showed
that 65% of patients had hypertension (Vs. 46%
in our study), 55% of patients had coronary heart
disease (Vs. 37% in our study) and mean left atrial
diameter of 46.25.5mm (Vs. 37.85.4mm in our
study). The high frequency of these strong predictors of AF recurrence may explain the higher recurrence of AF and attenuate the predictive power
of NT-pro-BNP. The mechanisms behind the atrial
release of natriuretic peptides in AF with normal
LV function are poorly understood. By time, future
studies may solve this question and determinants
of elevated natriuretic peptides in AF with normal
LV function may be identified. Better understanding
of these determinants may refine our knowledge
about the predictive power of natriuretic peptides
in AF recurrence.
All the 30 patients in our study maintained

sinus rhythm in the first 3 days post-cardioversion.
However, the median NT-pro-BNP level at 3 days
post-cardioversion is significantly higher than in
healthy control group (450 Vs. 77pg/ml). Possible
explanations of this finding may be: Atrial stunning
described by Manning et al (1994) (reflects impaired atrial function after cardioversion). In fact,
atrial stunning is no more than continuation of
atrial remodeling that occurs during AF. Also the
underlying medical diseases in our patients where
11 patients (37%) had CAD and 14 patients (47%)
had hypertension. Both diseases have been descibed
as confounders for increased NT-pro-BNP (Hess
et al, 2005).
In our study, comparison between the group
which maintained SR at 3 months postcardioversion and the group in which AF recurred shows
that baseline NT-pro-BNP was higher in the group
in which AF recurred. By using ROC a cutoff value
of >850pg/ml predicts AF recurrence with a sensitivity of 94.7%, a specificity of 90.9%.
The percentage reduction in NT-pro-BNP 3

days after cardioversion ( NT-pro-BNP/baseline
NT-pro-BNP %) is significantly higher in the group
which maintained SR than the group in which AF
recurred. That percentage reduction in NT-proBNP also predicts AF recurrence with a cutoff
value of 54.5% having 80% sensitivity and 86%
specificity. This is found to agree with the results
of Ari et al (2008) who found that that patients
who reverted to AF 6 months after cardioversion
showed a lesser decrease in BNP level. The possible
explanation is that patients who revert to AF have
little improvement in hemodynamic profile, higher
frequency of subclinical paroxysms of AF and
slower rate of elimination of BNP.
These findings may suggest that AF patients

with higher NT-pro-BNP at baseline are hemodynamically more unstable, and consequently, they
are more likely to revert to AF. A higher percentage
reduction reflects more improvement in hemodynamics, and thus, more stability in SR. So, we
conclude that baseline NT-proBNP might offer a
valuable aid in deciding for or against a rhythm
control strategy.
Our study revealed that: LA diameter and LA

maximum volume are independent predictors of
AF recurrence. Previous reports showed an association between LA size and AF recurrence rates.
Flaker et al (1995). Kallergis et al (2010) also
showed that increased LA diameter is an independent predictor of AF recurrence. Increased LA
This result is found to agree with findings of

previous studies. Mollmann et al, 2008, Sanna et
al. (2009) and Yalta et al (2009), Kallergis et al.
(2010) found that baseline NT-proBNP was an
independent predictor of AF recurrence at 6 months
after cardioversion.
379
diameter reflects advanced remodeling and fibrosis

of LA. The fibrosed areas of atrial myocardium
are vulnerable to stretch caused by any factor
increasing filling pressures. Myocyte stretch increases the dispersion of atrial effective refractory
period through mechano-electrical feedback and,
magnified by collagen deposition, lowers the arrhythmogenic threshold. Since LA volume is a
more accurate measurment of LA size, it was found
to be more important as a predictor of AF recurrence. Clara et al (2009).
results of a study conducted by Thomas et al (2003).

This difference was attributed to an atrial free-wall
motion higher than that of the bounded septum.
Furthermore, the larger pectinate muscle in the RA
can perhaps generate a more pronounced and sustained longitudinal movement in the relatively low
pressure system of the right ventricle.
Our study has showed that IACT at medial
mitral annulus 3 days after cardioversion is an
independent predictor of AF recurrence. So it can
guide further management of AF such as repeat
cardioversion. This result is similar, though not
identical, to that found by Cui et al (2008) who
found a correlation between IACT and recurrence
in paroxysmal AF. Roshanali et al (2007) used
IACT for prediction of AF post-coronary artery
bypass grafting. Because the prolongation of the
IACT can be explained by LA enlargement as well
as increased delay time from electric activation in
the atrium to atrial myocardial contraction, IACT
time can totally and significantly reflect the atrial
impairment and predict AF recurrence.
On the other hand, other studies fail to demonestrate the correlation between LA size and AF
recurrence. Spiecker et al (2006) found that LA
size had no correlation with AF recurrence. They
explained their finding by the fact of possible
discrepancy between electrical and geometric remodeling in AF where electrical changes can be
severe in small atria. So the different prevalence
of concomitant diseases such as hypertension may
account for the controversial correlations of LA
size to recurrence of AF. 40% of our patients
showed atrial stunning and this percentage is similar
to these in published reports (ranging from 38%
to 80%) (Mattioli et al, 2008). There is statistical
significance difference between patients with and
without AF recurrence. This result is identical to
that found by Mattioli et al (1996). We also found
that atrial stunning and peak A wave velocity can
predict AF recurrence at 3 months. This agrees
with results of Climent et al (2006). The loss of
contractile elements and replacement fibrosis, the
mechanisms behind stunning, are accused of facilitating AF recurrence. Spiecker et al (2005) correlating peak A wave velocity post-cardioversion
and AF recurrence.
There is a positive correlation between baseline

NT-pro-BNP and AF duration. This agrees with
findings of Ari et al (2008).
Also there is a significant positive correlation
between baseline NT-pro-BNP and LA diameter,
LA maximum volume and LA minimum volume.
This again confirms that NT-pro-BNP levels reflect
the degree of LA volume overload and atrial stretch.
This agrees with results of Lee et al (2006).
Study Limitations: The relatively short period
of patient follow-up in our study and the relatively
small number of patients (confounding factors of
AF recurrence such as age and gender are difficult
to be controlled in small samples). Doppler tissue
imaging is potentially affected by angle dependency, translational and tethering effects from neighboring myocardium. The technical limitations of
the VIDAS NT-pro-BNP method: the manufacturer states that interference may occur with certain
sera containing antibodies directed against reagent
components. We couldn't rule out the occurrence
of some undocumented episodes of AF in patients
who were considered in sinus rhythm during the
follow-up period.
A' velocity at lateral mitral annulus 3 days after

DCC is a predictor of AF recurrence. This is in
agreement to the previous observation regarding
atrial stunning. Dogan et al (2009) showed that A'
velocity at lateral mitral annunlus may be used as
a recent parameter for assessment of atrial stunning.
However, values at 3 months in patients with
maintained sinus rhythm had normalized A' at
lateral mitral annulus.
Our study proved the relative difference in
contractility between various regions within the
atria. The region with highest contractility are the
lateral part of the mitral annulus followed by the
medial part of the mitral annulus, the right atrial
mid-free wall, the left atrial mid-free wall and,
lastly, the inter-atrial mid-septum. This agrees with
Conclusions
Baseline NT-pro-BNP is elevated in patients
with AF with normal LV function with a cutoff
>850pg/ml predicts AF recurrence at 3 months
380
Current understanding, pathophysiologic correlates, and
prognostic implications. Am Heart J 2008; 156: 1056-64.
with a sensitivity 94.7% and a specificity of 90.9%

& decreases significantly after successful DCC.
The percentage reduction can predict short-term
to mid-term maintenance of SR. This may provide
an objective tool for management of early AF
recurrence. These parameters can also help the
decision making before attempting cardioversion
for persistent AF. Atrial stunning occurs after
successful cardioversion predicts AF recurrence.
Inter-atrial conduction time at medial mitral annulus
3 days after DCC can be used as a predictor of AF
recurrence and can guide further management of
AF such as repeat cardioversion.
8- Climent V, Mari F, Monmeneu J, Garcia F: Atrial stunning

as predictor of early relapse into atrial fibrillationafter
110: 427-428.
9- Dokainish H, Zoghbi WA, Lakkis NM, et al: Incremental
predictive power of B-type natriuretic peptide and tissue
Doppler echocardiography in the prognosis of patients
with congestive heart failure. J Am Coll Cardiol 2005;
45: 1223-6.
10- Cui Q, Wang H, Zhang W, et al: Enhanced left atrial
reservoir, increased conduit, and weakened booster pump
function in hypertensive patients with paroxysmal atrial
fibrillation. Hypertens Res 2008; 31: 395-400.
We recommend to measure NT-pro-BNP before

and after direct-current cardioversion (DCC) of
AF as this provides prognostic and therapeutic
implications for choosing a rhythm control versus
a rate control strategy. Also estimation of LA size,
The presence of atrial stunning and long IACT
after cardioversion using conventional
echocardiography and tissue Doppler imaging
before DCC are essential as this provides a useful
predictor of sinus rhythm maintenance.
11- Swinscow T: Statistics at square one. British medical

Journal 1994; 9: 412-418.
12- Wilber DJ: Pursuing sinus rhythm in patients with persistent
atrial fibrillation. When is it too late? JACC 2009; 54:
796-8.
13- Sanna T, Sonaglioni A, Pieroni M: Baseline NT-Pro-BNP
levels and arrhythmia recurrence in outpatients undergoing
elective cardioversion of Persistent atrial fibrillation: A
survival analysis. Indian Pacing and Electrophysiology
Journal 2009; 9: 15-24.
Acknowledgement: We are indebted to the

clinical pathology staff for excellent laboratory
technical assistance.
14- Kirchhof P, Bax J, Blomstrom-Lundquist C, et al: Early

and comprehensive management of atrial fibrillation:
Proceedings from the 2nd AFNET/EHRA consensus conference on atrial fibrillation entitled research perspectives
in atrial fibrillation. Europace 2009; 11: 860-885.
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fibrillation on plasma NT-proBNP in chronic heart failure.
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382
Cardiac Autonomic Neuropathy in Type 1 Diabetic Patients:

Prevalence and Utility of Corrected QT Interval in ECG for Diagnosis
SOHA M ABD EL DAYEM, MD; AHMED A BATTAH, MD*; RANDA ALI SOLIMAN, MD
Objective: To study prevalence and risk factors for cardiac autonomic neuroathy (CAN) and utility of prolongation of
corrected QT interval (QTc) to diagnose CAN in type 1 diabetic patients.
Patients and Methods: 177 patients with type 1 diabetes were originally studied using five cardiovascular autonomic tests.
Results: Prevalence of CAN was 20%, while prolonged QTc interval was 15.5%. Prolonged QTc interval was found to be
significantly higher in patients with abnormal CVRs. Patients with abnormal CAN had a significantly higher age and duration
of disease. Insulin dose/Kg showed a significant positive correlation with Q-T interval. Microalbuminuria showed a significant
positive correlation with blood pressure response to standing and negative correlation with blood pressure response to hand
grip. Age of patients and duration of disease were a significant risk factors of CAN. The sensitivity, specificity, PPV, NPV and
overall acurracy of QTc for diagnosis of CAN were 55%, 89.5%, 45.8%, 84.7% and 78.7% respectively.
Conclusions: The prevalence of CAN in IDDM patients is high. Age of patients and duration of disease are significant risk
factors of CAN. Q-T interval is an easy and specific test for autonomic dysfunction with reasonable sensitivity, specificity, PPV
and NPV.
Key Words: Cardiac autonomic neuropathy Type 1 diabetic patients Corrected QT interval.
Introduction
The pathogenesis of QTc prolongation remains

poorly understood, although cross-sectional studies
suggest a role for several risk factors, including
female sex, glycemic control, ischemic heart disease, gene mutations, and blood pressure [5,6]. The
identification of risk factors for prolonged QTc is
of clinical relevance because it would enable the
targeting of people at high risk of cardiovascular
events and, potentially, the application of risk
lowering strategies [7].
Cardiovascuular autonomic neuropathy (CAN)

is one of the most clinically significant complications of diabetes mellitus (DM), and one of the
least frequently diagnosed [1].
The QT interval on the electrocardiogram reflects the total duration of ventricular myocardial
depolarization and repolarization, and when corrected for heart rate (QTc) it is predictive of allcause and cardiovascular mortality in apparently
healthy people as well as in people with various
conditions, including diabetes [2,3] . Therefore,
measurement of QTc has been proposed as a simple
and noninvasive method for the assessment of
cardiovascular risk in the clinical setting [4].
A mechanistic link between the prolonged QTc

interval and increased risk of fatal arrhythmogenesis
is well established by the detailed investigation of
the relatively rare, monogenic long-QT syndromes.
However, QTc prolongation has also been associated with increased risk of sudden cardiac death
(SCD) in a non-long-QT syndrome communitybased cohort of unrelated individuals [8]. Prolonged
Q-T interval is associated with sudden death and
poor survival in healthy subjects and in a variety
of clinical conditions, including newly diagnosed
type 2 diabetes, nephropathy and type 1 diabetes
[9].
The Departments of Pediatrics and Critical Care*, National

Research Center and Kasr El-Aini Hospital*, Cairo University.
accepted 11 Feb., 2010, 2010.
Address for Correspondence: Dr. Soha M Abd El Dayem,
The Department of Pediatrics, National Research Center.
383
Cardiac Autonomic Neuropathy in Type 1 Diabetic Patients
Our aim is to study the prevalence and risk

factors for CAN and the utility of prolongation of
QTc in ECG to diagnose CAN in insulin dependent
diabetes mellitus patients.
Statistical method:
SPSS program version 9 was used for analysis
of data. t-test was used for analysis of 2 quantitative
data. Pearsons correlation was also done. Binary
Logestic regression analysis was carried out for
detection of the risk factor of CAN. The sensitivity,
specificity, positive predictive value (PPV), negative predictive value (NPV) and overall acurracy
of QTc prolongation for the diagnosis of CAN
were determined.

An informed written consent was obtained
from the patients and their parents and an approval
from the Ethical committe of the National Research
Center was taken.
A cross sectional study was done to include
177 patients with type 1 diabetes. Patients were
selected among those attending the endocrine clinic
at the National Reaearch Centre.
Results
The study including 177 patients with type 1
diabetes. Their mean age were (15.44.6 yrs)
(range: 7-22 yrs), mean duration of disease were
8.9 4.4 yr (range: 4-15 yr) and mean age of onset
of disease were 6.53.3 (range: 2.5-14 yrs). The
prevalence of CAN among our patients was 20%,
while prolonged QTc interval was 15.5%. QTc
interval was found to be significantly higher in
patients with abnormal CVRs than those with
normal CVRs (0.430.05 Vs 0.410.03, p=0.002).
Prolonged QT interval was found in 13 (10.5%)
patients with negative CVRs and in 11 (35.5%)
patients with abnormal CVRs with statistical significance (p=0.002). Patients with abnormal CAN
had a significantly higher age and duration of
disease (Table 1). Age of patients (OR : 1.1, 95%
CI : 1.0-1.3 and p-value=0.003) and duration of
disease (OR : 1.1, 95% CI : 1.0-1.2 and p-value
=0.03) were significant risk factors of CAN. However, age of onset of patients, systolic and diastolic
blood pressure, HbA1c, microalbminuria and insulin dose were not significant risk factors of CAN
(Table 2). The sensitivity, specificity, PPV, NPV
and overall acurracy of QTc prolongation for the
diagnosis of CAN were 55%, 89.5%, 45.8%, 84.7%
and 78.7% respectively. A significant negative
correlation was found between age of patients with
type 1 diabetes and heart rate response to deep
breathing, heart rate response to standing up and
heart rate response to valsalva manoeuver (p<0.05)
(Table 3). A significant negative correlation was
also found between heart rate response to deep
breathing, heart rate response to valsalva manoeuver
and duration of disease and a significant positive
correlation was found between blood pressure
response to hand grip and duration of disease (Table
3). Age of onset of disease showed a significant
positive correlation with QT interval and a significant negative correlation with heart rate response
to standing up and heart rate response to valsalva
The exclusion criteria of patients were as follows:

1- Patients during acute diabetic complications
e.g. diabetic ketoacidosis or hypoglycemia.
2- Patients suffering from cardiac diseases e.g.
congenital heart or rheumatic.
3- Patients younger than six years [in order to be
able to perform Cardiovascular reflex (CVR)
tests].
All patients were originally studied using a
battery of five cardiovascular autonomic tests
described by Ewing and Clark [10]. Diagnosis of
CAN was made when at least two tests were pathological [10].
Long lead II (on ECG) was done to calculate
basal heart rate and corrected Q-T interval by
Bazett's formula: Normal QTc <0.45.
Q Tc = Q T / R R
The following CVR tests were done in the same
sequence:
1- Heart rate response to valsalva maneuver.
2- Heart rate variation during deep breathing.
3- Immediate heart rate response to standing.
4- Blood pressure response to standing.
5- Blood pressure response to sustained hand grip.
Glycosylated hemoglobin (HbA1c) values were
collected from patients files for the past year (done
every 3 months), the method used was cation
exchange chromatography using kits provided by
Helena [11]. A morning urine sample was taken for
assessment of albumin/creatinine ratio by enzyme
linked immunosorbent assay (ELISA).
384
Soha M Abd El Da yem, et al
manoeuver (Table 3). Insulin dose/Kg showed a

significant positive correlation with Q-T interval
(Table 3). Twenty patients had albumin/creatinine
ratio >30g/gm creatinine. Albumin/creatinine
ratio showed a significant positive correlation with

blood pressure response to standing and negative
correlation with blood pressure response to hand
grip (Table 3).
Table 1: Comparison between demographic and clinical data of patients with type 1 diabetes
in relation to cardiac autonomic neuropathy.
Variables
Negative CAN
Mean SD
N=128
Positive CAN
Mean SD
N=32
p-value
14.74.5
8.54.4
6.23.4
9.41.6
14.220.5
1.31.5
75.011.1
110.514.2
17.64.8
10.44.7
7.13.1
10.01.5
23.536.9
1.21.0
77.210.0
109.714.5
0.004*
0.04*
0.07
0.08
0.2
0.4
0.5
0.8
Age of patients (yrs)

Durtion of disease (yrs)
Age of onset of disease (yrs)
HbA1 (%)
Albumin/creatinine ratio (g/mg creatinine)
Insulin dose (U/Kg)
Diastolic blood pressure (mmHg)
Systolic blood pressure (mmHg)
Table 2: Logistic regression for detection of risk factor of CAN in relation to demographic
and clinical data.
Variables
95% CI
Odds ratio
p-value
Age of patients (yrs)

Durtion of disease (yrs)
Age of onset of disease (yrs)
HbA1 (%)
Albumin/creatinine ratio (g/mg creatinine)
Insulin dose (U/Kg)
Diastolic blood pressure (mmHg)
Systolic blood pressure (mmHg)
0.1
0.1
0.1
0.2
0.01
0.04
0.02
0.004
1.0-1.3
1.0-1.2
1.0-1.2
1.0-1.6
1.0-1.0
0.7-1.4
1.0-1.1
1.0-1.0
1.1
1.1
1.0
1.0 0.1
0.1
1.0
1.0
1.0
0.003*
0.03*
0.2
0.1
0.1
0.8
0.3
0.8
p-value is significant if 0.05.

B: Is the estimated logit coefficient.
Odds ratio = P/ (1-P). P is the probability that the event y occurs.
C.I: Confidence interval (it is an interval in a true population parameters fall).
Dependant variables; Cardiac autonomic neuropathy.
Table 3: Correlation between age of patients, duration of disease, age of onset of disease, insulin dose and albumin/creatinine
ratio of type 1 diabetic patients with different cardiovascular reflex tests.
Variables
Age of patients
(yrs)
r
QTc intervale
Heart rate response to valsalva
maneuver
Heart rate response to deep
breathing (E/I ratio)
Heart rate response to standing up
(30/15 ratio)
Systolic blood pressure decrease
with standing (mmHg)
Diastolic blood pressure increase
with sustained hand grip (mmHg)
p-value
Duration of
disease (yrs)
r
p-value
0.3
0.0001*
0.2
0.02*
0.4
0.0001*
0.3
0.0001*
0.2
0.03*
0.2
0.004
385
Age of onset of
disease (yrs)
Insulin dose
(U/Kg)
p-value
p-value
0.2
0.2
0.005*
0.04*
0.2
0.01*
0.2
0.02*
Albumin/
creatinine ratio
(g/mg creatinine)
r
p-value
0.3
0.006*
0.2
0.2
Discussion
In the present study, the sensitivity, specificity,

PPV, NPV and overall acurracy of QTc prolongation
for the diagnosis of CAN were 55%, 89.5%, 45.8%,
84.7% and 78.7% respectively. However, Pappachan et al [16] , reported that the sensitivity,
specificity and PPV were 77%, 62.5% and 77%
respectively.
In the absence of a computerized system for

HRV spectral analysis, the four Ewing tests should
be performed for evaluation of CAN. These tests
are widely used because they are easily performed
and reliably provide the results compared with an
age-matched control group. The diagnosis of established CAN requires at least two abnormal tests.
When only one of them is abnormal (usually the
deep breathing test or the orthostatic one), the
diagnosis of early or incipient CAN is made. Later,
with the progression of CAN, the Valsalva manoeuver also becomes abnormal, characterizing the
diagnosis of intermediate CAN. Finally, when
orthostatic hypertension is present, severe CAN is
diagnosed [1,12,13].
This study disclosed significant negative correlation between age of diabetics and heart rate
response to deep breathing, heart rate response to
standing and heart rate response to valsalva
(p<0.05) (Table 3). Also our results showed significant negative correlation between duration of
illness and mean values of heart rate response to
deep breathing, heart rate response to valsalva and
significant positive correlation to blood pressure
response to hand grip (p<0.05, Table 3).
The prevalence of CAN among our patients

was 20%, while prolonged QTc interval was 15.5%.
This conicide with the result of Paries et al [14],
who reported that CAN was found in 20% to 70%
of diabetic subjects. This complication was associated significantly with retinopathy and peripheral
neuropathy. However, CAN was present in more
than half of patients without retinopathy or nephropathy and in one third of patients with normal
electrophysiological investigation. Veglio et al [15]
and Giunti et al [7], have previously reported that
the prevalence of QTc prolongation was 25.6%
and 25.2 per 1000 respectively in the diabetic
population.
A significant negative correlation was found

in the diabetic patients between the standard CAN
function tests and age, which points out the importance of interpreting the tests according to age.
Negative correlations were also found between
these tests and duration of diabetes as previously
reported [14].
On the other hand, Straub et al [18] reported no
correlation between duration of diabetes and any
of CVRs tests.
The impairment in the cardiac autonomic function tests in recently diagnosed type 1 diabetes
may result from autoimmune processes. Antisympathetic ganglia antibodies have been found in
some type 1 diabetic patients who had a reduced
increase in plasma catecholamines during the postural test [14].
In the current study, QTc interval was found to

be significantly higher in patients with abnormal
CVRs than those with normal CVRs (0.430.05
Vs 0.410.03, p=0.002). Prolonged QT intervale
was found in 13 (10.5%) patients with negative
CVRs and in 11 (35.5%) patients with abnormal
CVRs with statisitcal significance (p=0.002). Pappachan et al [16], reported that higher CAN scores
correlated with longer QTc intervals (coefficient
of correlation 0.73; p<0.001).
In this work, a significant negative correlation

was found between age of onset and heart rate
response to standing and heart rate response to
valsalva (p<0.05*, Table 3).
In our study, patients with abnormal CAN had

a significant higher age and duration of disease
(Tables 1,3). In type 1 diabetic subjects from the
EURODIAB cohort, female sex, HbA1C, and systolic blood pressure are predictive of prolonged
QTc, whereas physical activity and BMI within
the range of 21.5-23.2 kg/m2 play a protective role
[7]. On the contrary, Riabykina et al [17], reported
that there was no inter relationship in patients
between glycated hemoglobin, diabetes duration
and length of QTc.
In our diabetic population, Q-Tc was significantly prolonged and showed significant positive
correlation to age of onset of disease and insulin
dose/Kg, however no correlation was found to
HbA1c. The mechanism of Q-T prolongation is
not known, may be a form of diabetic cardiomyopathy [19] . Moderate correlation was revealed
between dose of insulin administered in 24 hours
and length of QTc [17].
386
Soha M Abd El Da yem, et al

3- Salles GF, Bloch KV, Cardoso CR: Mortality and predictors
of mortality in a cohort of Brazilian type 2 diabetic
patients. Diabetes Care 2004; 27: 1299-1305.
In the present study, twenty patients had albumin

/creatinine ratio >30g/gm creatinine. Albumin
/creatinine ratio showed a significant positive
correlation with blood pressure response to standing
and negative correlation with blood pressure response to hand grip (Table 3).
4- Rana BS, Lim PO, Naas AA, Ogston SA, Newton RW,
Jung RT, Morris AD, Struthers AD: QT interval abnormalities are often present at diagnosis in diabetes and are
better predictors of cardiac death than ankle brachial
pressure index and autonomic function tests. Heart 2005;
91: 44-50.
CAN is a marker of poor prognosis for microangiopathy, especially nephropathy, as demonstrated

by a prospective Swedish study with an elevenyear follow-up [1].
5- Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham

DJ: Risk factors for prolonged QTc among US adults:
Third National Health and Nutrition Examination Survey.
Eur J Cardiovasc Prev Rehabil 2005; 12: 363-368.
An increasing attenuation of 24-hour vagal

activity has also been found to be associated with
the severity of nephropathy, and the prevalence of
CAN has been shown to correlate with the urinary
albumin excretion rate. This association is consistent with common pathogenetic mechanisms, particularly those related to poor metabolic control.
Nevertheless this may also suggest that autonomic
neuropathy has a pathogenic role in the development of diabetic nephropathy. There is some evidence for a neural regulatory function of the kidney.
After renal nerve stimulation in rats, vascular
resistances increase with a consequent reduction
in the glomerular filtration rate, and proximal water
and sodium reabsorption is enhanced. A 10-year
prospective study has shown that the glomerular
filtration rate decreased more than expected in type
1 diabetic patients with autonomic neuropathy [14].
6- Suys B, Heuten S, De Wolf D, Verherstraeten M, de Beeck

LO, Matthys D, Vrints C, Rooman R: Glycemia and
corrected QT interval prolongation in young type 1 diabetic
patients: What is the relation? Diabetes Care 2006; 29:
427-429.
7- Giunti S, Bruno G, Lillaz E, Gruden G, Lolli V, Chaturvedi
N, Fuller JH, Veglio M, Cavallo-Perin P: EURODIAB
IDDM Complications Study Group. Incidence and risk
factors of prolonged QTc interval in type 1 diabetes.
Diabetes Care 2007; 30 (8): 2057-63.
8- Chugh SS, Reinier K, Singh T, Uy-Evanado A, Socoteanu
C, Peters D, Mariani R, EMT-P, Gunson K, Jui J: Determinants of Prolonged QT Interval and Their Contribution
to Sudden Death Risk in Coronary Artery Disease. The
Oregon Sudden Unexpected Death Study. Circulation
2009; 119: 663-670.
9- Veglio M, Giunti S, Stevens LK, Fuller JH, Perin PC (The
EURODIAB iDDM Comlication Study Group): Prevalence of Q-T interval dispersion in type 1 diabetes and
its relatin with cardiac ischemia. Diabetes Care 2002; 25
(4): 702-707.
Conclusion
The prevalence of CAN in type 1 diabetic
patients is high. Age of patients and duration of
disease is a significant risk factor of CAN. Q-T
interval is an easy and specific test for autonomic
dysfunction with reasonable sensitivity, specificity,
PPV and NPV. Patients with prolonged Q-T interval
should be closely monitored and special care should
be taken during anesthesia. As albumin/creatinine
ratio is related to cardiac autonomic tests, it should
be closely monitored especially in hypertensive
diabetics or those with family history of hypertension.
10- Ewing DJ, Clarke BF: Diagnosis and management of

diabetic autonomic neuropathy. BMJ 1982; 285: 916-8.
11- Trivill LA, Ranney HM, Dai HT: Hemoglobin components
in patients with diabetes mellitus. N Engl J Med 1971;
284: 353-57.
12- Vinik AI, Maser RE, Mitchell BD, Freeman R: Diabetic
autonomic neuropathy. Diabetes Care 2003; 26: 1553-79.
13- Vinik AI, Ziegler D: Diabetic cardiovascular autonomic
neuropathy. Circulation 2007; 115: 387-97.
14- Parie's PV, Attali JR and the French Group for Research
and Study of Diabetic Neuropathy: Cardiac Autonomic
Neuropathy in Diabetic Patients: Influence of Diabetes
Duration, Obesity, and Microangiopathic ComplicationsThe French Multicenter Study. Metabolism 2003; 52 (7):
815-820.
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1- Rolim LC, Roberto J, Chacra AR, Dib SA: Diabetic
cardiovascular autonomic neuropathy: Risk factors, clinical
imact and early diagnosis: Arq Bras Cardiol; 90 (4): e23e31, 2008.
15- Veglio M, Sivieri R, Chinaglia A, Scaglione L, CavalloPerin P: QT interval prolongation and mortality in type
1 diabetic patients: A 5 year Cohort prospective study.
Neuropathy study group of Italian Society of the study
of diabetes, Piemonte Affilate. Diabetes Care 2000; 23:
1381-1383.
2- Okin PM, Devereux RB, Lee ET, Galloway JM, Howard

BV: Electrocardiographic repolarization complexity and
abnormality predict all-cause and cardiovascular mortality
in diabetes: The Strong Heart Study. Diabetes 53: 434440, 2004.
387

16- Pappachan JM, Sebastian J, Bino BC, Jayaprakash K,
Vijayakumar K, Sujathan P, Adinegara LA: Cardiac autonomic neuropathy in diabetes mellitus: prevalence, risk
factors & utility of corrected QT interval in the ECG for
its diagnosis. Postgrad Med J 2008; 84 (990): 205-10.
18- Straub RH, Palitzsch KD, Ziez B, Scholmerick J: Impact

of disease duration on cardiovascular and papillary autonomic nervous system function in IDDM and NIDDM,
patients. Diabetes Care 1996; 14: 960-7.
19- Suys BE, Huybrechts SJA, De Wolf D, De Beeck LO,
Matthys D, Overmeire BV, Du Caju MV, Rooman RPA:
QTC interval prolongation and QTc dispersion in children
and adolescents with type I diabetes. J Pediatr 2002; 141:
59-63.
17- Riabykina GV, Laptev DN, Seid-Gusenov AA: Changes

of QT-interval duration in children and adolescents suffering from type 1 diabetes mellitus. Kardiologiia 2007;
47 (12): 35-8.
388
Pro-BNP Study of Patients Referred for Echocardiographic

Assessment of Left Ventricular Diastolic Function
DINA YI NASSAR, MD1; SALAMA H OMAR, MD2; AHMED SAID A ZAKY, MD3;
AIDA KORAYEM, MD4; AHMED DAWOOD, MD5; SAAD BAHER EL-BADAWY, MD6;
HODA EL-KHATEEB, MD7; M SHERIF HASHEM, MD7
Objective: This study examined the relationship of B-type natriuretic peptide (pro-BNP) to echocardiographic parameters
of cardiac diastolic function in patients referred to rule out abnormal diastolic function (DF) as a cause of heart failure (HF).
We studied the validity of Pro-BNP compared to trans-mitral Doppler recordings, in determining abnormal diastolic function
(DF: Grades II-IV).
Methods: Patients underwent standard trans-mitral Doppler interogation for E & A waves; E/A ratio & deceleration time
for DF determination. They had Pro-BNP assays using specific kits (Roche Diagnostics). Samples were drawn after a minimum
of 15 minutes resting in the supine position. We excluded patients with renal or hepatic failure.
Results: The study included 157 patients including: Normal filling in 52/157 (29.7%) with normal EF >50%; Delayed
relaxation in 88/157 (56%), of whom 55/88 had EF >50%, and finally, pseudonormal and restrictive filling in 10/157 (6.3%).
Total mean LVEF was 57.5% and mean Pro-BNP was 436.9pg/ml (range: 5.0-22943pg/ml). There was a significant correlation
between Pro-BNP and DF. The area under the curve (ROC) for Pro-BNP to detect DF (Grade ll and higher), was 78.3% (95%
CI=71.0%-85.6%). Pro-BNP cut-point of 89 pg/ml had a sensitivity of 66.3% and specificity of 79.6% and test accuracy of 78%
for DF Grade ll or higher (p<0.0001), compared to normal filling (DF Grade I).
Conclusion: Pro-BNP should be used to rule-out HF whenever the latter diagnosis is in question, due to diastolic dysfunction,
even in the presence of normal systolic function.
Key Words: Pro- BNP Echocardiographic Left ventricular diastolic function.
Introduction
Implicit in that physiological definition is that HF

can be caused by an abnormality in systolic function
leading to a defect in expulsion of the blood (systolic HF), or by an abnormality in diastolic function
leading to a defect in ventricular filling (diastolic
HF) [1]. The former is the more familiar, classic
HF in which an impaired inotropic state is responsible. Less familiar, but perhaps just as important,
is diastolic HF, in which the ability of the ventricle
(s) to accept blood is impaired [2]. This problem
is not rare, accounting in some series for as many
as one third of patients presenting with HF [3]. The
fraction of patients with diastolic dysfunction is
higher in elderly patients [4] . Classic causes of
isolated diastolic dysfunction include; Chronic
hypertension with LVH, Hypertrophic cardiomyopathy, Hypertensive hypertrophic cardiomyopathy
of the elderly and Aortic stenosis with a normal
ejection fraction [5]. Heart failure can be difficult
to diagnose accurately, because the signs and symp-
Congestive heart failure (HF) may be considered

a condition in which cardiac output is not adequate
to meet the metabolic needs of the body, either at
rest or with exercise, usually accompanied by an
increase in cardiac filling pressure and/or volume.
The Departments of Cardiology1, Al-Azhar University, School
of Medicine, Cairo Egypt; Critical Care2, Cairo University,
School of Medicine, Cairo Egypt; Internal Medicine &
Nephrology 3 , Cairo University, Cairo Egypt; Clinical
Pathologist4, Laboratory Medicine, EBH Jeddah, KSA; NonInvasive Cardiologist5, EBH Jeddah, KSA; Clinical Pathologist
& Director6, Laboratory Medicine, EBH and Cardiologist,
Head of Non-Invasive Cardiology7, EBH Jeddah, KSA.
Manuscript received 20 Dec., 2009; revised 25 Jan., 2010;
accepted 26 Jan., 2010.
Address for Correspondence: Dr. Dina YI Nassar,
The Department of Cardiology, Al-Azhar University,
School of Medicine, Cairo, Egypt.
389
Pro-BNP Study of Patients Referred for Echocardiographic Assessment
toms of this disorder are neither sensitive nor

specific [6].
evaluation of diastolic function patients underwent standard trans-mitral Doppler interrogation

for E & A waves; E/A ratio & deceleration time
for DF determination. All patients were subjected to echocardiographic examination by cardiology specialist and reviewed by consultant
non-invasive cardiologist.
Natriuretic peptide (BNP) is a polypeptide,

released by ventricular myocytes in direct proportion to wall tension, which lowers reninangiotensin-aldosterone activation.
In early pilot studies, raised concentrations of
Brain Natriuretic peptide (BNP) distinguished heart
failure from other causes of dyspnoea more accurately than did left-ventricular ejection fraction,
ANP, and N-terminal ANP, with a sensitivity of
greater than 90% and a specificity of 80-90% [7,8].
d- Blood sample drawn in the resting supine position for 15 minutes for pro-BNP assay using
specific kits (pro-BNP CalSet from Roche
Diagnostics). Thus, the sample was obtained at
the end of the echocardiographic examination.
e- All patients were reviewed by nephrologists to
rule out patients with significant renal dysfunction before enrolment in the study.
Objectives:
This study was planned as part one of a project
aiming to evaluate the correlation of echocardiographic findings in left ventricular dysfunction, as
a standard modality of evaluation of diastolic
dysfunction, with rapid non-invasive blood assay
of N terminal Brain Natriuretic peptide (NT Pro
BNP). This part of our project (part II) was aimed
mainly for examination of pro BNP in patients
with pure left ventricular diastolic dysfunction
(DF).
Kruskal Wallis was used to detect significant
differences between means.
Correlation coefficient of Pearson was used to
detect correlation between pro-BNP and Diastolic
Function (DF).
Results
The study included 157 patients (males: 71.3%

and females 28.7%). Mean age of the whole group
was 53.2 (14.5) years. Table (1) shows the results
for all patients diastolic function (DF) divided
according to sex distribution and NYHA classes.
The results included; Normal filling in 56/157
(29.7%) with normal EF >50%; Delayed relaxation
in 89/157 (56%), of whom 55/88 had EF >50%,
and finally, pseudonormal and restrictive filling in
10/157 (6.3%). Most patients had DF Grade I
(35.5%) or II (58.6%).
Our study included patients referred to the

Echocardiography Laboratory for left ventricular
(LV) function evaluation; they were enrolled after
an informed consent. Patients presenting to Internal
medicine or Cardiology outpatient clinics in the
hospital (Dr. Erfan & Bagedo general hospital) or
referred from other specialities for pre-operative
assessment prior to non-cardiac surgery or referred
to non-invasive cardiology lab from other hospitals
for echocardiography to rule out left ventricular
dysfunction, with or without hypertension, in patients presenting with effort intolerance or shortness
of breathing of possible cardiac etiology.
Mean pro-BNP (SD) in DF II-IV=148 (210),

and in normal=41.3 (40.8). The wide SD reflects
the marked heterogeneity in the study population.
Total mean LVEF was 57.5% and mean Pro-BNP
was 436.9pg/ml (range: 5.0-22943pg/ml). In Table
(2), sensitivity and specificity of different proBNP levels in patients with diastolic dysfunction
grades II-IV was shown. At level of 89pg/ml sensitivity of Pro-BNP to detect diastolic dysfunction
was 67% and specificity of 80%.
All referred patients were assessed for the following parameters:

a- Exclusion if they had history of recent (one
month) acute myocardial infarction or renal or
hepatic failure.
b- Thorough clinical examination especially for
evident clinical signs of heart failure or other
organ failure as renal failure.
In the included figure, receiver-operating characteristic curve (ROC) was fitted, so that pro-BNP
could be examined as a possible good measure for
detection of cases with abnormal DF grades II-IV
as compared to grade I, being correctly classified
c- M-mode; two-Dimensional & Doppler echocardiography was performed using Philips 5000
HDI scanners and scanheads (probes) P4-2. For
390
Dina YI Nassar, et al
in 78% of cases. There was a significant correlation

between Pro-BNP and DF. The area under the curve
(ROC) for Pro-BNP to detect DF (Grade II and
higher), was 78.3% (95% CI=71.0%-85.6%). ProBNP cut-point of 89pg/ml had a sensitivity of
66.3% and specificity of 79.6% and test accuracy
of 78% for DF Grade II or higher (p<0.0001),
compared to normal filling (DF Grade I).
Discussion
Although the clinical manifestations of HF with
and without systolic dysfunction are frequently
very similar, the pathophysiological processes
underlying the syndromes and consequently the
treatment are quite different. In marked contrast
to the fundamental defect in systolic HF, patients
with isolated diastolic HF have normal or often
even enhanced contractile function of the left
ventricle, which is intrinsically capable of responding normally to an increase in preload, and there
is no undue sensitivity of systolic performance to
increased afterload [9]. However, these patients
also have dyspnea and fatigue, often as severe as
that seen in patients with contractile dysfunction
[10] . The key problem in this syndrome is that
ventricular stiffness or reduced compliance leads
to limitations on the use of preload reserve because
of rapid increases in cardiac filling pressures at
normal or slightly increased cardiac volume. These
effects limit cardiac output and cause dyspnea
during exercise [11]. Loss of normal left ventricular
diastolic relaxation and distensibility, due to either
structural (hypertrophy) or functional (ischemia)
causes, impairs left ventricular filling, resulting in
increases in left ventricular diastolic, left atrial,
and pulmonary venous pressures, which directly
increases the pulmonary capillary pressure with a
relative shift of left ventricular filling to the later
part of diastole and a greater dependence on atrial
contraction [12]. One study found that the reduction
in left ventricular peak filling rate during exercise
was an important determinant of exercise performance in patients with coronary heart disease,
hypertension, and normal left ventricular systolic
function [13].
Table 1: Sex, diastolic function and NYHA distribution.

Diastolic function
I
II
No.
No.
III
%
IV
No. % No. %
Gender:
Male (N=112) 41 36.6
Female (N=45) 15 23.5
63 56.3
26 65
1
0
0.9
0.0
7
3
6.3
2.5
NYHA:
I (N=78)
II (N=56)
III (N=12)
IV (N=10)
33
44
11
1
0
0
1
0
0.0
0,0
8.3
0.0
0
5
0
5
0.0
5.4
0.0
83.3
45
9
0
0
57.7
16.1
0.0
0.0
42.3
78.6
91.7
16.7
Table 2: Sensitivity and specificity of Pro-BNP cut-points

compared to DF grades II-IV.
Cut Points
Sensitivity
Specificity
<9
9-<16
16-<30
30-<44
44-<89
89-<130
130-<214
214-<352
352-<768
768+
94.9
89.9
83.7
72.4
67.0
55.1
43.9
28.6
15.3
18.5
38.9
53.7
64.8
80.0
87.0
94.4
96.3
100.0
1.00
30
0.80
16
Diagnosis of DF is often challenging problem

in patients presenting to emergency room or admitted for monitoring because of severe shortness
of breathing. Electrocardiogram (ECG) may be
helpful but is not diagnostic. In patients with
marked left ventricular hypertrophy (due to hypertension, aortic stenosis, or hypertrophic cardiomyopathy), the ECG typically shows voltage criteria
for LVH with associated ST-T wave changes indicative of subendocardial ischemia. In some patients
with underlying coronary heart disease, there may
be evidence of a previous myocardial infarction
[14]. Chest X-ray has no specific pattern in diastolic
dysfunction apart from other manifestation as in
patients with congestive heart failure [15] . The
presence of pure diastolic dysfunction is established
Sensitivity
44
89
0.60
130
214
0.40
352
0.20
768
0.00
0.00
0.20
0.40
0.60
1-Specificity
0.80
1.00
Figure 1: ROC curve for Pro-BNP cut-point by DF stages IIIV.
391
Pro-BNP Study of Patients Referred for Echocardiographic Assessment
by demonstrating with echocardiography or radionuclide scanning that the left ventricular ejection
fraction and volume are normal [16]. During normal
sinus rhythm, Doppler echocardiography of the
mitral valve inflow may demonstrate Important
diagnostic parameters derived from the mitral
inflow signals include the ratio of peak early filling
velocity (E wave) to late filling velocity (A wave)
(E/A ratio), the deceleration time of the early filling
curve (DT), and the isovolumic relaxation time
(IVRT). The relationship between peak velocity
and deceleration in early diastole with late diastolic
velocities during atrial contraction is altered in
diastolic dysfunction) [16,17,18].
of 78% for DF Grade II or higher (p<0.0001),

compared to normal filling (DF Grade I). Results
confirm the previous data obtained by Lubein and
colleagues, his work included 294 patients with
normal systolic function. Patients were classified
as normal, impaired relaxation, pseudonormal, and
restrictivelike filling patterns. Patients with restrictive-like filling patterns on echocardiography had
the highest BNP levels (40866pg/mL), and patients with symptoms had higher BNP levels in all
diastolic filling patterns. The area under the receiver-operating characteristic curve for BNP to detect
any diastolic dysfunction was 0.92 (95% CI, 0.87
to 0.95; p<0.001). A BNP value of 62pg/mL had
a sensitivity of 85%, a specificity of 83%, and an
accuracy of 84% for detecting diastolic dysfunction.
In contrast with echocardiography that was

established as standard technique for detection of
diastolic heart failure, Pro BNP is technically easier
to perform as a quick blood screening test in
patients with severe dyspnea to differentiate between HF and other causes as pulmonary disease
or obesity. Still the test was not established in
diastolic dysfunction, but in early pilot studies,
raised concentrations of BNP distinguished heart
failure from other causes of dyspnoea more accurately than did left-ventricular ejection fraction,
ANP, and N-terminal ANP, with a sensitivity of
greater than 90% and a specificity of 80-90%
[19,20]. Previous studies proved that concentrations
of BNP are consistently raised in disorders associated with diastolic dysfunction, such as aortic
stenosis, hypertrophic cardiomyopathy, and restrictive cardiomyopathy [21,22,23]. The concentrations
are higher in patients with systolic dysfunction
than in those with isolated diastolic dysfunction,
and highest in those with both systolic and diastolic
dysfunction [24]. Among patients with preserved
left-ventricular function, BNP correlates with
doppler indices of diastolic dysfunction: Concentrations are raised among patients with evidence
of impaired relaxation and highest among those
with a restrictive filling pattern [25,26]. In a study
by Lubein et al, in 2002, accuracy of BNP for
diagnosis of isolated diastolic heart failure approaches that for diagnosis of heart failure due to
systolic dysfunction [26].
Seki et al studieded the relationship between

plasma BNP and various parameters including
echocardiography and ECG in 154 patients with
untreated hypertension. Their results showed that
patients with elevated BNP had a significant greater
ECG voltage criteria, left ventricular mass index
deceleration time as well as a smaller E/A ratio
p=0.0003 [28].
A comparative study by cyphan et al, 2008
investigate the ability of N-Terminal pro Brain
Natriuretic Peptide (NT-proBNP to detect diasolic
LV dysfunction By tissue Doppler. They found a
positive correlation with E/E' ratios (r=0.80,
p<0.0001) and A NT-proBNP value of 119pg/ml
had a sensitivity of 87%, a specificity of 100% for
predicting E/E' >15 [29].
A similar study by Tschpe C with the additional
use of invasive left and right heart catheterization
to tissue Doppler confirmed that NT-proBNP as
an independent predictor of diastolic dysfunction
with an Odds ratio of 1.2 (1.1-1.4, CI 95%) for
every unit increase of NT-proBNP [30].
Conclusion
In conclusion, Pro BNP is an important and
reliable diagnostic tool for patients with diastolic
heart failure presenting to emergency room with
severe dyspnea. It will significantly correlate with
the degree of diastolic dysfunction and help in
proving diagnosis in patients with normal systolic
function by echocardiography. Further research is
necessary to identify the specific relation between
increase in myocardial stiffness and increase in
marker on myocyte stretch as Pro BNP.
In our study, patients included had mostly DF

grade I and II with normal systolic function. There
was a significant correlation between Pro-BNP
and DF. The area under the curve (ROC) for ProBNP to detect DF (Grade II and higher), was 78.3%.
Pro-BNP cut-point of 89pg/ml had a sensitivity of
66.3% and specificity of 79.6% and test accuracy
392
Dina YI Nassar, et al
17- Cohen GI, Pietrolungo JF, Thomas JD, et al: A practical
guide to assessment of ventricular diastolic function using
Doppler echocardiography. J Am Coll Cardiol 1996; 27:
1753.
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18- Hatle L: Doppler echocardiographic evaluation of diastolic

function in hypertensive cardiomyopathies. Eur Heart J
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19- Labovitz AJ, Pearson AC: Evaluation of left ventricular

diastolic function: Clinical relevance and recent Doppler
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4- Vasan RS, Benjamin EJ, Levy D: Prevalence, clinical

features and prognosis of diastolic heart failure: An
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natriuretic peptide in assessment of acute dyspnoea.
Lancet 1994; 343: 440-44.
21- Cowie MR, Struthers AD, Wood DA, et al: Value of
natriuretic peptides in assessment of patients with possible
new heart failure in primary care. Lancet 1997; 350: 134953.
5- Topol EJ, Traill TA, Fortuin NJ: Hypertensive hypertrophic

cardiomyopathy of the elderly. N Engl J Med 1985; 312:
277.
6- Dao Q, Krishnaswamy P, Kazanegra R, et al: Utility of
B-type natriuretic peptide in the diagnosis of congestive
heart failure in an urgent-care setting. J Am Coll Cardiol
2001; 37: 379-85.
22- Mizuno Y, Yoshimura M, Harada E, et al: Plasma levels

of A- and B-type natriuretic peptides in patients with
hypertrophic cardiomyopathy or idiopathic dilated cardiomyopathy. Am J Cardiol 2000; 86: 1036-40.
7- Davis M, Espiner E, Richards G, et al: Plasma brain

natriuretic peptide in assessment of acute dyspnoea.
Lancet 1994; 343: 440-44.
23- Qi W, Mathisen P, Kjekshus J, et al: Natriuretic peptides

in patients with aortic stenosis. Am Heart J 2001; 142:
725-32.
8- Cowie MR, Struthers AD, Wood DA, et al: Value of

natriuretic peptides in assessment of patients with possible
new heart failure in primary care. Lancet 1997; 350: 134953.
24- Takemura G, Takatsu Y, Doyama K, et al: Expression of

atrial and brain natriuretic peptides and their genes in
hearts of patients with cardiac amyloidosis. J Am Coll
Cardiol 1998; 31: 754-65.
9- Goldsmith S, Dick C: " Differentiating Systolic From

Diastolic Heart Failure : Pathophysiologic and Therapeutic
Considerations ". The American Journal of Medicine
1993; Vol 95, Pages 645-655.
25- Maisel AS, Koon J, Krishnaswamy P, et al: Utility of Bnatriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine
left ventricular dysfunction. Am Heart J 2001; 141: 36774.
10- Packer M: Abnormalities in diastolic function as a potential

cause of exercise intolerance in chronic heart failure.
Circulation 1990; 81 (Suppl III): III-78.
26- Yu CM, Sanderson JE, Shum IO, et al: Diastolic dysfunction and natriuretic peptides in systolic heart failure:
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ventricular peak filling rate during exercise to exercise
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393
Predictors of in-Hospital Mortality in Patients with Cardiogenic Shock

Complicating Acute Myocardial Infarction
MOHAMMED SAAD, MD*,**; ALIA ABDEL-FATTAH, MD*;
AHMED ABDEL-AZIZ, MD*; AMR ELHADIDY, MD*; GERT RICHARDT, MD**
Purpose: Is to evaluate predictors of in-hospital mortality in patients with cardiogenic shock (CS) complicating acute
myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI).
Methods: We included 25 patients with acute myocardial infarction complicated by cardiogenic shock within 24h after
symptom treated with percutaneous coronary intervention.
Results: Total in-hospital mortality was 32%. In univariate analysis, plasma concentrations of LDH, level of CRP,
Noradrenalin, Adrenalin, aldosterone and creatinine were significantly higher in mortality group. (LDH: 1178705U/L Vs
563369U/L, p=0.012; CRP: 22.510.5mg/dl Vs 12.510.9mg/dl, p=0.027; Noradrenalin: 26932215ng/l Vs 789659ng/l,
p=0.002; Adrenalin: 231.6173ng/l Vs 130 354ng/l, p=0.007; Aldosterone: 282124pg/ml Vs 4850pg/ml, p=<0.001;
Creatinine: 2.431.0mg/dl Vs 1.230.86mg/dl; p=0.011). The occurrence of renal failure during in-hospital stay was associated
with significantly increased mortality (87% Vs 12%, p=0.001).
Multivariate logistic regression analysis revealed that renal failure (OR 12.4, 95% CI 0.001-2.47, p=0.001) and increased
creatinine level (OR 3.3, 95% CI 1.21-8.9, p=0.01) were independent predictors of in-hospital mortality in the study population
Conclusion: In patients with AMI complicated by CS successfully treated by primary PCI, total in-hospital mortality was
32%. Acute-phase plasma concentration of catecholamine, aldosterone and CRP are reliable predictors of mortality. The
occurrence of renal failure and high creatinine level are independent predictors of mortality.
Key Words: Cardiogenic shock Acute myocardial infarction Angioplasty Stents Peptides Prognosis.
Introduction
thermore, it is known that the concentrations of

these cardiovascular peptides in the early phase
are closely related to mortality in patients with
AMI [6].
Cardiogenic shock occurs in 7-10% of patients

after acute myocardial infarction (AMI). Untreated,
it causes an early mortality of about 80% [1,2] and
is the leading cause of death among patients hospitalised with AMI.
However, it is unclear which of these peptides

are the most useful acute-phase predictors of subsequent mortality in AMI patients with CS. All
patients were intended to be treated with immediate
primary percutaneous coronary intervention (PCI)
and were closely monitored for clinical complications till discharge. Therefore, the purpose of this
study was to evaluate the useful predictors of
mortality, including neurohumoral activation, in
the acute stage of AMI patients with CS.
Cardiovascular peptides like catecholamines,

aldosterone, renin and Pro-BNP are involved in
the neurohumoral activation [3-5] in patients with
AMI and heart failure, their plasma concentrations
increasing in proportion to clinical severity. FurThe Department of Critical Care*, Cairo University, Egypt
and Herz-Kreislauf-Zentrum**, Segeberger Kliniken GmbH
(Academic Teaching Hospital of the University of Kiel), Bad
Segeberg, Germany.

Twenty-five patients with acute myocardial
infarction complicated by cardiogenic shock within
24h after symptom treated with percutaneous coronary intervention from October 2007 to April
Manuscript received 2 April, 2010; revised 5 May, 2010;

Address for Correspondence: Dr. Amr El-Hadidy,
Critical Care Medicine Department, Cairo University.
395
2009 in the heart centre, Segeberger Kliniken,

Germany were considered for this analysis. All
patients gave informed consent, and the study was
approved by the local committee in the centre.
Glycoprotein IIb/IIIa inhibitors were given

according to the clinical and angiographic situation.
The indications for administration were: (1) the
presence of intracoronary filling defects or haze
after PCI, suggestive of thrombus; (2) slow flow
after intracoronary stenting; (3) persistent dissection
flaps; (4) suspected inlet or outlet dissection flaps
after stenting; and (5) after long or multiple stenting,
especially in the context of acute coronary syndromes or AMI.
Study patients and inclusion criteria:

The diagnosis of AMI was made on the basis of
the following criteria:
1- Chest pain.
2- Electrocardiographic ST segment elevation of
>0.1mV in 2 or more limb leads, or >0.2mV in
2 or more precordial leads, or presentation of
a newly developed left-bundle branch block.
3- Elevated total serum creatine kinase (CK) more
than twice the upper limit of the normal range.
Based on diagnostic coronary angiography, the

number, location, and characteristics of the target
vessel will be analyzed. Critical stenosis will be
defined as 75% diameter stenosis. Emergency
PCI was performed as soon as possible in patients
who were able to undergo coronary angiography.
Successful reperfusion was defined as TIMI 3 flow
in the infarct-related artery after PCI and 25%
residual stenosis.
Cardiogenic shock was defined as Blood pressure <90mmHg (without inotropic or intraaortic
balloon support), signs of hypoperfusion (cold
extremities, impaired mental status, or urine output
<30ml/h), evidence of pulmonary congestion on
chest X-ray or finally patient requiring inotropes,
intra-aortic balloon pump (IABP), or cardiopulmonary support to assist the circulation.
After coronary stenting, a loading dose of

600mg Clopidogrel was administered followed by
75mg once daily. Patients were subsequently nursed
on the coronary care unit or on the cardiac intensive
care unit if they were being ventilated.
Exclusion criteria:
Patients receiving thrombolysis before PCI,
Renal failure on admission (defined as serum
creatinine concentration >3.0mg/dl), Patients who
reached hospital >24h after onset patients with
cardiogenic shock caused by papillary muscle
rupture, interventricular septal defect, or cardiac
rupture before PCI, Patients for whom coronary
artery bypass grafting (CABG) was considered the
best initial revascularisation strategy and Patients
who died before the initial blood samples taken.
Definition of the risk factors:

Hypertension was present if it had been diagnosed and treated elsewhere or if the systolic blood
pressure was greater than 140mmHg or the diastolic
blood pressure exceeded 90mmHg on more than
2 occasions; diabetes mellitus was present if it had
been diagnosed and treated elsewhere or as a fasting
blood glucose 126mg/dl after admission; hypercholesterolemia was present if it had been diagnosed and treated elsewhere or the fasting serum
cholesterol concentration 200mg/dl.
Coronary angiography and intervention:

Coronary angiography was performed without
routine left ventriculography. The use of an IABP
in the catheterisation laboratory was left to the
discretion of the attending cardiologist, with insertion of the device either before or after PCI. The
strategy was percutaneous intervention to the culprit
vessel if this could be identified, with intervention
to other critical coronary stenoses only attempted
in the absence of early haemodynamic improvement. The aim was to keep the procedure as short
as possible and minimise the contrast load. The
use of adjunctive pharmacological treatment and
other mechanical devices in the catheterisation
laboratory was left to the discretion of the attending
cardiologist.
MACE was defined as the occurrence of death,

cerebrovascular accident, AMI, repeated PCI, coronary artery bypass grafting (CABG), renal failure
and bleeding requiring blood transfusion during
hospitalization.
Blood sampling:
The concentrations of the cardiovascular peptides are reported to peak approximately 24h after
the onset of AMI, [7,8,9] so we preferred that time
to take blood samples from all subjects. The concentrations of Pro-BNP, renin, epinephrine, norepinephrine, and aldosterone were all measured in
those blood samples. Cardiac enzymes and biochemical markers such as CRP were checked on
admission, followed by daily monitoring while in
396
Mohammed Saad, et al
Table 2: Baseline laboratory characteristics.
hospital. The levels of CRP, Troponin T, CK, CKMB, LDH and creatinine during hospital stay were
considered for the analysis.
Laboratory data
LDH (U/L)
Maximal CK (U/L)
Maximal CK-MB (U/L)
Troponin T (ng/ml)
CRP (mg/dl)
Adrenalin (ng/1)
Noradrenalin (ng/l)
Pro BNP (pg/ml)
Renin (pg/ml)
Aldosterone (ng/1)
ARQ
Creatinine (mg/dl)
Continuous variables were summarized as
meanSD and categorical variables as percentages.
Univariate analysis was performed with CHI-square
tests to compare each of the qualitative variables
and with Mann Whitney test for quantitative variables. All statistical tests were unpaired 2-tailed
tests and a p-value <0.05 was considered statistically significant. Multivariate analysis was done
with logistic regression to calculate p-value and
odds ratio for some of the quantitative variables
whose p-value in the univariate analysis is significant (<0.05) and so could be used as predictor for
mortality. All statistical calculations were made
with the SPSS software.
Baseline characteristics:
Patients were analyzed using their clinical status
at initial admission to the hospital. The baseline
clinical characteristics of these 25 patients are
shown in Table (1) and the baseline laboratory
characteristics in Table (2).
Male
Age (Years)
Current smokers
DM
Hyperlipidenua
Hypertension
Systolic BP (mmHg)
Diastolic BP (mmHg)
EF (%)
Atrial fibrillation
Previous NU
Previous PCI
Previous CABG
STEMI
NSTEMI
17 (68%)
6714
11 (44%)
10 (40%)
15 (60%)
14 (56%)
10424
6115
3416
2 (50%)
6 (24%)
3 (12%)
5 (20%)
13 (52%)
12 (48%)
2461
35580
1419
37
41.8
1498
7800
32415
721
463
61
3.8
760567
44167889
325398
5.37.9
15.811.5
162307
13981594
38196322
117168
178-144
4.5812
1.61.06
Angiographic characteristics and outcome of

PCI:
The infarct related artery was the left anterior
descending in 16%, the circumflex in 24%, the
right coronary artery in 52% and a bypass graft in
8% of the patients. Single, double and triple vessel
coronary artery disease was observed in 24%, 20%
and 56% of the patients, respectively. The mean
total procedural time was 7435min. The intervention resulted in a TIMI 3 flow in 88% while 22%
had a TIMI 0/1 flow in the infarct-vessel after PCI.
Table 1: Baseline patient characteristic.

Number (%)
143
45
10
0.02
0.1
2
75
549
4
32
0
0.6
Values are mean SD.

LDH
: Lactate dehydrogenase.
CK
: Creatine phosphokinase.
CK-MB : Creatine phosphokinase MB.
CRP
: C-reactive protein.
Pro BNP : Pro-beta natriuretic peptide.
ARQ
: Aldosterone-renin quotient.
Results
Clinical Characteristic
Minimum Maximum Mean SD
One stent was implanted in 32% of patients, 2

stents in 44% and more than 2 stents in 24%.
Mechanical support with an intra-aortic balloon
pump was used in only 9 (36%) patients, 4 (44.4%)
of these died. Glycoprotien IIb/IIIa inhibitors were
used in 56% of patients (Table 3).
In-hospital outcome:
The total in-hospital mortality was 32% (Fig.
1). During the hospital stay, 9 patients (36%) had
renal failure; of them 2 patients needed dialysis,
6 Patients suffered from bleeding that needed blood
transfusion and 11 patients (44%) required mechanical ventilation. Urgent coronary artery bypass
surgery was not needed in any patient. NO patient
suffered sub-acute in-stent thrombosis, acute closure, re-infarction, ventricular tachycardia or and
cardiac rupture (Table 4).
Values are n (%) or mean SD.

DM: Diabetes mellitus.
EF : Ejection fraction.
PCI: Percutaneous coronary intervention.
CABG : Coronary artery bypass graft.
STEMI : ST-elevation myocardial infarction.
NSTEMI: Non ST-elevation myocardial infarction.
397

Table 3: Angiographic characteristics and outcome of PCI.
Angiographic Characteristic
Coronary artery disease:
1-vessel
2-vessel
3-vessel
Target vessel:
LAD
LCX
RCA
Bypass graft
Number (%)
of intra aortic balloon pumping, use of Glycoprotien

IIb/IIIa inhibitors or patients who required a respirator.
6 (24%)
5 (20%)
14 (56%)
Table 5: Baseline and angiographic characteristics of group

S and group.
6 (24%)
13 (52%)
2 (8%)
Number of stent used:

1 stent
2 stents
>2 stems
8 (32%)
11 (44%)
6 (24%)
TIMI flow 3 after PCI

Glycoprotien IIb/IIIa inhibitors
LABP
Proced Duration (min)
22 (88%)
14 (56%)
9 (36%)
7435

LAD : Left anterior descending.
LCX : Left circumflex.
RCA : Right coronary artery.
PCI : Percutaneous coronary intervention.
IABP: Intra-aortic balloon pump.
Table 4: In-hospital outcome.

In hospital outcome
Renal failure
Dialysis
Bleeding
Mechanical ventilation
Hospital stay
Death
Number (%)
9 (36%)
2 (8%)
6 (24%)
11 (44%)
11.57
8 (32%)
Group S
(n=17)
Group D
(n=8)
p-value
Male Gender
Age (years)
Smoking
Dpi
Hperlipidemia
Hvpertension
BP systolic (mmHg)
BP diastolic (mmHg)
EF (%)
Atrial Fibrillation
Previous MI
Previous PCI
Previous CABG
STEMI
11 (65%)
6712
7 (41%)
6 (35%)
11 (65%)
9 (53o)
10227
6317
3514.6
1 (6%)
4 (24%)
2 (12%)
2 (12%)
8 (47%)
6 (75%)
6819
4 (50%)
4 (50%)
4 (50)
5 (63%)
10718
589
30.614.5
1 (13%)
2 (25%)
1 (13%)
3 (38%)
5 (63%)
0.96
0.82
0.7
0.8
0.8
0.98
0.26
0.95
0.5
0.57
0.94
0.96
0.33
0.77
CAD:
1
2
3
4 (24%) 2 (25%)
4 (24o) 1 (13%)
9 (52%) 5 (63%)
0.83
TIMI 3 after PCI

GP II-flow b/IIIa inhibitor
IABP
Proc duration (min)
15 (88%)
10 (59%)
5 (29%)
7136
0.96
0.68
0.58
0.4
7 (87%)
4 (50%)
4 (50%)
8035

DM: Diabetes mellitus.
BP : Blood pressure.
EF : Ejection fraction.
PCI: Percutaneous coronary intervention.
CABG : Coronary artery bypass graft.
STEMI: ST-elevation myocardial infarction.
CAD : Coronary artery disease.
GP
: Glycoprotein.
IABP : Intra-aortic balloon pump.
Univariate analysis:
We have divided our patient population according to the In-hospital fate into 2 groups, group S
includes 17 patients who survived till discharge
from the hospital and group D includes 8 patients
who suffered in-hospital mortality. The clinical
characteristics for the 2 groups are summarized in
Table (5). There were no significant differences in
age, gender, coronary risk factors, atrial fibrillation
or history of MI, previous PCI or previous CABG.
In other words, the background of both groups of
patients was not statistically different.
Table (6) shows the laboratory findings for the

2 groups. Plasma concentrations of LDH, level of
CRP, Noradrenalin, Adrenalin, aldosterone and
creatinine were significantly higher in group D
than in group S. (LD: 1178705U/L Vs 563
369U/L, p: 0.012, CRP: 22.510.5mg/dl Vs 12.5
10.9mg/dl, p: 0.027; Noradrenalin: 2693+2215ng/l
Vs 789659ng/l, p: 0.002; Adrenalin: 231.6
173ng/l Vs 130354ng/l, p: 0.007; Aldosterone:
282124pg/ml Vs 4850pg/ml, PL <0.001; Creatinine: 2.431.0mg/dl Vs 1.230.86mg/dl; p: 0.011)
(Figs. 2-6).
Regarding the clinical presentation and the

hemodynamic data at the time of admission, there
were no significant differences between the 2
groups in the number of patients with STEMI or
systolic blood pressure on arrival. Also, there were
no significant differences in the frequency of use
Plasma concentrations of Pro-BNP, Troponin

T and peak total CK tended to be higher in group
D than in group S.
398
There were no significant differences in peakCK-MB, renin, or adrenalin/renin ratio between 2

groups.
tivariate logistic regression analysis revealed that

renal failure (OR 12.4, 95% CI 0.001-2.47,
p=0.001) and increased creatinine level (OR 3.3,
95% CI 1.21-8.9, p=0.01) were independent predictors of in-hospital mortality in the study population.
Table 6: Laboratory characteristics of group S and group D.

Group S
(n=17)
Group D
(n=8)
563369
174212827
250351
2.973
12.510.9
789659
130354
22161837
78118
4850
2.02.4
1.230.86
1178705
1009911868
485467
1012
22.510.5
26932215
231.6173
722710478
198232
282124
1020.8
2.431.0
p-value
Table 8: Multivariate analysis.
LDH (U/L)
Peak CK (U/L)
Peak CK-MB (U/L)
Troponin T (ng/ml)
CRP (mg/dl)
Noradrenalin (ng/1)
Adrenalin (ng/l)
Pro BNP (pg/nil)
Renin (pg/nil)
Aldosterone (ng/l)
ARQ
Creatinine (mg/dl)
0.012
0.055
0.13
0.086
0.027
0.002
0.007
0.081
0.13
0.001
0.18
0.011
p-value Odds Ratio

Renal Failure
Mechanical Ventilation
LDH
Noradrenalin
Aldosterone
CK-MB (Max)
CK (Max)
CRP
Creatinine
Values are mean SD.

LDH
: Lactate dehydrogenase.
CK
CRP
Pro BNP : Pro-beta natriuretic peptide.
ARQ
: Aldosterone-Renin Quotient.
0.001
0.043
0.03
0.01
0.004
0.04
0.04
0.05
0.01
12.4
3.8
1
1.1
1.2
1
1.4
1.2
3.3
CI
0.001-2.47
0.02-0.94
1.000-1.005
1.000-1.003
1.007-1.035
1.006-1.008
1.000-1.001
0.997-1.118
1.21-8.9
LDH : Lactate dehydrogenase.

CK
CRP
No, 32
Major complications occurred during hospital

stay are shown in Table (7). The occurrence of
renal failure during in-hospital stay was associated
with significantly increased mortality in our patient
population (87% Vs 12%, p=0.001) (Fig. 7).
There were no significant differences in the
frequency of other complications, such as the
occurrence of bleeding requiring blood transfusion.
was increased need of mechanical ventilation in
group D more than group S; however the in-hospital
stay was significantly shorter (6.8 days Vs days;
p=0.03).
Table 7: Major complications occurred during hospital stay.
Renal failure
Bleeding
Mech. Vent.
Hosp. Stay (ds)
Discharged
(n=17)
Died
(n=8)
p-value
2 (12%)
4 (24%)
5 (29%)
136.4
7 (87%)
2 (25%)
6 (75%)
7.66.8
0.001
0.94
0.087
0.03
Yes, 68
Figure 1: In-hospital survival.

250
p=0.007
231.6
200
150
130
100
50
Multivariate analysis:
We performed a multivariate analysis with all
parameters which were significantly related to
mortality in a univariate analysis. The odds ratios
for these different parameters for the prediction of
in-hospital mortality are shown in Table (8). Mul-
0
Discharged
Died
Figure 2: Mean plasma concentrations of adrenalin was

significantly higher in group D (died) than in group
S (discharged).
399

3000
2693
p=0.002
22.5
25
2500
p=0.027
20
2000
12.5
15
1500
10
789
1000
500
0
0
Discharged
Died
Discharged
Figure 3: Mean plasma concentrations of Noradrenalin was

S (discharged).
300
Figure 6: Mean plasma concentrations of CRP was significantly higher in group D (died) than in group S
(discharged) (10.5mg/dl Vs 10.9mg/dl, p=0.027
respectively).
282
p0.001
Died
90
80
70
60
50
40
30
20
10
0
250
200
150
100
48
50
87
p=0.001
12
Discharged
0
Discharged
Died
Figure 4: Mean plasma concentrations of aldosterone was

S (discharged).
2.5
p=0.011
Discussion
In our study, the overall in-hospital mortality
rate was 32%. With regard to circulating hormones,
we founded that the concentrations of aldosterone,
Noradrenalin, Adrenalin, creatinine, LDH and level
of CRP may be reliable predictors of mortality in
AMI complicated by CS. In multivariate analysis,
high creatinin level and the occurrence of renal
failure were independent predictors of in-hospital
mortality in patients with cardiogenic shock complicating acute myocardial infarction and undergoing primary PCI.
2.43
2
1.5
1.23
1
0.5
Mortality in CS complicating AMI:

Cardiogenic shock occurs in 7-10% of patients
after acute myocardial infarction (AMI). Untreated,
it causes an early mortality of about 80% [1,2] and
is the leading cause of death among patients hospitalised with AMI.
0
Discharged
Died
Figure 7: Incidence of renal failure was significantly higher

in group D (died) in comparison to group S (discharged) (87% Vs 12%, p=0.001 respectively).
Died
Figure 5: Mean plasma concentrations of creatinine was

significantly higher in group D than in group S.
400
The total in-hospital mortality in our patient

population was 32%. This mortality rate is quite
similar to the earlier retrospective reports in highly
specialized centres that showed very low mortality
rates of around 30% with PCI in cardiogenic shock
[10].
constriction and increasing total peripheral resistance [16].

High renin concentration in the setting of CS
complicating AMI may be closely related to poor
patient outcomes, including mortality [17]. Another
study found increased plasma renin activation at
the time of hospital discharge in postinfarction
patients is an independent sign of poor prognosis
[18]. In our study, neither the concentration of rennin in blood nor adrenalin-renin quotient showed
significant difference between group D and group
S; however, mean renin concentration was higher
in group D than in group S (232pg/ml Vs 118pg/
ml). Our results were consistent as well with a
much larger study by Michorowski and Ceremuzynski of 95 patients that showed raised renin concentrations in 20 of 22 patients within six hours of
chest pain in the presence of heart failure, arrhythmias or shock, but no significant increase in patients
without clinical complications [19]. However, Wenting et al, found normal renin concentrations in four
patients with heart failure within 12 hours of acute
myocardial infarction in the absence of diuretic
treatment [20].
However, this mortality rate is lower than the

30-day mortality in the early invasive arm of the
prospective SHOCK trial which was 46.7% [11].
Still, these mortality rates are lower compared to
patients treated conservatively or with thrombolytic
therapy only.
Therefore an invasive strategy in patients with
cardiogenic shock is recommended since 2003 in
the guidelines of the European Society of Cardiology for patients with ST elevation myocardial
infarction [12].
Predictors of in-hospital mortality:
Cardiovascular peptides like catecholamines,
aldosterone, renin and Pro-BNP are involved in
the neurohumoral activation [3-5] in patients with
AMI and heart failure, their plasma concentrations
increasing in proportion to clinical severity. Furthermore, it is known that the concentrations of
these cardiovascular peptides in the early phase
are closely related to mortality in patients with
AMI [6].
Regarding the prognostic role of aldosterone,

many studies were consistent with our results
showing a highly prognostic role of plasma aldosterone levels at admission for acute STEMI and
the risk of early death or resuscitated cardiac death,
with a significant impact on mortality [17,21].
In our study, plasma hormonal concentrations

of Noradrenalin, Adrenalin and aldosterone were
significantly higher in group D than in group S
(Noradrenalin: 2215ng/l Vs 659ng/l, p=0.002;
Adrenalin: 173ng/l Vs 30 354ng/l, p=0.007; Aldosterone: 2 124pg/ml Vs 50pg/ml, p=<0.001).
It was previously reported that elevated CRP

concentration is associated with a poor prognosis
in ACS [22] and a high CRP concentration is related
to a poor prognosis in patients with AMI and poor
long-term clinical outcomes after primary or rescue
PCI [23].
Katayama et al, found that higher concentrations

of epinephrine and norepinephrine are associated
with increased mortality; however, they were not
a predictor of mortality because not all patients
who died had high concentrations [6].
Vaney et al described raised catecholamine and
renin concentrations on admission in 19 patients
with acute myocardial infarction and found that
concentrations were highest in four of eight patients
who subsequently developed cardiogenic shock or
ventricular fibrillation [13].
In our patient population, level of CRP was

significantly higher in group D than in group S
(10.9mg/dl Vs 10.5mg/dl, p=0.027) and can be
used as a prognostic value to predict in-hospital
mortality in patients with AMI and CS. This prognostic role of CRP in CS complicating AMI was
also proved by many other studies, either in predicting the course of HF, predicting in-hospital
mortality or mortality after one year providing a
tool to select high-risk patients [24-26].
In the acute stage of AMI, the acceleration of

the renin-angiotensin system hastens left ventricular
remodelling [14,15]. Catecholamine, renin and aldosterone increases blood pressure through vaso-
Brain natriuretic peptide (BNP) and pro-brain

natriuretic peptide (pro-BNP) are secreted from
cardiomyocytes in response to increased wall stress
[7,8] . BNP is known to have a cardioprotective
401
effect and to improve heart failure. Therefore, they

are increased in proportion to the severity of heart
failure and therefore elevation of these peptides
implies a poor clinical prognosis, including mortality, in AMI [27] . In many studies, high BNP
concentrations seemed to predict cardiac death in
AMI with CS [6,17].
PCI in elderly patients with CS complicating AMI

is highly feasible. The decision for interventional
therapy in the elderly (>75 years) patients should
be carefully weighted on the biological age and
the co-morbidity of the individual patient [34].
Final post-interventional TIMI flow was not
statistically significant between group S and group
D. This may be related to the small number of
patients in our study where the difference would
not be apparent. Previous studies demonstrated
that Primary PCI achieving TIMI 3 flow reduces
in-hospital death in AMI with CS [12] and patency
of the infarct-related artery in patients with cardiogenic shock was most strongly associated with inhospital and long-term mortality [35].
In our study, pro-BNP tended to be higher in

group D than in group S, however, this difference
seemed to be statistically insignificant (7227
10478pg/ml, p: 0.081).
Pro-BNP is enzymatically cleaved into the 32
amino acid BNP and the N-terminal part of the
pro-hormone, Nt-pro-BNP [8]. Elevated level of
Nt-pro-BNP as well is strongly associated with the
increased incidence of in-hospital mortality and
cardiogenic shock after MI [28,29].
On the other hand, baseline TIMI flow was also

found to have significant prognostic value for
patients with CS brought on by pump failure. Initial
TIMI grade 3 flow in the infarct vessel had substantially better in-hospital survival than those
with TIMI grade 0 or 1 flow [36].
Cardiac enzymes including peak-CK, CK-MB,

LDH and maximal level of troponin T reflect infarct
size, so has a close relation to severity in AMI,
including mortality. Multiple studies have shown
an increased risk of mortality with elevated levels
of creatine kinase (CK) and CK-MB isoenzymes
after PCI [30-31].
In our study, the presence of 3-VD in our patient

population did not affect inhospital mortality.
Again, this may be related to the small number of
our patients. It was reported that mortality rate for
an early revascularization strategy depends on
whether 2 or more vessels or a left main stem
lesion are involved [12]. It was also stated that if
either the left main or a vein graft was the culprit
vessel, the prognosis was particularly poor, with
in-hospital mortality of 70% [36].
In our patient population, plasma level of LDH

was significantly high in group D than in group S
(1178705U/L Vs 563369U/L, p: 0.012). Plasma
concentrations of Troponin T and peak total CK
tended to be higher in group D than in group S
without statistically significant difference. There
were no significant differences in peak-CK-MB
between 2 groups. These statistically insignificant
differences between the 2 groups may be related
to the sever extensive AMI and CS in both groups.
However 50% of Group D were diabetics in

comparison to 35% in group S, we did not find
any statistical difference between diabetics and
non-diabetics regarding inhospital mortality between the 2 groups. Theses results were similar to
those shown in the SHOCK trial where diabetics
with CS complicating AMI had in-hospital survival
only marginally lower than that of non-diabetics.
Despite their higher-risk profile, diabetics should
be strongly considered for early revascularization
for CS complicating AMI [37]. Similarly, Farkouh
et al found that diabetes mellitus is not a predictor
of 1-year mortality in CS after AMI and the benefit
from an ERV strategy is similar for DM and NDM
[38]. Regarding the use of IABP in the setting of
CS complicating AMI, it was previously reported
that the use of IABP before primary PCI for AMI
in all patients with CS is beneficial for patients
with depressed left ventricular function [39]. Kurisu
et al, reported that IABP was effective in patients
Despite more frequent adverse clinical characteristics and associated mechanical complications
in women with CS, gender was not an independent
predictor of in-hospital mortality in our study. In
the SHOCK Registry, after adjusting for differences
in patient characteristics between men and women,
gender was not an independent predictor of inhospital mortality as well, furthermore, the apparent
benefit derived from PTCA and CABG was similarly observed for both men and women [32].
As well, mean age in our patient population
was not a predictor of in-hospital mortality. Despite
age was a strong predictor of mortality among
elderly patients in other studies, the outcome after
successful PCI was better than previously reported,
[33] denoting that a strategy of routine emergency
402
with persistent ST elevation after PCI for AMI [40].

The SHOCK Trial Registry showed that revascularization by PTCA/CABG, IABP unloading and,
to a lesser extent, TT in patients with CS was
associated with lower in-hospital mortality rates
than treatment with standard medical therapy [41].
perform a full diagnostic hemodynamic study, such

as right-heart catheterization or measurement of
cardiac output, because we wanted to recanalize
the infarct-related artery as soon as possible. Another is that our study was a single-center study.
References
However, our results were consistent with a

recently published meta-analysis that has questioned the benefit of IABP support in the setting
of acute MI complicated by cardiogenic shock [42].
1- Holmes DR Jr, Bates ER, Kleiman NS, et al: Contemporary

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2- Goldberg RJ, Gore JM, Alpert JS, et al: Cardiogenic shock
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In univariate analysis, creatinine level was a
significant predictor of mortality between group
S and group D (1.230.86mg/dl Vs 2.431.0mg/dl,
p: 0.011). Multivariate logistic regression analysis
revealed that renal failure (OR 12.4, 95% CI: 0.0012.47, p: 0.001) and increased creatinine level (OR
3.3, 95% CI 1.21-8.9, p: 0.01) were independent
predictors of in hospital mortality in the study
population.
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404
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405
Leptin Axis and Plasma Ghrelin in Children with Congenital Cyanotic

Heart Diseases
YASSER F ALI, M.D.; SANAA M ABDEL SALAM, M.D.; HADEEL MA RAHMAN, M.D.;
REHAB A KARAM, M.D.*
Background: Malnutrition is a common cause of morbidity and mortality in children with congenital heart disease (CHD).
Listed among the possible causes of growth failure has been reduced peripheral blood flow with tissue hypoxia and acidosis,
repeated respiratory infections and pulmonary hypertension. Increased energy expenditure is a primary factor in the reduced
growth of children with cyanotic CHD.
Objective: Study some growth indices: Insulin-like growth factor-1 (IGF-1), Insulin-like growth factor binding protein 3
(IGFBP-3), leptin and ghrelin, in children with cyanotic CHD.
Study Design: Thirty consecutive children who were admitted to Pediatric Cardiology Unit, Zagazig University Hospitals
with proven diagnosis of cyanotic CHD of ages ranging from 6 to 70 months were recruited to the study. They were classified
according to the state of nutrition into well-nourished and malnourished patients. A control group of 15 well-nourished, ageand sex-matched children was used for comparison. For all children participated in this study serum levels of growth indices
were measured. A verbal and written consent was obtained from parent(s) of each child before inclusion in the study.
Results: The leptin regulating axis is intact in cyanotic patients and leptin does not contribute to the cachexia of cyanotic
heart disease. The malnourished group had the lowest IGF-I levels. In addition, we found a positive correlation between serum
IGF-I levels and oxygen saturation in well-nourished patients. Plasma ghrelin levels were significantly higher in malnourished
children with cyanosis and showed a significant negative correlation with BMI.
Conclusion: Malnutrition is a common problem in children with congenital cyanotic heart disease. Growth indices can be
used to monitor the nutritional status of this group of patients.
Key Words: Malnutrition Leptin axis Congenital heart disease Ghrelin.
Introduction
Insulin-like growth factor I (IGF-I) which was

once called somatomedin C, is a polypeptide protein
hormone similar in molecular structure to insulin.
IGF-1 consists of 70 amino acids in a single chain
with three intramolecular disulfide bridges and of
molecular weight 7649 Daltons [4]. IGF-1 is produced primarily by the liver as an endocrine hormone as well as in target tissues in a paracrine/
autocrine fashion. IGF-I production is stimulated
by growth hormone. It plays an important role in
childhood growth and continues to have anabolic
effects in adults [5]. IGF "axis", is also commonly
referred to as the Growth Hormone/IGF1 Axis,
plays an important role in the regulation of structure
and function of the cardiovascular system. IGF-I
acts on vascular cells as a potent stimulator of cell
proliferation and also as an inhibitor of apoptosis
[6]. Decreased levels of IGF-1 may be seen with
nutritional deficiencies (including anorexia nervosa), growth hormone insensitivity, or lack of
Malnutrition is a common cause of morbidity

in children with congenital heart diseases (CHD).
The hemodynamic changes present provoke nutritional alterations, growth deficit and complications
related to post-surgical survival [1]. In addition,
many children with CHD present nutritional difficulties during the first year of life, with vomiting
as one of the most common problems [2]. The best
approach before surgical repair in children with
CHD is providing caloric supplements, appropriate
management of congestive heart failure and timely
referral for corrective intervention [3].
The Departments of Pediatrics and Medical Biochemistry*,
Faculty of Medicine, Zagazig University, Egypt.
Address for Correspondence: Dr. Yasser F Ali, The Department
of Pediatrics, Faculty of Medicine, Zagazig University, Egypt.
407
Leptin Axis & Plasma Ghrelin in Children with Congenital Cyanotic Heart Diseases
growth hormone receptors and chronic kidney or

liver disease [5].
formed about the energy balance of the brain and

the body [15].
IGFs circulate in blood complexed to a family

of IGF-binding proteins, which not only extend
the half-life of the hormones, but modulate their
interaction with receptors. To date, at least six
distinct IGF-binding proteins have been identified
in humans [7]. Insulin-like growth factor binding
protein-3 (IGFBP-3), the most abundant of the
IGFBPs in the circulation, functions to transport
and modulate the actions of IGF-I and -II. IGFBP3
can both enhance the effects of IGF-I presumably
by delivering IGF-I to its plasma membrane receptor and compete with the receptor for binding IGFI and thereby inhibit IGF-I action [8].
The aim of this study was to evaluate serum

leptin, IGF-I, IGFBP-3 and ghrelin levels in children with cyanotic CHD. We tried to determine if
these parameters were correlated to the cyanosis,
oxygen saturation and nutritional status of the
patients.
Leptin is adipose derived hormone that was

initially believed to function in the prevention of
obesity [9]. It is the dominant hormone in a classic
endocrine negative-feedback loop that dynamically
regulates body weight. Leptin acts as starvation
hormone, which signals an energy deficit state in
the human body [10]. It circulates in proportion to
body fat content, crosses the blood-brain barrier
and interacts with soluble leptin receptor (SORR), a major leptin binding protein in blood, which
facilitates the transport of leptin from its peripheral
site of production to its central site of neuroactions
[11].
Inclusion criteria: Cardiac diagnosis was made

on the basis of clinical examination, ECG, chestX-ray and echocardiographic findings.

This case control study included total number
of 30 children with cyanotic CHD of ages ranging
from 6 to 70 months who were selected from the
pediatric cardiology outpatient clinic of Zagazig
University Hospitals during year 2009.
Exclusion criteria: All children were free from

other malformations, pulmonary hypertension or
signs of other disease.
According to Waterlaw's scores [16], patients were
divided into 2 groups:
Group I: Ten patients (6 males and 4 females) of
mean age 36.220.1 months with manifestations
of malnutrition.
Group II: Twenty patients (12 males and 8 females) of mean age 24.68.8 months who were
well nourished.
Ghrelin is synthesized as a preprohormone,

then proteolytically processed to yield a 28-amino
acid peptide [12]. The predominant source of circulating ghrelin is the gastrointestinal tract, primarily from the stomach, but also in smaller amounts
from the intestine. The hypothalamus in the brain
is another significant source of ghrelin; smaller
amounts are produced in the placenta, kidney, and
pituitary gland [13]. Ghrelin is known to encourage
the secretion of growth hormone from the anterior
pituitary gland. This is because the anterior pituitary
gland contains special ghrelin receptors, which
were discovered before ghrelin itself ever was. For
this reason, the ghrelin receptor is also referred to
as the growth hormone secretagoue receptor (GHSR). In addition to the anterior pituitary gland,
ghrelin receptors are also found in the heart, hypothalamus, and adipose tissue [14]. Ghrelin is responsible for stimulating the appetite and has been
found to increase the appetite before eating and to
decrease it afterward. Ghrelin appears to be at least
partially responsible for letting the body know
when it is hungry and for keeping the body in-
Fifteen well-nourished healthy children (8 males

and 7 females) of mean age 29.420.2 months
were taken as control group.
Malnutrition was described as mild, moderate,
or severe when patient weight was 80-90%, 7080%, and <70% of ideal weight for length, respectively. When both weight and length were below
the 5th centile for age, the condition was described
as ''failure to thrive'' [16].
All children were subjected to the following:
1- Full history taking with stress on time of onset
of cyanosis, feeding difficulties, and recurrent
chest infections physical examination for signs
of malnutrition.
2- Standardized measurements of weight, length,
body mass index (BMI) using the methods
described by Fomon [17] and oxygen saturation
in the blood (SO2) using pulse oximetery.
408
Yasser F Ali, et al
BMI, weight for age and height for age centiles

(Table 3).
3- Routine laboratory investigations including

complete blood count (CBC) using cell counter
(cell-Dyn 1700), plasma proteins and albumin
using automated analyzer dimension RXL (Behring), and arterial blood gasses.
4- Measurements of serum leptin, IGF-1, IGFBP3 and ghrelin.
As regard growth parameters and oxygen saturation, there was nonsignificant difference in leptin
level (p<0.05). Meanwhile significant differences
in IGF-1, IGF-BP3, gherlin and oxygen saturation
were observed in the studied groups (Table 4).
Blood sampling: Overnight fasting state, blood

samples (with and without K2 EDTA) were drawn
from patients and control. Blood collection was
performed between 8.00 and 9.00 am in order to
prevent the effect of circadian variation of leptin
concentration, and then centrifuged as soon as
possible at 2,000 rpm for 10 minutes. Serum &
plasma samples were stored at 20C until analysis.
There was a significant positive correlation

between IGFBP3 and BMI in cyanotic malnourished children (Fig. 1). Furthermore, serum IGF1 levels correlated significantly with SaO2 in wellnourished patients with cyanotic CHD (Fig. 2).
Also, plasma ghrelin levels showed a significant
negative correlation with BMI in well-nourished
patients with cyanotic CHD (Fig. 3).
Serum leptin was measured by the ELISA kit

(Diagnostic system laboratories, USA) [18].
Table 1: Nutritional status in children with cyanotic congenital

heart disease.
Serum IGF-1 and IGFBP-3 was measured by

the ELISA kit (BioVendor Laboratories Ltd., Hong
Kong, CHINA) [19].
Waterlaw's criteria
All patients (n=30)
Normal
Severe malnutrition
Moderate malnutrition
Mild malnutrition
Stunting
Plasma Ghrelin was measured using commercially available sandwich ELISA kit supplied by
DSL, INC, USA [20].
All data were analyzed by SPSS software,
version 11.0 for Windows. Data were presented as
mean standard deviation. The given data were
compared between groups using one-way ANOVA,
followed by Post-hoc; LSD test. Correlation between the studied parameters was explored with
Spearman's correlation. p-values less than 0.05
were considered statistically significant.
20 (66.7%)
2 (6.7%)
4 (13.3%)
3 (10%)
1 (3.3%)
Table 2: Cardiac diagnoses in the studied patients.

Diagnosis
Group I
(n=10)
Group II
(n=20)
Tetralogy of Fallot
Transposition of great arteries
Truncus arteriosus
Tricuspid atresia
Pulmonary stenosis
4 (40%)
2 (20%)
1 (10%)
3 (30%)
0 (0%)
12 (60%)
2 (10%)
2 (10%)
1 (5%)
3 (15%)
Results
Table 3: Demographic data of the studied groups.
According to our results using Waterlaw's scores

[16] 6.7% of patients with cyanotic CHD had severe
malnutrition, 13.3% had moderate malnutrition,
10% had mild malnutrition and 3.3% were stunted
(Table 1).
Table (2) shows that Tetralogy of Fallot (TOF)
constitutes a large proportion (40% of group I,
60% of group II) of patients. Tricuspid atresia was
more common in group I than in group II (30% Vs
5%) while pulmonary stenosis was commoner in
group II than group I (15% Vs 0%).
Data
Group I
(n=10)
Age (mo)
(Mean SD)
(8-70)
(6-36)
36.220.1 24.68.8
(7-63)
NS
29.420.2
Sex (M:F)
6:4
8:7
NS
(25-95)
(25-95)
HS
61.523.4 65.324.3
Height/age centile (5-25)

1710.3
(25-95)
6218.02
(50-95)
HS
69.315.6
(12.3-18.3) (16.5-18.9) (20.2-23.8) HS

14.92.1
17.90.65 21.81.09
BMI: Body mass index.

NS : Nonsignificant.
HS : Highly significant.
409
12:8
Control
(n=15)
Weight/age centile (5-25)

11.49.4
BMI (kg/m2)
There were nonsignificant differences between

the studied groups regarding age and sex (p<0.05)
but significant differences were observed as regard
Group II
(n=20)
Table 4: Growth indices and oxygen saturation in the studied
groups.
19.5
19
Group II
(n=20)
Control
(n=15)
IGF-1 (ng/ml)
53.34.3
19.21.6
12.051.1
HS
IGFBP3 (ng/ml)
2030850
1605414
1122316
Leptin (ng/ml)
5.30.5
4.81.01
4.90.9
NS
Ghrelin (ng/ml)
8.80.9
12.13.5
26.48.7
HS
O2 (%)
94.12.69
80.44.97
73.053.5
HS
18.5
BMI
Parameters
Group I
(n=10)
BMI
7.5
17
16.5
16
NS : Nonsignificant.
HS : Highly significant.
S : Significant.
O2 : Saturation of arterial blood with oxygen.
IGF1: Insulin like growth factor-1.
IGFBP3: Insulin like growth factor binding protein-3.
10
15
Ghrelin (ng/ml)
20
25
Figure 3: Correlation between plasma ghrelin levels and BMI

in group II (Pearson's r=0.5, p<0.01).
20
18
16
14
12
10
8
6
4
2
0
Discussion
500
1000
1500
Malnutrition is the most important risk factor

in morbidity and mortality in childhood. It affects
life quality of children negatively. Its detection
and treatment are important components in the
clinical management of many conditions [21]. It is
well documented published reports that infants
with congenital heart disease (CHD) gain less
weight and length than normal infants of the same
age. CHD may affect the growth of children and
lead to malnutrition. The speed of growth is more
rapid during the first three years and nutritional
needs are greatest at this point [22]. Cardiac malformations may be responsible for malnutrition
and the degree of malnutrition is related to hemodynamic status [23].
2000
IGFBP3 (ng/ml)
Figure 1: Correlation between insulin-like growth factor
binding protein-3 (IGFBP-3) and body mass index
(BMI) in group I (Pearson's r=0.6, p<0.3).
Hornbya et al [24] suggest that incorporating

simple anthropometric and functional measurement
into protocols of nutritional assessment for patients
with CHD can identify patients at risk. Inadequate
caloric intake, malabsorption, and increased energy
requirements caused by increased metabolism may
all contribute to malnutrition and growth failure
in patients with cyanotic CHD [25,26].
80
78
76
SaO2
18
74
72
IGF-1 is a peptide hormone secreted from many

different cells. Their designation as "insulin-like"
originated from experiments in which treatment
of serum with antibodies to insulin failed to eliminate all insulin activity; the remaining activity
was ultimately ascribed to IGFs. It is largely responsible for the growth-promoting properties of
growth hormone [27]. In our present study, IGF-1
levels were significantly lower in malnourished
cyanotic patients than in other groups (p<0.05).
70
68
0
10
15
20
25
IGF (ng/ml)
Figure 2: Correlation between insulin-like growth factor-1
(IGF-1) levels and oxygen saturation in group II
(Pearson's r=0.44, p<0.04)
410
Yasser F Ali, et al
These results were in agreement with Dndar et

al [28], who found that the malnourished cyanotic
patients had the lowest IGF-1 levels which may
be attributed to the effect of chronic hypoxia on
serum IGF-1 concentrations.
The present study revealed that there was a

significant positive correlations between IGFBP3
and BMI in malnourished cyanotic patients (r=0.6,
p<0.3). Also, plasma ghrelin showed a significant
negative correlation with BMI in well-nourished
cyanotic patients (r=0.5, p<0.01). This result was
in agreement with Kandil et al [35] who proved
that circulating ghrelin level was elevated in children with cyanotic CHD, and was associated with
a decrease in BMI. This elevation in ghrelin level
may represent malnutrition and growth retardation
in those patients as obvious by anthropometric
measures too. This may suggest that ghrelin may
have an important role as a compensatory mechanism in the regulation of the metabolic balance in
them.
Leptin is an adipocyte-derived hormone that

acts to reduce food intake and increase energy
expenditure by binding and activating its specific
receptor in the hypothalamus [29]. Furthermore,
leptin can be a metabolic signal that regulates GH
section. Thus, the study of leptin concentration
and its relationship with growth parameters and
IGF-I in malnourished children may increase the
understanding of the mechanisms behind the lack
of growth in many of these [26]. In this study, there
was nonsignificant difference between the studied
groups as regard leptin levels. These results were
in agreement with Hallioglu et al [30] who concluded that the leptin regulating axis is intact in cyanotic
patients and leptin does not contribute to the
cachexia of cyanotic heart diseases. On the other
hand, Halil et al [31] observed that serum leptin
concentrations were higher in cyanotic subjects
who had relatively lower BMI scores than in acyanotic subjects.
Correlation between IGF-1 and SaO2 in wellnourished cyanotic patients showed a significant
relationship between both (r=0.44, p<0.04). This
result was in agreement with Dnbar et al [28].
In conclusion, serum IGF-1 and IGFBP3 levels
are decreased in malnourished cyanotic patients
which may be due to the effect of chronic hypoxia.
Also, plasma ghrelin levels are increased in malnourished cyanotic patients which may be contributed to anabolic-catabolic imbalance. Meanwhile
serum leptin levels are not affected in patients with
congenital cyanotic heart disease. So, we recommend incorporating anthropometric measurements
into protocols of nutritional assessment for patients
with CHD and also further studies over a large
scale of patients before and after surgical corrections.
Ghrelin is responsible for stimulating the appetite and has been found to increase the appetite
before eating. It is accepted as a good marker of
the nutritional state, mainly in the situation of
malnutrition, owing its fast recovery after weight
gain [32]. Ghrelin concentrations in blood are reduced in obese humans compared to lean control
subjects, but whether this is cause or effect is not
defined [12] . In this study, ghrelin levels were
significantly higher in malnourished cyanotic patients than in other groups (p<0.001). These results
were in agreement with Nagaya et al [33] who
found that plasma ghrelin levels were increased in
cachectic patients with congenital heart diseases
owing to a compensatory mechanism in response
to anabolic-catabolic imbalance.
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IGFBP3, the most abundant of the IGFBPs in

the circulation, binds IGFs in blood which not only
extend the half-life of the hormones, but also
modulate their interaction with receptors. In our
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THE EGYPTIAN HEART JOURNAL

Importance of Inflammatory Cytokines and Endothelial Peptides in Predicting Hypertensive

Relevance of Homocysteine on Brachial Flow-Mediated Vasodilation and Carotid and Femoral

Coronary Heart Disease:

Serum Adiponectin Levels in Patients with Coronary Artery Disease

Clinical Implications of Adipocytokine, Serum Resisten in Diabetics with Coronary Artery

Multigated Radionuclide Study of Systolic Function after Cardiac Resynchronization Therapy

Valvular Heart Disease:

Pro-BNP Study of Patients Referred for Echocardiographic Assessment of Left Ventricular

Egypt Heart J 62 (2): 205-218, June 2010

Usefulness of Tissue Doppler Imaging Versus Radionuclide Scintigraphy

Right ventricular myocardial infarction (RV

Two dimensional echocardiography is not feasible in assessment RV function. In addition two

Usefulness of Tissue Doppler Imaging Versus Radionuclide Scintigraphy

dimensional echocardiography doesn't provide

ence for RVEF, and has often been performed in

Patients and Methods

Interest in recognizing RVMI non-invasively

The study population consisted of twenty five

In approximately 30% of patients with inferior

3- Creatinine kinase 210IU and creatinine kinase

Right ventricular function is less often measured

Cardiac markers (CK, CKMB, LDH).

Isovolumic relaxation time (IVRT):

Myocardial performance index (MPI):

Each patient was examined in the left lateral

Peak myocardial systolic velocity (Sm):

A- Routine echocardiographic study:

First pass radionuclide angiography (FPRNA):

1- Left ventricular end diastolic dimension

The images are acquired in anterior view, (the

4- Right ventricular dimensions (normal range

Isovolumic contraction time (IVCT):

Usefulness of Tissue Doppler Imaging Versus Radionuclide Scintigraphy

Views were taken in the right oblique with

III- First pass radionuclide angiography (FPRNA)

Sensitivity, specificity, positive and negative

We excluded pts with acuter inferior MI in who

Negative predictive value = [TN + FN] / TN.

The following parameters were analyzed:

Figure 1: The percentage of males and females in the study

to 41%) was found in 13 (52%) and 12 pts (48%)

3- Complications (Table 1):

ST: Sinus tachycardia.

SB: Sinus bradycardia.

4- Pulsed wave tissue Doppler parameters:

Table 3: Agreement between the 2 techniques; tissue Doppler

Table 2: Variable levels of tissue Doppler parameters.

Peak myocardial systolic velocity

+ve for right ventricular

+ve for right

(Kappa = 0.759, p: 0.0001).

A significant agreement between the two methods

5- First pass radionuclide angiography (FPRNA)

6- Coronary angiography (Fig 8):

Right ventricular ejection fraction 45% with

Usefulness of Tissue Doppler Imaging Versus Radionuclide Scintigraphy

occlusion site before and 9 (45%) had it after

and 6 (66.67%) had additional variable chronic

Based on the occluded artery and the level of

Out of 11 pts with RCA occlusion before the RV

Regarding the 14 pts in whom the site of acute

Figure 3: ROC curve to assess the newly introduced method

Study group (25 pts)