High-density lipoproteins, Part 1. Epidemiology, antiatherogenic effects, and therapies designed to increase their...

Historically high-density lipoproteins (HDL) have been viewed as antiatherogenic and beneficial. This conclusion was based on early prospective longitudinal cohorts and the broad functionality of these lipoproteins which include reverse cholesterol transport as well as activities that antagonize oxidation, inflammation, thrombosis, and endothelial dysfunction. It is also a key participant in immunity, engages in glucose homeostasis, and is a critical vehicle for microRNA translocation between tissues. The HDLs are polymolecular assemblies of enormous complexity. These lipoprotein particles are highly responsive in terms of cargo specificity to the interior milieu. In response to a broad range of supportive evidence, therapies have been developed that increase either serum levels of HDL particles or the mass of cholesterol in circulating HDL. Therapies that raised serum HDL-C using such agents as nicotinic acid, fibrates, or cholesterol ester transfer protein inhibitors were unsuccessful at impacting residual cardiovascular risk over and above baseline statin therapy. Although an early trial with apo-AI_Milano fueled initial enthusiasm, a subsequent trial with a recombinant form of this agent was unable to reproduce its capacity to induce plaque regression as measured by IVUS. Infusible HDL mimetics have also been largely unsuccessful in reducing non-calcified plaque volume, myocardial infarct size, or cardiovascular events. More trials of longer duration and in greater numbers of patients need to be performed. Recent epidemiological studies indicate that the relationship between HDL-C and risk for cardiovascular morbidity and mortality is more complex than previously thought. Depending upon the cohort and the intensity of adjustment for risk factor covariates, the relationship is no longer viewed as inverse linear; rather, it is more U-shaped (with some exceptions) with high and low levels of HDL-C both being associated with heightened risk for events. The issue clearly requires much greater investigation. Given the enormous complexity of the HDL proteome and lipidome and the range of functions it has the capacity to participate in, the potential to harness beneficial effects from HDL remain a viable possibility. However, the HDL code is yet to be fully deciphered. A polymolecular assembly as complex as mature HDL is not a simple task to study. Risk algorithms need to reassess the validity of attributing cardioprotection from high HDL-C as this may lead to underestimation of true risk.