Is ischemia a disease or syndrome, the cause of angina, and now even a trial?

The clinical manifestations of myocardial ischemia are protean in nature and include a variable combination of typical or atypical angina symptoms, electrocardiographic changes, noninvasive findings of regional wall motion abnormalities, and reversible scintigraphic perfusion defects—the changes of which, importantly, may or may not be of epicardial coronary origin. Thus, mounting evidence indicates that the presence or absence of atherosclerotic coronary artery disease (CAD) should no longer be considered a surrogate marker for myocardial ischemia, as suggested by the high prevalence of minor or absent coronary obstruction among patients with proven myocardial ischemia. Whereas the management of CAD has been largely predicated on the plausible assumption that flow-limiting obstructions of the epicardial coronary arteries are the proximate cause of both angina and myocardial ischemia, there is scant evidence from many randomized trials and several meta-analyses that treating epicardial coronary obstructions in patients with stable CAD, particularly with percutaneous coronary intervention (PCI), reduces mortality and morbidity, as compared with optimal medical therapy (OMT). A crucial scientific question for which evidence has been lacking is whether more severe and extensive myocardial ischemia is the driver of adverse cardiovascular outcomes and whether an invasive strategy with myocardial revascularization would be superior to OMT alone in such patients. The results of the recent ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), however, have failed to show—even in this higher-risk CAD subset—any incremental clinical benefit of revascularization as compared with OMT alone on cardiac event reduction.