Abstract Background In patients with heart failure with reduced ejection fraction (HFrEF), the severity of functional mitral regurgitation (MR) is a major predictor of worsened symptoms and poor outcomes. Percutaneous MR repair has been shown to improve outcomes in HFrEF with MR. However, because MR is related to abnormal myocardial function and adverse remodeling, the optimization of guideline-directed medical therapy (GDMT) could improve loading conditions, reversal remodelling and left ventricle function and also may reduce MR severity. We sought to evaluated whether the left ventricle reverse remodeling induced by the addition of sacubitril/valsartan may reduce MR severity sufficiently to avoid need for percutaneous MR repair approach. Methods We performed a single-center, prospective assessor-blinded study to determine the reverse remodeling response of sacubitril/valsartan therapy in HFrEF patients (NYHA class II-IV) with MR evaluated for percutaneous MR repair. Echocardiographic images were assessed offline by 2 investigators blinded to both the clinical data and timing of echocardiograms. Doses of sacubitril/valsartan were optimized to individual tolerance. A clinical and echocardiographic 1 year follow-up was performed. Results Thirty-nine HFrEF patients with MR grade 3-4 were included (mean age 63 years old, 69,2% male). Optimal dose of sacubitril/valsartan was reached in 63,2% of patients. After 1-year follow-up, only 1 patient died and, as we show in Table 1, a significant improvement on NYHA functional class and NT-ProBNP values were present. Left ventricle ejection fraction improved (29.7 ± 6.7% vs 41.3 ± 13.2%; P < 0.001) and left ventricular end-diastolic and end-systolic volume indexed to body surface area decreased (123.4 ± 35.7 mL/m2 vs 98.4 ± 39.7 mL/m2; P < 0.001 and 87.7 ± 30.0 mL/m2 vs 61.9 ± 35.3 mL/m2; P < 0.001, respectively). Volumetric remodeling was associated with a reduction in the degree of mitral regurgitation (64.1% grade 3 and 35.9% grade 4 at the beginning to 28.9% grade 1, 36.8% grade 2, 21.5% grade 3 and 13.2% grade 4 after one year of follow-up; [scale from 0-4]). Conclusion The optimization of GDMT with sacubitril/valsartan induced an improvement on functional class and a beneficial reverse cardiac remodelling, with enhancement of left ventricle function and reducing MR severity, enough in 24 patients to avoid need for percutaneous MR repair. In HFrEF patients with grade 3-4 mitral regurgitation, our results reinforce importance of ensuring optimal GDMT before a percutaneous mitral valve repair approach.Table 1.Changes during follow-up.