Elevated high-density lipoprotein triglycerides increase atherosclerotic risk

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Genetics

Background:

• High-density lipoprotein (HDL) particle heterogeneity complicates understanding its role in atherosclerotic risk.
• Hypertriglyceridemia is linked to changes in HDL composition and function.
• The specific impact of elevated triglycerides on HDL and coronary artery disease (CAD) risk requires further elucidation.

Purpose of the Study:

• To investigate how elevated triglycerides affect HDL composition and size.
• To determine the association between altered HDL and CAD risk.
• To explore the causal role of HDL triglycerides (HDL-TG) in CAD development and potential therapeutic targets.

Main Methods:

• Analysis of a large prospective cohort study examining HDL parameters and CAD events.
• Mendelian randomization (MR) analyses to assess the causal relationship between HDL-TG and CAD.
• Drug-target MR to identify potential pharmacological interventions.

Main Results:

• Elevated triglycerides correlated with smaller HDL particle size, reduced HDL components, and increased HDL-TG.
• The protective effect of HDL on CAD risk diminished with rising triglyceride levels.
• Higher HDL-TG levels independently predicted incident CAD events and were causally linked to CAD development via MR.
• Omega-3 fatty acids (OM3-FA) showed a potential association with lower HDL-TG, implicating LPL and DGAT2.

Conclusions:

• Elevated triglycerides adversely modify HDL, increasing CAD risk.
• HDL-TG is an independent positive risk factor and potential causal agent in CAD.
• OM3-FA supplementation may be a viable strategy to reduce CAD risk associated with elevated HDL-TG.