PT - JOURNAL ARTICLE AU - Angela C. Rieger AU - Luiza L Bagno AU - Alessandro Salerno AU - Victoria Florea AU - Jose Rodriguez AU - Marcos Rosado AU - Darren Turner AU - Lauro M. Takeuchi AU - Raul Dulce AU - Wayne Balkan AU - Ivonne H. Schulman AU - Andrew Schally AU - Joshua M. Hare TI - Effectiveness of Growth Hormone–Releasing Hormone Agonists (GHRH-A) in Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction AID - 10.1101/2020.05.30.111476 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.05.30.111476 4099 - http://biorxiv.org/content/early/2020/06/02/2020.05.30.111476.short 4100 - http://biorxiv.org/content/early/2020/06/02/2020.05.30.111476.full AB - Background Therapies that improve morbidity and mortality in heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone releasing hormone analogues (GHRH-A) reverse fibrosis and improve cardiac function in ischemic and non-ischemic animal models. We tested the hypothesis that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large animal model.Methods Female Yorkshire pigs (n=16) underwent 5/6 nephrectomy via renal artery embolization, which induced HFpEF, and 12-weeks later received daily subcutaneous injections of GHRH-A (n=8) or placebo (n=8). Kidney function, renal and cardiac MRI, pressure-volume loops, and electrical stimulation were assessed at baseline, 12-weeks, and 16-18 weeks post-embolization.Results The CKD model was confirmed by increased creatinine and BUN. HFpEF was demonstrated at 12 weeks by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickening, end-diastolic pressure (EDP), end-diastolic pressure-volume relationship (EDPVR), and tau. After 6 weeks of treatment, diastolic function improved in the GHRH-A group, evidenced by normalization of EDP (p=0.03) associated with improved diastolic compliance as measured by EDP/EDV ratio (p=0.018).Conclusion A beneficial effect of GHRH-A in diastolic function was observed in a CKD large animal model that manifests the characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.Competing Interest StatementDr. Joshua Hare owns equity in Biscayne Pharmaceuticals, licensee of intellectual property used in this study. Biscayne Pharmaceuticals did not provide funding for this study. Dr. Joshua Hare is the Chief Scientific Officer, a compensated consultant and advisory board member for Longeveron and holds equity in Longeveron. Dr. Hare is also the co-inventor of intellectual property licensed to Longeveron. Longeveron did not play a role in the design, conduct, or funding of the study. Angela C. Rieger has no disclosures, Luiza Bagno has no disclosures, Alessandro Salerno has no disclosures Victoria Florea has no disclosures, Jose Rodriguez has no disclosures, Marcos Rosado has no disclosures, Lauro Takeushi has no disclosures, Raul Dulce has no disclosures, Wayne Balkan has no disclosures, Ivonne H. Schulman has no disclosures and contributed to this manuscript in her personal capacity. The opinions expressed in this article are the author's own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.