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Coronary microvascular dysfunction has recently emerged as a major independent prognostic factor and can be invasively assessed by coronary flow reserve (CFR) and the index of microvascular resistance (IMR). The incremental prognostic value of myocardial ischemia from SPECT myocardial perfusion imaging (MPI) over clinical characteristics, cardiac risk factors, and stress test data for the prediction of hard cardiac events (myocardial infarction and cardiac death) has been well demonstrated over the last two decades regardless of the absence or presence of epicardial CAD. Recently developed semi-conductor, cardiac-dedicated cameras allow for decreased acquisition times and systematic procubitus and decubitus acquisitions thereby limiting the occurrence of false positives historically attributable to artefactual motion, attenuation, and digestive artifacts. It is therefore likely that pathophysiological causes rather than acquisition artifacts might underlie SPECT perfusion abnormalities. Here, we report four representative examples of patients presenting with ischemia in the setting of no obstructive CAD and normal fractional flow reserve together with elevated IMR and low CFR. The results indicate that ischemia from SPECT MPI could result from microvascular dysfunction in patients without obstructive CAD and should be considered as a prognostic factor for hard cardiac events. [ABSTRACT FROM AUTHOR]