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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Nils Johnson reports that within the past 3 years his institution has received research support from Shockwave Medical for the PET core lab of COSIRA-2, NCT05102019. Drs. Johnson and Gould and their co-inventors have pending patents to the University of Texas on diagnostic methods for quantifying aortic stenosis and TAVI physiology (research and non-commercial license with OpSens Medical), and also algorithms to correct pressure tracings from fluid-filled catheters. Dr. Johnson is frequently invited by academia and industry to speak at educational meetings/conferences on hemodynamic physiology or cardiac PET (recently by Boston Scientific, Bracco Diagnostics, and CDL Nuclear Technologies) and receives travel expenses and sometimes an honorarium, which are donated to the University of Texas. Dr. K Lance Gould is the 510(k) applicant for several cardiac PET software packages approved by the FDA (K113754, K143664, K171303, K202679, K231731) but neither Dr. Gould not Dr. Johnson receives any licensing fees paid to the University of Texas Health Science Center in Houston from commercial companies such as Bracco Diagnostics or GE Medical.
(Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)