© 1996 American Heart Association, Inc.
Articles |
Race and Gender Differences in the Association of Lp(a) With Carotid Artery Wall Thickness
The Atherosclerosis Risk in Communities (ARIC) Study
From the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis (P.J.S.); the Department of Epidemiology, School of Public Health, University of North Carolina (G.H., H.A.T.), and the ARIC Coordinating Center, Collaborative Studies Coordinating Center (C.E.D.), Chapel Hill, NC; the Department of Medicine, Baylor College of Medicine and The Methodist Hospital, Houston, Tex (J.D.M.); and the Mississippi Family Health Center, Jackson (R.S.).
Correspondence to Pamela J. Schreiner, PhD, Division of Epidemiology, School of Public Health, University of Minnesota, Suite 300, 1300 S Second St, Minneapolis, MN 55454-1015. E-mail schreiner@epivax.epi.umn.edu.
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Abstract |
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Abstract The association of lipoprotein(a) [Lp(a)] with preclinical atherosclerotic disease is not well established in any race group, particularly African Americans. This report examined the association of Lp(a) with preclinical extracranial carotid atherosclerosis in middle-aged black and white participants in the Atherosclerosis Risk in Communities (ARIC) Study. Study participants (15 124: 2417 black women, 1522 black men, 5907 white women, and 5278 white men) who were 45 to 64 years old at baseline were examined during the period 1987 to 1989. Carotid intimal-medial far-wall thickness was determined by B-mode ultrasonography and expressed as the overall wall thickness mean at six sites to approximate atherosclerosis in the carotid system. Lp(a) was measured as its total protein component, Lp(a) protein, by a double-antibody ELISA for apolipoprotein(a) detection. Mean Lp(a) protein levels were higher in blacks than whites (169.1 and 147.0 µg/mL in black women and black men, respectively, compared with 86.6 and 75.1 µg/mL in white women and white men). Mean carotid wall thickness (in millimeters) varied by race and gender: 0.798 in white men, 0.779 in black men, 0.718 in black women, and 0.695 in white women. Multivariable-adjusted Lp(a) protein was independently associated with wall thickness (in millimeters) in white men and black men; among women, however, this association appeared to be stronger when smoking and diabetes were present. A 100-µg/mL difference in Lp(a) protein level was associated with 0.049- and 0.043-mm higher wall thickness values in black men and white men, respectively. Among white women who smoked, the difference in wall thickness was 0.051 mm compared with 0.032 mm for former/never smokers and 0.21 mm in black female diabetics compared with 0.031 mm in black female nondiabetics. These results suggest that Lp(a) is associated with preclinical carotid atherosclerosis in both blacks and whites, but that this association may be affected by the presence of other cardiovascular risk factors, particularly in women.
Key Words: lipoprotein(a) • race • gender • atherosclerosis
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Introduction |
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Elevated mean plasma levels of Lp(a) have been reported to be an independent risk factor for both coronary1 2 3 4 and cerebrovascular5 6 7 8 disease end points. Lp(a) is believed to be a genetic risk factor for these conditions and varies either inconsistently or minimally in response to environmental, lifestyle, or physiological conditions, such as age, diet, cigarette smoking, and gender.9 Other factors, including physical activity,10 11 ethanol consumption,12 13 control of diabetes,14 15 and hormone replacement therapy in postmenopausal women,16 17 18 are equivocally associated with altered Lp(a) levels.
Lp(a) has been shown to be a correlate of coronary atherosclerosis in white19 20 21 and Asian6 populations, predominantly in men. In addition, restenosis of coronary artery vein-graft bypasses is more prevalent in patients with elevated levels of plasma Lp(a).22 23 24 25 The relationship between Lp(a) and atherosclerosis at other arterial sites has been demonstrated in the extracranial carotid arteries among white survivors of ischemic stroke.8 In all of these studies, atherosclerosis is manifested as a clinically relevant, pronounced stenosis of the arterial lumen. The role of Lp(a) in the preclinical thickening of the intimal-medial layer without lumen involvement has not been elucidated, although recent evidence in animal models suggests that elevated levels of apo(a) are associated with reduced transforming growth factor–ß activity.26
Furthermore, although Lp(a) levels for whites and Asians have been extensively analyzed in both healthy and diseased populations, few studies have focused on Lp(a) in blacks. These few studies suggest that African and American blacks, in aggregate, have median plasma Lp(a) values that are two to three times higher than the median values in Caucasians27 28 29 30 31 ; however, no information on Lp(a) and disease status in blacks exists.
The primary goal of this investigation was to assess the status of Lp(a) as an independent, positive risk factor for preclinical atherosclerosis in middle-aged participants of the ARIC Study and to determine how this association between Lp(a) and atherosclerosis varied by race and gender. In addition, potential contributions from "traditional" cardiovascular risk factors as confounders of the Lp(a)-atherosclerosis relationship were examined in this large, population-based sample.
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Methods |
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The ARIC Study is a prospective, multicenter investigation of atherosclerotic clinical events and noninvasively measured atherosclerosis, consisting of both a cohort and a community surveillance component. The subjects in the study reported here were selected from among the 15 800 individuals who were participating in the cohort component of the ARIC Study between 1987 and 1989 in four US communities. Three of these communities—Forsyth County, North Carolina; Minneapolis, Minn; and Washington County, Maryland—examined a general population sample from the appropriate age range. The fourth center, Jackson, Miss, derived its study population entirely from the black residents of that city. The objectives and design of the ARIC Study have been cited elsewhere.32
All black and white study participants between the ages of 45 and 64 years for whom wall thickness measurements at the carotid artery and complete, relevant laboratory data were available were included here; the sole exclusion criterion was a history of carotid endarterectomy. The individuals in the study population represent a large, ambulatory, population-based sample in whom preclinical atherosclerosis can be examined.
In the ARIC Study wall thickness was measured by B-mode ultrasonography using the technique of Pignoli et al.33 Repeatability of the scanning and reading procedures has been reported elsewhere,34 35 with an intraclass correlation coefficient of .81 for repeated scans by the same sonographer and a correlation of .93 for blinded, repeated readings of the same scan by different sonographers. The degree of atherosclerosis was approximated by measuring and then averaging the intimal-medial far-wall thickness of the extracranial common carotid artery, internal carotid artery, and carotid bifurcation at 1-mm intervals along a 1-cm segment of the carotid wall (total of 11 measurements).34 All of these are potential sites of atherosclerotic lesions.36 37 38
Wall thickness measurements were obtained as both empirical, splined (observed) data and imputed data, as described by Dempster et al.39 Imputed data were derived from multivariate linear models for mean far-wall thickness at six carotid sites: the right and left common, internal, and bifurcation. Each race-and-gender–specific linear model was a function of site, arterial depth from the skin surface, BMI, and the product of BMI and depth, with an unstructured covariance matrix. Data obtained by imputation had weights associated with them, depending on the number of sites that were observed or imputed. Imputation of incompletely visualized (missing) ultrasound data results in a greater sample size as well as a lower variance; in addition, the potential for bias that results from exclusion of observations with incompletely visualized ultrasound images decreases. The average of the six imputed mean far-wall thicknesses was used in these analyses as an indicator of generalized atherosclerosis in the carotid territory.
Lp(a) was measured in plasma samples from fasting participants as the
total protein component [Lp(a) protein] by a double-antibody
ELISA technique for apo(a) detection.40 41 For this
assay
at Lp(a) protein levels in the range 10 to 100 µg/mL, the
contribution from plasminogen at
physiological concentrations (200 mg/dL) was
negligible.40 In a 40-person subsample, the assay
reliability (between-person component of the variance divided by
the total variance) was .90, with essentially no within-person
variability (indicative of a largely genetic measurement), and 9% of
the total variance was associated with the assay method
itself.42 Data collection at each ARIC field center and
centralized processing of lipid and clinical chemistry measurements
have been reviewed elsewhere.43 Measurements specific to
this study were as follows. Diabetes was defined for those subjects who
had an 8-hour fasting glucose level 
140 mg/dL, a nonfasting glucose
level 200 mg/dL, a history of diabetes, or current use of a blood
glucose–regulating medication. TG measurements were used for those
individuals who had fasted for 12 hours or more. HDL-C was assayed
after dextran sulfate–magnesium precipitation44 ;
LDL-C was estimated from the Friedewald equation.45
Ethanol consumption was measured in grams per week, and cigarette
smoking status was defined by the number of pack-years of smoking
(cigarette-years divided by 20). Hypertension was defined for those
subjects with an SBP 140 mm Hg, a diastolic blood
pressure 90 mm Hg, or current use of antihypertensive medication.
Menopausal status for women was determined by the presence or absence
of menstrual periods during the 2 years prior to participation in the
ARIC Study.
Because of the highly right-skewed distribution of Lp(a) protein values in both race groups, the natural logarithm of Lp(a) protein was used to normalize its distribution. Race-and-gender–specific quartiles of Lp(a) protein were generated from logarithmically transformed Lp(a) protein values as well.
All statistical analyses were performed using SAS version 6.08.46 The association of Lp(a) protein level with mean wall thickness was assessed with linear regression techniques. Testing for statistical interaction was accomplished by partial F tests for the initial model (that contained the interaction terms) compared with reduced models, first globally and then in a hierarchical sequence.47 Because there were multiple comparisons of interactions, statistical significance was assessed at the 99% confidence level (P<.01). Confounding of the main effect association by independent risk factors for atherosclerosis was examined by comparing the magnitude of the main effect parameter estimate for the initial, fully parameterized model with the estimates for reduced models that were derived by backward elimination of covariates.
Because descriptive statistics demonstrated that mean wall thickness was greater in white men than black men and greater in black women than white women while mean Lp(a) protein levels were greater in black participants regardless of gender [suggestive of a three-way interaction for Lp(a) by race and by gender], race-and-gender–specific models were tested.
Potential confounding factors to the association between Lp(a) protein and carotid wall thickness were age, LDL-C, HDL-C, hypertension, amount of cigarette smoking, plasma fibrinogen level, diabetic status, ethanol consumption, and BMI; for models with women only, menopausal status was included. Because Lp(a) values vary markedly between races and LDL-C is a derived variable that includes Lp(a)-C, an "adjusted" LDL-C was also examined as a covariate. The Lp(a) mass consists of approximately one third cholesterol/cholesteryl esters, one third phospholipids, and one third protein, on the basis of the average value for Lp(a) protein mass that ranges between 29% and 36%, depending on the apo(a) isoform present.48 49 This approximation implies that Lp(a)-C has approximately the same concentration as Lp(a) protein and was therefore subtracted from the Friedewald equation–derived LDL value in each race group to obtain an LDL-C that was adjusted for Lp(a)-C.
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Results |
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Means and distributions for continuous and categorical cardiovascular risk factors are presented by race and gender in Table 1
. Age and LDL-C level were
similar for all groups. The adjusted LDL-C value [Friedewald
equation–estimated LDL-C minus Lp(a)-C], however, was higher in
whites than blacks, particularly white men. Adjustment for Lp(a)-C
reduced the derived LDL levels by 12.3%, 10.5%, 6.5%, and 5.4% in
black women, black men, white women, and white men, respectively,
reflective of the relatively higher Lp(a) protein [and Lp(a)-C]
levels among the black participants in this cohort. Black men had
higher HDL-C levels than did white men, whereas these levels were
similar for women in both race groups. In this study population, blacks
(men and women) had higher average fibrinogen levels and a higher
prevalence of both diabetes and hypertension than whites but lower
fasting TG values. Men in general smoked more and consumed more ethanol
than did women. Black women had the highest BMI and the highest
prevalence of diabetes of any race/gender group; they also had a higher
prevalence of self-reported menopause than did white women,
potentially due to a combination of hysterectomy, low prevalence of
bleeding associated with hormone replacement therapy, and natural
menopause.
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The Figure shows the distribution of Lp(a) protein for
each race and gender group. Women had slightly higher Lp(a) protein
levels than did men regardless of race, but mean Lp(a) plasma
concentrations in blacks were approximately twice those of whites
(169.1 and 147.0 µg/mL in black women and men, respectively, compared
with 86.6 and 75.1 µg/mL in white women and men); median values were
as much as three times higher in blacks (138.0 and 120.0 µg/mL in
black women and men, respectively, compared with 48.0 and 40.0 µg/mL
in white women and men). Based on the assumption that Lp(a) protein
accounts for approximately one third of the total Lp(a) mass, a value
of 100 µg/mL Lp(a) protein is comparable to a total Lp(a) value of 30
mg/dL. In all race/gender groups, Lp(a) protein exhibited a
right-skewed distribution across the population. However, this
skewness was more pronounced in whites, with the median value far below
the mean.
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Table 2 shows the Spearman correlation coefficients
between Lp(a) protein and selected independent risk factors for
cardiovascular disease. These unadjusted correlations
suggest that Lp(a) protein is not associated with BMI, SBP, cigarette
smoking level, or ethanol consumption in this population, although a
few of these weak correlations reached statistical significance owing
to the large sample size. Lp(a) protein was correlated with LDL-C
[both LDL and Lp(a) contain an apoB-100 moiety] and with fibrinogen.
However, LDL-C after adjustment for Lp(a)-C was either very weakly
associated or unassociated with Lp(a) protein. Age was weakly
correlated with Lp(a) protein in women (r=.0678 and .0361 in
white and black women, respectively) but not in men.
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Table 3 further examines the association between age and
Lp(a) protein levels by 5-year increments. For men, Lp(a) protein
values remained relatively constant across age groups, with the
P for trend equal to .1297 in blacks and .4897 in whites.
For women of either race, however, Lp(a) protein values increased
significantly with increasing 5-year increments: 159.1, 165.6, 177.6,
and 181.3 µg/mL in blacks (P for trend=.0008) and 80.4,
87.3, 90.1, and 89.5 µg/mL in whites (P=.0063).
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Age-adjusted mean carotid intimal-medial far-wall thickness
values for race-and-gender–specific Lp(a) protein
quartiles are presented in Table 4. In all race
and gender groups, the linear trend for wall thickness at each Lp(a)
protein quartile was statistically significant. Mean age-adjusted
wall thicknesses overall varied by race and gender, with white men
having the thickest walls, followed by black men, black women, and
white women (0.798, 0.779, 0.718, and 0.695 mm, respectively).
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Table 5 shows the multivariable-adjusted and
unadjusted associations between logarithmically transformed Lp(a)
protein values and mean carotid intimal-medial far-wall
thickness by race and gender, with multivariable statistics in
the upper portion of the table and comparable unadjusted statistics in
the lower. Because there was a statistically significant interaction
between Lp(a) protein and wall thickness by diabetes status
(P=.0001) for black women, parameter estimates
have been stratified on diabetes. Among diabetic black women, Lp(a)
protein was significantly associated with wall thickness (ß=.0326,
P=.0098), whereas for nondiabetics, this association was
absent (ß=.0028, P=.4485). For black men, a
positive
association was suggested between Lp(a) protein and wall thickness
(ß=.00639, P=.2394), with no apparent effect
modification
due to any of the covariates (including P=.66 for smoking
and P=.21 for diabetes). For white women, the association
between Lp(a) protein and wall thickness varied by smoking status
(P for interaction, .0001), with both stratified
parameter estimates approaching statistical significance:
ß for current smokers was .00750 and for former/never smokers .00355.
The association between Lp(a) protein and wall thickness for white men,
as in black men, was not modified at different levels of the measured
covariates (including P=.69 for smoking and
P=.95
for diabetes). This association was similar in magnitude to the
parameter estimate in black men (ß=.00586,
P=.0127). The unadjusted association between logarithmically
transformed Lp(a) protein values and wall thicknesses varied to some
extent from the multivariable estimates. For all race/gender
groups, age and LDL-C were significant confounding variables; in
addition, among white women smokers and white men, fibrinogen was also
a confounding variable. Interestingly, when adjusted LDL-C was
introduced into the aforementioned models in place of the Friedewald
equation–derived LDL-C, it was no longer a confounding
variable in any race/gender group (not shown).
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Table 6 shows the difference in mean carotid artery
intimal-medial far-wall thickness for a 100-µg/mL increment
in Lp(a) protein, after adjustment for the same covariates as in Table
5
. Mean wall thickness increased by 0.15 mm in diabetic black
women
(P=.0098); by 0.013 mm in nondiabetic black women
(P=.4485); by 0.029 mm in black men (P=.2394);
by
0.035 mm in white women who were current smokers (P=.0596);
by 0.016 mm in white women who were former/never smokers
(P=.0674); and by 0.027 mm in white men
(P=.0127). When the Friedewald equation–derived LDL-C
was replaced by LDL-C minus Lp(a)-C in the same multivariable
models, the wall thickness estimates obtained from the same 100-µg/mL
increment of Lp(a) protein were larger in all race/gender groups, with
stronger statistical associations.
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Discussion |
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The study presented here has shown that Lp(a) protein is positively associated with a continuous measure of carotid artery wall thickness in a biracial population–based cohort. These data corroborate previous reports that have implicated plasma Lp(a) in both coronary atherosclerosis and carotid atherosclerosis manifested as plaque in stroke patients.6 7 The associations found in this investigation were obtained noninvasively from a randomly selected population that was largely asymptomatic for clinical manifestations of cardiovascular disease.
Although univariate associations of Lp(a) protein with carotid atherosclerosis suggest that wall thickness increases monotonically with Lp(a) protein levels, multivariable linear regression analysis of this cohort revealed both race and gender differences in the magnitude of this association. The Lp(a) protein/carotid wall thickness relationship was enhanced by diabetic status and cigarette use in black women and white women, respectively. Although a biologic mechanism is not readily apparent for this gender difference in the association of Lp(a) with carotid atherosclerosis, effects of menopause and the resultant increase in many cardiovascular risk factors, community and socioeconomic differences between race groups that may affect lifestyle or access to health care, or other unmeasured risk factors may account for the differential impact of diabetes and smoking in women. Interactions between Lp(a) and total cholesterol or LDL-C have been previously reported for Lp(a) and CHD among hypercholesterolemics,20 50 51 52 53 54 55 but no evidence of an effect modification by these factors was observed for any race/gender group in this study.
White men had, on average, the greatest mean carotid intimal-medial
far-wall thickness of the four race/gender groups (0.798 mm
compared with 0.779, 0.718, and 0.695 mm in black men, black women, and
white women, respectively). Nonetheless, a 100-µg/mL increase in
Lp(a) protein level was associated with the greatest increase in wall
thickness among diabetic black women—0.15 mm—followed by
substantially smaller increases among white female smokers, similar
increases among white and black men, and smaller but comparable
increases among nondiabetic black women and white female former/never
smokers. These wall thickness estimates were obtained from
multivariable linear regression models after adjustment for
LDL-C values that were calculated by the Friedewald equation. Because
LDL-C calculated in this way contains Lp(a)-C, the Friedewald equation
tends to overestimate LDL, particularly for the higher mean Lp(a)
levels observed in blacks. This overestimation of LDL was shown to
produce an underestimate of the association between Lp(a) protein and
carotid wall thickness in these models, with estimated wall thicknesses
substantially higher in those models that were adjusted for Lp(a)-C
(Table 6). Directly measured LDL compared with Friedewald
equation–estimated LDL is needed to verify this underestimation of
Lp(a) as a cardiovascular risk factor.
The strength of the association between Lp(a) protein and carotid wall thickness was similar between black men and white men. Although blacks of both genders had Lp(a) protein values approximately twice those of whites, this difference did not translate into a corresponding increase in arterial thickness per unit of Lp(a) protein by race. These results suggest that Lp(a) is a significant but relatively weak risk factor for carotid atherosclerosis when compared with other risk factors that vary by race, such as blood pressure and HDL-C level, and that in women the magnitude of the association between Lp(a) protein and carotid atherosclerosis may be influenced by diabetes and cigarette smoking.
Lp(a) has been reported to be a largely genetic risk factor that is unaltered by age, diet, gender, or smoking cigarettes.9 Other reports have indicated that Lp(a) levels can be reduced by niacin therapy,56 57 58 estrogen replacement therapy in postmenopausal women,16 17 18 and glycemic control in diabetic patients14 15 ; equivocal changes have been produced by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors,59 consumption of n-3 fatty acids,60 61 consumption of ethanol sufficient to produce cirrhosis or alcoholism,12 13 and physical activity.10 11 62 In the current study, no changes in the parameter estimate for the linear association between Lp(a) protein and wall thickness were observed with BMI, ethanol consumption, fasting TG concentrations, SBP, or HDL-C; these results were also supported by the Spearman correlation coefficients between Lp(a) protein and these factors. However, in addition to the effect modification in women by smoking and diabetic status, the association between Lp(a) protein and wall thickness was confounded by LDL-C and age in all race/gender groups and by fibrinogen in white women smokers and white men. Although LDL-C was no longer a confounding variable after adjustment for Lp(a)-C, cigarette smoking may contribute to the initiation of atherosclerosis, both through direct toxicity to the endothelial surface and through increased fibrinogen levels in the presence of high Lp(a).
Among female participants in the baseline ARIC Study cohort, 69% of whites and 77% of blacks reported that they had undergone menopause, defined as the absence of menstruation in the 2 years prior to participation in the study. Nabulsi et al16 found that 83% of these postmenopausal women were not taking any hormone replacement therapy at baseline and the remainder were using either estrogen alone (14%) or an estrogen-progestin combination (3%). Although neither dosage nor duration data were collected, estrogen users had unadjusted mean Lp(a) protein values of 99 µg/mL compared with 118 µg/mL for postmenopausal women who had never used hormone replacement therapy. The female participants in the study presented here had higher levels of Lp(a) protein than did men, regardless of race: 169.1 versus 147.0 µg/mL for black women and men, respectively, and 86.6 versus 75.1 µg/mL for white women and men. Women in general also showed a slight increase in Lp(a) protein level with each 5-year age increment, while men showed no such increase. These data suggest that Lp(a) protein may be higher in postmenopausal women who do not use hormone replacement therapy, because the number of women in this cohort using such therapy was relatively small and few of them were premenopausal. In multivariable regression analysis, however, the association of menopausal status with both Lp(a) protein level and wall thickness was not statistically significant when age was also entered into the model.
The ARIC Study cohort was 45 to 64 years old at baseline, a relatively young age group to exhibit clinically manifest atherosclerosis and plaque formation.63 Therefore, this study presented ultrasonographic data for a global measure of carotid intimal-medial wall thickness as an indicator of preclinical atherosclerosis. The association between Lp(a) protein and wall thickness has also been demonstrated in a case-control study of a subgroup from this population who exhibited markedly thickened intimal-medial walls compared with a control group: mean Lp(a) protein values were 110.8 µg/mL in cases compared with 79.3 µg/mL in matched control subjects.64 The case selection criteria for this study made "cases" more likely to have wall thickening attributable to atherosclerosis than did the study population as a whole. The earliest documented evidence of Lp(a) as a risk factor for atherosclerotic cardiovascular disease was observed from the relation between elevated plasma Lp(a) levels and myocardial infarction.1 2 3 4 In our population, Lp(a) protein levels among participants with a self-reported history of heart attack were 115.9 µg/mL compared with 101.0 µg/mL among those with no history of myocardial infarction; each race/gender group showed similar trends (not shown). From these cross-sectional data, however, no conclusions can be drawn about the relationship between coronary and carotid atherosclerosis.
Recent data have indicated that the effect of Lp(a) on CHD may be a product of the hypervariable apo(a) gene locus, resulting in multiple apo(a) phenotypes.65 In Chinese66 and Caucasian50 67 populations, lower-molecular-weight apo(a) isoforms are associated with high plasma Lp(a) concentrations and an increased risk of CHD. Sandholzer et al68 have shown that in Asian and Caucasian ethnic groups, apo(a) size variability is highly correlated with Lp(a) levels; in Sudanese blacks, however, apo(a) size explains only 19% of the total variability in Lp(a) concentration. Sudanese blacks have a lower proportion of a low-molecular-weight apo(a) isoform (the S2 phenotype) that is generally associated with high plasma Lp(a) levels than do Caucasians or Asians. This suggests that in blacks, the apo(a) isoform is either influenced to a greater extent by environmental factors (not supported by our data), produced at a greater rate, or catabolized at a reduced rate. The association between total Lp(a) or apo(a) isoforms and cardiovascular disease in blacks has not been established.
The ARIC Study is the first investigation of both Lp(a) and noninvasively determined carotid artery wall thickness in blacks. In the study reported here, black men on average exhibited less carotid atherosclerosis than did white men, a finding consistent with the lower coronary risk status predicted by a greater proportion of the high-molecular-weight isoform [despite their higher plasma Lp(a) concentrations]. Apo(a) phenotypic differences between men and women are unknown, as are effects of hormone replacement therapy on Lp(a) levels for different isoform sizes in postmenopausal women. Conversely, black women in this study had thicker arterial walls than did white women, but the relationship between Lp(a) and wall thickness was modified by diabetic status, which is highly prevalent in the former subgroup.
In contrast to the cross-sectional and case-control evidence, studies on the effect of Lp(a) on cardiovascular disease progression are limited and inconsistent. In both population-based and clinical trials, the association between Lp(a) and incident fatal and nonfatal CHD has been reported to be positive69 70 or absent.71 72 Given the inconsistency of elevated Lp(a) level as a risk factor for incident CHD, limited ability to lower Lp(a) concentrations in vivo, and lack of evidence to suggest that lowering Lp(a) levels without modifying other risk factor leads to a reduction in coronary events, the role of Lp(a) as a causal risk factor remains unclear. Population-attributable risk estimates for excess CHD cases associated with elevated Lp(a) concentrations fall in the 20% to 30% range3 70 but are not as high as risks attributed to smoking, elevated total cholesterol, or hypertension and presently do not warrant screening for plasma Lp(a) at the population level. However, evidence that correlates elevated Lp(a) level with preclinical, noninvasively obtained evidence of carotid artery wall thickening may offer clues about the initiation of atherosclerotic disease, particularly in women with readily modifiable cardiovascular risk factors like diabetes and cigarette smoking. Race and gender differences in these associations point to the need for further research into the role of Lp(a) as a cardiovascular and cerebrovascular risk factor in blacks as well as the impact of apo(a) isoform distributions on Lp(a) levels among women.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by contract N01-HC-55018 from the National Heart, Lung, and Blood Institute, Bethesda, Md. The authors wish to acknowledge the following ARIC investigators: University of North Carolina, Chapel Hill: Phyllis Johnson, Marilyn Knowles, Catherine Paton, and Carmen Woody; University of North Carolina, Forsyth County: Pamela Williams, Jeannette Bensen, Kay Burke, and Wilhelmenia Cheeks; University of Mississippi Medical Center, Jackson: Mattye L. Watson, Nancy G. Wilson, Bobbie J. Alliston, and Faye A. Blackburn; University of Minnesota, Minneapolis: Gail Murton, Linda Neal, Marilyn Nelson, and Gerda Nightingale; The Johns Hopkins University, Baltimore, Md: Carole Shearer, Rita Timmons, Joyse B. Chabot, and Carol Christman; University of Texas Medical School, Houston: Valarie Stinson, Pam Pfile, Hoang Pham, and Terri Trevino; The Methodist Hospital, Atherosclerosis Clinical Laboratory, Houston, Tex: Doris J. Epps, Charles E. Rhodes, and Selma M. Soyal; Bowman-Gray School of Medicine, Ultrasound Reading Center, Winston-Salem, NC: Tiffany Robertson, Linda Allred, Carolyn Bell, and Roberta Black; University of North Carolina, Chapel Hill, Coordinating Center: Debbie Rubin-Williams, Skai Schwartz, Bedhri N. Srinivasan, and Patsy H. Tacker.
Received September 13, 1995; accepted November 6, 1995.
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