{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T11:18:49Z","timestamp":1788261529949,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Cardiovasc. Dev. Dis.","JCDD"],"abstract":"<jats:p>Coronary microvascular dysfunction (CMD) is a prevalent and clinically important cause of myocardial ischemia across the spectrum of coronary artery disease, including patients with angina and nonobstructive coronary arteries, persistent symptoms after revascularization, and acute coronary syndromes. Despite its prognostic significance, CMD remains underrecognized due to the limitations of angiography-centered evaluation and the heterogeneity of underlying biological mechanisms. This review presents a physiology-based framework for the assessment of CMD, emphasizing the role of invasive coronary function testing in defining mechanistic endotypes and informing clinical interpretation. We summarize the biological foundations of CMD, including endothelial dysfunction, vascular smooth muscle hyperreactivity, structural remodeling of the microcirculation, and extravascular myocardial influences, and describe how these processes manifest as distinct but overlapping clinical phenotypes. Contemporary invasive physiologic tools\u2014coronary flow reserve, index of microcirculatory resistance, and vasomotor testing with acetylcholine\u2014are reviewed with a focus on their complementary roles in localizing disease within the coronary circulation. The clinical application of microvascular testing is discussed in both stable coronary syndromes and acute coronary syndromes, highlighting differences in diagnostic intent, prognostic implications, and therapeutic relevance. We distinguish chronic CMD in stable syndromes from post\u2013myocardial infarction microvascular injury, in which invasive indices have primarily prognostic implications. By integrating coronary biology, invasive physiology, and clinical context, this review supports a shift from purely anatomic assessment toward a mechanism-based, physiology-driven approach to ischemic heart disease.<\/jats:p>","DOI":"10.3390\/jcdd13090426","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:32:18Z","timestamp":1788258738000},"page":"426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Coronary Microvascular Dysfunction: Pathophysiology, Clinical Phenotypes, and Mechanism-Guided Diagnostic Strategies"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8966-4189","authenticated-orcid":false,"given":"Divyansh","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Bishev","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shudipan","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3376-4608","authenticated-orcid":false,"given":"Michael V.","family":"DiCaro","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"KiBuom","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3696-195X","authenticated-orcid":false,"given":"KaChon","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Scripps Clinic, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Shah","sequence":"additional","affiliation":[{"name":"New York University, New York, NY 10003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chowdhury","family":"Ahsan","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1056\/NEJMoa0907272","article-title":"Low diagnostic yield of elective coronary angiography","volume":"362","author":"Patel","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1161\/CIRCULATIONAHA.107.743963","article-title":"Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: Results from the COURAGE trial nuclear substudy","volume":"117","author":"Shaw","year":"2008","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1056\/NEJMoa1415516","article-title":"Outcomes of anatomical versus functional testing for coronary artery disease","volume":"372","author":"Douglas","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1001\/archinternmed.2009.50","article-title":"Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: A report from the Women\u2019s Ischemia Syndrome Evaluation Study","volume":"169","author":"Gulati","year":"2009","journal-title":"Arch. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2825","DOI":"10.1016\/j.jacc.2010.01.054","article-title":"Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia: Results from the WISE study","volume":"55","author":"Pepine","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/j.jacc.2005.01.072","article-title":"Insights from the NHLBI-sponsored Women\u2019s Ischemia Syndrome Evaluation (WISE) Study","volume":"47","author":"Shaw","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1056\/NEJMra061889","article-title":"Coronary microvascular dysfunction","volume":"356","author":"Camici","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1016\/j.jacc.2018.09.042","article-title":"Coronary microvascular disease pathogenic mechanisms and therapeutic options","volume":"72","author":"Taqueti","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1161\/CIRCULATIONAHA.112.120402","article-title":"Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus","volume":"126","author":"Murthy","year":"2012","journal-title":"Circulation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1161\/01.CIR.0000128669.99355.CB","article-title":"Microvascular resistance is not influenced by epicardial coronary artery stenosis severity: Experimental validation","volume":"109","author":"Fearon","year":"2004","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1161\/CIRCULATIONAHA.112.000298","article-title":"Prognostic value of the index of microcirculatory resistance measured after primary percutaneous coronary intervention","volume":"127","author":"Fearon","year":"2013","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1161\/01.CIR.0000061950.24940.88","article-title":"Intracoronary and intravenous adenosine 5\u2032-triphosphate, adenosine, papaverine, and contrast medium to assess fractional flow reserve in humans","volume":"107","author":"Pijls","year":"2003","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1161\/CIRCRESAHA.119.315344","article-title":"Optimized treatment of ST-elevation myocardial infarction","volume":"125","author":"Niccoli","year":"2019","journal-title":"Circ. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1093\/eurheartj\/ehz425","article-title":"2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes","volume":"41","author":"Knuuti","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e368","DOI":"10.1161\/CIR.0000000000001029","article-title":"2021 AHA\/ACC guideline for the evaluation and diagnosis of chest pain","volume":"144","author":"Gulati","year":"2021","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1161\/CIRCULATIONAHA.114.012636","article-title":"Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease","volume":"131","author":"Lee","year":"2015","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ijcard.2017.08.068","article-title":"International standardization of diagnostic criteria for microvascular angina","volume":"250","author":"Ong","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1161\/CIRCULATIONAHA.111.037283","article-title":"Mechanisms of coronary artery spasm","volume":"124","author":"Lanza","year":"2011","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.jacc.2016.05.067","article-title":"Standardization of fractional flow reserve measurements","volume":"68","author":"Toth","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_20","first-page":"546","article-title":"Impact of coronary microvascular dysfunction on long-term cardiac mortality in patients with stable coronary artery disease","volume":"128","author":"Bax","year":"2013","journal-title":"Circulation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jacc.2013.02.092","article-title":"A novel paradigm for heart failure with preserved ejection fraction","volume":"62","author":"Paulus","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1093\/eurheartj\/ehy531","article-title":"Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction","volume":"39","author":"Shah","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_23","first-page":"864","article-title":"Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction","volume":"137","author":"Taqueti","year":"2018","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1152\/physrev.00045.2006","article-title":"Regulation of coronary blood flow during exercise","volume":"88","author":"Duncker","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.jacc.2011.11.015","article-title":"High prevalence of coronary microvascular spasm in patients with chest pain and normal coronary angiograms","volume":"59","author":"Ong","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2772","DOI":"10.1016\/j.jacc.2016.03.584","article-title":"Invasive FFR and noninvasive CFR in the evaluation of ischemia","volume":"67","author":"Johnson","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1016\/j.jacc.2018.09.006","article-title":"Stratified medical therapy using invasive coronary function testing in angina: The CorMicA trial","volume":"72","author":"Ford","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.jjcc.2012.12.008","article-title":"Clinical impact of coronary artery spasm in patients with no significant coronary stenosis who are experiencing acute coronary syndrome","volume":"61","author":"Satoh","year":"2013","journal-title":"J. Cardiol."},{"key":"ref_29","first-page":"587","article-title":"Prognostic value of microvascular resistance in patients with ST-segment elevation myocardial infarction treated with primary PCI","volume":"60","author":"Yong","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/j.jacc.2015.12.053","article-title":"Coronary flow reserve and microcirculatory resistance in patients with intermediate coronary stenosis","volume":"67","author":"Lee","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1016\/j.jacc.2013.07.076","article-title":"Anatomic versus physiologic assessment of coronary artery disease","volume":"62","author":"Gould","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1161\/CIRCULATIONAHA.111.050427","article-title":"Improved cardiac risk assessment with noninvasive measures of coronary flow reserve","volume":"124","author":"Murthy","year":"2011","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e008126","DOI":"10.1161\/CIRCINTERVENTIONS.119.008126","article-title":"Ischemia and no obstructive coronary artery disease: Prevalence and correlates of coronary vasomotion disorders","volume":"12","author":"Ford","year":"2019","journal-title":"Circ. Cardiovasc. Interv."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4396","DOI":"10.1093\/eurheartj\/ehaf580","article-title":"Coronary function testing vs angiography alone to guide treatment of angina with non-obstructive coronary arteries: The ILIAS ANOCA trial","volume":"46","author":"Boerhout","year":"2025","journal-title":"Eur. Heart J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41591-025-04044-4","article-title":"Endotyping-informed therapy for patients with chest pain and no obstructive coronary artery disease: A randomized trial","volume":"32","author":"Bradley","year":"2026","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1016\/j.jacc.2009.04.098","article-title":"Women and ischemic heart disease","volume":"54","author":"Shaw","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1016\/j.jacc.2017.04.019","article-title":"A test in context: Fractional flow reserve","volume":"69","author":"Jeremias","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.jacc.2015.02.032","article-title":"Evolving therapies for myocardial ischemia\/reperfusion injury","volume":"65","author":"Ibanez","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1161\/CIRCRESAHA.116.308925","article-title":"Myocardial ischemia: Lack of coronary blood flow or myocardial oxygen supply-demand imbalance?","volume":"119","author":"Heusch","year":"2016","journal-title":"Circ. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1093\/eurheartj\/ehaa575","article-title":"2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation","volume":"42","author":"Collet","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e85768","DOI":"10.1172\/jci.insight.85768","article-title":"Microvascular resistance of the culprit coronary artery in acute STEMI","volume":"1","author":"Carrick","year":"2016","journal-title":"JCI Insight"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1093\/eurheartj\/ehaf917","article-title":"Stratified treatment of myocardial infarction with non-obstructive coronary arteries: The PROMISE trial","volume":"47","author":"Montone","year":"2025","journal-title":"Eur. Heart J."}],"container-title":["Journal of Cardiovascular Development and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2308-3425\/13\/9\/426\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:53:00Z","timestamp":1788259980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2308-3425\/13\/9\/426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":42,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jcdd13090426"],"URL":"https:\/\/doi.org\/10.3390\/jcdd13090426","relation":{},"ISSN":["2308-3425"],"issn-type":[{"value":"2308-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}