Lp(a) drives coronary microvascular dysfunction via antifibrinolytic and oxidised-phospholipid pathways, review (Life Sci 2026)

Coronary microvascular dysfunction (CMD) is increasingly recognized as a major driver of myocardial ischemia, with important implications for cardiovascular prognosis and quality of life, particularly in populations with ischemia and non-obstructive coronary arteries (INOCA) and heart failure with preserved ejection fraction (HFpEF). Despite increasing recognition of its importance, the mechanisms underlying CMD remain incompletely defined, and disease-modifying therapies are lacking. Lipoprotein(a) [Lp(a)], a genetically determined and causal cardiovascular risk factor, has been extensively studied in epicardial coronary atherosclerosis; however, its role in the coronary microcirculation has received comparatively limited attention. Lp(a) exhibits unique structural and biological properties, including the antifibrinolytic effects of apolipoprotein(a) and carriage of oxidized phospholipids, which promote endothelial dysfunction, oxidative stress, inflammatory activation, microvascular remodeling, and microthrombotic susceptibility-key processes implicated in CMD pathophysiology. Observational studies link elevated Lp(a) levels to impaired coronary flow reserve and endothelial dysfunction in patients with microvascular angina and related syndromes. Imaging and interventional studies further suggest that reduction of Lp(a)-associated circulating factors can improve myocardial perfusion and perfusion reserve in clinical settings dominated by microvascular disease. This review synthesizes current mechanistic, translational, and clinical evidence linking Lp(a) to CMD, identifies key knowledge gaps, and highlights future research priorities.