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Background: Extracorporeal shockwave myocardial revascularization (ESMR) is a non-invasive treatment designed to improve symptoms in refractory angina (RA) patients. Enhanced perfusion through local vasodilation and neo-capillarization is postulated to be the mechanism of the observed clinical benefit. However, the impact of ESMR on the ischemic burden of RA patients has not been adequately assessed., Methods: One-hundred twenty-one consecutive RA patients suitable for ESMR were treated. Twenty-nine RA patients not suitable for treatment were clinically followed-up as a control group for clinical endpoints. ESMR-treated patients underwent baseline and 6-month single photon emission computed tomography (SPECT) to evaluate the changes in ischemic burden. The operator was blinded to the pre/post-treatment status of the SPECT exam. The primary endpoint was the difference in summed stress score (SSS) and summed difference score (SDS) between follow-up and baseline SPECTs. Secondary endpoints included the changes in Canadian Cardiovascular Society (CCS) angina class and nitroglycerin use between 6-month follow-up and baseline. Clinical endpoints were further compared between ESMR-treated patients and the control group., Results: Following ESMR, a significant reduction in the ischemic burden was observed (follow-up SSS: 14.2±10 vs. baseline SSS: 21.2±9.42, P<0.0001; follow-up SDS: 4.6±5.9 vs. baseline SDS 10.2±7.9, P<0.0001) including less patients with moderate to severe ischemia (19% vs. 46% P<0.0001). CCS class and nitroglycerin use were significantly reduced (CCS: 1.5±0.6 vs. 2.7±0.6, P<0.0001; patients needing nitroglycerin: 24% vs. 64%, P<0.0001). When compared to the control group, CCS class reduction, nitroglycerin use and hospitalizations were significantly lower for ESMR treated vs. non-treated RA patients at 6-month follow-up., Conclusions: In this single-center cohort of RA patients undergoing ESMR treatment and serial myocardial perfusion imaging, ESMR was associated with a significant reduction in the ischemic burden. These findings provide a physiological rationale and mechanism for the observed clinical benefit.