The alternative "ischemic" cascade in coronary microvascular disease.

The conceptual model of the classical "ischemic cascade" has served cardiologists well for decades. It correctly predicts clinical findings during imaging stress testing in the presence of coronary artery disease or epicardial coronary artery spasm, where perfusion and wall motion abnormalities provide a substantially higher sensitivity than ECG changes. However, empirical experience has taught us that stress-induced ischemic-like ECG changes, often accompanied by perfusion abnormalities, are the rule rather than the exception in pathophysiological conditions during which the occurrence of ischemia usually cannot be proven, characterized by angiographically normal arteries and reduced flow reserve, such as syndrome X, arterial hypertension and hypertrophic cardiomyopathy. These stress-induced "echocardiographically silent" ST segment changes may be associated with impaired coronary flow reserve and systemic endothelial dysfunction. In hypertrophic cardiomyopathy stress-induced ischemic-like ST segment depression is linked to higher long-term incidence of adverse events. It is entirely likely that our monolithic view of ischemia mirrored in the classical ischemic cascade should be integrated by the awareness of the reverse or alternative "ischemic" cascade best describing microvascular disease, with ECG changes coming first, perfusion abnormalities second, and echocardiographic changes usually being absent. Not all forms of myocardial ischemia are the same, and milder, patchy degrees of myocardial ischemia--as those hypothesized, but not proven, in microvascular angina--remain silent in its mechanical functional manifestations and may well represent a physiological scotoma of stress echocardiography. "Anatomic lies" on the ECG may be overturned into "physiologic truths" when coronary flow reserve or systemic endothelial function is considered.