Concentration of Smaller High‐Density Lipoprotein Particle (HDL‐P) Is Inversely Correlated With Carotid Intima Media Thickening After Confounder Adjustment: The Multi Ethnic Study of Atherosclerosis (MESA)

BACKGROUND Recent studies have failed to establish a causal relationship between high-density lipoprotein cholesterol levels (HDL-C) and cardiovascular disease (CVD), shifting focus to other HDL measures. We previously reported that smaller/denser HDL levels are protective against cerebrovascular disease. This study sought to determine which of small+medium HDL particle concentration (HDL-P) or large HDL-P was more strongly associated with carotid intima-media thickening (cIMT) in an ethnically diverse cohort. METHODS AND RESULTS In cross-sectional analyses of participants from the Multi Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of nuclear magnetic resonance spectroscopy-measured small+medium versus large HDL-P with cIMT measured in the common and internal carotid arteries, through linear regression. After adjustment for CVD confounders, low-density lipoprotein cholesterol (LDL-C), HDL-C, and small+medium HDL-P remained significantly and inversely associated with common (coefficient=-1.46 μm; P=0.00037; n=6512) and internal cIMT (coefficient=-3.82 μm; P=0.0051; n=6418) after Bonferroni correction for 4 independent tests (threshold for significance=0.0125; α=0.05/4). Large HDL-P was significantly and inversely associated with both cIMT outcomes before HDL-C adjustment; however, after adjustment for HDL-C, the association of large HDL-P with both common (coefficient=1.55 μm; P=0.30; n=6512) and internal cIMT (coefficient=4.84 μm; P=0.33; n=6418) was attenuated. In a separate sample of 126 men, small/medium HDL-P was more strongly correlated with paraoxonase 1 activity (rp=0.32; P=0.00023) as compared to both total HDL-P (rp=0.27; P=0.0024) and large HDL-P (rp=0.02; P=0.41) measures. CONCLUSIONS Small+medium HDL-P is significantly and inversely correlated with cIMT measurements. Correlation of small+medium HDL-P with cardioprotective paraoxonase 1 activity may reflect a functional aspect of HDL responsible for this finding.