Lipoprotein(a) and its Significance in Cardiovascular Disease

Abstract

ipoprotein(a) (Lp[a]) is a low-density lipoprotein (LDL) cholesterol-like particle that was first identified by Kåre Berg, MD, in 1963. 1 Its concentration is largely genetically determined, with marked variations across populations. 2 Epidemiologic and observational studies suggest a potential causal association between elevated Lp(a) and an increased risk of atherosclerotic cardiovascular disease (ASCVD) 3,4 and calcific aortic valve stenosis (AS). 5,6 These findings have been recently supported by genetic studies. 7,8 While no universally accepted absolute risk threshold exists, approximately 20% to 25% of the global population have an Lp(a) level of 50 mg/dL (to convert to milligrams per liter, multiply by 10) or greater, 2 which according to the European Atherosclerosis Society (EAS) confers an increased cardiovascular risk 9 despite traditional risk factor optimization. 10 This article aims to review Lp(a) biology and pathophysiology, data with current therapies, and novel therapies under development. Structure and MetabolismLp(a) assembly occurs either on the hepatocyte surface or in the space of Disse. Its core composition resembles LDL and consists of triglycerides and cholesteryl esters surrounded by an outer membrane of phospholipids and free cholesterol. Its protein moiety comprises a single copy of apolipoprotein B-100 (apoB) bound to a single apolipoprotein(a) (apo[a]) particle through covalent and noncovalent bonds (Figure 1). 11 Lp(a) synthesis is primarily determined through the LPA gene, which codes for 2 kringle domains (kringles IV-V [KIV-KV]). KIV expands into 10 subtypes (KIV 1 -KIV 10 ), while KV is attached to both KIV 10 and an inactive protease domain. Expansion of KIV 2 results in a variable intragenic copy number variation resulting in 1 to more than 40 identically repeated copies. This leads to heterogeneous apo(a) isoform sizes, a unique occurrence among proteins. The other KIV IMPORTANCE Lipoprotein(a) (Lp[a]) is a low-density lipoprotein (LDL) cholesterol-like particle bound to apolipoprotein(a). This novel marker of cardiovascular disease acts through induction of vascular inflammation, atherogenesis, calcification, and thrombosis. While an absolute risk threshold remains to be universally accepted, an estimated 20% to 25% of the global population have Lp(a) levels of 50 mg/dL or higher, a level noted by the European Atherosclerosis Society to confer increased cardiovascular risk.OBSERVATIONS Compelling evidence from pathophysiological, observational, and genetic studies suggest a potentially causal association between high Lp(a) levels, atherosclerotic cardiovascular disease, and calcific aortic valve stenosis. Additional evidence has demonstrated that elevated Lp(a) levels are associated with a residual cardiovascular risk despite traditional risk factor optimization, including LDL cholesterol reduction. These findings have led to the formulation of the Lp(a) hypothesis, namely that Lp(a) lowering leads to cardiovascular risk reduction, intensifying the search for Lp(a)-reducing...

Prognostic Impacts of LL-37 in Relation to Lipid Profiles of Patients with Myocardial Infarction: A Prospective Cohort Study

“…Despite controversies regarding its synthesis and metabolism, the pathogenic role and prognostic impact of lp(a) have been established in the field of atherosclerosis and coronary heart disease after decades of research [ 4 ]. Evidence from large-scale cohort studies demonstrates the increased risk of atherosclerotic cardiovascular disease for patients with elevated lp(a), which is mainly attributed to its pro-inflammatory and prothrombotic effects by contents of oxidized phospholipids (OxPL) and apolipoprotein(a) [ 15 ].…”

“…However, medications to tackle cardiovascular risk caused by lp(a) elevation are quite limited. So far, lipoprotein apheresis is proven to effectively reduce circulating lp(a) levels by 53% to 73% from baseline, followed by 23% with PCSK9 inhibitors, while traditional statin medications even paradoxically drive up lp(a) concentrations up to 30% [ 4 ]. Dietary, lifestyle, and medical interventions are generally ineffective for reducing lp(a), as 90% of its plasma levels are genetically determined and remain stable throughout a lifetime, for which nucleic acid-based therapies have shown promising results.…”

“…Since dyslipidemia could be effectively controlled with intensive secondary preventions, risk reduction associated with LL-37 might not be detected when stratifying patients with LDL-C, HDL-C, or triglyceride, as these lipid contents could be restored to safer ranges with adequate lipid-lowering medications [ 5 ]. However, lifelong exposure to high lp(a) determined by genes is hard to resolve with currently available medications, while lp(a) particles acquire a more atherogenic nature than LDL-C particles [ 4 , 5 , 15 ]. OxPL is proven to play a major role in arterial inflammation induced by lp(a), as it could predispose in the vessel wall, promote monocyte infiltration, and increase the secretion of pro-inflammatory cytokines (e.g., interleukin (IL)-8, monocyte chemoattractant protein-1), causing endothelial dysfunction, lipid accumulation, and regional inflammation within coronary plaques [ 4 , 15 ].…”

“…However, lifelong exposure to high lp(a) determined by genes is hard to resolve with currently available medications, while lp(a) particles acquire a more atherogenic nature than LDL-C particles [ 4 , 5 , 15 ]. OxPL is proven to play a major role in arterial inflammation induced by lp(a), as it could predispose in the vessel wall, promote monocyte infiltration, and increase the secretion of pro-inflammatory cytokines (e.g., interleukin (IL)-8, monocyte chemoattractant protein-1), causing endothelial dysfunction, lipid accumulation, and regional inflammation within coronary plaques [ 4 , 15 ]. Meanwhile, over 80% of circulating LL-37 bind with a wide range of lipoproteins, such as LDL or very low-density lipoprotein [ 10 , 18 ].…”

“…According to the latest guidelines, a low-density lipoprotein cholesterol (LDL-C) level of 1.4–1.8 mmol/L or lower is recommended for patients with myocardial infarction (MI) to achieve with the routine use of lipid-lowering medications [ 3 ]. Although statins demonstrate high efficacy in lowering LDL-C, recent studies report that the use of statins could increase circulating levels of lipoprotein(a) (lp(a)), an increasingly important risk factor for atherosclerosis [ 4 , 5 ]. Meanwhile, over 40% of patients fail to achieve LDL-C targets despite statin medications of high intensity, and many patients still suffer from residual ischemic risk caused by persistently high levels of LDL-C [ 6 ].…”