Coronary microvascular dysfunction in INOCA: Diagnostic advances and therapeutic strategies

Background: Up to 70% of patients undergoing invasive coronary angiography for suspected angina have no obstructive coronary artery disease, and roughly two-thirds of this group have demonstrable coronary microvascular dysfunction (CMD). Ischaemia with non-obstructive coronary arteries (INOCA) is not benign, yet it remains under-diagnosed and under-treated. Objectives: To synthesise contemporary evidence on (i) diagnostic methods for CMD in INOCA, (ii) the prognostic weight of abnormal microvascular physiology, and (iii) the efficacy of therapeutic strategies, including stratified medicine and disease-modifying pharmacotherapy. Methods: A systematic review conducted according to PRISMA 2020. MEDLINE/PubMed, Embase, Cochrane CENTRAL and Web of Science were searched from January 2010 to June 2026 for consensus statements, diagnostic accuracy studies, prognostic cohorts and randomised controlled trials addressing CMD in INOCA. Risk of bias was appraised with RoB 2, QUADAS-2 and the Newcastle–Ottawa Scale. Given marked heterogeneity in index tests, thresholds and endpoints, synthesis was predominantly narrative, with quantitative pooling restricted to published meta-analytic estimates. Results: Thirty-eight records informed the synthesis. Invasive coronary function testing combining bolus thermodilution-derived coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) with acetylcholine provocation now permits endotype-specific diagnosis; microvascular resistance reserve (MRR) and hyperaemic stenosis resistance refine assessment where epicardial disease coexists, with an MRR cut-off of 3.0 independently predicting 5-year major adverse cardiovascular events (MACE; HR 0.78, 95% CI 0.63–0.95). Abnormal CFR carried a pooled hazard ratio of 3.78 (95% CI 2.39–5.97) for all-cause mortality and 3.42 (95% CI 2.92–3.99) for MACE across 59,740 subjects; in isolated CMD the mortality signal was stronger still (HR 5.44, 95% CI 3.78–7.83). Stratified medical therapy guided by invasive testing improved the Seattle Angina Questionnaire summary score by 11.7 units at 6 months and 13.6 units at 12 months versus standard care. By contrast, two trials of disease-modifying strategies were neutral: zibotentan did not improve exercise duration (−4.26 s, 95% CI −19.60 to 11.06), and intensive medical therapy did not reduce MACE in 2,476 women (HR 1.13, 95% CI 0.94–1.37). Conclusions: Diagnosis of CMD in INOCA has matured from exclusion to precise, reproducible endotyping, and physiological abnormality is robustly prognostic. Therapeutic progress lags: stratified therapy reliably improves symptoms and quality of life, but no intervention has yet been shown to modify hard outcomes. Adequately powered, endotype-enriched outcome trials are the principal unmet need.