Mechanism-Informed Drug Repurposing in MINOCA: Therapeutic Rationale and Trial Framework for Empagliflozin and Colchicine

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a clinically important but heterogeneous syndrome associated with substantial long-term morbidity and adverse cardiovascular outcomes. Pharmacologic management remains largely extrapolated from obstructive coronary artery disease, creating a persistent mismatch between treatment strategies and the diversity of underlying mechanisms. Accurate diagnostic adjudication using cardiac magnetic resonance imaging, intracoronary imaging, coronary functional testing, and mechanistic biomarkers is therefore central to a phenotype-guided therapeutic approach. Inflammation, endothelial dysfunction, oxidative stress, autonomic dysregulation, coronary microvascular dysfunction, plaque-related injury, and adverse ventricular remodeling represent potentially targetable biological domains across selected MINOCA phenotypes. Empagliflozin and colchicine exert overlapping but distinct effects on several of these pathways and have demonstrated cardiovascular benefits in related clinical settings; however, direct evidence in MINOCA remains limited and predominantly observational. This article integrates the available mechanistic and clinical evidence into a comparative, phenotype-linked therapeutic framework and proposes a pragmatic trial strategy incorporating diagnostic adjudication, phenotype enrichment, biomarker-guided stratification, and adaptive or factorial designs. The proposed framework is hypothesis-generating and is intended to inform prospective investigation rather than support off-label prescribing or changes to current clinical practice.