Abstract 11979: Activation of Growth Hormone Releasing Hormone Receptor Signaling as Potential Therapeutic Approach to Treat Heart Failure With Preserved Ejection Fraction

Abstract

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) represents about 50% of the HF cases and is steadily rising. To date, there no effective therapies for HFpEF. Growth hormone-releasing hormone (GHRH) has shown a broad range of regulatory influences in the cardiovascular system, aging and obesity in preclinical and clinical studies; therefore, we hypothesize that GHRH-agonists (GHRH-A) can attenuate/reverse the HFpEF phenotype. Methods: C57BL6N mice received a high fat diet (HFD) plus L-NAME for 5 weeks (HFD+L-NAME) to induce HFpEF. Cardiac morphology and function was then assessed by echocardiography, and animals were randomized to receive daily injections of GHRH-A (200 μg/Kg) or placebo (vehicle). Control animals received neither HFD+L-NAME nor treatment. Mice were acclimated to treadmill exercise testing and for systolic blood pressure (SBP) measurements. Results: Baseline characteristics following 5 weeks of HFD+L-NAME showed no difference in ejection fraction (EF), but isovolumetric relaxation time (IVRT) and E/A ratio were increased, while E/E’ ratio decreased compared to control (Fig1A-D, *p<0.05, ****p<0.0001 t-test). Running distance (Fig1E) after 1-week of GHRH-A treatment suggests improvement over placebo-treated mice. Similarly, SBP (Fig1F) appears to be returning to normal after 10 days (**p<0.01, Kruskal-Wallis test). Conclusions: Our results corroborate exercise intolerance and hypertension in the HFD+L-NAME placebo and suggest that even short-term GHRH-A treatment produces beneficial effects on exercise tolerance and SBP. Thus, GHRH-A therapy may be a potential therapeutic strategy for treatment of cardiometabolic HFpEF phenotype.