Beruflich Dokumente
Kultur Dokumente
Rukma juslim
Bagian Kardiologi FK. UHT /
RSAL Dr. Ramelan Surabaya
Definition of Heart Failure
• Heart failure is the pathophysiological
state in which the heart is unable to pump
blood at a rate commensurate with the
requirements of the metabolizing tissues
or can do so only from an elevated filling
pressure.
• Heart failure is a complex clinical
syndrome that can result from any
structural or functional cardiac disorder
that impairs the ability of ventricle to fill
with or eject blood.
100
Progression Further damage
Excessive wall stress
Neurohormonal activation
Patients surviving %
Annual mortality
<5% 10% 20 to 30% 30 to 80%
0
Asymptomatic Mild Moderate Severe
90 Males
80
Females
70
50
40
30
20
10
0
45-54 55-64 65-74 75-84 85-94
Age (yr)
Coronary
Peripheral
Neuroendocrine
• Autonomic NS • Hepatic
• Metabolic • Skeletal muscle
• Renal • Other
Neurohormonal Activation
• Cathecholamines
Vasoconstriction • RAS
• AVP
• Endothelin
Low BP Baroreflexes
JVP kidney
Adrenergic stimulation
RV failure RV ANP
LA RENIN
EXCESS
back Angiotensin AFTERLOAD
big liver
edema ward Aldosterone
Left pressure
ventricle
Increasing
Na+ loss Na+ retension
forward
Edema
failure
INCREASING heart
BACKWARD
FAILURE
Increasing EXCESS
BLOOD VOLUME
low renal
preload blood flow
(Opie, 1994)
“Betablocker and beta adrenergic
receptor in heart failure”
Adrenergic Renin-angiotensin
?
Vasoconstriction
Direct
cardiotoxicity Increased Volume
heart rate and overloaded
contractility
Increased Increased
MVO2 wall stress
Myocyte
damage Hypertrophy
Decreased contractility
(Bristow, 1993)
Adaptive Mal-
Myocyte adaptive
slippage Increased
Remodeling O2 demand
Ischemia
Increased Increased
myocardial stroke volume
volume (Starling)
Myocyte
Stretch hypertrophy Increased
myocardial Decreased
Humoral mass Wall stress Impaired
(Laplace) Contractility
RAAS
Epinephrine Interstitial
Arrhythmo-
Endothelin fibrosis genesis
Growth factors
Acute Infarction
(hours)
Infarct Expansion
(hours to days)
Global Remodeling
(days to months)
CARDIAC REMODELING
Cardiac remodeling may be defined as genome expression,
molecular, cellular and interstitial changes that are
manifested clinically as changes in size, shape and
function of the heart after cardiac injury.
Remodeling encompasses cellular changes including
myocyte hypertrophy, necrosis, apoptosis, fibrosis,
increased fibrillar collagen and fibroblast
proliferation.
(Cohn et al, 2000)
Index Event (myocardial injury)
0.60
LV Ejection Fraction
0.20
Asymptomatic Symptomatic
Myocardial injury
• Myocardial infarction
• Hemodynamic overload
• Inflammation
Secondary mediators
• Norepinephrine
• Angiotensin Aldosterone
• Endothelin
• Cytokines
• Oxidative stress
• Mechanical stress
Ventricular Remodeling
• Myocyte hypertrophy
• Myocyte apoptosis
• Fetal phenotype
• Extracellular matrix changes
The Role of Angiotensin II in the progression of Heart Failure
Renin release
Edema
Angiotensinogen
Bradykinin
Renin
Angiotensin I
ACE Degradation
Chymase
Angiotensin II
NO
CHF
SOD
Vasoconstriction
Oxydative
Endothelial dysfunction Vascular remodeling
stress
Exercise
capacity
(Drexter, 1998)
(Mann, 2004)
New therapeutic options in the treatment
of heart failure
Rukma juslim
Annual mortality
<5% 10% 20 to 30% 30 to 80%
0
Asymptomatic Mild Moderate Severe
Neurohormonal Activation
• Cathecholamines
Vasoconstriction • RAS
• AVP
• Endothelin
CHF
Valvular Pump
Cardiomyopathy failure
disease
• Neurohormonal stimulation
• Endothelial dysfunction Symptoms: Chronic
Noncardiac Dyspnea
• Vasoconstriction heart
factors Fatigue
Edema failure
• Renal sodium retention
(Abraham, 2000)
Risk
Factors HEART FAILURE SPECTRUM
Heart disease
Asymptomatic
LV Dysfunction
Symptoms
NYHA II-III Symptoms
NYHA - IV
Symptoms
ECHO / LV dysfunction
? BNP
Stages of Heart Failure
Stages Examples
Stage A: At high risk for HF but HTN, CAD, DM, cardiotoxins,
without structural heart disease FHx of CM
or symptoms of HF
CHF
Increased
Afterload
Low BP Baroreflexes
JVP kidney
Adrenergic stimulation
RV failure RV ANP
LA RENIN
EXCESS
back Angiotensin AFTERLOAD
big liver
edema ward Aldosterone
Left pressure
ventricle
Increasing
Na+ loss Na+ retension
forward
Edema
failure
INCREASING heart
BACKWARD
FAILURE
Increasing EXCESS
BLOOD VOLUME
low renal
preload blood flow
(Opie, 1994)
Chronic Congestive Heart Failure
DIURETICS
Thiazides
Inhibit active exchange of Cl-Na
Cortex in the cortical diluting segment of the
ascending loop of Henle
K-sparing
Inhibit reabsorption of Na in the
distal convoluted and collecting tubule
Loop diuretics
Medulla Inhibit exchange of Cl-Na-K in
the thick segment of the ascending
loop of Henle
Loop of Henle
Collecting tubule
LOW VS HIGH CEILING DIURETICS
High-ceiling
Dose for Loop diuretics
oliguria
Dose for
severe CHF
EFFICACY
Dose for
mild CHF
Low-ceiling
Dose for Thiazides
hypertension
K+ -sparing
Opie (2001)
DOSE
Inotropic agent Congestive
+ vasodilator symptoms
Inotropic agent
+ vasodilator Inotropic
Vasodilator agent only
+ diuretic only
Stroke volume
Diuretic
only
Congestive
and low-
Low-output output
symptoms symptoms
5 small trials
Pooled odds ratios (and 95% confidence intervals) describing the effect
of blockers on mortality in patients with heart failure (fixed effects model)
Total
40
30
20
Placebo
10
P = 0.80
Digoxin
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Months
40
30
Placebo
20
10
Digoxin P < 0.001
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Months
Probability of Survival
0.85
0.80
0.75
0.70 Spironolactone
0.65
0.60
0.55 Placebo
0.50
0.45 p<0.001
0.00
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
No. At Risk
Placebo 841 775 723 678 628 592 565 483 379 280 179 92 36
Spironolactone 822 766 739 698 669 639 608 526 419 316 193 122 43
P = 0.0002
0.8
0.6
0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4
-Receptor
Na+/H2O retention signaling pathway Sympathetic
Vasoconstriction ACE/AII
Vascular remodelling Aldosterone
Sympathetic Sympathetic
RAAS activation
Neurohormonal
activation Wound healing fibrosis
hypertrophy
Neurohormonal
activation
Remodelling
Ca2+ homeostasis
Metabolism
Remodelling
Vasoconstriction
SR/Mitochondrial
abnormalities LV dysfunction
Stunning Endothelin
Cytokines
Ischaemia TNF
Injury
Contractile
depression iNOS/NO-O•
radicals
Neurohormonal
O• radicals AII?
Apoptosis
Ischaemia
Reperfusion Remme, 1998
HEMODYNAMICS OF VASODILATORS IN CHF
+ Inotropic
Increased cardiac output
Decreased fatigue
Normal
AFTERLOAD
REDUCTION
PRELOAD REDUCTION
Decreased pulmonary wedge pressure
Decreased dyspnea
Theoretical Frank-Starling curves in CHF. (Opie, 2001)
THE STRATEGY IN THE MANAGEMENT
OF HEART FAILURE
• Prevention and early intervention
before the disease progresses to
a later stage.
• Prevention should include detection
and treatment of aetiological factors
and risk factors
• Early intervention is directed towards
treatment of acute coronary syndrome
DIASTOLIC HEART FAILURE
( Definition, Pathofisiology, Diagnosis and Treatment)
Rukma Juslim
Bagian Kardiologi, Sub Bagian Kardiologi Ilmu Penyakit
Dalam
FK. UHT / RSAL. Dr. Ramelan Surabaya
SCOPE OF THE PROBLEM
• Epidemiological studies of HF have
suggested that 30-50% of cases of HF
have preserved LV systolic function.
• It is assumed that these cases represent
DHF, this suggests that DHF contributes
significant to the huge burden of disease
caused by HF.
• If the epidemiology evidence is accurate,
a large proportion of the HF population is
left with no proven, effective treatment.
PULMONARY VENOUS
PRESSURE
Input
Filling Emptying
Stroke
ED volume x EF effective = volume
LV Distensibility Contractility x
Relaxation Afterload Heart
Left atrium Preload
Mitral valve rate
Structure
Pericardium
Diastolic function Systolic function
Output
CARDIAC OUTPUT
A : Normal
LV Pressure
B : Diastolic Dysfunction
P
V
P
V
LV Volume
( Little & Downes, 1990 )
Fibrosis
Passive
Cellular disarray chamber
stiffness
Hypertrophy Diastolic
pressure
Asynchrony
Ischemia
Decreased
Normal diastolic
diastolic chamber
Normal
chamber
Left Ventricular Pressure
Minor Criteria
Bilateral ankle edema
Nocturnal cough
Dyspnea on ordinary exertion
Hepatomegaly
Pleural effusion
Decrease in vital capacity by one third from maximal value recorded
Tachycardia (rate > 120 beats min)
The diagnosis of CHF in this study required that two major
or one major and two minor criteria be present concurrently, Minor Criteria
were acceptable only if they could not be attributed to another medical condition.
( Ho KL, et al., 1993 )
Sensitivity and specificity of clinical
features in the diagnosis of CHF
Sensitivity Specificity
Symptom
Dyspnoea 66 % 52 %
Orthopnoea 21 % 81 %
Paroxysmal nocturnal dyspnoea 33 % 76 %
Oedema (by history) 23 % 80 %
Sign
AND
Definitive evidence of CHF Includes clinical symptoms and signs, supporting laboratory test (such
as chest X-ray), and a typical clinical response to treatment with
AND diuretics, with or without documentation of elevated LV filling pressure
(at rest, on exercise, or in response to a volume load) or a low cardiac index
Objective evidence of normal LV systolic LV EF > 0.50
function, but not at the time of the CHF event
AND
Objective evidence of LV diastolic dysfunction No conclusive information on LV diastolic function
is lacking
( Vasan & Levy, 2000 )
Treatment of Diastolic Heart Failure
Nonpharmacological treatment
Restrict sodium to prevent volume overload
Restrict fluid to prevent volume overload
Perform moderate aerobic exercise to improve cardiovascular
conditioning, decrease heart rate and maintain skeletal muscle
function
Pharmacological treatment
Diuretics including loop diuretics thiazides, spironolactone
Long-acting nitrates, -Adrenergic blockers
Calcium channel blockers
Renin angiotensin-aldosterone antagonists including ACE
inhibitors, angiotensin II receptor blockers and aldosterone
antagonists
Diuretics reduce stroke volume more in diastolic than in
systolic dysfunction
Systolic dysfunction Diastolic dysfunction
Without Without
diuretics diuretics
Left ventricular pressure
With With
diuretics Systole diuretics
Steeper slope
indicates increased
stiffness of
left ventricle
Diastole End-diastolic
End-diastolic
pressure pressure
Disease-targeted treatment
Prevent/treat myocardial ischemia
Age, y
Prevalence 15 33 50
Mortality 15 33 50
Morbidity 25 50 50
Trial Comparison Follow-up (n) Diagnostic Criteria Other Important Main Outcomes
for DHF Inclusion/ Exclusion
Criteria
PEP-CHF Placebo 1.000 3 of 9 clinical and Age > 70 years Death or HF-related
Perindopril Minimum 18 months 2 of 4 echocardiographic Diuretics hospitalization
criteria
Hospital admission in last
3 months
CHARM-2 Placebo 2.500 EF > 40% None Death or hospitalization
Candesartan Minimum 24 months for HF
I-PRESERVE Placebo 3.600 EF > 45% Clinical diagnosis of HF Death and hospitalization
Irbesartan Approx 48 months cardiovascular disease
SENIORS Placebo 2.000 EF > 35% and a cardiac Aged > 70 years
(diastolic subset) Nebivolol (% DHF uncertain) abnormality Hospital admission within
last 12 months
Hong Kong Placebo 450 Doppler criteria Diuretics Death or hospitalization
Ramipril Minimum 12 months for HF
Irbesartan Quality of life 6-minute
walk test
SWEDIC Placebo 140 Doppler criteria AF excluded Regression of diastolic
Carvedilol 9 months dysfunction
AO
Aortic
Aortic closure
pressure
Ventricular
pressure
Cross- MO
over Atrial
pressure
M1 A2
Heart S4 T1 P2 S
3
sounds
Cardiologic
systole
a c
v
JVP
Opie (2001)
T P
P
ECG
Q S
0 800 msec
e iso
a b c d
iso
increased
contractility normal
contractility
LV pressure, mmHg
120
increased
afterload
80
40 increased
preload
60 120
LV volume, mL
The effect of increased contractility upon the left ventricular end-systolic pressure-volume relationship
Diuresis Antimitogenic
Vasodilatation
Prostaglandins Natriuretic
NO
peptides
Myocardial
dysfunction Free radicals
Cytokines
Growth
AVP Renin
hormone
Endothelins
All
Catecholamines
Aldosterone Apoptosis
Hypertrophy
Vasoconstriction
Salt and water
retention
-OH/1O2
Myocardial Dysfunction
Heart Failure
Schematic presentation of antioxidant protective strategies in heart failure. Ischemia followed by reperfusion generates superoxide anion (-O2-), which rapidly
dismutates to hydrogen peroxide (H2O2). In the presence of iron, -OH radical or possibly 1O2 may be formed via iron-catalyzed. Haber weiss reaction. These
highly destructive species initiate lipid peroxidation in the cell membranes, damage proteins and cause DNA fragmentation resulting in the apoptotic
(programmed) cell death of myocly. Traditional enzymatic antioxidants that scavenge oxyradicals or prevent their formation are not always effective because of
their limited accessibility to the free radical generation. However, a large number of netural orsynthetic compaunds have the ability to inhibit the oxidative
Damage either by scavenging free radicals or inhibiting lipid peroxidation. TMZ=trimetazidine.
Proinflammatory cytokines involved with heart failure
and dilated cardiomyopathy
Source
Cytokine
Macrophages
Interleukin-1 alpha (IL-1)
Macrophages
Interleukin-1 beta (IL-1β)
T lymphocytes and endothelial cells
Interleukin-2 (IL-2)
Membrane of T cells
Soluble interleukin-2 receptor
(sIL-2R)
Macrophages, endothelial cells,
Tumor necrosis factor (TNF )
myocytes (in certain conditions)
T lymphocytes
Interferon (INF)
Myocytes (atrial myocytes)
Atrial natriuretic factor (ANF)
Myocytes, endothelial cells,
Interleukin 6 (IL-6)
T lymphocytes
(
Two Minute Assessment of Hemodynamic Profile
Congestion at rest?
A B Orthopnea
NO Elevated JVP
Low perfusion
YES Edema (25%)
at rest? Cold & Wet Pulsatile hepatomegaly
Cold & Dry
Ascites
L C Rales (rare in chronic
HF)
Louder S3
Evidence for low perfusion
Narrow pulse pressure8 P2 radiation leftward
Cool extremities* Abdomino-jugular reflex
May be sleepy, obtunded Valsalva square wave
Suspect from ACEI hypotension
And low serum Sodium
One cause of worsening renal fn
* Most helpful
Treating Hemodynamic profiles
DRY WET
WARM
A B Vasodilators
Natriuretic peptides
Nitroprusside
COLD L C nitroglycerin
Inotropic drugs
Dobutamine
Milrinone
(levosimendan)
(enoxinune)
Suggestions for how the hemodynamic profiles may be used to conceptualize initial
therapy for patients with advanced heart failure, patients who are wet and warm
(profile B) generally can be “dried out” without complex intervention. patients who
are “cold and wet” (profile C) often require addition of other therapy to “Warm up”
before they can “dry out”.Concepts are further discussed in text and in Ref [30].
CARDIAC STRESS
Exogeneous Antioxidants
Oxidative Stress
Heart Failure
RV-LV asynchrony
(activation and contraction)
RV asynchrony LV asynchrony
Activation/contraction No contraction
(early low load) (early high load)
Relaxation Contraction
(high late load) (overstretched segmens)
Perfusion mismatch
Extracellular/cellular matrix
modifications
Schematic representation of possible electrical and mechanical effects determined by ventricular conduction
delay, and more specifically left bundle branch block. LV=left ventricle/left ventricular; RV=right ventricle/right
Ventricular.
OXYGEN FREE RADICALS PRODUCTION
IN THE CARDIOVASCULAR SYSTEM
LV systolic pressure N + + +
LV radius N + + +
LV
+ wall thickness N N + +
LV
N diastolic volume N + + ++
Systolic
N wall stress N + N +
Diastolic wall stress N + N +
The normal (N) relationship between left ventricular wall thickness (h) and
chamber radius (r) is shown (first panel).
Remodeling stimuli Increased wall stress
Wall stress
Cytokines
Neurohormones
Oxidative stress
Myocyte hypertrophy
Ventricular
enlargement
Altered intestinal matrix
-Myocyte death
Contractile state
of myocardium
B 3’
Walking
Exercise
D 3 Heart failure
Rest
A Rest
E Fatal
4 myocardial
Dyspnea Pul. edema depression
Ventricular EDV
Stretching of
myocardium
Decreased Progressive
Energy supply Dilatioon
(remodeling)
Apoptosis
Angiotensin Extracellular
receptors intracellular
Intemalization Gene Regulation
Inactivation Angiotensinogen
Cellular Response Renin
Contraction ACE
Secretion Angiotensin
Receptor
The systemic and tissue components of the renin-angiotensin system. Several tissues, including
myocardium, vasculature, kidney, and brain, have the capacity to generate angiotensin II independent of
the circulating renin-angiotensin system. Angiotensin II produced at the tissue level may
Play an important role in the pathophysiology of heart failure. ACE = angiotensin-converting enzyme.
(Modified from timmermans PB, Wong PC, Chiu AT, et al : Angiotensin II receptors and angiotensin II
Receptor antagonists. Pharmacol Rev 45:205, 1993).
Angiotensin II
TNF alpha
Endothesin β1-adrenergic
α 1-adrenergic Mechanical strain Angiotensin II
Low High
NADPH
Cocidase
ROS Cytochrome c
ROS release
Myocardial Sodium
failure reabsorption
-
Atrial or ventricular NAP
Distention, or both release
Glossopharryngeal
And vagal afferents
From high-pressure
baroreceptors
Sympathetic
trunk
Sympathetic
ganglion AVP
Aldosterone
Sympathetic
nerves
Angiotensin II
release
+ CNS Heart
Ach
Arterial rate
chemoreceptors
-
Arterial NE
barorecaptors Parasympatetic
NE
- Contraction
Cardiopulmonary
sympathetic
baroreceptores Na+reabsorption
-
E Renin
NE Renal vascular
Muscle NE resistance
mataboreceptors
Peripheral
NE Vascular
resistance
+ CNS Heart
Arterial rate
cemoreceptors Ach
-
Arterial
NE
barorecaptors Parasympatetic
NE Adverse
-
Cardiopulmonary Cardiac effects
sympathetic
baroreceptores
- Na+reabsorption
E Renin
NE Renal vascular
Muscle NE resistance
mataboreceptors
+ Peripheral
NE Vascular
resistance
Overload/
Energy supply:
Preload Myocyte loss
demand ratio
Afterload
Remodelling
Inotropy
Cardiac output
Baroreflex Neurohormonal
response activation
• Natriuretic • Renin-angiotensin-
peptides aldosterone
• Prostaglandins • Sympathetic Arrhythmias
• Bradykinin Ca2-
nervous system Sudden death
• Endothelin
Response • Arginine vasopressin
to stress
Fluid & salt
retention
Vasoconstriction, vascular remodelling, endothelial dysfunction
Peripheral
maintains blood pressure perfusion
resistance
Altered skeletal muscle redistributes cardiac output of vital
blood flow and metabolism organs
The pathophysiology of heart failure involves the interaction of intrinsic cardiac function wit neurohormonal activation, peripheral
vasoconstriction and volume expansion. Neurohormonal activation may increase vasoconstriction and lead to a vicious cycle of
worsening cardiac function. Natriuretic peptides and other hormones with vasodilating properties may have potentially beneficial
effects on vasoconstriction and volume expansion. This complex model is influenced by numerous factors, including age of patient,
drugs, presence of coronary artery disease and the constant feedback of the various regulatory systems. Demonstrated effect;
Possible effect; + Positive feedback; - Negative feedback; Decrease; Increase; Ca2+ Intracellular calcium concentrations
Diuresis
Vasodilatation Antimitogenic
Natriuretic
Prostaglandins peptides No
Myocardial
Free radicals
dysfunction
Cytokines
Renin Growth
AVP
Endothelins hormone
All
Catecholamines Apoptosis
Aldosterone
Hypertrophy
Vasoconstriction
Salt and water
retention
Low BP Baroreflexes
JVP kidney
Adrenergic stimulation
RV failure RV ANP
LA RENIN
EXCESS
back Angiotensin AFTERLOAD
big liver
edema ward Aldosterone
Left pressure
ventricle
Increasing
Na+ loss Na+ retension
forward
Edema
failure
INCREASING heart
BACKWARD
FAILURE
Increasing EXCESS
BLOOD VOLUME
low renal
preload blood flow
(Opie, 1994)
Bisoprolol pooled (2 trials)
5 small trials
Pooled odds ratios (and 95% confidence intervals) describing the effect
of blockers on mortality in patients with heart failure (fixed effects model)
Probability of Survival
0.85
0.80
0.75
0.70 Spironolactone
0.65
0.60
0.55 Placebo
0.50
0.45 p<0.001
0.00
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
No. At Risk
Placebo 841 775 723 678 628 592 565 483 379 280 179 92 36
Spironolactone 822 766 739 698 669 639 608 526 419 316 193 122 43
Preventive
Pacing therapies
VT/VF
Ventricular
ATP/DC
DDDR-pacing
Brady
Resynchronization therapy
CHF
(a) The coexistence of heart failure and arrhythmias (bradycardias [Brady], atrial fibrillation [AF],
ventricular tachycardia [IVT] and ventricular fibrillation [VF]) is mirrored by (b) the coexistence of
various treatment modalities in a single electrical device. ATP=antitachycardia pacing;
CHF=congestive heart failure; DC=direct-current cardioversion defibrillation.
Hormones Abnormal External
Inflammatory Oxygen
(catecholamines, Nitric oxide Genetic factors baroceptor factors
cytokines free radicals
ET-1, steroids) reflexes
Metabolic status
(Global/local factors)
Energy Resting energy Skeletal muscle Skeletal muscle Cardiac muscle Cardiac muscle Endothelial
reserves expenditure function apoptosis function apoptosis function
Deterioration of CHF
Complex interactions between different body systems in the pathogenesis of chronic heart failure.
CHF=chronic heart failure; ET=endothelin.
Overload / Energy supply :
Preload Myocyte loss demand ratio
Afterload Remodelling
Cardiac output Inotropy
Baroreflex Neurohormonal
response activation
• Natriuretic • Renin-angiotensin-
peptides aldosterone Arrhythmias
• Prostaglandins • Sympathetic nervous Ca2+
• Bradykinin system
• Endothelin Sudden death
Response to • Arginine vasopressin
stress
Fluid & salt
retention
Vasoconstriction, vascular remodelling, endothelial dysfunction
P = 0.0002
0.8
0.6
Heart disease
Asymptomatic
LV Dysfunction
Symptoms
NYHA II-III Symptoms
NYHA - IV
Symptoms
ECHO / LV dysfunction
? BNP
100
Progression Further damage
Excessive wall stress
Neurohormonal activation
Patients surviving %
Annual mortality
<5% 10% 20 to 30% 30 to 80%
0
Asymptomatic Mild Moderate Severe
ml
120
sv
80 LV Volume
40
RV
0
R
T ECG
P P
Q S
Relaxation
Passive stiffness Factors
influencing
Elastic recoil
LV diastole
Atrial reserve
M-mode
AO MI achocardio-
cm/s graphy
80
40
Dopplerecho
E A
0
Neurohormonal Activation
• Cathecholamines
Vasoconstriction • RAS
• AVP
• Endothelin
Peripheral Organ
Cardiac Remodelling
Blood Flow
CONTRACTILITY
PRELOAD AFTERLOAD
STROKE
VOLUME
• Synergistic LV contraction
HEART
• LV wall integrity
RATE
• Valvular competence
CARDIAC OUTPUT
Processes Occuring
in Ventricular Remodeling
Cardiomyocyte lengthening
Ventricular wall thins
Infarct expansion rather than extension occurs
Inflammation and reabsorption of necrotic tissue
Scar formation
Caontinued expansion of infarct zone
Dilation and reshaping of the left ventricle
Myocyte hypertrophy
Ongoing myocyte loss
Excessive accumulation of collagen in the
cardiac interstitium
(Cohn et al, 2000)
Epidemiology
Epidemiology of CHF in the community
Age Prevalence Incidence
(years) (%) (new cases per 1000 per year)
50 1 2
80 9 14
Survey Admissions
USA hospital admissions
per year
Gillum (1985) 585 000
Yancy and Firth (1988) 900 000
UK Hillingdon survey
Parameshwar (1990) 4.9% of medical hospital admissions
Injury to myocytes and extracellular matrix
• neurohumoral
activation • oxidative stress
• increased cytokine • apoptosis
expression Ventricular • altered gene
• immune and remodeling
expression
inflammatory
• energy starvation
changes
• altered fibrinolysis
CHF
Rukma Juslim
Division of Cardiology, Department of Internal Medicine
Hang Tuah University, Dr. Ramelan Hospital
Semarang
Aging: The Major Risk Factor for
Cardiovascular Morbidity and Mortality
STROKE STROKE
Disease
Increasing Age
Increasing Age
Clinical
Practice LV RESERVE
Threshold
“normal” Aging
Prevention
Stage
ARTERIAL
STIFFENING
AND
THICKENING
Endothelial dysfunction
From first decade From third decade From fourth decade
Smooth muscle Thrombosis,
Growth mainly by lipid accumulation and collagen haematoma
A B C D E F
The Spectrum of Vascular Remodeling
Vessel A represents hypertensive vascular disease with vascular hypertrophy, in which the
medial layer is thickened and the luminal diameter is reduced; vessel B, hypertensive vascular
disease without medial hypertrophy, in which the luminal diameter is reduced; vessel C,
decreased vessel dimensions is response to a long-term decrease in flow; vessel D, increased
vessel dimentions in response to a long-term increase in flow; vessel E, neointimal hyperplasia
(migration and proliferation of vascular smooth-muscle cells) in response to vascular injury; and
vessel F, atherosclerosis in response to vascular injury of conduit vessels.
(Gibbons & Dzau, 1994)
VASCULAR REMODELING
Vascular remodeling is an active process of
structural alteration that involves changes
in at least four cellular process – cell growth, cell
death, cell migration, and production or
degradation of ECM – and is dependent on a
dynamic interaction between locally generated
growth factors, vasoactive substances, and
hemodynamic stimuli.
Remodeling is usually an adaptive process that
occurs in response to long-term changes in
hemodynamic conditions, but it may subsequently
contribute to the pathophysiology to vascular
diseases and circulatory disorders.
(Gibbons & Dzau, 1994)
Endothelial dysfunction leads to imbalance
of factors resulting in vascular disease
Normal endothelium Abnormal endothelium
Hypertension Diabetes
Triglycerides
Oxidative
damage
Upregulation of
Endothel Dysfunction angiotensin II
Vascular Retard Inhibit SMC Barrier to receptors
tone platelet & migration & LDL cholesterol.
leukocyte proliferation Degrade VLDL &
adhesion chylotriglyceride
(lipase) Vasoconstriction Increased SMC Increased lipid
platelet & migration deposition.
leukocyte & growth Reduced
adhesion clearance
Adherence
BLOOD
LDL
Entry
+
MCP-1 Endothelial Foam Cells
+ Damage
M-CSF Oxidation
Growth and + MM-LDL
change of
phenotype Oxidation
Accumulation
+ OX-LDL
of cholesterol-
loaded
Macrophage macrophage
Receptor-mediated
Uptake of Ox-LDL
ARTERY WALL
(Steinberg, 1991)
Characteristics of the
stable atherosclerotic plaque
Fibrous cap
(VSMCs and matrix) Intimal VSMCs
Endothelial (repair phenotype)
cells
Lipid core
Adventitia
Medial VSMCs
(contractile phenotype)
Advanced Atherosclerosis
Activated macrophages
induce intimal VSMC
apoptosis and degrade the
Intimal VSMCs matrix in the fibrous cap
become senescent
lipid
Lipidcore
core
Adventitia
VSMC–inflammatory cell interactions
in atherosclerosis
MMPs secreted by
macrophages degrade
the extracellular matrix
Macrophages
induce
VSMC
apoptosis
TNF-
IL-1
Fibrous
Macrophage
cap
T-lymphocyte IFN-g
PDGF Inflammatory
cytokines
inhibit matrix
protein
production
Macrophages secrete growth factors that by VSMCs
promote VSMC recruitment and proliferation
MMPs and Arterial Remodelling
plaque Rupture
plaque
Lumen
Intimal MMP-9
Hyperplasia MMP-1,2,3,8,9,14 (Definitely “ugly”)
MMPs ?
MMP-2,9
MPP-9
Non-lipid
Lipid mechanisms mechanisms
Measurable Measurable
indicators indicators
Endothelial NOS