HDL Functionality As A New Pharmacological Target On CVD: Unifying Mechanism That Explains HDL Protection Towards The Progression Of Atherosclerosis

The formation of the atherosclerotic plaque that is characterized by the accumulation of abnormal amounts of cholesterol-loaded macrophages in the artery wall is mediated by both inflammatory events and alterations of lipid/lipoprotein metabolism. Reverse transport of cholesterol (RCT) opposes the formation and development of atherosclerotic plaque through high density lipoprotein (HDL) metabolism, promoting the removal of cholesterol from peripheral macrophages and its delivery back to the liver for excretion into the bile. Although an inverse association between HDL plasma levels and the risk of CVD has been demonstrated over the years, several studies have recently shown that the antiatherogenic functions of HDL appear to be mediated by their functionality, not always associated to their plasma concentrations. Therefore, assessment of HDL function, evaluated as the capacity to promote cell cholesterol efflux may offer a better prediction of CVD than HDL levels alone. In agreement with this idea, it has recently shown that the assessment of serum cholesterol efflux capacity (CEC), as a metric of HDL functionality, may represents a predictor of atherosclerosis extent in humans. The purpose of this narrative review is to summarize the current evidence concerning the role of CEC that is important for evaluating cardiovascular disease (CVD) risk, focusing on pharmacological evidences and its relationship with inflammation. We conclude that HDL therapeutics are a promising area of investigation but strategies for identifying efficacy must move beyond the idea of simply raising static HDL-cholesterol levels and towards methods of measuring the dynamics of HDL particle remodeling and the generation of lipid-free apolipoprotein A-I (apoA-I). In this way, apoA-I, unlike mature HDL can promote the greatest extent of cholesterol efflux relieving cellular cholesterol toxicity and the inflammation it causes.