ABSTRACT
INTRODUCTION:
Recent results from clinical trials indicate that
the absolute level of low-density lipoprotein cholesterol
(LDL-C) may not be of importance in determining the
amount of risk reduction produced by cholesterol lowering
therapies. High-density lipoprotein cholesterol (HDL-C)
has been shown to be a reciprocal, independent risk
factor for coronary heart disease (CHD).
The purpose of this study was to compare the
predictive power of HDL-C with LDL-C for coronary
calcification. METHODS:
A total of 6,199 subjects were studied with
respect of coronary calcification, serum cholesterol
indices, personal health history and body morphology. Analyses consisted of correlation coefficients, one-way ANOVA and
logistic regression techniques to determine the strength
of association between HDL-C and coronary calcification
after controlling for covariates. RESULTS: HDL-C
had higher correlation coefficients than LDL-C. Individuals with a HDL-C level <40
mg/dL had significantly higher calcium scores, plaque
volume and number of lesions.
Subjects found to have a HDL-C level that was
5 mg/dL higher had a 10% reduction in risk of any
plaque development.
Subjects whose LDL-C was 10 mg/dL higher had
an odds that was 1.04 times higher for having any
calcified plaque.
Results of multivariate logistic regression
revealed that HDL-C is predictive of calcified plaque
development independent of LDL-C.
CONCLUSIONS: HDL-C is a stronger predictor
for the presence of any calcified atherosclerotic
plaque than is LDL-C. These results support the epidemiologic finding of an antiatherogenic
effect of HDL-C based on the finding of a negative
correlation between HDL-C and coronary calcium score.
Key
Words
Cholesterol,
Coronary, Calcification, Correlation
INTRODUCTION
Serum
lipoproteins are currently employed as the focus for
primary and secondary prevention of coronary heart
disease (CHD). According
to the NCEP ATP III guidelines, treatment strategies
are based on the number of cardiovascular risk factors
present and the serum low-density lipoprotein cholesterol
(LDL-C) level.[1]
Under these guidelines the percent increase
in patients being treated compared to ATP II would
be 140% overall, 157% among males, 122%
among females, 131% among those 
65 years old, and 201% among those <45
years old.[2] Recent results from clinical trials indicate
that the absolute level of LDL-C may not be of importance
in determining the amount of risk reduction produced
by cholesterol lowering therapies.[3] Furthermore, a lack of association between
LDL-C levels and the amount of calcified atherosclerotic
plaque as measured by electron beam computed tomography
(EBCT) has been demonstrated previously.[4]
METHODS
Subjects
From
October 1999 to February 2002, 8,101 consecutive patients
who presented for preventive medicine services at
a private, university affiliated disease prevention
center in San Diego, California, were eligible for
initial enrollment in the study. Patients evaluated at the center more than
once were included with their original data only. Patients with a history of any coronary artery procedure or who
were taking lipid-altering medications were excluded. These medications included HMG CoA reductase inhibitors, niacin,
oral chelation therapies, fibrates and hormonal therapies. Individuals with triglyceride values > 400
mg/dL were unable to be included in the analysis
due
to the inability to calculate LDL-C values using
the Friedewald formula. Of the initial sample, a total of 6,199 subjects were available
for analysis. Most
patients were self referred or referred from their
local doctors and were seeking preventive health information
as a supplement to their routine medical care.
Imaging
All
patients underwent imaging with an Imatron C-150 scanner. Images were obtained with 100-ms scan time. Using 3 mm slices starting at the level of
the carina and proceeding to the level of the diaphragm,
approximately 40 to 45 slices of each subject’s heart
were obtained. Tomographic
imaging was electrocardiographically triggered at
40 or 65% of the R-R interval, depending on the subject’s
heart rate. Coronary calcification was defined as a plaque
of >= 2 pixels (area = 1.37 mm2) with
a density of greater than or equal to 130 Hounsfield
unites (HU). Quantitative
calcium scores were calculated according to the method
described by Agatston et al.[13] Coronary calcium scoring
was performed by either a physician or computed tomography
technician with specific training for the methodology
described above.
In addition to a calcium score, this methodology
produces a total plaque volume and calculates the
total number of lesions present in the coronary arteries.
Laboratory
All patients underwent
random serum lipid analysis using the Cholestex LDXÒ
system. In
brief, capillary whole blood specimens were obtained
by finger stick with the subject in the seated position
using a 35 ml
lithium heparin-coated capillary tube.
Body mass index was calculated with the patient
clothed without shoes.
Body fat measurement was conducted using the
OmronÔ HBF-300 body fat analyzer.
Statistical
Analysis
Univariate
associations between the outcomes and the continuous
predictor variables were calculated using the Spearman
rank correlation. Comparison of group means for categorical variables was conducted
using a one-way ANOVA.
Tukey’s test was used for multiple comparisons
of the stress variable.
Transformation
of coronary calcium score failed to normalize the
distribution of this variable.
Coronary calcium scores were therefore dichotomized
for use in logistic regression with the 2 categories
being a score of 0 and a score > 0 (i.e. presence
or absence of plaque).
Univariate logistic regression was conducted
for all predictor variables.
Variables that were significantly associated
with the outcome at a p-value of £
0.10 were included in multivariate logistic regression. Stepwise regression was performed to construct
the most parsimonious multivariate model. Predictor variables that changed the odds ratio for HDL cholesterol
by more than 5% were retained in the final model. A significance level of 0.05 was used for all analyses. All statistical analyses were conducted using
SAS version 8.0 statistical package (Cary, NC). The study protocol complies
with the Declaration of Helsinki and was approved
by the committee for protection of human subjects
at San Diego State University.
RESULTS
Univariate
associations between plaque score, volume and lesions
and categorical predictor variables are shown in Table
3. Significant
associations were found between all predictor variables
except for being a current smoker and having a family
history of premature coronary heart disease in a parent
or sibling. Individuals
with a HDL-C level < 40 mg/dL had significantly
higher calcium scores, plaque volume and number of
lesions. For men, the average score, volume and number
of lesions were double that of women. Individuals with a diagnosis of hypertension
had nearly twice the score, volume and number of lesions
as those who were not hypertensive.
Former smokers were found to have a similar
relationship. Diabetic
subjects had nearly 3 times the amount of plaque as
those who were not diabetic.
DISCUSSION
In
this cross-sectional, analytic observational study,
we found that HDL cholesterol is a stronger predictor
for the presence of any calcified atherosclerotic
plaque than is LDL cholesterol. We also found that HDL-C had a higher correlation coefficient than
LDL-C with the coefficient value for the latter approaching
zero. There was a reciprocal relationship between
HDL-C and coronary plaque indicating that as HDL-C
levels increases, the amount of plaque decreases.
There was essentially no relationship between
LDL-C and coronary calcium score, volume or number
of lesions.
We
have previously found in a similar analysis with LDL-C
as the primary predictor variable and coronary calcium
score as the outcome, that inclusion of HDL-C cholesterol
in the final multivariate model changed the odds ratio
by more than 10% after controlling for age and gender[15]. Therefore, the predictive power of LDL-C cholesterol
was not independent of HDL.
In the current study, including LDL-C in the
final model did not significantly change the odds
ratio indicating that the predictive power of HDL-C
is independent of LDL-C.
The
results of our study support the epidemiologic finding
of an antiatherogenic effect of HDL cholesterol based
on the finding of a negative correlation between HDL-C
and coronary calcium score.
It appears that patients with higher serum
HDL-C levels have less coronary plaque and that the
risk of having any plaque decreases by 8% for every
5 mg/dL increase in HDL-C.
Prior
observational studies have shown that HDL-C is an
independent inverse predictor of cardiovascular event
risk.[16] The mechanism by which
HDL-C reduces the
risk of adverse coronary heart disease outcomes is
unknown. Postulated mechanisms include HDL’s role in
reverse cholesterol transport[17], inhibition of oxidation
of LDL cholesterol[18] and prolonging the half-life
of prostacyclin[19], a vasodilator and inhibitor
of platelet aggregation. Recently, two proteins (ABCA1 and SR-BI) have been identified that
are reportedly involved in the process of reverse
cholesterol transport and are mediated by HDL-C.[20] The direct participation of HDL in this process
may explain the significant correlation with reduced
amounts of plaque in patients with higher levels of
HDL-C. However,
some studies have demonstrated that the in vivo rate
of reverse cholesterol transport do not depend on
the HDL-C concentration.[21] Further research into the exact mechanism of
this process is necessary in order to elucidate the
antiatherogenic role of HDL-C.
The
relationship between LDL-C and atheroma development
is dependent on the oxidized form of LDL.
Biochemical research has provided evidence
that low-density lipoprotein cholesterol can promote
atherosclerotic calcification of vascular cells.[22] However, this effect was found to be due to
products of lipid oxidation and not a function of
native LDL or its concentration in serum.
These findings are consistent with our findings
of a very modest association between LDL-C levels
and the amount of calcified atherosclerotic plaque
present.
Despite
the conflicting evidence for the mechanism by which
HDL cholesterol confers a protective effect, observational
and interventional studies have demonstrated a decrease
in event rates for individuals with a higher serum
HDL-C or increasing the HDL-C level, respectively.
For example, the FATS[23] and HOPE[24]
trials showed that increasing the HDL cholesterol
predicted lowered risk of CHD.
In the HOPE trial, the benefits of raising
HDL were in addition to lowering LDL cholesterol levels
by simvastatin. The
observational Prospective Cardiovascular Munster Study
(PROCAM) found similar results.[25] Thus, from a pragmatic point of view raising
the HDL-C level appears to confer protection from
future coronary events.
Limitations
of this study include the cross-sectional design and
the use of random serum lipid measurements.
The former reduces the ability to assess true
causality between the predictor variables and the
outcomes. The
latter will result in LDL-C values that are lower
than fasting levels. The use of random lipid levels has been associated with a 7 and
3% decrease in LDL cholesterol at 3 and 5 hours postprandially,
respectively[26]. However, since the LDL-C variable was used
in the continuous form and patients were not categorized
based on LDL-C level, misclassification bias will
not occur. In
effect, even if the LDL values were 3 – 7% higher,
the correlation would remain modest and nonlinear.
The use of random HDL-C values is recommended
by the NCEP ATP III guidelines.1
ACKNOWLEDGEMENTS
The
authors would like to thank the following individuals
who contributed to this project and manuscript: Marianne
Saulino, ARRT, Steve Knox, ARRT, Mandy Ludden, CMA,
Shacole Simmons, CMA, and Miranda Lerario, CMA.
REFERENCES