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.

Keywords: Lp(a); atherosclerotic disease; cardiovascular disease; genetic variations; inflammation; lipoprotein(a); thrombosis; treatment.

Figure 1

Structure of lipoprotein(a) and plasminogen. Human Lp(a) consists of an LDL-like particle and an apoB-100 particle, in which glycoprotein apo(a) is disulfide-linked. Apo(a) contains 10 different types of plasminogen-like kringle IV domains (KIVs), composed of 1 copy of KIV1, multiple copies of KIV2 and 1 copy of KIV3-10 as well as a single kringle V domain followed by an inactive protease domain. KIV2 repeats of apo(a) determine the size of different Lp(a) isoforms. Apo(a) and plasminogen share high amino acid sequence similarity, including the protease domain and kringles type IV and type V. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/) (accessed on 4 November 2022).

Figure 2

Differences between Lp(a), LDL and HDL. Lipoprotein(a) is composed of one LDL particle containing apo-B100 and apo(a). HDL is composed of a high-density lipid core, and the most common apolipoproteins found on its surface are apo A-I and apo A-II. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/) (accessed on 4 November 2022).

Figure 3

The impact of lipoprotein(a) on atherosclerotic process and atherothrombosis. Lp(a) increases atherosclerotic plaque vulnerability, vascular smooth muscle cell proliferation and adhesion of molecules, chemotactic factors and plasma cytokines. Moreover, Lp(a) enhances platelet activation and aggregation and inhibits fibrinolysis by inhibiting plasminogen activation. Lp(a) inhibits TFPI and enhances expression of TF. Moreover, Lp(a) induces increased expression of PAI-1. Lipoprotein(a): Lp(a); TFPI: tissue factor pathway inhibitor; PAI-1: plasminogen activator inhibitor-1; TF: tissue factor; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule 1; MAC-1: macrophage-1 antigen; MCP-1: monocyte chemoattractant protein-1; PLTs: platelets; IL-1β: interleukin 1 beta; TNF-α: tumor necrosis factor alpha; c-AMP: cyclic adenosine monophosphate; ox Lp(a): oxidized lipoprotein(a); IL-8: interleukin-8; ↓: downregulation; ↑: upregulation. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/) (accessed on 4 November 2022).