Synthetic Agonist of Growth Hormone-Releasing Hormone as Novel Treatment for Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is characterized by a myocardium with impaired relaxation, fibrosis and ventricular stiffness. Despite the rapidly increasing prevalence of HFpEF, no effective therapies have emerged. Here we show that a potent synthetic agonist of growth hormone-releasing hormone (GHRH-A) both prevents and reverses the HFpEF phenotype generated in mice through continuous infusion of angiotensin-II (Ang-II). Animals treated with Ang-II had diastolic dysfunction, and isolated cardiomyocytes (ex vivo) exhibited incomplete relaxation, depressed contractile responses and altered myofibrillar protein phosphorylation. Calcium handling mechanisms were disturbed in cardiomyocytes from mice with HFpEF. The GHRH-A MR-356 prevented the development of the pathological phenotype and reversed the phenotype in vivo and ex vivo in mice with established HFpEF. Taken together these findings indicate that the GHRH receptor signaling pathway represents a new molecular target to counteract HFpEF-associated cardiomyocytye dysfunction by targeting myofilament phosphorylation. Accordingly, activation of the GHRH receptor with potent synthetic GHRH agonists may provide a novel therapeutic approach to management of HFpEF syndrome.