Therapeutic potential of Relaxin-2 in Heart Failure with preserved Ejection Fraction (HFpEF)

Salama, G.; Palma, J. B.; Gabris-Weber, B.; McMahon, B.; Mauro, A. J.; St.Hilaire, C.; Cuevas, R. A.; Dschietzig, T. B. B.; Romero, G.

doi:10.64898/2026.05.14.725229

bioRxiv · 10.64898/2026.05.14.725229

Therapeutic potential of Relaxin-2 in Heart Failure with preserved Ejection Fraction (HFpEF)

Salama, G.·Palma, J. B.·Gabris-Weber, B.·McMahon, B.·Mauro, A. J.·St.Hilaire, C.·Cuevas, R. A.·Dschietzig, T. B. B.·Romero, G.

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Abstract

AimsHeart failure with preserved ejection fraction (HFpEF) afflicts millions annually and current treatments provide symptomatic relief. Here, we investigate the therapeutic potential of synthetic human Relaxin-2 (RLX) at reversing diastolic dysfunction (DD) and reducing arrhythmia vulnerability. Methods and ResultsMale ZSF1 rats were placed on a normal diet (ND, N=10 controls) or a high-fat diet (HFD, N=11), resulting in the development of DD in 11-weeks, based on serial echocardiograms (enlarged left atrium (LA), wall thickness, doppler flow: E/e). Once HFpEF was confirmed, control and HFpEF rats were randomly treated with Relaxin (400{micro}g/kg/day RLX, N=6) or the vehicle (N=5) for 2-weeks using implanted minipumps. Echocardiograms were repeated at weeks 1 and 2, then hearts were isolated, optically mapped, subjected to programmed electrical stimulation (PES) and tissues dissected for immuno-fluorescence (IF), and qPCR analysis. Circulating levels of glucose, RLX and NT-pro-ANP were measured, pre- and post-treatment. Echocardiograms indicated that RLX reversed DD by reducing LA dimensions and E/e. Optical mapping revealed that 1/3 of HFpEF hearts exhibited sustained atrial and ventricular arrhythmia which were blocked by RLX as it tended to increase conduction velocity (CV). Based on IF, RLX increased Nav1.5, Connexin-43, {beta}-catenin and Wnt1 expression. There were no significant changes in fibrosis in this HFpEF model. NT-pro-ANP was elevated in HFpEF and reduced towards control values by RLX. qPCR analysis showed that RLX decreased DKK1 and MMP1A and increased SCN5A expression compared to Vehicle treatment (N=6 and 5, respectively). ConclusionsThe ZSF1 model showed clear signs of HFpEF, including DD, enlargement of the LA, enhanced hemodynamic stress, increased vulnerability to sustained AF and VF, and elevated glucose and blood pressure. RLX treatment largely reversed DD, hemodynamic stress, and suppressed sustained arrhythmias. RLX elicited cardiac genomic changes, most likely through Wnt/canonical signaling, demonstrating RLXs potential as a therapy for HFpEF.

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Salama, G., Palma, J. B., Gabris-Weber, B., McMahon, B., Mauro, A. J., St.Hilaire, C., Cuevas, R. A., Dschietzig, T. B. B., Romero, G.. 2026-05-18. Therapeutic potential of Relaxin-2 in Heart Failure with preserved Ejection Fraction (HFpEF). https://doi.org/10.64898/2026.05.14.725229

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