Therapies targeting high-density lipoprotein cholesterol content (HDL-C) have not improved coronary heart disease (CHD) outcomes. High-density lipoprotein particle concentration (HDL-P) may better predict CHD. However, the impact of race/ethnicity on the relations between HDL-P and subclinical atherosclerosis and incident CHD events has not been described. Participants from the Dallas Heart Study (DHS), a multiethnic, probability-based, population cohort of Dallas County adults, underwent the following baseline measurements: HDL-C, HDL-P by nuclear magnetic resonance imaging, and coronary artery calcium by electron-beam computed tomography. Participants were followed for a median of 9.3 years for incident CHD events (composite of first myocardial infarction, stroke, coronary revascularization, or cardiovascular death). The study comprised 1,977 participants free of CHD (51% women, 46% black). In adjusted models, HDL-C was not associated with prevalent coronary artery calcium (p = 0.13) or incident CHD overall (hazard ratio [HR] per 1 SD 0.89, 95% confidence interval [CI] 0.76 to 1.05). However, HDL-C was inversely associated with incident CHD among nonblack (adjusted HR per 1 SD 0.67, 95% CI 0.46 to 0.97) but not black participants (HR 0.94, 95% CI 0.78 to 1.13, p interaction = 0.05). Conversely, HDL-P, adjusted for risk factors and HDL-C, was inversely associated with prevalent coronary artery calcium (p = 0.009) and with incident CHD overall (adjusted HR per 1 SD 0.73, 95% CI 0.62 to 0.86), with no interaction by black race/ethnicity (p interaction = 0.57). In conclusion, in contrast to HDL-C, the inverse relation between HDL-P and incident CHD events is consistent across ethnicities. These findings suggest that HDL-P is superior to HDL-C in predicting prevalent atherosclerosis as well as incident CHD events across a diverse population and should be considered as a therapeutic target.
High-density lipoprotein (HDL) particle concentration (HDL-P) is an emerging marker that may better predict coronary heart disease (CHD) and response to therapy than does high-density lipoprotein cholesterol content (HDL-C). A population-based study from the Multi-Ethnic Study of Atherosclerosis (MESA) revealed that HDL-P was independently associated with reduced risk for incident CHD, even when adjusting for HDL-C, but the inverse association between HDL-C and CHD was attenuated after adjustment for HDL-P. More recently, post hoc analysis of the Justification for the Use of Statins in Prevention: Intervention Trial Evaluating Rosuvastatin (JUPITER) study showed that among subjects randomized to high-potency statin therapy, on-treatment HDL-P was the only HDL composition marker that was significantly associated with CHD events. Although the variation in HDL-C across race/ethnicities is well described, little is known about the race/ethnicity-specific cardiovascular epidemiology of HDL-P. The aims of this study were to compare the determinants of HDL-C and HDL-P and to examine race/ethnicity-specific associations between HDL-P and subclinical and clinical atherosclerotic phenotypes.
Methods
The Dallas Heart Study (DHS) is a multiethnic, probability-based, population cohort study of Dallas County residents, with deliberate oversampling of black participants. The study design has been extensively described previously. Briefly, from 2000 to 2002, 2,971 participants completed a detailed in-home survey, laboratory testing, and imaging studies. For the present study, the study population comprised 1,977 participants who, at study entry, were not taking any lipid-lowering medications or hormone replacement therapy; were free of malignancy, connective tissue disease, and human immunodeficiency virus infection; and who survived ≥1 year after the baseline clinic visit. All participants provided written informed consent, and the protocol was approved by the institutional review board of the University of Texas Southwestern Medical Center.
Race/ethnicity, gender, smoking status, history of CHD, menopause status, exercise amount, and alcohol intake were self-reported. Blood pressure measurements were taken at rest, while seated. Five measurements were taken and the last 3 readings were averaged. Hypertension was defined as average systolic blood pressure ≥140 mm Hg, average diastolic blood pressure ≥90 mm Hg, or use of any antihypertensive medication. Diabetes was defined as fasting glucose level ≥126 mg/dl or use of any hypoglycemic medication. Smoking was defined as any current smoking.
Venous blood was collected in a fasting state in ethylenediaminetetraacetic acid tubes. They were maintained at 4°C for ≤4 hours before centrifugation at 1,430g for 15 minutes. Plasma was then extracted and frozen at −80°C until assays were performed by blinded researchers. High-sensitivity C-reactive protein (hs-CRP) was analyzed using a previously described technique. The homeostasis model assessment of insulin resistance index (HOMA-IR) was calculated as fasting insulin (μIU/ml) × fasting glucose (mmol/L)/22.5. HDL particle sizes and HDL-P were measured by LipoScience, Inc. (Raleigh, North Carolina) using nuclear magnetic resonance spectroscopy.
Coronary artery calcium (CAC) was measured by electron-beam computed tomography in duplicates 1 to 2 minutes apart using an Imatron 150 XP scanner (Imatron Inc., San Bruno, California). CAC scores were expressed in Agatston units, with the mean of 2 consecutive scans used as the final score.
All participants were followed for a median of 9.3 years (interquartile range 8.8 to 9.8). CHD events were adjudicated by 2 blinded cardiologists and defined as nonfatal myocardial infarction, stroke, coronary artery bypass graft surgery, percutaneous coronary intervention, or cardiovascular death.
HDL-C, HDL-P, and HDL particle size were expressed as medians with interquartile ranges. Levels of each parameter were compared across race/ethnicities in men and women separately using Wilcoxon rank sum tests. Gender-specific linear regression models using multiple covariates were used to model HDL-C and HDL-P. Contribution of the models to the variance in HDL-C and HDL-P was assessed by adjusted R 2 values. Individual covariates’ contributions within these models were compared by their standardized β coefficients (SD unit change in HDL-C or HDL-P per 1 SD change in the covariate). The independent associations of HDL-C and HDL-P with coronary calcium were assessed in models adjusted for age, gender, hypertension, diabetes, smoking, body mass index, non-HDL, log-transformed triglyceride, menopause status, and alcohol (grams/week) and include HDL-C and HDL-P. Cox proportional hazards models were used to determine hazard ratios (HRs) for 1-SD increases in HDL-C and HDL-P for time to first incident CHD events, adjusted for the same covariates listed previously. In these models, participants with histories of lipid-lowering therapy, hormone replacement therapy, and cardiovascular disease were also included, and models were additionally adjusted for these covariates. HRs were then determined for nonfatal and fatal events separately. Interactions with gender and race/ethnicity (black vs nonblack) were tested for all models. Two-sided p values <0.05 were considered to indicate statistical significance. All analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, North Carolina).
Results
The study comprised 1,977 adult participants; 51% were women, and 46% were black. Among men, blacks had highest median HDL-C and HDL-P and the largest median HDL particle size ( Table 1 ). However, the magnitudes of the differences in median HDL-P (2%) and HDL particle size (3%) were smaller than those for HDL-C (17%). Among women, white women had the highest median HDL-C and HDL-P ( Table 1 ). Unlike black men, black women had discordant HDL composition compared with white women (similar median HDL-C but the lowest median HDL-P and the largest HDL particles). Black women, Hispanic women, and white men had HDL-C levels ranging from 41 to 52 mg/dl despite all having the same median HDL-P level of 32 μmol/L.
| N | HDL-C (mg/dL) | HDL-P (μmol/L) | HDL size (nm) | |
|---|---|---|---|---|
| Men | ||||
| Black | 425 | 48 (40 – 57) | 33 (29 – 37) | 8.9 (8.6 – 9.3) |
| White | 337 | 41 (35 – 48) | 32 (29 – 35) | 8.7 (8.5 – 8.9) |
| Hispanic | 168 | 41 (36 – 49) | 30 (27 – 35) | 8.7 (8.6 – 8.9) |
| p-value | <0.0001 | 0.0055 | <0.0001 | |
| Women | ||||
| Black | 492 | 52 (45 – 62) | 32 (29 – 37) | 9.2 (8.9 – 9.5) |
| White | 297 | 53 (44 – 63) | 35 (31 – 39) | 9.1 (8.8 – 9.4) |
| Hispanic | 210 | 48 (40 – 55) | 32 (28 – 36) | 9.1 (8.9 – 9.3) |
| p-value | <0.0001 | <0.0001 | 0.0053 |
Measured risk factors explained a larger proportion of the variance in HDL-C than HDL-P in men and women. This difference was greater in men, in whom measured risk factors accounted for more than twice the variability in HDL-C compared with HDL-P (R 2 = 0.29 for HDL-C vs 0.13 for HDL-P in men; Table 2 ). Alcohol intake was the only risk factor associated with HDL-C and HDL-P in both men and women.
| Men | n = 848 | HDL-C | HDL-P | |||
|---|---|---|---|---|---|---|
| R2 = 0.29 | R2 = 0.13 | |||||
| Std β | p-value | Std β | p-value | |||
| Age | -0.0038 | 0.91 | 0.0069 | 0.85 | ||
| Black | 0.18 | <0.00010 | 0.056 | 0.15 | ||
| Hispanic | 0.019 | 0.56 | -0.036 | 0.34 | ||
| Hypertension | -0.018 | 0.57 | 0.020 | 0.58 | ||
| Diabetes mellitus | 0.10 | 0.0045 | 0.051 | 0.19 | ||
| Smoking history | 0.0063 | 0.84 | -0.051 | 0.13 | ||
| HOMA-IR | -0.095 | 0.0069 | -0.14 | 0.0004 | ||
| Exercise | 0.11 | 0.00020 | 0.060 | 0.068 | ||
| Alcohol use | 0.20 | <0.00010 | 0.24 | <0.0001 | ||
| Log triglyceride | -0.35 | <0.00010 | 0.00079 | 0.98 | ||
| Family history | 0.0020 | 0.95 | -0.040 | 0.24 | ||
| hs-CRP | -0.088 | 0.0037 | -0.19 | <0.0001 | ||
| Women | n = 935 | R2 = 0.21 | R2 = 0.13 | ||
|---|---|---|---|---|---|
| Std β | p-value | Std β | p-value | ||
| Age | 0.25 | <0.00010 | 0.21 | <.00010 | |
| Black | -0.012 | 0.74 | -0.13 | 0.0011 | |
| Hispanic | -0.066 | 0.072 | -0.15 | 0.00010 | |
| Hypertension | -0.064 | 0.059 | 0.020 | 0.56 | |
| Diabetes mellitus | 0.013 | 0.71 | 0.015 | 0.68 | |
| Smoking history | -0.085 | 0.0053 | -0.078 | 0.014 | |
| HOMA-IR | -0.079 | 0.026 | -0.073 | 0.052 | |
| Exercise | 0.097 | 0.0013 | 0.033 | 0.29 | |
| Alcohol use | 0.16 | <0.00010 | 0.11 | 0.00060 | |
| Menopause | 0.018 | 0.55 | 0.027 | 0.38 | |
| Log triglyceride | -0.29 | <0.00010 | 0.11 | 0.0024 | |
| Family history | -0.033 | 0.28 | 0.016 | 0.62 | |
| hs-CRP | -0.080 | 0.0098 | 0.055 | 0.093 | |
Among men, factors positively associated with HDL-C included black ethnicity, diabetes, exercise, and alcohol intake, and factors inversely associated with HDL-C included HOMA-IR, triglycerides, and hs-CRP ( Table 2 ). In contrast, only HOMA-IR, alcohol intake, and hs-CRP were significantly associated with HDL-P in men. Among women, factors positively associated with HDL-C included age, exercise, and alcohol intake, whereas inverse associations included hypertension, smoking, HOMA-IR, triglycerides, and hs-CRP ( Table 2 ). Factors associated with HDL-P included age, black and Hispanic ethnicity, smoking, alcohol, and triglycerides. Notable sex-based differences in determinants of HDL composition included age and smoking (associated in women but not in men for HDL-C and HDL-P; Table 2 ). Interestingly, black race/ethnicity was positively associated with HDL-C only in men and inversely associated with HDL-P only in women.
HDL-C was not associated with prevalent CAC in adjusted models (p = 0.13). However serial adjustment for HDL-P resulted in a positive association between HDL-C and CAC (standardized β = 0.07, p = 0.008). HDL-P was inversely associated with prevalent CAC in fully adjusted models including HDL-C (standardized β = −0.06, p = 0.009). There were no statistically significant interactions by gender or ethnicity for associations between either HDL-C or HDL-P and prevalent CAC.
HDL-C was inversely associated with incident CHD in unadjusted models (HR per 1 SD 0.84, 95% confidence interval [CI] 0.73 to 0.97; Table 3 ). This association was partially attenuated in models adjusted for traditional risk factors and fully attenuated with further adjustment for HDL-P (fully adjusted HR per 1 SD 1.07, 95% CI 0.89 to 1.29; Table 3 ). However, there was a significant interaction between HDL-C and ethnicity (p interaction = 0.05) such that HDL-C was inversely associated with incident CHD in nonblack participants (adjusted HR per 1 SD 0.67, 95% CI 0.46 to 0.97) but not among Black participants (adjusted HR per 1 SD 0.94, 95% CI 0.78 to 1.13; Figure 1 ). This interaction between HDL-C and black ethnicity was driven by nonfatal events ( Figure 1 ).
