Lipoprotein(a) as a Stroke Biomarker: Pathophysiological Pathways and Therapeutic Implications

Abstract

Lipoprotein(a) [Lp(a)] has attracted widespread interest as a potential biomarker for cerebrovascular diseases due to its genetically determined and stable plasma concentration throughout life. Lp(a) exhibits pro-atherogenic and pro-thrombotic properties that contribute to vascular pathology in both extracranial and intracranial vessels. Elevated Lp(a) levels are strongly associated with large-artery atherosclerotic stroke, while data on its role in other ischemic subtypes and hemorrhagic stroke remains limited and inconsistent. Recent advances in Lp(a)-lowering therapies, such as antisense oligonucleotides and RNA-based agents, have demonstrated significant efficacy in reducing plasma Lp(a) levels. These advances have prompted increasing research into their potential application in the prevention and treatment of cerebrovascular diseases, aiming to determine whether Lp(a) reduction may translate into a reduced risk of stroke and large-artery atherosclerosis. This narrative review summarizes the current evidence on the association between Lp(a) and stroke, focusing on its utility in patient risk stratification. It also highlights existing knowledge gaps and outlines directions for future research, particularly in understanding subtype-specific effects and evaluating the clinical benefits of Lp(a)-targeted therapies.

Keywords: antisense oligonucleotides; atherosclerosis; carotid artery diseases; intracranial atherosclerosis; lipoprotein(a); small interfering RNA; stroke.

Figure 1

The structure of Lp(a). Lp(a) consists of an LDL-like lipid core connected to ApoB-100. A unique glycoprotein, Apo(a), is covalently attached to ApoB-100 via a disulfide bond. Apo(a) contains multiple KIV domains, including variable KIV2 repeats, single copies of KIV1 and KIV3-KIV10, and a single KV domain. Apo(a) also possesses an inactive protease domain. Variability in the KIV2 repeat number contributes to the heterogeneity of Apo(a) isoforms and influences Lp(a) plasma levels. Greater variability in KIV2 repeats leads to larger Apo(a) isoforms, which are less efficiently produced in the liver, resulting in lower Lp(a) plasma levels. Conversely, fewer repeats produce smaller isoforms that are more efficiently synthesized and secreted, leading to higher Lp(a) levels in the blood. Abbreviations: Apo(a): Apolipoprotein(a); ApoB-100: Apolipoprotein B-100; LDL: Low-density lipoprotein; KIV: Kringle IV; KV: Kringle V.

Figure 2

Pathophysiology of Lp(a)-induced intracranial atherosclerosis. Lp(a) contributes to atherosclerosis in large intracranial vessels through several mechanisms. (1) Plaque progression: Lp(a) promotes smooth muscle cell proliferation by inhibiting the conversion of plasminogen to plasmin, which prevents plasmin-mediated activation of TGF-β, an autocrine inhibitor of smooth muscle cell growth. Additionally, Lp(a) facilitates foam cell formation and calcification, accelerating plaque progression. Ox-Lp(a) delivers excess OxPLs to the arterial wall, driving inflammation and plaque instability. (2) Inflammatory cell recruitment: Lp(a) upregulates adhesion molecules such as ICAM-1 and VCAM-1, facilitating the adhesion and infiltration of monocytes and macrophages into the vascular wall, further amplifying local inflammation. (3) Vascular inflammation: Lp(a) carries OxPLs, which promote endothelial dysfunction and trigger the release of inflammatory cytokines, such as IL-1β and TNF-α. (4) Plasminogen inhibition: The structural similarity between Apo(a) and plasminogen allows Lp(a) to competitively inhibit plasminogen activation, impairing fibrinolysis and increasing thrombogenicity. Abbreviations: Lp(a): Lipoprotein(a); OxPLs: Oxidized phospholipids; Ox-Lp(a): Oxidized lipoprotein(a); IL-1β: Interleukin-1 beta; TNF-α: Tumor necrosis factor-alpha; ICAM-1: Intracellular adhesion molecule-1; VCAM-1: Vascular cell adhesion molecule-1.