High-Density Lipoprotein Subspecies Defined by Apolipoprotein C-III and Subclinical Atherosclerosis Measures: MESA (The Multi-Ethnic Study of Atherosclerosis)

Abstract

Background: Apolipoprotein C-III (apoC-III), a small proinflammatory protein present on 6% to 7% of high-density lipoprotein (HDL) particles, defines a subspecies of HDL adversely associated with coronary heart disease in primarily white cohorts. In a multi-ethnic population free of clinical cardiovascular disease, we evaluated the relationship between apoC-III-defined HDL subspecies and subclinical markers of atherosclerotic pathology.

Methods and results: We investigated cross-sectional associations between apolipoprotein A-I concentrations of apoC-III-defined HDL subspecies, measured via ELISA and imaging measures of subclinical atherosclerosis, among 4659 participants in the MESA (The Multi-Ethnic Study of Atherosclerosis) at baseline (2000-2002). HDL particles containing and lacking apoC-III were divergently associated with coronary artery calcification in women (P-heterogeneity=0.002) but not in men (P-heterogeneity=0.31) and with carotid plaque score (P-heterogeneity=0.02) and intima-media thickness (P-heterogeneity=0.06) in the overall study population. HDL lacking apoC-III was inversely associated with all outcome measures (coronary artery calcification, women: odds ratio per SD=0.81 [95% confidence interval [CI], 0.73-0.90]; carotid plaque, overall: odds ratio per SD=0.92 [95% CI, 0.84-1.00]; intima-media thickness, overall: mean difference per SD=-14.0 µm [95% CI, -21.1 to -6.7 μm]), whereas HDL containing apoC-III was positively associated (coronary artery calcification, women: odds ratio=1.10 [95% CI, 0.99-1.22]; plaque, overall: odds ratio=1.10 [95% CI, 1.01-1.19]) or unassociated. Neither total HDL nor HDL subspecies was associated with changes in subclinical atherosclerosis measures up to 10 years later.

Conclusions: The presence of apoC-III defined a subspecies of HDL not inversely associated with baseline measures of subclinical atherosclerosis, supporting a role of apoC-III in the pathophysiology of cardiovascular disease.

Keywords: apolipoprotein; atherosclerosis; coronary artery calcium; high‐density lipoprotein; plaque.

Figure 1

A through D, Baseline multivariable associations for total high‐density lipoprotein (HDL) and apolipoprotein C‐III (apoC‐III)–based HDL subspecies with coronary artery calcification (CAC) in men (A) and women (B) and with carotid plaque (C) and carotid intima‐media thickness (IMT; D) (men and women combined). Lipid‐lowering medication users excluded. Models adjusted for age, sex, race/ethnicity, study site, body mass index, smoking, alcohol, systolic blood pressure, diabetes mellitus, income, and antihypertensive medication use. HDL assessed via concentrations of apolipoprotein A‐I (apoA‐I). Total apoC‐III, SD=0.04 g/L; total apoA‐I in HDL, SD=0.37 g/L; apoA‐I in HDL lacking apoC‐III, SD=0.35 g/L; apoA‐I in HDL containing apoC‐III, SD=0.03 g/L. CI indicates confidence interval and OR, odds ratio.