Subendocardial ischemia: does CMD really exist?

Patients with angina but without obstructive epicardial coronary disease still require a specific mechanistic diagnosis to enable targeted treatment. The overarching term "coronary microvascular dysfunction" (CMD) has been applied broadly - but is it correct? We present a series of case examples culminating a systematic exploration of our large clinical database to distinguish among four categories of coronary pathophysiology. First, by far the largest group of "no stenosis angina" patients exhibits subendocardial ischemia during intact flow through diffuse epicardial disease during dipyridamole vasodilator stress. Second, rare patients indeed have ischemic signs or symptoms due solely to reduced flow attributable to microvascular dysfunction but without subendocardial hypoperfusion. Third, a previously unrecognized group of patients displays significant ST-segment changes and rare angina but normal high dipyridamole induced coronary flow and intact normal subendocardial uptake, perhaps due to a stretch mechanism from hyperemia. Fourth, ischemia due to reduced flow plus a subendocardial defect can arise as a secondary effect of a variety of global cardiac pathology, for example severe diffuse atherosclerosis, severe aortic stenosis, or a primary cardiomyopathy. Because subendocardial ischemia dominates the pathophysiologic epidemiology of these patient categories, understanding its mechanisms and therefore potential treatment targets will bring the largest clinical benefits to the largest number of patients. However, its diagnosis requires meticulous attention to exclude caffeine that can lead to a "false positive" diagnosis of CMD, absolute flow quantification to avoid confusing high resting flow with normal stress flow from reduced flow capacity, and quantification of subendocardial blood flow.