HDL Hypothesis: Where Do We Stand Now?

Abstract

There is robust epidemiological evidence dating back to the original Framingham Heart Study from 1977 that indicates an important inverse relationship between high-density lipoprotein cholesterol (HDL-C) and risk of incident coronary artery disease (CAD). Despite this body of scientific information demonstrating that low levels of HDL-C are an independent predictor of subsequent CAD events, multiple therapeutic attempts to raise HDL-C levels have failed to demonstrate a consistent reduction in prognostically important endpoints such as death, myocardial infarction (MI), and stroke. Recently, several major randomized trials using different therapeutic interventions have raised appropriate concerns about our basic understanding of HDL-C and whether the "HDL hypothesis" of lowering cardiovascular events through therapeutic interventions directed at raising HDL-C is a scientifically viable one. While two recent randomized controlled trials (AIM-HIGH and HPS2-THRIVE) failed to show a reduction in cardiovascular events in patients treated to optimally low levels of low-density lipoprotein cholesterol (LDL-C) at baseline with extended-release niacin on a background of simvastatin, these clinical trials studied specific populations of stable ischemic heart disease patients. The data from these two contemporary trials cannot be extrapolated to all patient populations, such as those with acute coronary syndromes or myocardial infarction or those with significant residual mixed dyslipidemia not treated with optimal doses of intensive statin therapy, as these patients were excluded by trial design in both studies. Therefore, at the present time, there is insufficient evidence from clinical trials to recommend HDL-targeted therapy for additional event reduction in CAD patients. However, we will review the relevant data from recent major trials (AIM-HIGH, HPS2-THRIVE, ILLUMINATE, and dal-OUTCOMES) and highlight the potential clinical implications of these trials in modern pharmacotherapy as it relates to HDL-C raising and potential cardiovascular event reduction.

Cardio-ankle vascular index predicts for the incidence of cardiovascular events in obese patients: A multicenter prospective cohort study (Japan Obesity and Metabolic Syndrome Study: JOMS)

“…There is robust epidemiological evidence including the original Framingham Heart Study from 1977 that indicates an important inverse relationship between HDL-C and the risk of incident CAD [42]. Our result is coincident with the fact showing that HDL itself is included in ASCVD risk score.…”

miRNAs and High-Density Lipoprotein metabolism

“…However, both human genome-wide association studies and clinical trials using HDL-c raising compounds (niacin, CETP inhibitors, apoA-1 transcriptional upregulators; all very effective in raising plasma HDL-c) quickly cast doubts on this simplified HDL hypothesis [25]. This led to its reformulation into the “functional HDL hypothesis”, which establishes that it is not the amount of HDL-c, but the ability of HDL particles to mobilize cholesterol through the RCT pathway, what determines their antiatherogenic properties [26, 27].…”

Consecutive formation of the functions of high-, low-density and very-low-density lipoproteins during phylogenesis. Unique algorithm of the effects of lipid-lowering drugs

“…В кровотоке превращение поляр-ного ХС в его неполярную форму моно-ЭХС происходит только в ЛПВП. В них секреторный белок гепатоцитов -лецитинхоле-стеринацилтрансфераза, при действии кофактора апоА-II осво-бождает эндогенную ω-9 С18:1 олеиновую ЖК из второй пози-ции (sn-2) фосфатидилхолин (ФХ) и этерифицирует ее с поляр-ным спиртом ХС, образуя моно-ЭХС [15]. Согласно канонам хи-мии, в реакции этерификации спирт этерифицирует ЖК; на ос-новании этого все эфиры называют исходя из названия спирта -ЭХС, эфиры глицерина.…”