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 (r (p)=0.32; P=0.00023) as compared to both total HDL‐P (r (p)=0.27; P=0.0024) and large HDL‐P (r (p)=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.