High-Density Lipoprotein Particle Subclass Heterogeneity and Incident Coronary Heart Disease

Abstract

Background Raising the cholesterol of HDL particles is targeted as a cardiovascular disease prevention strategy. However, HDL particles are heterogeneous in composition and structure, which may relate to differences in antiatherogenic potential. We prospectively evaluated the association of HDL subclasses, defined by a recently proposed nomenclature, with incident coronary heart disease (CHD). Methods and Results Baseline HDL particle concentrations were measured by nuclear magnetic resonance spectroscopy and categorized into five subclasses (very large, large, medium, small, and very small) among 26,332 initially healthy women. During a median follow-up of 17 years, 969 cases of incident CHD (myocardial infarction, revascularization, and CHD death) were ascertained. In Cox models that adjusted for age, race/ethnicity, blood pressure, smoking, postmenopausal status, and hormone therapy, associations with incident CHD were inverse (p-trend<0.0001) for concentrations of very large (hazard ratio [HR] for top versus bottom quartile 0.49, 95% confidence interval [CI] 0.41–0.60), large (0.54, 0.45–0.64), and medium (0.69, 0.58–0.83) HDL subclasses. Conversely, HRs (95% CIs) for small and very small HDL were 1.22 (1.01–1.46, p-trend=0.08) and 1.67 (1.39–2.02, p-trend<0.0001), respectively. However, after additionally adjusting for metabolic and lipoprotein variables, associations for the spectrum of large, medium, and small HDL subclasses were inverse (p-trend<0.05 for large and small, and 0.07 for medium), while subclasses at either end of the spectrum were not associated with CHD (p-trend=0.97 for very large and 0.21 for very small HDL). Conclusion In this prospective study, associations with incident CHD differed by HDL particle subclass, which may be relevant for developing HDL-modulating therapies.

A comparison of the cardiometabolic profile of black South Africans with suspected non-alcoholic fatty liver disease (NAFLD) and excessive alcohol use

“…Specific types of polymorphisms of HDL-C are known to lead to very high serum HDL-C levels of larger particle size which has been associated with an increased risk for CVD (Van der Steeg et al, 2008). To the contrary, very recently excessive alcohol intake was positively associated with small-sized HDL-C particles and increased risk for coronary heart disease (Akinkuolie, Paynter, Padmanabhan, & Mora, 2014;Tsuzaki et al, 2014). This suggests that the elevated HDL-C previously reported to be associated with alcohol overuse, may have detrimental cardiovascular effects based on the HDL-C particle size and may also be influenced by genetic and metabolic factors influencing HDL-C particle size.…”

HDL subclasses are heterogeneous in their associations with body fat, as measured by dual-energy X-ray absorptiometry: The Kitakata Kids Health Study

“…Thus, the concentration of large HDL cholesterol is decreased and the concentration of small HDL cholesterol is increased in the obese state. Regarding the relationships between HDL subclasses and coronary heart disease, prospective research from the Women's Health Study provided evidence that concentrations of HDL particle subclasses are differentially related to incidence of coronary heart disease [13]. Very large, large, and medium HDL subclasses were shown to have inverse associations with coronary heart disease, whereas small and very small HDL subclasses had positive associations [13].…”

“…Using this method, HDL is classified into five distinct subclasses: very large, large, medium, small, and very small [11]. It has been reported that large HDL particles may be associated with protection against atherosclerosis, whereas high concentrations of small HDL particles may be associated with atherosclerosis [12,13]. Therefore, HDL subclasses may also be differentially associated with body fat.…”

Beginning to Understand High-Density Lipoproteins

“…However, even only considering the JUPITER results one must take into account the clinical relevance of HDL-C versus HDL-P. Most importantly, as previously explained, HDL-P concentration has emerged as a predictor of CVD risk that may be superior to that of HDL-C in both population studies [84][85][86] and randomized clinical trials of lipid-modifying therapies. 87,88 In the MultiEthnic Study of Atherosclerosis (MESA), HDL-C was not associated with cIMT after adjusting for HDL-P and LDL-P; however, low HDL-P predicted higher risk of elevated cIMT regardless of HDL-C level, 85 , and for HDL-L/HDL-VL particles (with low capacity to regain cholesterol) it was nonsignificant.…”