Value of High-Density Lipoprotein (HDL) Subpopulations in Predicting Recurrent Cardiovascular Events in the Veterans Affairs HDL Intervention Trial
Objective— To test the hypothesis whether determination of high-density lipoprotein (HDL) subpopulations provides more power to predict recurrent cardiovascular disease (CVD) events (nonfatal myocardial infarction, coronary heart disease death, and stroke) than traditional risk factors in the Veterans Affairs HDL Intervention Trial (VA-HIT).
Methods and Results— Apolipoprotein A-I (apoA-I)–containing HDL subpopulations were quantitatively determined by nondenaturing 2D gel electrophoresis. Hazard ratios of recurrent CVD events were calculated by comparing VA-HIT subjects with (n=398) and without (n=1097) such events. Subjects with new CVD events had significantly lower HDL-C, apoA-I, and large cholesterol-rich HDL particle (α-1, α-2, pre–α-1, and pre–α-2) levels, significantly higher triglyceride, and small poorly lipidated HDL particle (pre–β-1 and α-3) levels than subjects without such events. Multivariate analyses indicated that α-1 and α-2 particle levels were significant negative risk factors, whereas α-3 level was a significant positive risk factor for new CVD events. Pre–β-1 level was a significant risk factor for new CVD events only in univariate analysis. A forward selection model indicated that α-1 was the most significant risk factor for recurrent CVD events among HDL particles.
Conclusions— An altered HDL subpopulation profile marked with low α-1 and α-2 levels and a high α-3 level in coronary heart disease patients indicated an elevated risk for new CVD events. Moreover, α-1 and α-2 levels were superior to HDL-C levels in risk assessment in patients with low HDL-C in VA-HIT.
A low level of plasma high-density lipoprotein (HDL) cholesterol level is recognized as a major independent risk factor for the development of coronary heart disease (CHD).1–3 However, HDL is a heterogeneous class of lipoprotein particles with subspecies that differ in apolipoprotein and lipid composition, size, density, and charge, and different subspecies appear to have different physiological functions.4–7 Traditionally, HDL has been separated into major subclasses by either polyanion precipitation and ultracentrifugation (HDL2 and HDL3) or by the apolipoprotein content, distinguishing particles containing only apolipoprotein A-I (apoA-I; lipoprotein A-I [LpA-I]), the major apolipoprotein of HDL, from particles containing apoA-I and apoA-II (LpA-I:A-II). None of these techniques have provided any convincing evidence that one kind of HDL subfraction has any greater cardioprotective function than another,8–14 probably because of the fact that all of these HDL subfractions are themselves heterogeneous, containing a variety of different HDL subspecies with possibly different physiological functions.
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Our laboratory uses native 2D gel electrophoresis, immunoblotting, and image analysis to determine HDL subpopulations from whole plasma quantitatively with high resolution based on electrophoretic charge and particle size.15 We determine apoA-I contents, not cholesterol, in these particles. This method has been useful in studies of plasma cholesterol metabolism and cholesterol transport from cells because it separates intermediates in these processes.16 We documented that CHD patients not only had HDL deficiency but also had a major rearrangement in the apoA-I–containing HDL subpopulation profile, with significantly lower levels of the large, cholesterol-rich (α-1 and pre–α-1) and higher levels of the small, lipid-poor (α-3 and pre–β-1) HDL particles than controls.17–20 Also, low α-1 HDL particle level was significantly associated with CHD prevalence and was superior to HDL cholesterol (HDL-C) in risk assessment in the Framingham Offspring Study (FOS), suggesting that specific subcomponents of HDL provide more power to predict likelihood of CHD than HDL-C.20 We have also shown that changes in the concentration of α-1 HDL were significantly and inversely correlated with the rates of coronary artery narrowing in CHD patients after treatment with simvastatin-niacin versus placebo for 2 years in the HDL Atherosclerosis Treatment Study (HATS).19
The Veterans Affairs HDL Intervention Trial (VA-HIT) provided us with an opportunity to study HDL subpopulations in a well-characterized cohort of CHD patients selected with low HDL-C and normal low-density lipoprotein (LDL) cholesterol levels. In this subanalysis, we tested the hypothesis whether specific HDL subpopulations provide more power to predict recurrent cardiovascular disease (CVD) events (nonfatal myocardial infarction [MI], CHD death, and stroke) than HDL-C in the VA-HIT.
The VA-HIT study design has been described in detail previously.21 Briefly, men were recruited at 20 VA medical centers throughout the United States. Eligibility for the trial required a documented history of CHD (including previous MI, coronary revascularization, or angiographic evidence of stenosis >50% of the luminal diameter in ≥1 major epicardial coronary arteries), an absence of serious coexisting conditions, an HDL-C level ≤40 mg/dL (1 mmol/L), an LDL cholesterol (LDL-C) level ≤140 mg/dL (3.6 mmol/L), a triglyceride (TG) level ≤300 mg/dL (3.4 mmol/L), and an age <74 years. Participants in VA-HIT were randomly assigned to 2 groups receiving either gemfibrozil or matching placebo treatment. For these analyses, all 398 subjects with cardiovascular end points (CHD death, MI, or stroke), and 1097 subjects without such events were selected based on power calculations (see statistical analyses). In 5.1 years of follow-up, 339 subjects had new CHD events (CHD death or MI), and 59 subjects had stroke.
From FOS, 431 male participants were selected as low HDL-C (≤40 mg/dL) controls based on the following exclusion criteria: any evidence of cardiovascular, hepatic, or kidney disease, thyroid dysfunction, or drug or alcohol abuse.
FOS is a long-term, community-based, prospective observational study of risk factors for CVD.22 During cycle 6 of FOS (1995 to 1998), participants had a standardized medical history, physical examination, and fasting lipid measurements.
Total cholesterol, TG, and HDL-C concentrations were determined by standard enzymatic methods. HDL-C was isolated from the supernatant after dextran-sulfate magnesium precipitation. LDL-C was calculated according to the Friedewald formula. Total plasma apoA-I concentrations were measured with a turbidimetric immunoassay (Wako Diagnostics) on a Hitachi 911 analyzer. ApoA-I–containing HDL subpopulations were determined by 2D nondenaturing gel electrophoresis, immunoblotting, and image analysis as described.15,17 All measurements were performed in our laboratory in the same way in both cohorts, and strict quality control procedures were followed. The interassay and intra-assay coefficients of variation were <5% for the lipid measurements and <10% for the apoA-I and HDL subpopulation determinations. All plasma samples were stored at −80°C and were never thawed until analysis. The effects of long-term storage on HDL subspecies were investigated, and no significant changes in the values obtained after the measurement of the same samples fresh and from short-term and long-term storage were observed.17
Descriptive statistics, means±SD for continuous variables, or proportions for categorical variables were computed for all study variables and all study groups: (1) subjects without new CVD events in VA-HIT (n=1097); (2) subjects with new CVD events in VA-HIT (n=398); (3) subjects without new CVD events in the placebo arm of VA-HIT (n=741); (4) subjects with new CVD events in the placebo arm of VA-HIT (n=230); and (5) FOS subjects with low (≤40 mg/dL) HDL-C and no history of CVD (n=431).
All subjects with recurrent CVD events were included in the analyses. Power calculations for selecting subjects without new CVD events were based on comparing the upper versus the lower tertile of α-1. With a log-rank test, we had 80% power of detecting a risk ratio of 1.52 or higher unadjusted. Using the proportional hazard ratios (HRs) and adjusting for age, smoking, hypertension, body mass index (BMI), and diabetes, our actual risk ratio was 1.47 (95% CI, 1.10 to 2.04; P=0.02) for cardiovascular end points.
Cox proportional hazard models were used to determine the HRs for new CVD events in follow-up (5.1 years). Four models were used for each analysis: in model 1, data were adjusted for lipid-lowering medication when applicable; in model 2, data were adjusted for nonlipid CHD risk factors (age, smoking, hypertension, BMI, and presence of diabetes); in model 3, data were adjusted for lipid (HDL-C, LDL-C, and TG) and nonlipid risk factors; and in model 4, data were adjusted for each HDL particle level in addition to all of the above factors.
Descriptive statistics and means±SD for continuous variables or proportions for categorical variables were computed for all study variables when CHD patients in the placebo arm of VA-HIT were compared with CVD-free participants in FOS. The distribution of the variables was compared between VA-HIT and FOS subjects using 2-sample t tests for continuous variables and χ 2 tests for categorical variables. For HDL subpopulations, adjusted means±SE were calculated for CHD- and CVD-free subjects using analysis of covariance techniques that adjusted for age, smoking, hypertension, diabetes, and BMI, as well as LDL-C, HDL-C, and TG levels. In these analyses, each HDL subpopulation was used as a dependent variable, CHD status as a primary independent variable, and the potential confounding factors listed above were used as covariates.
To evaluate the association between HDL subpopulations and the odds of CHD prevalence, logistic regression models with CHD status as a dependent variable and the HDL subpopulations as independent variables were used. For each HDL subspecies and levels of HDL-C and LDL-C, we considered the models 1 through 3 as described above.
Because the HDL subpopulations are highly correlated with each other and with HDL-C, we also evaluated all of these variables jointly. To assess the relative importance of these variables, we calculated the standardized logit coefficients and the corresponding odds ratios (ie, odds ratios computed after standardizing the variables to 0 mean and unit variance).
Results with P values <0.05 were considered statistically significant. The SAS statistical package version 8 was used in all analyses.
The study design prevented all laboratory personnel from identifying samples. All measurements were conducted blind, and data were sent to the study statisticians for analyses. The study was approved and continually monitored by the subcommittee on human studies at Tufts University/New England Medical Center. All subjects gave written informed consent.
Table 1 shows the comparison of VA-HIT subjects with new CVD events to those without such events in the 5.1-year follow-up. Subjects with new CVD events had significantly lower mean HDL-C (4%) and apoA-I (2%) levels and had significantly higher mean TG levels (8%) and prevalence of diabetes (24%). The apoA-I concentrations in all of the HDL subpopulations were significantly different between the 2 groups. The apoA-I concentrations in the 2 small, poorly lipidated HDL particles (pre–β-1 and α-3) were significantly higher (9% and 3%, respectively), whereas apoA-I concentrations in the more-lipidated HDL particles were significantly lower in subjects with new events. ApoA-I concentration was lower in subjects with new events by 1.1 mg/dL (12%) in α-1 and by 2.3 mg/dL (7%) in α-2 than in subjects without new events.
Cox proportional hazard models were used to determine the HRs for new CVD events in follow-up for 1 SD unit increase in the measured parameters (Table 2). Data were adjusted for lipid-lowering treatment and nonlipid CHD risk factors. Univariate analysis indicated that HDL-C, apoA-I, and all HDL particles, except pre–α-1, were significant predictors of recurrent CVD events. Pre–β-1 and α-3 particles were positive risk factors for recurrent CVD events, whereas all other particles and HDL-C presented negative risk for recurrent CVD events. Multivariate analysis produced very similar results, with the exception of pre–β-1, which lost significance in this analysis. However, a quartile analysis indicated that subjects with the lowest pre–β-1 levels had significantly lower relative risk (RR) for recurrent CVD events than subjects with the highest pre–β-1 levels (Table 3). In contrast, subjects with the highest levels of pre–β-2, α-1, α-2, pre–α-1, pre–α-2, and pre–α-3 had lower RR than subjects with the lowest levels of those parameters. The Cochran–Armitage trend test associated pre–β-1 (P<0.0004) and α-3 (P<0.04) levels positively; pre–β-2 (P<0.0001), α-1 (P<0.0005), α-2 (P<0.0001), pre–α-1 (P<0.002), pre–α-2 (P<0.0001), and pre–α-3 (P<0.0004) levels inversely with RR for recurrent CVD events (Table 3). A positive association between the mean levels of pre–β-1 and α-3 and the percentiles of new CVD events, as well as an inverse association between the mean levels of α-1 and α-2 and percentiles of new CVD events in each quartile are demonstrated by linear regression analysis in the Figure.
Table 4 shows the HRs of new CVD events as calculated for each 1 SD increase of α-1 and HDL-C. Each 1 SD increase in α-1 (5.1 mg/dL) and HDL-C (6.3 mg/dL) decreased hazard of new CVD events by 18% (P=0.002) and 15% (P=0.015), respectively, after adjusting data for treatment and established lipid and nonlipid risk factors (model 3). Contrary to α-1, whose significance was not influenced by HDL-C levels, HDL-C lost power to predict new CVD events after any of the HDL particles representing significant risk for new CVD events was added to the model (data shown for adjusting for α-1 HDL particle level only in Table 4; model 4).
Cox regression analyses for HRs of recurrent CVD events were also evaluated using data on subjects in the placebo arm of VA-HIT (n=741) to exclude the possible effects of gemfibrozil treatment. All the results obtained on subjects in the placebo arm were very similar to those obtained from all participants in VA-HIT. In a forward selection model, α-1 was selected first and was the most significant risk factor for recurrent CVD events. Moreover, the analysis on data, obtained from the placebo arm, indicated that 1 SD increase in α-1 decreased hazard of new CVD events by 12% (P=0.005) after adjusting data for established lipid and nonlipid risk factors.
To study the associations between HDL particles and CHD prevalence in low HDL-C subjects, we compared FOS subjects with HDL-C ≤40 mg/dL (control) and VA-HIT subjects from the placebo arm with HDL-C ≤40 mg/dL (CHD cases; Table 5). Despite the selection criteria, VA-HIT subjects had 1 mg/dL (P<0.01) lower HDL-C and 3 mg/dL lower apoA-I than FOS controls. VA-HIT subjects had lower LDL-C and higher prevalence of hypertension and diabetes. CHD cases had a higher mean level of the small, poorly lipidated pre–β-1 and lower mean levels of the larger, lipid-rich α-1, α-2, and pre–α-1 particles. Logistic regression analyses indicated that only the levels of α-1 among HDL particles were significantly associated with the prevalence of CHD (Table 6). Each 1 mg/dL decrease in α-1 increased the odds of CHD with 13% (P<0.0001) in low HDL-C subjects after adjusting data for lipid and nonlipid CHD risk factors.
Our previous results indicated that measurement of HDL subpopulations was more informative than HDL-C measurement in assessing CHD-risk.17,20 We demonstrated that CHD patients had a major rearrangement in their HDL subpopulation profile compared with HDL-C–matched controls. The HDL subpopulation profile of CHD patients was marked with significantly increased pre–β-1 and significantly decreased α-1 levels. Moreover, each 1 mg/dL increase in α-1 particle level was associated with a 21% (P<0.0001) decrease in CHD prevalence, and α-1 level was superior to HDL-C in risk assessment in a case-control setting in male participants in FOS.20
Based on these findings, we hypothesized that the concentrations of specific HDL particles were significantly associated with CHD prevalence in subjects with low (<40 mg/dL) HDL-C levels. We also hypothesized that the concentrations of specific HDL particles were independent predictors of recurrent CVD events. The VA-HIT study provided an excellent opportunity to investigate the associations between HDL particles and CVD risk in subjects selected for CHD and low HDL-C levels.
To estimate the predictive values of specific HDL particles for recurrent CVD events, patients with and without recurrent events were compared in VA-HIT. Levels of the highly lipidated α-1 and α-2 particles had a significant inverse association with new CVD events in univariate and multivariate analyses after adjusting data for established CHD risk factors. Levels of the small, lipid-poor α-3 particles had a significant positive association with new CVD events in these same analyses.
Because others have reported significant associations between elevated pre–β-1 levels and CHD prevalence,23 we carefully investigated the relationship of recurrent CVD events with this particle. We found that the mean pre–β-1 level was significantly higher in the recurrent events group than in the group without new events. However, pre–β-1 level was significantly associated with recurrent CVD events only in univariate analysis and not in multivariate analysis. This finding is in agreement with our data generated in a case-control study using the FOS cohort in which the mean pre–β-1 level was significantly higher in CHD cases than in HDL-C–matched controls but was not significantly associated with CHD prevalence in a multivariate analysis.20
To evaluate the influence of gemfibrozil, the same analyses were performed separately using data from all subjects and from subjects in the placebo arm of VA-HIT. The data indicated no significant influence of gemfibrozil treatment on the results.
We hypothesize that an HDL subpopulation profile marked with high levels of α-1 and α-2 or with high ratios of α-1/α-3 or α-1/pre–β-1 is generally atheroprotective. However, there are exceptions (eg, high levels of large HDL particles can be a result of low scavenger receptor-BI [SR-BI] expression in the liver). Specific HDL subspecies are involved in certain steps of reverse cholesterol transport (RCT).24,25 Recently, we demonstrated that human HDL particles (large LpA-I particles, of which >85% were represented in α-1) injected into human SR-BI transgenic mice were converted into small, α-3–size particles within 3 hours, indicating that SR-BI selectively removes cholesterol from α-1 particles.26 We also documented that the ATP-binding cassette transporter-A1 (ABC-A1)–mediated cell cholesterol efflux correlates positively with pre–β-1 level, whereas SR-BI–mediated cholesterol efflux correlates positively with α-1 and α-2 levels.27 We also reported that patients with ABC-A1 mutations and documented defects in cellular cholesterol efflux have only pre–β-1 HDL in the homozygous state (Tangier disease) and a marked decrease in α-1 HDL in the heterozygous state.28 These data suggest that cells need small, lipid-poor HDL particles for cholesterol efflux, and that if this process is impaired, as it may be in some patients with premature CHD, then relative portion of pre–β-1 HDL is increased.
Recently, there has been great clinical interest in CHD risk reduction by achieving subpopulation-specific increases in HDL level. Human studies have indicated that intravenous injection of specific HDL-like particles (apoA-I/lecithin discs) increases plasma pre–β-1 HDL concentration and stimulates RCT in humans.29 Moreover, recombinant apoA-I Milano/phospholipid complex produced significant regression of coronary atherosclerosis as measured by intravascular ultrasound in 5 weeks.30 This may well be the consequence of providing the ABCA1 transporter on a variety of cells, especially macrophages, in the arterial wall, with a marked increase in acceptors for cellular-free cholesterol.
After pre–β-1 HDL picks up free cholesterol from cells via ABCA1, it becomes a small discoidal HDL particle of α-mobility. In order for this particle to become a large spherical HDL particle, the free cholesterol must be esterified via the action of lecithin cholesterol acyltransferase, which has been reported to be low in CHD patients.3 These findings may also account for more pre–β-1 and α-3 HDL and less α-1 HDL in CHD patients. High pre–β-1 levels can also result from accelerated pre–β-1 formation from large α-1–mobility HDL particles, which may be the result of high activities of cholesterol ester transfer protein (CETP), phospholipid transfer protein, or hepatic lipase. Therefore, a high pre–β-1 level or, more precisely, a low α-1/pre–β-1 ratio, in our view, is a signature pattern of disturbed HDL metabolism and RCT.
The most consistent finding in our studies is that CHD patients have marked reductions in large α-1 HDL. Patients with low HDL often have obesity, hypertriglyceridemia, and insulin resistance. Such patients have been reported having increased CETP activity. When we examined plasma from patients with heterozygous CETP deficiency or subjects given CETP inhibitors, we noted relative decreases in pre–β-1 HDL and significant increases in large α-1 HDL, the opposite of the pattern we observed in CHD patients.31 Moreover, we reported that statins, or more significantly statin–niacin combination, also cause a significant rise in the α-1 HDL particle, and that this increase was associated with significant inverse correlation with change in the degree of coronary artery stenosis.18,19,32 The level of α-1 HDL may merely be a pattern consistent with much less cholesteryl ester being transferred to atherogenic TG-rich lipoproteins of liver and intestinal origin.
The brief summary of our results is HDL-C level is a significant predictor of new CVD events in the VA-HIT population after adjusting data for traditional risk factors. However, when any of the HDL subpopulations representing significant CVD risk are included as a covariant in the analyses, the predictive value of HDL-C for new CVD events is no longer significant. In contrast, specific HDL subpopulations are either significant positive or significant negative predictors of recurrent CVD events in the VA-HIT, and some of these particles, above all α-1 and α-2, are superior to HDL-C in risk assessment in patients whose primary lipid disorder is low HDL-C level. We conclude that the measurement of HDL subpopulations provides information about CVD risk above and beyond that obtained from HDL-C.
This study was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (HL-64738 PI; B.F.A.) and by the VA Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, Washington, DC.
The views expressed in this article do not necessarily represent the views of the Department of Veterans Affairs.
- Received February 25, 2005.
- Accepted July 28, 2005.
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