Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association

Abstract

High levels of lipoprotein(a) [Lp(a)], an apoB100-containing lipoprotein, are an independent and causal risk factor for atherosclerotic cardiovascular diseases through mechanisms associated with increased atherogenesis, inflammation, and thrombosis. Lp(a) is predominantly a monogenic cardiovascular risk determinant, with ≈70% to ≥90% of interindividual heterogeneity in levels being genetically determined. The 2 major protein components of Lp(a) particles are apoB100 and apolipoprotein(a). Lp(a) remains a risk factor for cardiovascular disease development even in the setting of effective reduction of plasma low-density lipoprotein cholesterol and apoB100. Despite its demonstrated contribution to atherosclerotic cardiovascular disease burden, we presently lack standardization and harmonization of assays, universal guidelines for diagnosing and providing risk assessment, and targeted treatments to lower Lp(a). There is a clinical need to understand the genetic and biological basis for variation in Lp(a) levels and its relationship to disease in different ancestry groups. This scientific statement capitalizes on the expertise of a diverse basic science and clinical workgroup to highlight the history, biology, pathophysiology, and emerging clinical evidence in the Lp(a) field. Herein, we address key knowledge gaps and future directions required to mitigate the atherosclerotic cardiovascular disease risk attributable to elevated Lp(a) levels.

Keywords: AHA Scientific Statements; apolipoprotein B100; atherosclerotic cardiovascular disease; cholesterol, low-density lipoprotein; lipoprotein(a).

Figure.. Lp(a) structure, properties, regulation, and relation to disease.

Lipoprotein(a) [Lp(a)] consists of a lipid-rich domain, primarily cholesteryl esters, and apolipoprotein(a) [apo(a)]. Apo(a) binds to apolipoprotein B100 (apoB) via a single disulfide bond (a) at a location close the low-density lipoprotein receptor binding site of apoB (b). Apo(a) contains repeated kringle (K) structures (KIV and KV), comparable with those in plasminogen. There are 10 different subtypes of apo(a) KIV, where type 2 is present in multiple copies, resulting in a highly variable molecular mass (300–800 kDa). Apo(a) is compositionally unique among apolipoproteins with a high carbohydrate content (≈28%). Proinflammatory and proatherogenic oxidized phospholipids bind to apo(a) KIV type 10 (c) and can also be found in the lipid phase. Apo(a) contains a protease domain (d) that lacks enzymatic activity. The Lp(a) concentration is heterogeneous and, to a major extent, controlled by genetics, inversely related to the copy number variation in the LPA gene. Other factors such as ethnicity and race and medical and environmental conditions also play roles in Lp(a) regulation. Lp(a) has been associated with increased risks of atherosclerosis, thrombosis, and aortic valve calcification.