Objective: In light of the continuous lack of evidence-based therapies, heart failure with preserved ejection fraction (HFpEF) has been recently recognized as the single greatest unmet need in cardiovascular medicine. The pregnancy-related hormone human Relaxin-H2 (RLN) exerts pleiotropic cardioprotective actions via its cognate receptor relaxin family peptide receptor 1 (RXFP1). Recent data not only demonstrated positive inotropic effects of cardiac RXFP1 overexpression but pointed to attenuation of cardiac fibrosis, hypertrophy and diastolic dysfunction. Thus, the present study aimed to investigate whether cardiac RXFP1 overexpression is able to rescue HFpEF in an Ang II-induced in vivo model.

Methods and Results: Transgenic mice with cardiac myocyte-specific overexpression of RXFP1 (Tg(RXFP1)) and wild-type animals were subjected to 14-day Ang II infusion (1.5 mg/kg/d) using subcutaneous osmotic mini-pumps. Mice underwent serial echocardiographic evaluation, followed by left heart catheterization and sacrifice at day 14. In vivo characterization of wild-type mice infused with Ang II revealed severe diastolic dysfunction accompanied by left ventricular (LV) hypertrophy, while systolic function was preserved. In contrast, Ang II-infused Tg(RXFP1) mice presented a maintained diastolic function with significantly reduced E/e’ ratio and left ventricular end-diastolic pressure (LVEDP). In addition, relative lung weight was significantly lower in Tg(RXFP1), suggesting reduced pulmonary congestion. Cardiac fibrosis and hypertrophy, two main contributors to maladaptive remodeling in HFpEF, were strongly induced by Ang II infusion in wild-type mice. These alterations were attenuated by cardiac RXFP1 overexpression: Tg(RXFP1) mice presented not only a mitigated hypertrophic response including lower heart to body weight ratio and cardiomyocyte cross-sectional area but also reduced activation of the fetal gene program. Finally, Tg(RXFP1) mice displayed a diminished interstitial and perivascular fibrosis in the histological analysis as well as a reduced expression of collagens I, III, and VIII. These findings are in line with a significant modulation of mediators of extracellular matrix (ECM) remodeling seen in Tg(RXFP1) mice, including connective tissue growth factor (CTGF), matrix metalloproteinase 13 (MMP13), and tissue inhibitor of matrix metalloproteinase (TIMP)-1.

Conclusion: Cardiac overexpression of RXFP1 counteracts diastolic dysfunction and cardiac remodeling in an in vivo model of Ang II-induced HFpEF. Of note, our results suggest that RXFP1 exerts potent antifibrotic and antihypertrophic effects rendering RXFP1 signaling a potential approach for HFpEF therapy.