Functional coronary vascular disease: endotype-based classification, diagnosis, and targeted management

Background Angina and exertional dyspnea are hallmark manifestations of coronary artery disease (CAD), traditionally linked to obstructive epicardial lesions. However, a substantial subset of patients experience angina despite angiographically non-obstructive coronary arteries (<50%), termed angina with non-obstructive coronary arteries (ANOCA). ANOCA may progress to ischemia with non-obstructive coronary arteries (INOCA), myocardial infarction with non-obstructive coronary arteries (MINOCA), and ischemic cardiomyopathy. Despite advances in diagnostic modalities, the underlying pathophysiology remains underappreciated, and management often lacks precision. Pathophysiology ANOCA and INOCA encompass heterogeneous functional and structural coronary abnormalities, including endothelial dysfunction, impaired vasodilation, and inappropriate vasoconstriction of epicardial or microvascular vessels. Epicardial arteries serve primarily as conduits, whereas the microcirculation regulates coronary flow, mediating myocardial perfusion through nitric oxide, adenosine, and prostacyclin signalling. Disruption of these mechanisms precipitates ischemia despite normal epicardial anatomy, defining distinct endotypes with diagnostic and therapeutic relevance. Diagnosis and management Evaluation involves stepwise assessment from non-invasive testing, including ECG, laboratory studies, echocardiography, and coronary computed tomography, to invasive functional testing for endotype characterization. Management should integrate endotype-specific pharmacologic therapies such as calcium channel blockers, nitrates, ranolazine, ACE inhibitors, and beta-blockers with non-pharmacologic interventions including lifestyle modification and overall cardiovascular risk reduction. Conclusion Personalized, endotype-guided strategies targeting both pathophysiology and modifiable risk factors are essential to optimize symptom control, prevent disease progression, and reduce major adverse cardiovascular events in patients with ANOCA and INOCA.