European Atherosclerosis Society Consensus Panel Releases Statement on Role of LDLs in ASCVD

The European Atherosclerosis Society Consensus Panel released a consensus statement discussing pathophysiological, genetic, and therapeutic insights into the causative role of low-density lipoproteins (LDLs) in atherosclerotic cardiovascular disease (ASCVD), which was published in the European Heart Journal.

The panel reviewed more than 300 journal articles, clinical trials, and studies to identify and highlight knowledge gaps regarding the pathophysiological and genetic components of ASCVD and the impact of LDL in disease risk.

Involvement of the LDL Subfraction Profile

LDLs are important drivers of atherogenesis, under specific cardiometabolic conditions. Small dense LDLs may enter the arterial intima at a faster rate than larger LDLs and may predict incident coronary heart disease better than large LDLs. Small dense vs large LDLs are better able to penetrate the arterial wall and have a higher susceptibility to glycation. These small dense LDLs can represent the primary driver of atherogenesis, due in part to the release of postoxidation bioactive proinflammatory lipids or their fragments, as well as to the formation of extracellular lipid deposits on particle denaturation, particularly in the form of cholesterol crystals. In addition to LDL, lipoprotein(a) [Lp(a)] and cholesterol-enriched remnant particles may also exacerbate this process.

Genetic Determinants of Arterial Wall Susceptibility

Studies have implicated genetic mutations affecting plasma LDL concentrations in an increased risk for ASCVD. Several variants of arterial wall protein genes have been identified in genome-wide association studies as being associated with a risk for ASCVD. These proteins are involved in modulating LDL retention susceptibility and in the response in arteries to accumulating LDLs.

The heritability of atherosclerosis may be explained by genes that act outside core mechanistic pathways (ie, noncanonical LDL-associated genes).

Apolipoprotein AI (apoAI) and High-Density Lipoprotein (HDL)

The putative direct role of HDL along with apoAI in the pathophysiology of atherogenesis remains unclear. Functional properties of HDL and apoAI (eg, cellular cholesterol efflux capacity and antioxidative and anti-inflammatory activity) that may attenuate the atherogenic ability of LDL particles are associated with plaque progression. ApoIA, which is abundant in human atheroma tissue, is often dysfunctional, predominantly due to extensive oxidation.

Emerging Mechanistic Features of Atherosclerosis

Emerging mechanistic atherosclerosis features may have implications in how researchers examine new therapeutic targets important for arterial wall biology and stability of plaque. These features include endothelial transcytosis of atherogenic lipoproteins, monocyte/macrophage and smooth muscle cell biology, efferocytosis, innate and adaptive immune responses to the intimal retention of apoB-containing lipoproteins, inflammation, and calcification.

Further Research Needs

Several outstanding questions remain, many of which, if answered, may have implications for future prevention strategies of ASCVD. Additional research should examine whether the mechanisms by which LDL, Lp(a), and remnant particles promote ASCVD differ from one another. The role of omega-3 fatty acids in modulating atherogenic properties of lipoproteins should also be investigated.

 “The unequivocal body of evidence for LDL causality in ASCVD will [have an] impact on future international recommendations for the management of atherogenic and ASCVD-promoting dyslipidaemias and will guide the rational use of both existing and new therapies,” concluded the panel authors.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel [published online February 13, 2020]. Eur Heart J. doi:10.1093/eurheartj/ehz962