Aims
To test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signaling pathway within the myocardium both prevents and reverses diastolic dysfunction and pathophysiologic features consistent with heart failure with preserved ejection fraction (HFpEF). Impaired myocardial relaxation, fibrosis and ventricular stiffness, among other multi-organ morbidities, characterize the phenotype underlying the HFpEF syndrome. Despite the rapidly increasing prevalence of HFpEF, few effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, cardiomyocyte hypertrophy and improve performance in animal models of ischemic cardiomyopathy, independently of the growth-hormone axis.
Methods and Results
CD1 mice received 4- or 8-week continuous infusion of angiotensin-II (Ang-II) to generate a phenotype with several features consistent with HFpEF. Mice were administered either vehicle or a potent synthetic agonist of growth hormone-releasing hormone, MR-356 for 4-weeks beginning concurrently or 4-weeks following the initiation of Ang-II infusion.
Ang-II treated animals exhibited diastolic dysfunction, ventricular hypertrophy, interstitial fibrosis and normal ejection fraction. Cardiomyocytes isolated from these animals exhibited incomplete relaxation, depressed contractile responses, altered myofibrillar protein phosphorylation and disturbed calcium handling mechanisms (ex vivo). MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. Activation of the GHRH receptors increased cAMP and cGMP in cardiomyocytes isolated from control animals, but only cAMP in cardiac fibroblasts, suggesting that GHRH-A exert differential effects on cardiomyocytes and fibroblasts.
Conclusion
These findings indicate that the GHRH receptor signaling pathway(s) represents a new molecular target to counteract dysfunctional cardiomyocyte relaxation by targeting myofilament phosphorylation and fibrosis. Accordingly, activation of GHRH receptors with potent, synthetic GHRH-agonists may provide a novel therapeutic approach to management of the myocardial alterations associated with the HFpEF syndrome.
Translational Perspective
Heart failure with preserved ejection fraction (HFpEF) presents with left-ventricular hypertrophy (LVH), diastolic dysfunction and a spectrum of systemic co-morbidities. Developing animal models and successful therapeutics is notoriously challenging. Here, we used low dose angiotensin-II infusion in mice, which produced LVH, diastolic dysfunction, myocardial fibrosis, and heart failure, and tested growth hormone releasing hormone (GHRH)-agonists, known to have cardiac anti-hypertophic and pro-regenerative effects, on reversing and preventing the angiotensin-II phenotype. We demonstrate improved myocardial relaxation, diastolic calcium handing, and cardiac fibrosis, opening the possibility of using GHRH-agonists for HFpEF. Testing in other animal models and clinical studies are warranted.
