The inverse relationship between low plasma high-density lipoprotein cholesterol (HDL-C) concentrations and increased risk of Atherosclerotic Cardiovascular Disease (ASCVD) is well-known. However, plasma HDL-C concentrations are highly variable in subjects with ASCVD. In clinical outcome trials, pharmacotherapies that increase HDL-C concentrations are not associated with a reduction in ASCVD events. A causal relationship between HDL-C and ASCVD has also been questioned by Mendelian randomization studies and genome-wide association studies of genetic variants associated with plasma HDL-C concentrations. The U-shaped association between plasma HDL-C concentrations and mortality observed in several epidemiological studies implicates both low and very high plasma HDL-C concentrations in the etiology of ASCVD and non- ASCVD mortality. These data do not collectively support a causal association between HDL-C and ASCVD risk. Therefore, the hypothesis concerning the association between HDL and ASCVD has shifted from focus on plasma concentrations to the concept of functionality, in particular cellular cholesterol efflux and HDL holoparticle transport. In this review, we focus on these new concepts and provide a new framework for understanding and testing the role of HDL in ASCVD.

Biotechnology Research Center Pharmaceutical Technology Institute Mashhad University of Medical Sciences Mashhad Iran

Cardiometabolic Service Department of Cardiology Royal Perth Hospital School of Medicine University of Western Australia Perth Western Australia Australia

Department of Hypertension Chair of Nephrology and Hypertension Medical University of Lodz Poland

Department of Medical Biotechnology and Nanotechnology Mashhad University of Medical Sciences Mashhad Iran

Faculty of Pharmacy in Hradec Kralove Department of Biological and Medical Sciences Charles University Hradec Kralove Czech Republic

University Hospital Centre Zagreb School of Medicine University of Zagreb Department of Internal Medicine Zagreb Croatia

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