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Aim: The aim of our study is to assess the predictors and the prognostic role of left ventricle ejection fraction (LVEF) recovery after Impella-supported percutaneous coronary intervention (PCI) in patients presenting with acute myocardial infarction (AMI). Methods: This retrospective, observational study included patients admitted for AMI who underwent Impella-supported PCI in two Italian high-volume cardiac catheterization laboratories. Only patients who underwent an echocardiographic assessment of left ventricle ejection fraction (LVEF) before the procedure (acute LVEF) and during follow-up (follow-up LVEF) were included in the present analysis. Patients with a baseline LVEF >= 40% were excluded from the present analysis. LVEF recovery was calculated as the difference between follow-up LVEF and acute LVEF. A delta >= 5% was considered significant and was used to define the responder group. Results: From April 2007 to December 2020, 64 consecutive patients were included in our study. A total of 55 patients (86%) received hemodynamic support with Impella 2.5, and 9 patients (14%) with Impella CP. Median LVEF at follow-up was significantly higher compared to baseline (36% (30-42) vs. 30% (24-33), p < 0.001). Based on LVEF recovery, 37 patients (57.8%) were deemed responders. According to multivariate analysis, complete functional revascularization was an independent predictor of a significant EF recovery (OR: 0.159; 95% CI: 0.038-0.668; p = 0.012). At three-year follow-up, lack of LVEF recovery was the only predictor of mortality (HR: 5.315; 95% CI: 1.100-25.676; p = 0.038). Conclusions: Functional complete revascularization is an independent predictor of the recovery of LVEF in patients presenting with AMI who underwent Impella-supported PCI. The recovery of LV function is associated with improved prognosis and could be used to stratify the risk of future events at long-term follow-up.