Drugs in the PipelineHigh-Density Lipoprotein Functionality as a New Pharmacological Target on Cardiovascular Disease: Unifying Mechanism That Explains High-Density Lipoprotein Protection Toward the Progression of AtherosclerosisFavari, Elda PhD*; Thomas, Michael J. PhD†; Sorci-Thomas, Mary G. PhD‡Author Information *Department of Food and Drug, University of Parma, Parma, Italy; †Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI; and ‡Division of Endocrinology, Metabolism and Clinical Nutrition, Department of Medicine and Senior Investigator, Blood Research Institute, Blood Center of Wisconsin, Medical College of Wisconsin, Milwaukee, WI. Reprints: Elda Favari, PhD, Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy (e-mail: [email protected]). Supported by a grant from the NIH HL127649 to MGST The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). Journal of Cardiovascular Pharmacology: June 2018 - Volume 71 - Issue 6 - p 325-331 doi: 10.1097/FJC.0000000000000573 Buy SDC Metrics Abstract 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 opposes the formation and development of atherosclerotic plaque by promoting high density lipoprotein (HDL)-mediated 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 cardiovascular disease (CVD) has been demonstrated over the years, several studies have recently shown that the antiatherogenic functions of HDL seem to be mediated by their functionality, not always associated with 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 been shown that the assessment of serum cholesterol efflux capacity (CEC), as a metric of HDL functionality, may represent a predictor of atherosclerosis extent in humans. The purpose of this narrative review is to summarize the current evidence concerning the role of cholesterol efflux capacity that is important for evaluating 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 toward 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. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.