HDL-cholesterol and cardiovascular disease: rethinking our approach

Area of Science:

• Cardiovascular Science
• Metabolic Research
• Molecular Biology

Background:

• Low high density lipoprotein cholesterol (HDL-C) is a known risk factor for atherosclerotic cardiovascular disease (ASCVD).
• Recent large studies show interventions to increase HDL-C have not improved cardiovascular outcomes.
• Genetic studies do not consistently link higher HDL-C to reduced coronary heart disease risk, challenging the 'HDL hypothesis'.

Purpose of the Study:

• To review current data on the HDL hypothesis regarding HDL-C and ASCVD.
• To present a revised paradigm for understanding HDL's role in the atherosclerotic pathway.
• To explore emerging therapeutic targets beyond simply increasing HDL-C levels.

Main Methods:

• Review of recent large-scale clinical studies and genetic association studies.
• Analysis of data on HDL function, specifically cholesterol efflux and reverse cholesterol transport (RCT).
• Evaluation of preclinical and early-phase clinical trial results for novel HDL-targeting therapies.

Main Results:

• Evidence suggests HDL's ability to promote cholesterol efflux from macrophages is inversely associated with ASCVD risk, independent of HDL-C levels.
• This supports the 'HDL flux hypothesis,' proposing that interventions targeting macrophage cholesterol efflux and RCT may reduce ASCVD risk.
• Preclinical and early clinical studies of these novel interventions show promising results.

Conclusions:

• The precise role of HDL-C in modulating atherosclerotic disease remains uncertain.
• Emerging findings and therapies targeting HDL's functional capacity, such as cholesterol efflux and RCT, show early promise.
• These novel approaches may offer important future interventions for reducing the burden of ASCVD.