High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis)

Abstract

Objectives: The purpose of this study was to evaluate independent associations of high-density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary heart disease (CHD).

Background: HDL-C is inversely related to CHD, and also to triglycerides, low-density lipoprotein particles (LDL-P), and related metabolic risk. HDL-P associations with CHD may be partially independent of these factors.

Methods: In a multiethnic study of 5,598 men and women ages 45 to 84 years old, without baseline CHD, excluding subjects on lipid-lowering medications, triglycerides >400 mg/dl, or missing values, we evaluated associations of HDL-C and nuclear magnetic resonance spectroscopy-measured HDL-P with cIMT and incident CHD (myocardial infarction, CHD death, and angina, n = 227 events; mean 6.0 years follow-up). All models were adjusted for age, sex, ethnicity, hypertension, and smoking.

Results: HDL-C and HDL-P correlated with each other (ρ = 0.69) and LDL-P (ρ = -0.38, -0.25, respectively, p < 0.05 for all). For (1 SD) higher HDL-C (15 mg/dl) or HDL-P (6.64 μmol/l), cIMT differences were - 26.1 (95% confidence interval [CI]: -34.7 to -17.4) μm and -30.1 (95% CI: -38.8 to - 21.4) μm, and CHD hazard ratios were 0.74 (95% CI: 0.63 to 0.88) and 0.70 (95% CI: 0.59 to 0.82), respectively. Adjusted for each other and LDL-P, HDL-C was no longer associated with cIMT (2.3; 95% CI: - 9.5 to 14.2 μm) or CHD (0.97; 95% CI: 0.77 to 1.22), but HDL-P remained independently associated with cIMT (-22.2; 95% CI: - 33.8 to -10.6 μm) and CHD (0.75; 95% CI: 0.61 to 0.93). Interactions by sex, ethnicity, diabetes, and high-sensitivity C-reactive protein were not significant.

Conclusions: Adjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL-related risk.

Figure 1

Scatterplot of HDL-C with HDL-P All results except Fig 1 are adjusted for base covariates (base cov.): age, sex, ethnicity, hypertension, and smoking. Error bars are standard errors; p values are for linear trend.

Figure 2

Mean cIMT (μm) across quartiles of HDL-C or HDL-P, before and after adjusting for LDL-P and each other (n=5541). A. Mean cIMT (μm) across HDL-C quartiles, adjusted for base covariates, p <0.001; adjusted for base covariates plus LDL-P, p=0.01; adjusted for base covariates plus HDL-P, p=0.051, and adjusted for base covariates plus LDL-P and HDL-P, p=0.75. B. Mean cIMT (μm) across HDL-P quartiles; adjusted for base covariates, p <0.0001; adjusted for base covariates plus LDL-P, p=0.0001; adjusted for base covariates plus HDL-C, p=0.002; adjusted for base covariates plus LDL-P and HDL-C, p<0.001 All results except Fig 1 are adjusted for base covariates (base cov.): age, sex, ethnicity, hypertension, and smoking. Error bars are standard errors; p values are for linear trend.

Figure 3

Mean cIMT (μm) by joint tertiles of HDL-C and HDL-P, entire group, and stratified by median LDL-P (1236.5 nmol/l). All models adjusted for base covariates. HDL-C tertiles (mg/dl): low HDL-C (≤42), medium HDL-C (43-54), high HDL-C: (≥55.) HDL-P tertiles (μmol/l): low HDL-P (≤30.5), medium HDL-P (30.6-36.1), high HDL-P: (≥30.6). A. Entire study sample. P for HDL-C trend within each HDL-P tertile= not significant. P for HDL-P trend <0.05 for both low and high HDL-C tertiles, not significant for medium HDL-C tertiles. B. Participants with LDL-P below the median. P for HDL-C trend within each HDL-P tertile: not significant. P for HDL-P trend within HDL-C tertile= 0.06, 0.09, 0.02 for low, medium and high HDL-C tertiles, respectively. C. Participants with LDL-P above the median. Neither HDL-C trends within each HDL-P tertile, nor HDL-P trends within each HDL-C tertile were significant. All results except Fig 1 are adjusted for base covariates (base cov.): age, sex, ethnicity, hypertension, and smoking. Error bars are standard errors; p values are for linear trend.

Figure 3

Mean cIMT (μm) by joint tertiles of HDL-C and HDL-P, entire group, and stratified by median LDL-P (1236.5 nmol/l). All models adjusted for base covariates. HDL-C tertiles (mg/dl): low HDL-C (≤42), medium HDL-C (43-54), high HDL-C: (≥55.) HDL-P tertiles (μmol/l): low HDL-P (≤30.5), medium HDL-P (30.6-36.1), high HDL-P: (≥30.6). A. Entire study sample. P for HDL-C trend within each HDL-P tertile= not significant. P for HDL-P trend <0.05 for both low and high HDL-C tertiles, not significant for medium HDL-C tertiles. B. Participants with LDL-P below the median. P for HDL-C trend within each HDL-P tertile: not significant. P for HDL-P trend within HDL-C tertile= 0.06, 0.09, 0.02 for low, medium and high HDL-C tertiles, respectively. C. Participants with LDL-P above the median. Neither HDL-C trends within each HDL-P tertile, nor HDL-P trends within each HDL-C tertile were significant. All results except Fig 1 are adjusted for base covariates (base cov.): age, sex, ethnicity, hypertension, and smoking. Error bars are standard errors; p values are for linear trend.