One of the main achievements of modern Cardiology has certainly been the possibility of visualizing and studying epicardial coronary arteries through selective angiography and consequently of evaluating the presence of more or less significant stenoses. 1 Moreover, it is possible to find some acute obstructions, due to fissuring and disruption of an atherosclerotic unstable plaque and the production of an obstructive thrombus. 2 The introduction of increasingly sophisticated methods has given the possibility of reopening critical coronary stenoses in order to achieve reperfusion of the ischemic myocardial areas.Also the coronary artery spasm, an intense and acute vasoconstriction of an epicardial coronary artery that causes vessel narrowing or occlusion, has been described and the complex pathophysiological aspects and the clinical relevance have been studied. 3 Revascularization for stable coronary artery disease by either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) is indicated in patients with persistence of symptoms despite medical treatment and/or in order to improve the prognosis in flow-limiting coronary stenoses, by reducing myocardial ischemia and its adverse clinical manifestations. 4 As regards the ST-elevation myocardial infarction (STEMI), caused in most cases by acute thrombotic obstruction of a coronary artery, primary PCI is the recommended method of reperfusion when it can be promptly performed by experienced operators. 5 Thus the substantial improvement of medical care (which includes optimal pharmacological therapy and early revascularization) significantly decreased in-hospital mortality (approximately 5% to 6%) and 1-year mortality (approximately 7% to 18%) from STEMI. 6,7 But, almost paradoxically, while it is relatively easy to study and, if necessary, to reopen epicardial coronary arteries, the pathophysiological problem of coronary ischemia in its various clinical aspects cannot absolutely be explained only at this level. The clinical practice has clearly demonstrated that ischemia and angina cannot always be cured by removing a plaque which causes critical coronary stenosis. Some patients with angina pectoris do not have visible coronary atherosclerosis at angiography. In other patients, treated by PCI, myocardial ischemia persists despite stenosis removal. Many of these cases can be explained by a coronary microvascular dysfunction (CMD). 8 A dysfunction of the coronary pre-arterioles (from 100 to 500 mm in diameter) and of the small coronary intramural arterioles (<100 mm in diameter) can underlie microvascular angina. 9 Coronary flow reserve may be impaired, in the absence of epicardial artery obstructions, by many and complex pathophysiological mechanisms: non-homogeneous metabolic vasodilation that may favor the steal phenomenon, inappropriate pre-arteriolar/arteriolar vasoconstriction, or other alterations. 10 The diagnosis (electrical, mechanical, perfusive) of myocardial ischemia in CMD is most difficult, also for the peculiar distribution of ...