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Objectives: Our study aimed to assess the safety and efficacy of cardiac contractility modulation (CCM) therapy in patients with heart failure with reduced ejection fraction (HFrEF) depending on HF etiology. Methods: We enrolled 166 patients with optimal medical therapy-resistant HFrEF (median age 59 years, 83.7% males, median NYHA class − 2, median left ventricular ejection fraction (LVEF) − 29.0%) who underwent CCM therapy device implantation from 2013 to 2019 in four medical centers in Russia. The HF etiology was determined based on invasive coronary angiography or cardiac MRI data. Transthoracic echocardiography (TTE), 6-minute walking test (6MWT), and NTproBNP-tests were performed at a baseline and 12 months after the implantation. Results: The ischemic etiology of HF was revealed in 100 patients (61.5%) (ICM group); the non-ischemic group (NICM) evolved 66 patients (38.5%). Patients in the ICM group were significantly older (61[57–69] vs. 55 [42.8–61], p < 0.001), more frequently had hypertension (79% vs. 42.4%, p < 0.001) and chronic kidney disease (43% vs. 22.7%, p = 0.012). Patients in the NICM group had significantly more often atrial fibrillation (AF) (58% vs. 74%, p = 0.048), larger end-diastolic volume (EDV) (249 [208–309] vs. 220 [192–271], p = 0.019) and end-systolic volume (ESV) (183 [147–230] vs. 154 [128–199], p = 0.003). There were no significant differences in mortality between ICM and NICM groups (14.4 vs. 10.8%, p = 0.51). In 12 months, there was a significant increase in LVEF in the NICM group (+ 2.0 [2–6] vs. +7.7 [2–12], p < 0.001), while the improvement in the 6MWT (+ 75 [22–108] vs. +80 [10–160], p = 0.851) and NYHA class did not reach the level of significance. The subanalysis between patients with improved NYHA class and those without improvement revealed that patients without improvement more frequently had AF (56% vs. 89%; p < 0.01), chronic obstructive lung disease (18% vs. 35% p = 0.047), higher blood pressure (110 [105–120] vs. 120[110–129]; p = 0.032). Conclusion: In this multicenter retrospective study, patients with non-ischemic HFrEF showed a significantly higher improvement in LVEF and LV reverse remodeling following CCM therapy device implantation. There was no significant association between HF etiology and survival in drug-resistant HFrEF patients following CCM therapy. [ABSTRACT FROM AUTHOR]