Subfractions of High-Density Lipoprotein-Cholesterol and Carotid Intima-Media Thickness

High-density lipoprotein-cholesterol (HDL-C) is one of the most commonly measured biomarkers integrated into public health prevention guidelines. Major epidemiological studies have demonstrated strong, inverse, and independent relationships between HDL-C and cardiovascular disease (CVD) and stroke. However, several recent clinical trials have challenged the value of raising HDL-C pharmacologically and the validity of the HDL-C antiatherosclerotic hypothesis. In addition to HDL-C quantity, HDL-C quality, such as HDL-C subfractions and their function may have differential effects on atherosclerosis and CVD risk. Variability of the levels of HDL-C subfractions and their function in total HDL-C may, in part, explain unexpected results of HDL-C– based interventions. HDL-C consists of 2 principal subfractions: larger size (8.7–12.5 nm), more buoyant (density, 1.06–1.13 g/mL) HDL2-C and smaller (<8.7 nm), less buoyant (density, 1.13– 1.21 g/mL) HDL3-C. High-density lipoprotein subfractions Background and Purpose—Recent drug trials have challenged the high-density lipoprotein-cholesterol (HDL-C) antiatherosclerotic hypothesis, suggesting that total level of HDL-C may not be the best target for intervention. HDL-C subfractions may be better markers of vascular risk than total levels of HDL-C. The objective of this cross-sectional study was to investigate the relationship between HDL2-C and HDL3-C fractions and carotid intima-media thickness (cIMT) in the population-based Northern Manhattan Study. Methods—We evaluated 988 stroke-free participants (mean age, 66±8 years; 60% women; 66% Hispanic, and 34% nonHispanic) with available data on HDL-C subfractions using precipitation method and cIMT assessed by a high-resolution carotid ultrasound. The associations between HDL-C subfractions and cIMT were analyzed by multiple linear regression models. Results—The mean HDL2-C was 14±8 mg/dL, HDL3-C 32±8 mg/dL, and the mean total HDL-C was 46±14 mg/dL. The mean cIMT was 0.90±0.08 mm. After controlling for demographics and vascular risk factors, HDL2-C and total HDL-C were inversely associated with cIMT (per 2 SDs, β=−0.017, P=0.001 and β=−0.012, P=0.03, respectively). The same inverse association was more pronounced among those with diabetes mellitus (per 2SDs, HDL2-C: β=−0.043, P=0.003 and HDL-C: β=−0.029, P=0.02). HDL3-C was not associated with cIMT. Conclusions—HDL2-C had greater effect on cIMT than HDL3-C in this large urban population. The effect of HDL2-C was especially pronounced among individuals with diabetes mellitus. More research is needed to determine antiatherosclerotic effects of HDL-C subfractions and their clinical relevance. (Stroke. 2016;47:1508-1513. DOI: 10.1161/STROKEAHA.115.012009.)