Effectiveness of Growth Hormone Releasing Hormone Agonists (GHRH A) in Chronic Kidney Disease Induced Heart Failure with Preserved Ejection Fraction

Rieger, A. C.; Bagno, L. L.; Salerno, A.; Florea, V.; Rodriguez, J.; Rosado, M.; Turner, D.; Takeuchi, L. M.; Dulce, R. A.; Balkan, W.; Schulman, I. H.; Schally, A.; Hare, J. M.

doi:10.1101/2020.05.30.111476

bioRxiv · 10.1101/2020.05.30.111476

Effectiveness of Growth Hormone Releasing Hormone Agonists (GHRH A) in Chronic Kidney Disease Induced Heart Failure with Preserved Ejection Fraction

Rieger, A. C.·Bagno, L. L.·Salerno, A.·Florea, V.·Rodriguez, J.·Rosado, M.·Turner, D.·Takeuchi, L. M.·Dulce, R. A.·Balkan, W.·Schulman, I. H.·Schally, A.·Hare, J. M.

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Abstract

BackgroundTherapies 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. MethodsFemale 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. ResultsThe 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). ConclusionA 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.

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Rieger, A. C., Bagno, L. L., Salerno, A., Florea, V., Rodriguez, J., Rosado, M., Turner, D., Takeuchi, L. M., Dulce, R. A., Balkan, W., Schulman, I. H., Schally, A., Hare, J. M.. 2020-06-02. Effectiveness of Growth Hormone Releasing Hormone Agonists (GHRH A) in Chronic Kidney Disease Induced Heart Failure with Preserved Ejection Fraction. https://doi.org/10.1101/2020.05.30.111476

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