Comparison of the Plasma Levels of
Apolipoproteins B and A-l, and Other Risk
Factors in Men and Women with Premature
Coronary Artery Disease
Peter 0. Kwiterovich, Jr., MD, Josef Coresh, PhD, Hazel H. Smith, MT, Paul S. Bachorik, PhD,
Carol A. Derby, PhD, and Thomas A. Pearson, MD, PhD
The predictors of premature coronary atheroscie-
rosis were examined in 203 patients (66 men
aged 150 years, and 104 women aged 160
years) undergoing elective diagnostic coronary ar-
teriography. Age, cigarette smoking, hyperten-
sion, obesity, diabetes, positive family history of
premature coronary artery disease (CAD), and
plasma levels of total cholesterol, triglyceride, ii-
poproteins (i.e., very low, intermediate-, low-, and
high-density [HDL] iipoprotehts and their subfrac-
tions [HDLe and HDLs], and lipoprotein [a]) and
apoiipoproteins (apoA-1, apoA-2 and apoB, re-
spectively) were examined using univariate anaiy-
ses and multivariate logistic regression. in men,
age (p <O.OS), smoking (p <O.OS), and plasma tri-
glyceride (p <0.02) and apoA-1 (p CO.05) levels
were independently associated with CAD. in wom-
en, smoking (p <O.OOl) and plasma apoB levels (p
<0.04) were the strongest variables independently
associated with CAD. it is concluded that the
“nontraditional” risk factors (plasma apoA-1 and
apoB levels) are better predictors of premature
CAD than are plasma lipoproteins and that smok-
ing is the strongest of the traditional noniipid risk
factors.
(Am J Cardioi 1662;69:1OlS-1021)
From the Lipid-Research Atherosclerosis Unit, Departments of Pediat-
rics, Medicine, and Epidemiology, the Johns Hopkins Medical Institu-
tions, Baltimore, Maryland. This study was supported by Grant HL
31497 from the National Institutes of Health, Bethesda, Maryland.
Manuscript received September 9, 1991; revised manuscript received
and accepted December 11,199 1.
Address for reprints: Peter 0. Kwiterovich, Jr., MD, the Johns
Hopkins Medical Institutions, 600 N. Wolfe Street/CMSC 604, Balti-
more, Maryland 21205.
PREDICTORS OF PREMATURE CORONARY ATHEROSCLEROSIS
he plasma levels of total, low-density lipoprotein
T (LDL) and very low density lipoprotein (VLDL)
cholesterols,and triglyceride are usually higher,
whereas those of high-density lipoprotein (HDL) cho-
lesterol and its 2 major subfractions (HDLz and HDL3
cholesterols) are usually lower in patients with than in
those without coronary atherosclerosis(defined by coro-
nary arteriography).‘-lo In some but not all reports,
nonlipid risk factors such as increased blood pressure,
cigarette smoking, diabetes and excess body weight
were also considered Only approximately half of coro-
nary artery disease(CAD) is explained by these lipid-
and nonlipid-related risk factors.‘l Thus, more recent
studiesalso measuredplasma levelsof apolipoproteins B
and A-l (apoB and apoA-1; the major proteins of LDL
and HDL, respectively), and lipoprotein (a) [Lp(a)], a
plasma lipoprotein consisting of an LDL molecule cova-
lently bound to apolipoprotein (a), a protein homolo-
gous to plasminogen.*-lo However, less comparative in-
formation is available in subjects (particularly women)
with premature coronary atherosclerosis.
METHODS
Study populationr The study population comprised
99 white men (aged 150 years) and 104 white women
(aged 560 years) who underwent elective, diagnostic
coronary arteriography at the Johns Hopkins Hospital
between April 1985 and April 1988. Sixty years was
chosenas the cut point in women, becausethey general-
ly present with premature CAD 10 years later than
men, and very few women aged GO years undergo cor-
onary arteriography.‘,‘*,13The number of nonwhite sub-
jects was too small to constitute a subgroup, and thus
only white subjectswere studied. Patients were excluded
for the following reasons: age, distance (lived >lOO
miles from the Johns Hopkins Hospital), undergoing
unscheduledor emergent cardiac catheterization or cor-
onary angioplasty, receiving lipid-lowering medication
or had a myocardial infarction within the previous 12
weeks.Ninety-three percent of the men, and 91% of the
women who were eligible and were contacted agreed to
participate in the study. Informed consentwas obtained
from each participant. The study was approved by the
Johns Hopkins Joint Committee on Clinical Investiga-
tion.
Patients were recruited for the study as follows.
Each week a complete list of age- and sex-eligible pa-
tients scheduledfor elective arteriography was obtained
101s
 from the catheterization laboratory. Potentially eligible
patients were approached systematically, starting with
the beginning of the list and proceedingdown. No more
than 4 subjects were studied each week, becauseof the
time limitation posedby the large number of laboratory
analysesneededfor the study. Eighty-eight of the men
(88.8%), and 89 of the women (85.5%) underwent angi-
ography for evaluation of ischemic heart disease(typi-
cal angina or a positive exercisetolerance test, or both);
10%of the men, and 13.5%of the women had arteriog-
raphy for valvular heart disease.
Definitions of coronary artery disease: To insure
misclassification of <3%,12,13coronary arteriograms
were reviewed by a panel of 3 cardiologists who had no
prior knowledge of the clinical history or laboratory
data of patients. The presenceof stenosisin the 15 coro-
nary artery segments designated by the American
Heart Association was determined.i4 CAD was consid-
ered to be present if I1 lesion narrowed the lumen of
any of the 15 coronary arterial segmentsby 150%. Pa-
tients with such lesions were considered to be cases,
whereas those without narrowings 150% were consid-
ered to be control subjects.The study group was further
divided into patients with 0, 1, 2 or 3 diseasedcoronary
arteries according to the number of major coronary
arteries (right, left anterior descendingor left circum-
flex) that had 150% diameter narrowings). Quantita-
tive digital methodswere not usedto assessthe extent of
coronary atherosclerosis.Visual interpretation of an ar-
teriogram generally provides an underestimation of cor-
onary atherosclerosis.*Analyses related to risk factors,
number of diseasedvessels,and a continuous score of
CAD will be the subject of a separate report.
Plasma lipid, lipoprotein and apolipoprotein dster-
minations: BLOOD COLLECTION: After a 12-hour fast,
blood (60 ml) was drawn into evacuatedtubes contain-
ing disodium ethylenediaminetetraacetic acid (1.5 mg/
ml of blood), cooled to 4’C and transported to the
Johns Hopkins Lipoprotein Analytical Laboratory.
Cells were removed by centrifugation (1,500 X g, 30
minutes, 4°C) within 3 hours of collection, and plasma
was stored at 4°C before analysis or at -70°C (for
Lp(a) and apoA-2 measurements). Leukocytes were
harvested for isolation of DNA.
TOTALANDHIGH-DENSITY LIPOPROTEIN CHOLESTEROLS:
Cholesterol in plasma and the lipoprotein fractions was
determined enzymatically as describedpreviously.15To-
tal HDL cholesterol was determined after precipitation
of the apoB-containing lipoproteins with heparin and
manganese chloride. When patients were sampled,
manganesechloride was used at a final concentration of
0.046 M; this was changed to 0.092 M for the analysis
of HDL cholesterol in the relatives of the patients, be-
cause the lower concentration does not completely pre-
cipitate apoB-containing lipoproteins.16To allow a cor-
rection for the incomplete precipitation, a separate
substudy was performed in which 188 relatives of pa-
tients had HDL cholesterol measured using both con-
centrations of manganesechloride. The lower concen-
tration gave a positive mean bias of 3.1 f 0.3 mg/dl.
The bias was independent of HDL cholesterol concen-
1016 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
tration (r = 0.018). The HDL cholesterol concentra-
tions in patients were therefore corrected by subtracting
3 mg/dl from the measuredvalues.
HIGH-DENSITY LIPOPROTEIN CHOLESTEROL SUBFRAC-
TIONS: Four milliliters of the heparin-manganesechlo-
ride supernate was adjusted to a density of 1.12517and
centrifuged at 105,000 X g for 40 hours, the bottom
fraction containing HDLs was recoveredby tube slicing,
and its cholesterolconcentration was determined. HDL2
cholesterol was calculated as the difference betweento-
tal HDL and HDL3 cholesterol.
VERY LOW,INTERMEDIATE- AND LOW-DENSITY LIPOPRO-
TEIN CHOLESTEROLS, AND TRIGLYCERIDE: PlBSIlla (5 ml),
at its own density (1.006 g/ml), and plasma (10 ml)
after adjustment to d 1.019 g/ml with liquid potassium
bromide (17), were centrifuged at 105,000 X g for 18
hours. The infranate fractions were collected by tube
slicing, and their cholesterol contents were determined.
VLDL cholesterol was calculated by subtracting the
cholesterol in the 1.006g/ml infranate from the plasma
total cholesterol. IDL cholesterol was calculated as the
difference between the cholesterol in the 1.006 and
1.019 g/ml infranates. LDL cholesterol was calculated
as the difference between the cholesterol in 1.019 g/ml
infranate and total HDL cholesterol. Plasma triglycer-
ide was measuredenzymatically.l 5
APOLIPOPROTEIN MEASUREMENTS: ApoA-1 and ApoB
levels were measuredby radial immunodiffusion, as de-
scribed previously.l5 ApoA-2 was measured in frozen
plasma by radial immunodiffusion in 10% agarose,us-
ing an antibody to apoA-2, and serum pools with known
apoA-2 levels obtained as gifts from John Albers, PhD.
Plasma was diluted lo-fold and applied to the wells.
Ring diameters were measuredafter 72 hours. The as-
say for apoA-2 had a coefficient of variation of 6.1%.
Lp(a) was measured on frozen plasma using a mono-
clonal antibody-based sandwich enzyme-linked immu-
nosorbent assay18available commercially (MACRA
Lp(a) Terumo, Elkton, Maryland). The coefficient of
variation for Lp(a) was 6.9%, and the method doesnot
detect plasminogen.l8
OTHER RISK FACTORS AND CLINtc,4LDAr.4:Interviews
were conducted and clinical data collected using a com-
mon protocol and standardized forms.12~‘g~20 Medica-
tions used during the preceding 2 weekswere recorded.
Hypertension was defined as a self-reported history of
high blood pressure,or treatment with antihypertensive
agents. Cigarette smoking was categorized as ever ver-
sus never smoked. Current smoking was defined as
smoking cigarettes within the past month. Weight and
height (without shoes)were measuredusing a standard
scaleand recorded to the nearesttenth of a kilogram or
centimeter. Family history of premature CAD (defined
as myocardial infarction [fatal or nonfatal] or angina
pectoris before the age of 60 years in either parent) was
obtained by questionnaire.Blood (3 ml) was collected in
fluorinated tubes, and glucose determined at the Johns
Hopkins Clinical Chemistry Laboratory using a glucose
oxidasemethod. Diabeteswas defined as a fasting blood
sugar > 140 mg%*l or a diagnosis of diabetes needing
diet or drug therapy.
APRIL 15, 1992
 TABLE I Characteristics of Subjects Undergoing Coronary
Arteriography for Premature Atherosclerosis
rTABLE II Medication Use by Subjects
Medications Taken Men Women Total
Men Women in Previous 2 Weeks (n = 97) (n = 103) (n = 200)
(n = 99)* (n = 104)*
p blockers 44 44 88 (44.0%)
Age (yr) 44 52 Calcium antagonists 37 50 87 (43.5%)
Range 24-50 36-60 Diuretics 17 34 51 (25.6%)
Coronary arteries Long-acting nitroglycerins 15 33 48 (24.0%)
Narrowed 2 50% in diameter (any) 61% 49% Digitalis preparations 5 13 18 (9.0%)
It 14% 13% Antiarrhythmics 4 8 12 (6.0%)
2 15% 15% Thyroid medications 2 8 10 (5.0%)
3 31% 23% Other hormones 0 10 10 (5.0%)
Previous myocardial infarction 24% 26% Anticoagulants 0 9 9 (4.5%)
Positive Rose questionaire 4 1% 40% Corticosterords 2 3 5 (2.5%)
Stroke 2% 5% Oral contraceptives 0 1 1 (0.5%)
H/O hypertension 45% 54% Cholesterol-lowerrng agents 0 0 0 (0.0%)
Drabetes mellitus 8% 17%
Ever smoked crgarettes 76% 59%
Current cigarette smokers 20% 24%
levels of total and HDL cholesterols,triglyceride, apoB
‘Questionawe data available from 97 men and 103 women.
tin 8 ang~ograms, coronary atherosclerosis was present. but not all vessels were and apoA-1 were similar (p >O.lO) between subjects
completely vlsualtzed.
H/O = hIstory of. receiving and not receiving any 1 of thesemedications.**
Association of lipid-related variables with prema-
ture coronary atherosclerosis: For men, the plasma lev-
Statistical analyses: Univariate distributions of all els of total cholesterol, triglyceride, apoB in plasma and
variables were examined, and all outliers confirmed. d > 1.006 g/ml infranate, and apoA-1 were significant
The associationof lipid and other risk factors with CAD univariate discriminators of CAD (Table III). However,
was studied using logistic regressionfor men and wom- after adjusting for age, only the triglyceride and apoA- 1
en separately, and for the entire study population. Be- levels remained significant predictors of CAD in men
causepatients with CAD were older than those without (Table III). The results in women differed from those in
CAD, measures of association were adjusted for age. men. First, before adjustment for age, the plasma levels
The age-adjustedp value and the correlation coefficient of total, VLDL, and total HDL and HDLs cholesterols,
for each risk factor were calculated from a logistic re- triglyceride, and apoB in whole plasma and in d > 1.006
gression model with CAD as the dependent variable, and >1.019 g/ml infranates, and apoA-2 were all sig-
and age and the risk factor of interest as the indepen- nificantly associatedwith CAD (Table III). Adjustment
dent variables. All continuous variables were divided for age removedonly total HDL cholesterol and plasma
into quartiles and examined as categorical variables. apoA-2 as significant indicators of premature CAD in
The results of the continuous and categorical analyses women. The ratio of plasma apoB to apoA-1 was signif-
were similar. Therefore, only the continuous models are icantly associatedwith premature CAD in both men
presented. and women (Table III). Lp(a) levels were higher in
Multivariate logistic regression models were con- those with than in those without CAD, but did not
structed by considering all the variables that were asso- reach statistical significance.
ciated with CAD after adjustment for age only. Odds Becausethe levels of apoB were clearly stronger in-
ratios for continuous variables were calculated for a 1 dicators of CAD in women than in men, whereas the
SD difference in the variable. This allows for compari- level of apoA-1 was stronger in men, the distributions of
son of the strength of associationof CAD with different plasma levels of these apolipoproteins were examined.
variables. For men, the plasma apoB levels were shifted toward
higher values in those with CAD (Figure l), whereasin
RESULTS women, the distribution of plasma apoB levels in those
Characteristics of study population: The character- with CAD appearedbimodal (Figure 1). The distribu-
istics of the study population are summarized in Table tion of plasma apoA-1 levels was shifted toward lower
I. A higher proportion of men than women had prema- values in men with CAD; in contrast, the distributions
ture and more severe (3-vessel) CAD, but these differ- of apoA-1 levels in the women with and without prema-
ences did not reach statistical significance. In subjects ture CAD were much broader and relatively similar
without CAD, the distribution of the most severely af- (Figure 1).
fected segment <50% was as follows: no lesion (70.1%), Multivariate analysis of lipid-related didmhmtors
1 to 20% lesion (17.2%), 21 to 40% lesion (12.6%) and and premature coronary artery disease in men and
41 to 49% lesion (none). History of hypertension and women: Logistic regression models showed that the
diabetes was more prevalent in women than in men. plasma apoB level was more closely associated with
Medication use: The most frequently taken medica- CAD than were total and LDL cholesterols,or apoB in
tions in the previous 2 weeks (in order of use) were: /3 the 1.006 and 1.019 g/ml infranates among men, wom-
blockers, calcium antagonists, diuretics and long-acting en and the total study population. When each of the
nitroglycerines (Table II). The mean differences be- latter variables was modeled simultaneously with plas-
tween subjects with and without CAD in the plasma ma apoB (and age), the association of plasma apoB

PREDICTORS OF PREMATURE CORONARY ATHEROSCLEROSIS 1017

 TABLE III Association of Plasma Levels (mg/dl) of Lipids, Lipoprotein Cholesterols and Apolipoproteins with Premature Coronary
Atherosclerosis in Men and Women
Men Women

With Without Age- With Without Age-

CAD CAD Unadjusted Adjusted CAD CAD Unadjusted Adjusted
(n = 60) (n = 39) p Value* p Valuet (n = 51) (n = 53) p Value* p Valuet
Age (yrs) 45.8 41.5 0.0001~ - 53.9 51.8 0.06 -
Total cholesterol 240 221 0.04 0.30 255 220 0.0007 0.002
VLDL cholesterol 53 45 0.20 0.69 55 37 0.005 0.007
IDLcholesterol 16 15 0.69 0.74 18 13 0.18 0.31
LDL cholesterol 127 119 0.35 0.68 135 119 0.09 0.07
HDL cholesterol 46 48 0.60 0.57 51 58 0.03 0.06
HDLz cholesterol 17 16 0.68 0.84 21 24 0.27 0.35
HDL3 cholesterol 31 33 0.28 0.23 31 36 0.03 0.03
Triglycerides 208 143 0.0004 0.006 202 128 0.009 0.014
Plasma apoB 153 135 0.01 0.13 159 126 0.0001 0.0003
ApoB > 1.006 g/ml 135 119 0.02 0.13 139 110 0.0004 0.0016
ApoB > 1.019 g/ml 127 119 0.31 0.66 135 110 0.003 0.007
Plasma apoA-1 131 147 0.02 0.02 147 163 0.07 0.09
Plasma apoA-2 28 28 0.69 0.93 27 28 0.04 0.07
Lp(a) 19 15 0.43 0.29 19 12 0.07 0.09
Plasma apoB/apoA-1 1.23 0.97 0.002 0.02 1.17 0.82 0.0001 0.0001
WnadJusted p value from Student’s t test.
tAdjusted for age only in logisbc regression model.
$p values ~0.05 level are underlined.
§Triglyceride values were log transformed for 2 reasons. First, they were markedly skewed toward high values (p < 0.01). Second, log triglyceride was more strongly associated with
CAD, indlcatlng that log transformabon allowed for better description of its association with CAD. Values reported are antIlog of result m log scale.
Thefollowlngmeasurementswere not performed in Indicated numberofsamples: VLDL (n = l), IDL (n = 21, LDL(n = 3), HDL (n = 11, HDLz (n = 17), HDL, (n = 16). plasma
apoB (n = 3),.apoB I” d > 1.006 g/ml (n = l), apoB in d > 1.019 g/ml (n = 3), apeA- (n = 11, apoA-2 (n = 361, Lp(a) (n = 31) and apoB/apoA-1 (n = 4).
Apo = apollpoproteln; CAD = coronary artery disease; HDL = high-density lipoprotein; IDL = Intermediate-densaty lipoprotein; LDL = low-density Ilpoproteln; Lp (a) = kpoprotein
(a); VLDL = very low density lipoprotein.

Apolipoprotein B Level (mgldl) in Men Apolipoprotein Al Level (mgldl) in Men

*opw-v

Apolipoprotein B Level (mgldl) in Women Apolipoprotein Al Level (mgldl) in Women

FIGURE 1. The disfriion of plasma levefs of wns B (left) and A-l (right) in men (fop) and women (boffom) with
(/J/a& bars) and without (cfod-hfcfld liars) comnary artery drease (CAD).

1018 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69 APRIL 15, 1992

 r TABLE V
1
r I

TABLE IV Multivariate Comparison of Plasma Levels of Lipids, Association of Nonlipid Risk Factors with Premature
Lipoprotein, Cholesterol and Apolipoproteins as Predictors of Coronary Atherosclerosis in Men and Women
Premature Coronary Atherosclerosis in Men and Women
Men Women
Men Women (n = 97) (n = 103)
(n = 98) (n = 101)
With Without p With Without
Vanable r Value p Value* r Value p Value* CAD CAD Value* CAD CAD p Value*

Age 0.236 0.002 0.000 0.24 H/O hypertension 51% 37% 0.39 62% 47% 0.15
Tnglyceridet 0.190 0.009 0.064 0.11 Diabetes 15% 3% 0.20 27% 8% 0.03
Plasma apoB 0.000 0.258 0.195 0.007 Ever smoked 88% 58% 0.005 82% 38% 0.0001
Plasma apoA-1 -0.150 0.026 0.000 0.29 Fasting blood 101 90 0.36 109 99 0.39
sugar (mg/dl)
‘pvalues co.05 are underlined.
tTr@yceride values were log transformed. Body mass Index 28 28 0.74 26 26 0.83
Correlation coefficient(r) is from multiple logistic regresw3n. (kg/m2)
ape = apolipoprotein
I I
Family history of
CAD before
age 60 yearst
Father 29% 28% 0.74 22% 24% 0.83
with CAD was stronger, and the association between Mother 5% 13% 0.17 15% 18% 0.83
the other risk factor and CAD was weak and not sta- Either parent 28% 34% 0.28 33% 37% 0.82
tistically significant. The only exception to this state- Both parents 2% 6% 0.62 4% 2% 0.81
ment was that among men, plasma apoB and apoB in *Age-adjusted p value from a logistic regrew%; values ~0.05 are underlined.
tFamlly hlstory of CAD, defmed as myocardial infarction (fatal or nonfatal) or anglna
the 1.006 g/ml infranate were equally associatedwith pectons.
The folIowIng measures were not performed I” the lndlcated number: fasting blood
CAD. Similarly, the log of plasma triglyceride was sugarh = 5) and family hlstoty (n = 25).
more closely associated with CAD than was plasma CAD = coronary artery disease: H/O = history of.

VLDL, log of plasma VLDL or plasma triglyceride lev-

els before log transformation. ApoA-1 was more closely
associatedwith CAD in men, women and the total sam- premenopausal.Menopausal status could not be deter-
ple than were HDL and HDL2 cholesterols. However, mined for 24 women (23%) who had hysterectomies.
HDLj cholesterol was more closely associated with Plasma apoB level was higher in the 36 postmenopausal
CAD than was apoA-1 among women (p = 0.08 and women with CAD than in the 25 without CAD (156 vs
0.53, respectively, when HDLj and ApoA-1 were mod- 132 mg/dl; p = 0.03). Among premenopausalwomen,
eled simultaneously with age). The significance of this this difference was even more striking (mean plasma
finding is uncertain, particularly becauseneither apoA- apoB level 184 mg/dl in those with (n = 3) vs 114
1 nor HDL3 were associatedwith CAD in women after mg/dl in those without (n = 16) CAD; p = 0.01). Thus,
adjustment for plasma apoB level. For men, age, log plasma apoB level was associatedwith CAD in both
triglyceride and apoA-1 levels were independently asso- pre- and postmenopausalwomen, and the association
ciated with CAD, whereas the additional contribution may be stronger for premenopausalones.
of plasma apoB level was not statistically significant Association of nonlipid risk factors with premature
(Table IV). In women, plasma apoB level was the best We next determined whether
coronary artery disease:
nonlipid risk factors such as hypertension, diabetes,
indicator for CAD. Log triglyceride was mildly associ-
ated and apoA-1 levels were only weakly associated smoking, family history of premature myocardial in-
with CAD after adjustment for apoB level (Table IV).farction, and so forth were significantly associatedwith
Menopausal status and plasma apolipoprotein B premature CAD (Table V). Using univariate analysis,
levels in women: Sixty-one women (59%) in the study history of ever smoking was strongly and significantly
were postmenopausal, whereas eighteen (17%) were associatedwith premature CAD in both men and wom-

TABLE VI Multiple Logistic Regression Models of Lipid- and Nonlipid-Related Risk Factors as Predictors of Premature Coronary
Atherosclerosis in Men and Women I
All Men Women
(n = 196) (n = 96)* (n = lOO)*

Variable OR 95% Cl p Valuet OR 95% Cl p Valuet OR 95% Cl p Valuet

Age (10 yrs) 2.7 1.3 5.5 0.007 8.4 1.9 36.9 0.01 1.8 0.7 4.2 0.2
Smoking (ever) 5.0 2.3 10.7 0.001 3.3 1.0 11.1 0.05 6.0 2.2 16.6 0.001
Triglyceride (0.3 logsIS 1.7 1.1 2.7 0.011 2.4 1.1 5.2 0.02 1.5 0.9 2.6 0.13
ApoB (40 mg/dl) 1.6 1.1 2.4 0.016 1.4 0.8 2.6 0.27 1.7 1.0 2.9 0.04
ApoA-1 (40 mg/dl) 0.8 0.5 1.1 0.16 0.5 0.3 1.0 0.05 0.9 0.6 1.4 0.60
Sex (men) 2.3 0.9 5.8 0.08
*Three men and 4 women were not Included due to m,ss,ng data.
tp values co.05 are underllned.
tTrlglyceride levels were log transformed.
APO = apollpoproteln; Cl = confidence Interval: OR = odds ratio.

PREDICTORS OF PREMATURE CORONARY ATHEROSCLEROSIS 1019

en. The other variables did not differ significantly be-
tween men with and without CAD (p >0.05). In wom-
en (but not in men) history of diabetes reached statisti-
cal significance (Table V).
Considefatien ef the strangest lipid- and nonfipid-
relatarI varIaMer simuttaneourly: Using multiple logis-
tic regressionmodels,plasma levels of apoB and apoA- 1
were better predictors of CAD than was LDL or HDL
cholesterol (and subfractions) for the entire study popu-
lation (Table VI). Total cholesterol level was not a pre-
dictor of CAD after adjustment for the plasma apoB
levels, but triglyceride level remained a significant indi-
cator of premature CAD. Smoking and age were
strong, nonlipid predictors (Table VI). For men, triglyc-
eride level followed by apoA-1 were the best lipid-relat-
ed predictors, whereasfor women, plasma apoB was the
best independent lipid predictor (Table VI). Ever smok-
ing remained a strong, independent predictor of prema-
ture CAD in both men and women.
DlSClSSlON
There are few, if any, previous studies of a compara-
ble number of women with premature CAD. The plas-
ma apoB level was the strongestindicator of premature
CAD in these women. Data from prospective studies
indicated that total cholesterol level was clearly an im-
portant predictor of CAD among women as well as
men, whereas the association of LDL cholesterol level
with CAD in women was lessclear.23Our findings were
consistent with these studies. An increased number of
small, dense LDL particles (hyperapoB)24is often ac-
companied by increasedlevels of VLDL cholesterol and
triglyceride. Plasma apoB seems even higher in pre-
menopausalwomen with CAD, indicating the influence
of an endogenous(perhaps genetic) factor on apoB lev-
els that was not obviated (or prevented) by the presence
of female hormones. Campos et a125found that post-
menopausalwomen had significantly smaller LDL-par-
title size than did premenopausalones, but such differ-
ences were not associated with significant changes in
apoB levels. Interestingly, in a study of black men and
women catheterized for chest pain and an abnormal
stress test, Ford et a126found that plasma apoB levels
were more strongly associated with CAD in women
than men. In an older (mean age 60 years) group of 37
women, Sedlis et al3 found that only triglyceride and
apoB levels correlated with severity of CAD. Reardon
et al* reported that CAD in women was related to tri-
glyceride, cholesterol and apoB concentrations in IDL.
The bimodal distribution of plasma apoB levels in
women with premature CAD suggestsstrongly the in-
fluence of a major gene. Further family studies in the
relatives of these index casesshould elucidate this hy-
pothesisand determine more precisely the etiologic het-
erogeneity of genetic factors (such as the contribution of
the genesfor hyperapo and familial combined hyperlipi-
demia).27
The dyslipidemic pattern in men with premature
CAD generally differed from that in women. First, age
adjustment removed much of the associationof plasma
apoB with CAD in men; a low level of apoA- 1, and a
1020 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
high level of triglyceride were the best indicators of
CAD. The significantly lower level of apoA-1 in men
with premature CAD was clearly not accompaniedby a
lower level of HDL cholesterol (or its subfractions). In a
previous angiographic study,r3 we also found that plas-
ma total HDL cholesterol did not significantly predict
the presenceof l-, 2- or 3-vesselCAD in men aged 30
to 49 years, but did so in those aged 50 to 70.13More
recently, Heam et al2 similarly found that older men
(mean age 57 years) with CAD had lower HDL choles-
terol levels. In agreement with our previous report of
another cohort, plasma levels of total HDL cholesterol
in women with premature CAD was significantly lower
than in those without CAD.21 In the present study, this
observation was expanded to include levels of HDL3
cholesterol and apoA-1, which were also lower in wom-
en with premature CAD.
Hypertension, diabetes and cigarette smoking were
more prevalent in those with than without premature
CAD in both men and women (Table V). However, cig-
arette smoking emerged as the strongest nonlipid risk
factor. The magnitude of the associationbetweensmok-
ing and CAD was comparable to the strongest lipid-
related risk factors. After considering the influence of
triglyceride, apoB and apoA- 1 levels,smoking remained
independently associatedwith premature CAD. The in-
ability of somestudies1,2,5to find such a significant con-
tribution of smoking to CAD may be related to the size
or nature of the control groups, or to not using ever
smoking instead of current smoking.
We are unable to explain why there was so little ap-
parent difference betweenthose with and without CAD
in regard to family history of premature CAD. How-
ever, not all studies found such an association.28Such
discrepanciesmay be related to patient selection (e.g.,
using family history as a criterion for angiography), the
high prevalenceof CAD in American society, or other
biases.28
We found Lp(a) levels to be higher in those with
than without CAD. However, unlike previous re-
p~rts,~~i~this trend did not reach statistical significance.
These differencesdo not appear to be due to our youn-
ger population, becauseDahlen et allo found that Lp(a)
was a better predictor in younger (aged <55 years)
than older men. We did find (data not presented)a sub-
group of caseswith premature CAD and normal lipo-
protein profiles who had increased Lp(a) levels.
Adunwledgement: We thank StephenAchuff, MD,
and Jorge Trejo, MD, for reading the coronary arterio-
grams. The assistanceof Teresa Cloey, BS, Lorraine
Donovan, BS, and the staff of the lipoprotein analytical
laboratory is gratefully acknowledged.We thank Brian
McCrindle, MD, for performing the plasma apoA-II
measurements,and Pauline Gugliotta for help with pre-
paring the manuscript.
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OF PREMATURE CORONARY ATHEROSCLEROSIS 1021