The role of Lipoprotein(a) in cardiovascular disease: Current concepts and future perspectives

Abstract

High lipoprotein(a) [Lp(a)] levels are associated with the development of atherosclerotic cardiovascular disease (ASCVD) and with calcific aortic valve stenosis (CAVS) both observationally and causally from human genetic studies. The mechanisms are not well characterized but likely involve its role as a carrier of oxidized phospholipids (OxPLs), which are known to be increased in pro-inflammatory states, to induce pro-inflammatory changes in monocytes leading to plaque instability, and to impair vascular endothelial cell function, a driver of acute and recurrent ischemic events. In addition, Lp(a) itself has prothrombotic activity. Current lipid-lowering strategies do not sufficiently lower Lp(a) serum levels. Lp(a)-specific-lowering drugs, targeting apolipoprotein(a) synthesis, lower Lp(a) by up to 90% and are being evaluated in ongoing clinical outcome trials. This review summarizes the current knowledge on the associations of Lp(a) with ASCVD and CAVS, the current role of Lp(a) assessment in the clinical setting, and emerging Lp(a)-specific-lowering therapies.

Keywords: Cardiovascular disease; Lipoprotein(a).

Figure 1.

Lipoprotein [Lp(a)] is composed of apolipoprotein B-100 (apoB-100) covalently bound to apolipoprotein (a) [apo(a)], which is derived from Kringle IV (KIV) and KV, and the protease domain of plasminogen. Plasminogen has 1 copy each of KI to KV and an active protease domain. Apo(a) contains 10 subtypes of KIV repeats, composed of 1 copy each of KIV1, multiple copies of KIV2, and 1 copy of KIV310, KV, and an inactive protease-like (P) domain. In these examples, apo(a) isoforms of 4, 8, 24, and 40 KIV2 repeats are shown, representing 13, 17, 33, and 49 total KIV repeats. Oxidized phospholipids (OxPL), represented here by 1-palmitoyl-2-oxovaleroyl-sn-glycero-3- phosphocholine (POVPC), are present covalently bound to apo(a), and also dissolved in the lipid phase of apoB-100 (11). Reproduced with permission from “A Test in Context: Lipoprotein(a). Diagnosis, Prognosis, Controversies, and Emerging Therapies”(11).