Prevalence of Emerging Cardiovascular

Risk Factors in Younger Individuals with

a Family History of Premature Coronary
Heart Disease and Low Framingham
Risk Score
Vivek Sailam, MD,

Dean G. Karalis, MD,

Ashish Agarwal, MD,

Firas Alani, MD,

Susan Galardi, RN,

Veronica Covalesky, MD,

Christian Athanassious, AfliateResident

Department of Cardiology;

Department of Cardiovascular Disease;

Department of Internal
Medicine; Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
Address for correspondence:
Vivek Sailam, MD
760 N. Broad St., Ste. 200
Woodbury, NJ 08096, USA
vsailam@hotmail.com
Introduction: The purpose of this study was to assess the prevalence of emerging cardiac risk factors in
individuals with a family history of premature coronary heart disease (CHD) and who were predicted to be
low-risk for cardiovascular (CV) disease based on their Framingham risk score.
Methods: We prospectively evaluated 89 younger men and women with a family history of premature CHD
and who had a low Framingham risk score. Patients with CHD or CHD equivalents were excluded. All patients
were screened for emerging clinical and lipid risk factors.
Results: Coronary calcium was present in 38% of patients and C-reactive protein >3 mg/dl was present in
24% of patients. Low levels of high-density lipoprotein (HDL
2
) cholesterol were the most prevalent emerging
lipid risk factor and was present in 72%of the study group. More individuals had lowlevels of HDL
2
than total
HDL (34% versus 71%; p-value =0.001). Triglyceride- (TG)-rich remnant lipoproteins were present in 49% of
patients.
Conclusions: The Framingham risk score poorly predicts CV risk in younger healthy persons with a family
history of premature CHD. The prevalence of subclinical CHD and emerging clinical and lipid risk factors is
high in these patients. The most prevalent lipid risk factor was low levels of HDL
2
. Individuals with a family
history of premature CHD may benet from screening for emerging risk factors to better assess their CV risk.
Key words: coronary calcium, Framingham risk score, premature coronary heart disease
Introduction
Individuals whose parents or siblings develop coronary
heart disease (CHD) at a young age are at increased
risk of developing CHD themselves. A family history of
premature CHD is recognized as a major risk factor
for CHD in the National Cholesterol Education Program
(NCEP) adult treatment panel (ATP) III guidelines,
1
and
recent emphasis has been placed on screening individuals
with a family history of premature CHD for established
cardiovascular (CV) risk factors in order to reduce their risk
of developing CHD. However, previous studies have shown
that individuals with a family history of premature CHD
often have normal lipid levels and few identiable major
risk factors for CHD, despite having a high prevalence of
subclinical coronary artery disease (CAD).
24
We hypothesized that the CV risk in the offspring of
individuals with premature CHD would be underestimated
by the Framingham risk score, and that their increased CV
risk might be explained by factors beyond traditional CV
risk factors. The NCEP ATP III guidelines have identied
several emerging clinical and lipid risk factors that may
contribute to CHD risk,
1
and previous studies have shown
a high prevalence of these emerging risk factors in patients
who develop premature CHD.
5,6
In this study, we sought to
determine the prevalence of these emerging risk factors in
younger individuals with a family history of premature CHD
and whose predicted CV risk using the Framingham risk
score was low.
Methods
Individuals for the study were recruited from a large clinical
cardiology practice. Study patients were eligible to be
enrolled in the study if they were men between the ages
of 35 y and 54 y or women between the ages of 40 y and
64 y, and had a rst-degree male relative with CHD before
the age of 55 y or a rst-degree female relative with CHD
before the age of 65 y. Patients were excluded if they had a
history of CHD or were considered a CHD risk equivalent
as dened by the NCEP ATP III guidelines.
1
Selected patients had an initial ofce visit to review the
study protocol and obtain informed consent. The study
was approved by an independent Internal Review Board.
All study patients underwent a thorough history and a
physical examination by a physician. Blood samples were
obtained for a lipid prole, routine chemistries, thyroid
function, and complete blood count. Patients were screened
542
Clin. Cardiol. 31, 11, 542545 (2008) Received: October 21, 2007
Accepted: November 27, 2007
Published online in Wiley InterScience. (www.interscience.wiley.com)
DOI:10.1002/clc.20355 2008 Wiley Periodicals, Inc.
for the metabolic syndrome, as dened by the NCEP
ATP III guidelines,
1
for the presence of coronary calcium,
high sensitivity C-reactive protein, lipoprotein(a) (Lp[a]),
triglyceride- (TG)-rich remnant lipoproteins, low-density
lipoprotein (LDL), and high-density lipoprotein (HDL) sub-
classes were measured. A level of C-reactive protein was
measured from a commercially available assay. The lipid
prole and other emerging lipid risk factors were measured
by vertical density ultracentrifugation using the Vertical
Auto Prole (VAP) lipid test (Atherotech, Birmingham,
Ala., USA). The VAP test is a single-spin, density-gradient,
ultracentrifugation method followed by enzymatic determi-
nation of cholesterol in all lipoprotein fractions to measure
the lipid subclasses. We used the VAP test to measure LDL
density (pattern A or B), the levels of intermediate-density
lipoprotein (IDL), the levels of very low-density lipoprotein
(VLDL), and HDL subclasses, as well as the concentrationof
Lp(a). Triglyceride-rich remnant lipoproteins were dened
as the concentration of VLDL3 and IDL. Small, dense LDL
cholesterol was denedas pattern Band large HDL particles
were dened as the subclass HDL
2
. Coronary calcium was
measured using an Imatron electron beam computerized
tomography (EBCT) scanner (Imatron Inc, San Francisco,
Calif., USA). A coronary artery calcium (CAC) score was
determined according to the method of Agatston.
7
Statistical analysis was performed using a statistical
package from the Social Sciences proprietary software. The
program enabled p-value calculations for HDL
2
versus HDL
and TGs versus remnant lipoproteins via t test bivariate
analysis. The software was also used to calculate mean
values and standard deviations for the presented data.
Prevalence values for emerging risk factors were calculated
using Microsoft Excel software (Microsoft Corp., Redmond,
Wash., USA).
Results
The study subjects consisted of 34 men and 55 women. The
mean age for both men and women in the study was 47 y.
The demographics, prevalence of traditional risk factors,
and lipid levels are displayed in Table 1. The distribution of
LDLcholesterol levels amongstudy patients were as follows:
11% had LDL levels 190 mg/dL, 15% had LDL levels >160
to 189 mg/dL, 35% had levels between 130 to 159 mg/dL,
31% had levels between 100 to 129 mg/dL, and 8% had levels
<100 mg/dL. Only 11% of patients would have qualied for
pharmacologic lipid-lowering therapy based on current ATP
III guidelines. Low levels of HDL cholesterol (<50 mg/dL)
were present in 34% of women, while HDL cholesterol levels
were low (<40 mg/dL) in 35% of men. Triglyceride levels
were elevated (150 mg/dL) in 27% of patients.
The prevalence of emerging CV risk factors are displayed
in Table 2. Low levels of HDL
2
were present in 72% of
patients. Low levels of HDL
2
(<15 mg/dL) were present
in 74% of women and low levels of HDL
2
(<10 mg/dL)
TABLE 1: Mean values and standard deviations
Variable
Age of men and women (y) 47 y of age (5.3)
Men 38%
Women 62%
Hypertension 14%
Cigarette smoking 13%
Systolic blood pressure (mm Hg) 120 mm Hg (14.3)
Diastolic blood pressure (mm Hg) 75 mm Hg (9.4)
Total cholesterol (mg/dL) 217 mg/dL (43.4)
TGs (mg/dL) 120 mg/dL (68)
LDL cholesterol (mg/dL) 144 mg/dL (37.5)
HDL cholesterol (mg/dL) 51 mg/dL (13.7)
Abbreviations: HDL =high-density lipoprotein; LDL =low-density lipo-
protein; TG=triglyceride.
TABLE 2: Emerging clinical and lipid risk factors
Emerging clinical risk factors
Hs-CRP >3 24%
Positive calcium score 38%
Metabolic syndrome 14%
Emerging lipid risk factors
Lp(a) elevation 22%
Low HDL
2
in women 74%
Low HDL
2
in men 67%
Small, dense LDL pattern 19%
Mixed LDL pattern 41%
Elevated remnant lipoproteins 49%
Abbreviations: HDL =high-density lipoprotein; Hs-CRP =high-sensiti-
vity C-reactive protein; LDL =low-density lipoprotein; Lp(a) =lipopro-
tein(a).
were present in 67% of men. More individuals had low levels
of HDL
2
than total HDL (34% versus 71%; p-value =0.001).
Triglyceride-rich remnant lipoproteins (VLDL
3
and IDL)
were elevated in 49% of the patients. More patients had
elevatedlevels of TG-richremnant lipoproteins thanelevated
levels of TG (49% versus 27%; p-value =0.0001). Low-density
lipoprotein cholesterol was predominately small and dense
in 19% of patients, while 41% had a mixed pattern of large and
Clin. Cardiol. 31, 11, 542545 (2008)
543
V. Sailam et al.: Risk factors in younger individuals with a family history of CHD
Published online in Wiley InterScience. (www.interscience.wiley.com)
DOI:10.1002/clc.20355 2008 Wiley Periodicals, Inc.
Clinical Investigations
continued
small dense LDL cholesterol particles. Lipoprotein(a) levels
were elevated in 22% of patients. Coronary artery calcium
was present in 38%of patients witha mean score of 67 (range
of 3-300). Among patients with a positive CAC score, 79%
had scores greater than the seventy-fth percentile and 33%
hadscores greater thanthe ninetiethpercentile for their age.
Discussion
For the primary prevention of CHD, current guidelines
recommend screening for traditional risk factors and
calculating the Framingham risk score to determine an
individuals risk for CHD. Our study adds to the growing
evidence that the Framinghamrisk score is a poor predictor
of CV risk in younger individuals with a family history
of premature CHD. In our study of patients with a low
predicted risk of CV disease, the prevalence of subclinical
atherosclerosis as measured by coronary calcium was 38%.
Other studies have shown similar ndings. Michos et al.
8
screened 102 younger women with a family history of
premature CHD and low Framinghamrisk score, and found
40% had detectable coronary calcium. In the Study of the
Inherited Risk for Coronary Atherosclerosis (SIRCA), 52%
of women and 78% of men with a family history of premature
CHD and without CHD or diabetes had a positive coronary
calciumscore.
9
The mean age of men in SIRCAwas 45 y and
the mean age of women was 50 y. These ndings suggest
a high prevalence of subclinical CAD in healthy younger
individuals with a family history of premature CHD.
In asymptomatic individuals, the presence of coronary
calcium has been associated with an increased risk of CV
events, and the higher the CAC score the greater the
CV risk.
10
Although the average CAC score in our study
was low, most patients with detectable CAC had calcium
scores greater than the seventy-fth percentile for their age.
Recent studies suggest that individuals with low calcium
scores often have signicant noncalcied plaques present
as well, suggesting that they remain at increased risk for
CV events even though their CAC scores may be low.
11
The CV risk in individuals with a family history of
premature CHD cannot fully be explained by traditional
CV risk factors. In SIRCA, traditional risk factors accounted
for less than one-third of the variations in coronary calcium.
9
Akosah et al.
12
evaluated 222 younger patients admitted to
the hospital with an acute myocardial infarction and found
that most had fewtraditional CVrisk factors. Only 17%would
have been predicted as being at high risk based solely on
their Framingham risk score, and almost 75% would not
have qualied for lipid-lowering therapy based on current
lipid-lowering guidelines. In the Framingham Offspring
Study, a sibling history of CV disease was associated with
a signicant risk of developing CV disease in other siblings
initially free from CHD.
13
This increased risk could not be
explained fully by the presence of traditional risk factors.
This suggests that there are other risk factors responsible
for the increased risk of CV disease in individuals with a
family history of premature CHD.
To investigate what other factors may explain the
increased risk of CV disease in individuals with a family
history of premature CHD, we screened our study patients
for emerging CV risk factors. We identied a high
prevalence of both emerging clinical and lipid risk factors.
The most prevalent emerging clinical risk factor was a
signicantly elevated C-reactive protein (>3 mg/l) present
in 24% of our study patients. Numerous studies have shown
that in asymptomatic men and women, C-reactive protein is
a strong and independent predictor of myocardial infarction
and stroke.
1415
In a recent analysis from the Womens
Health Study, Ridker et al. added C-reactive protein and
a family history of CHD to traditional risk factors in
order to assess CV risk.
16
This new risk score (Reynolds
risk score) more accurately predicted CV risk than the
Framingham risk score, and reclassied almost 50% of low
and intermediate risk women into either higher or lower
risk categories.
The most prevalent emerging lipid risk factor in our study
was low levels of HDL
2
present in 72% of our study patients.
High-density lipoprotein is categorized by size and density
into 2 major subclasses: HDL
2
, which is larger and more
enriched in cholesterol; and HDL
3
, which is smaller and has
lower cholesterol content. The levels of HDL
2
are thought to
be a measure of reverse cholesterol transport, with higher
levels reecting more efcient reverse cholesterol transport.
Low levels of HDL
2
are associated with an increased risk
of CV disease, and in the Framingham Offspring Study, the
measurement of larger HDL
2
particles better differentiated
those individuals who developed CHD from controls than
did levels of either HDL or LDL cholesterol.
17
As with traditional CV risk factors, the more emerging
risk factors present in an individual patient the higher the CV
risk. Wang et al.
18
measured multiple emerging biomarkers
in 3,209 participants from the Framingham Heart Study,
and found persons with high multi-marker scores had a risk
of death 4-fold higher than persons with low multi-marker
scores.
Our study has several limitations. The sample size was
small, mostly Caucasian, and there were more women than
men in the study. However, the demographics of patients
likely represent the demographics of the larger group of
younger patients seen in our clinical practice. Furthermore,
the study lacked a control group. However, the prevalence
of coronary calcium and other emerging risk factors in our
patient population is higher than would be expected in an
otherwise young and healthy group of patients.
Conclusion
We found a high prevalence of subclinical CAD in a young
population of patients with a family history of premature
CHD and who were predicted to be at low risk based on
544
Clin. Cardiol. 31, 11, 542545 (2008)
V. Sailam et al.: Risk factors in younger individuals with a family history of CHD
Published online in Wiley InterScience. (www.interscience.wiley.com)
DOI:10.1002/clc.20355 2008 Wiley Periodicals, Inc.
their Framingham risk score. This higher risk is likely
explained by the presence of risk factors beyond those
traditional CV risk factors typically screened for in clinical
practice. The Framingham risk score underestimates CV
risk in individuals with a family history of premature CHD,
and screening for emerging CV risk factors may better
assess CV risk in these patients.
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Published online in Wiley InterScience. (www.interscience.wiley.com)
DOI:10.1002/clc.20355 2008 Wiley Periodicals, Inc.