Angiotensin Receptor Neprilysin Inhibitor in Heart Failure with Preserved Ejection Fraction and Secondary Mitral Regurgitation: the PRAISE-MR Randomized Trial

Background: Atrial functional mitral regurgitation (AFMR) characterizes a high-risk phenotype in heart failure with preserved ejection fraction (HFpEF). Although sacubitril/valsartan reduces functional MR in HF with reduced EF (HFrEF), its impact on exercise hemodynamics and the dynamic burden of AFMR in HFpEF remains to be elucidated. Methods: This multicenter, randomized, open-label trial with blinded primary endpoint assessment assigned 84 patients with symptomatic HFpEF and ≥moderate AFMR within the previous year to sacubitril/valsartan (n=41) or standard-of-care (SOC; n=43). The primary outcome was the 6-month change in the exercise mean pulmonary arterial pressure to cardiac output (mPAP/CO) slope, assessed using cardiopulmonary exercise testing with simultaneous echocardiography (CPETecho). Secondary outcomes included changes in peak oxygen consumption (peak VO 2 ), Kansas City Cardiomyopathy Questionnaire (KCCQ), NT-proBNP levels, LA volume and function, and AFMR severity in rest and during stress. Results: At 6 months, sacubitril/valsartan significantly improved the mPAP/CO slope compared to SOC (adjusted between-group difference in change: -0.93mmHg/L/min; 95%CI: -1.80 to -0.07; p=0.035). This hemodynamic benefit was accompanied by improvements in peak VO2 (mean change: +0.9 vs. -0.6mL/kg/min; p=0.002) and KCCQ (median increase: 10 vs. 2 points; p=0.002). Significant reductions in NT-proBNP and LA volume were observed (p<0.001 for both), alongside a significant blunting of the dynamic MR increase during exercise (p=0.020). Target dose was achieved in 60% of patients, with symptomatic hypotension as the primary titration-limiting factor. Conclusions: In HFpEF and AFMR, sacubitril/valsartan was associated with improvements in exercise hemodynamics and peak VO 2 , along with attenuation of the exercise-induced increase in AFMR. These findings suggest a phenotype-specific benefit, warranting confirmation in larger, placebo-controlled, clinical outcome trials.