Lipoprotein(a) in Atherosclerotic Diseases: From Pathophysiology to Diagnosis and Treatment

Abstract

Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) cholesterol-like particle bound to apolipoprotein(a). Increased Lp(a) levels are an independent, heritable causal risk factor for atherosclerotic cardiovascular disease (ASCVD) as they are largely determined by variations in the Lp(a) gene (LPA) locus encoding apo(a). Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), and its role adversely affects vascular inflammation, atherosclerotic lesions, endothelial function and thrombogenicity, which pathophysiologically leads to cardiovascular (CV) events. Despite this crucial role of Lp(a), its measurement lacks a globally unified method, and, between different laboratories, results need standardization. Standard antilipidemic therapies, such as statins, fibrates and ezetimibe, have a mediocre effect on Lp(a) levels, although it is not yet clear whether such treatments can affect CV events and prognosis. This narrative review aims to summarize knowledge regarding the mechanisms mediating the effect of Lp(a) on inflammation, atherosclerosis and thrombosis and discuss current diagnostic and therapeutic potentials.

Lp(a) and inflammation: a new insight into atherosclerosis

“…11 The structure of Lp(a) includes three main components: (1) LDL-like particles (LDL particles, including apoB100), which are an important component of total cholesterol in plasma; (2) apo(a) is a highly glycosylated hydrophilic protein that primarily determines the pathophysiological function of Lp(a) by binding to apoB100 on the surface of LDL-like particles through disulfide bonds. 12 Apo(a) contains 10 isoforms of kringle domain IV (KIV 1-10 ) and kringle domain V (KV), as well as an inactivated protease domain. Among these, KIV 2 can form up to 40 repeats, which is the main reason for inter-individual differences; (3) oxidized phospholipids (OxPL), which in human Lp(a) bind to other components through a lysine binding site (LBS) in KIV-10 and act as an important pro-inflammation factor.…”

“… 10 However, in some individuals, the molar ratio of phospholipids, free cholesterol, cholesteryl esters, and triglycerides is slightly higher in Lp(a) than in LDL, suggesting that the apolipoprotein density of Lp(a) may be lower than that of LDL 11 . The structure of Lp(a) includes three main components: (1) LDL‐like particles (LDL particles, including apoB100), which are an important component of total cholesterol in plasma; (2) apo(a) is a highly glycosylated hydrophilic protein that primarily determines the pathophysiological function of Lp(a) by binding to apoB100 on the surface of LDL‐like particles through disulfide bonds 12 . Apo(a) contains 10 isoforms of kringle domain IV (KIV 1‐10 ) and kringle domain V (KV), as well as an inactivated protease domain.…”

The Association of High Lipoprotein(a) Concentration and Risk of Ischaemic Stroke in Atrial Fibrillation Patients

“…Lp(a) functions against vascular inflammation and atherosclerosis lesions. 10 Lp(a) can promote thrombosis by influencing platelets and the coagulation system, resulting in thromboembolism. 11 , 12 ASCVD, including IS, has been linked to high levels of Lp(a).…”

Should dual antiplatelet treatment be guided by lipoprotein(a) concentration?

“…Lipoprotein(a) (Lp(a)) is a low-density lipoprotein-like molecule, composed of the apolipoprotein (a) (apo(a)), which is attached to the apolipoprotein B-100 by a single disulfide bond [ 1 ]. It is recognized as an independent risk factor for cardiovascular events.…”

“…It is recognized as an independent risk factor for cardiovascular events. Lp(a) favors initiation of atherogenesis by modulating recruitment of inflammatory cells in the vessel wall, increases atherosclerotic plaque vulnerability by provoking local inflammation, and adversely affects discrete key points in primary and secondary hemostasis as well as in fibrinolysis [ 1 ]. Due to the high degree of homology between apo(a) and plasminogen, Lp(a) potentiates thrombosis through inhibiting plasminogen activation and fibrin degradation, and promoting endothelial plasminogen activator inhibitor expression, tissue factor pathway inhibitor activity.…”