HDL-cholesterol and cardiovascular disease: rethinking our approach.

Abstract

A low level of plasma high density lipoprotein cholesterol (HDL-C) is a strong and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). However, several large studies recently revealed that pharmacologic interventions that increase HDL-C concentration have not improved cardiovascular outcomes when added to standard therapy. In addition, specific genetic variants that raise HDL-C levels are not clearly associated with reduced risk of coronary heart disease. These observations have challenged the 'HDL hypothesis' that HDL-C is causally related to ASCVD and that intervention to raise HDL-C will reduce ASCVD events. This article will present the current data on the HDL hypothesis and provide a revised paradigm of considering HDL in the atherosclerotic pathway. Recent evidence has shed light on the complex nature of HDL-C metabolism and function. There are compelling data that the ability of HDL to promote cholesterol efflux from macrophages, the first step in the 'reverse cholesterol transport' (RCT) pathway, is inversely associated with risk for ASCVD even after controlling for HDL-C. This has led to the 'HDL flux hypothesis' that therapeutic intervention that targets macrophage cholesterol efflux and RCT may reduce risk. Preclinical studies of such interventions show promise and early phase clinical studies, though small, are encouraging. The role of HDL-C in modulating atherosclerotic disease is as yet uncertain. However, new findings and therapies targeting HDL-C show early promise and may provide an important intervention in attenuating the burden of ASCVD in the future.