HDL and cardiovascular risk: is cholesterol in particle subclasses relevant?

This editorial refers to ‘HDL cholesterol subclasses, myocardial infarction, and mortality in secondary prevention: the Lipoprotein Investigators Collaborative’†, by S.S. Martin et al. on page 22. Dyslipidaemia is one of the major risk factors for the development of cardiovascular disease, which remains the leading cause of death in the world. Despite major advances in the treatment of dyslipidaemia, residual cardiovascular risk remains high in a significant number of patients, a fact that has prompted intensive investigation of medications raising HDL-cholesterol (HDL-C). Indeed, robust epidemiological evidence had shown that low HDL-C was inversely related to coronary outcomes in the pre-statin era, and even in patients treated aggressively with statins in the Treating-to-New-Targets (TNT) trial. However, the failure of several HDL- C-raising drugs including torcetrapib and niacin in statin-treated patients, combined with genetic studies, has recently challenged the relevance of the cholesterol content of HDL (i.e. HDL-C) (reviewed in Tujeda and Rader1). As a consequence, the focus on HDL-C has now started to shift away from a cholesterol-centric view towards alternative indexes of HDL such as particle size, subclass distribution, and measures of HDL functionality. However, this approach remains vague, and further progress is hampered by the facts that HDLs are highly heterogeneous particles and various HDL subfractionation methods exist, which also differ in their nomenclature, making comparisons across these methods challenging. This complexity has been compounded over the last 10 years by inconsistencies in the literature on HDL-C subclasses and function.