Genetics and Causality of Triglyceride-Rich Lipoproteins in Atherosclerotic Cardiovascular Disease

Abstract

Triglycerides represent 1 component of a heterogeneous pool of triglyceride-rich lipoproteins (TGRLs). The reliance on triglycerides or TGRLs as cardiovascular disease (CVD) risk biomarkers prompted investigations into therapies that lower plasma triglycerides as a means to reduce CVD events. Genetic studies identified TGRL components and pathways involved in their synthesis and metabolism. We advocate that only a subset of genetic mechanisms regulating TGRLs contribute to the risk of CVD events. This "omic" approach recently resulted in new targets for reducing CVD events.

Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease

“…69 Further new insights from genetics involving various proteins influencing lipoprotein lipase function, in the APOA5, APOC3, and ANGPTL3 genes, have likewise strongly supported the idea that elevated triglyceride-rich lipoproteins are causally related to ASCVD. 35,37 Lipoprotein lipase is the key enzyme in plasma-degrading triglycerides, whereas apoC3, apoA5, and ANGPTL3 modulate lipoprotein lipase function and influence liver uptake of remnants.…”

“…88,89 However, once these triglyceride-rich lipoproteins have entered into the intima, they may get trapped preferentially to LDL-possibly simply because of the larger molecular size, making reentry into the arterial lumen against a blood pressure gradient even more difficult than for LDL particles or because of entrapment by components of the arterial intima. 88,92,[95][96][97][98] On entrance and possible trapping within the arterial intima, it seems likely that lipoprotein lipase either at the endothelial surface or within the arterial intima degrades triglycerides leading to liberation of free fatty acids and monoacylglycerols, both of which are toxic to tissues and thus likely will generate local inflammation (Figure 7) 18,37,[98][99][100] ; however, evidence that liberated free fatty acids and monoacylglycerols induce intimal inflammation in vivo in humans is not so strong. Nevertheless, lipoprotein lipase is expressed in macrophages and foam cells in human atherosclerotic plaques, [101][102][103] and lipoprotein lipase may have a stimulatory role in human foam cell formation from triglyceride-rich lipoproteins.…”

Residual Risk of Atherosclerotic Cardiovascular Events in Relation to Reductions in Very‐Low‐Density Lipoproteins

“…Such residual risk may reflect aspects of atherogenesis not captured by LDL‐C, including effects of very‐low‐density lipoproteins (VLDLs) and their contents (cholesterol and triglycerides) 5, 6, 7, 8, 9. Enzymatic hydrolysis of VLDL results in the formation of smaller, cholesterol‐enriched lipoprotein particles,5, 10, 11 which experimental studies suggest could contribute to the development of ASCVD 5, 7, 10, 12, 13, 14, 15, 16. Clinically, however, there has been uncertainty as to whether ASCVD events could be further reduced by reducing these triglyceride‐rich lipoproteins, with several neutral trials examining this strategy to date 10, 17…”

Efficacy and Safety of the Pcsk9 Inhibitor Evolocumab in Patients With Mixed Hyperlipidemia

“…The American Heart Association/American College of Cardiology guidelines recognize LDL as the major atherogenic lipoprotein and consequently identify LDL-C as the primary target of therapy [17]. However, triglyceride-rich particles (e.g., VLDL) also increase the risk of CVD, and the combination of high LDL-C coupled with high triglycerides represents a particularly atherogenic phenotype [18][19][20]. Consequently, professional societies have endorsed [18,20,21] non-HDL-C (LDL-C + VLDL-C) as the preferred target in patients with mixed hyperlipidemia [22].…”