Abstract 13371: Beneficial Effects of Growth Hormone Releasing Hormone Agonist in a Murine Model of Cardiometabolic Heart Failure With Preserved Ejection Fraction

Abstract

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major unmet medical need due to its complex pathophysiology and lack of effective therapies. We previously showed that growth hormone-releasing hormone (GHRH)-agonists improve the phenotype of models of HF with reduced EF (HFrEF) and cardiorenal models of HFpEF. Hypothesis: We tested the hypothesis that the GHRH-agonist, MR-356 mitigates/reverses the cardio-metabolic HFpEF phenotype. Methods: C57BL6N mice received a high-fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of the HFD+L-NAME diet, animals were randomized to receive daily injections of MR-356 or placebo for 4-weeks. Control animals received no HFD+L-NAME or agonist treatment. Cardiac performance was assessed by echocardiography and hemodynamic measurements. Blood pressure, glucose tolerance, and exercise capacity, as well as cardiac hypertrophy, fibrosis, capillary density, and lung congestion were evaluated. Results: After 5 weeks of HFD+L-NAME diet, the placebo group showed impaired diastolic function (increased E/E’ratio, EDPVR, end-diastolic pressure), glucose intolerance and reduced global longitudinal strain and exercise capacity (p<0.05). MR-356 treatment improved all of these parameters (p<0.05). Cardiac hypertrophy, fibrosis, and capillary rarefaction in the placebo group (p<0.05) were completely restored by MR-356 (p<0.05). The increased expression of cardiac pro-BNP, and inducible nitric oxide synthase (iNOS) in the placebo group (p<0.05) was brought to normal levels by MR-356 (p<0.05). Hypophosphorylation of the titin isoforms in the placebo group (p<0.05) was attenuated in the MR-356 group. Conclusions: Our data show the unique potential of MR-356 to treat several HFpEF-like features including diastolic dysfunction, cardiac hypertrophy, fibrosis, and exercise intolerance, suggesting that MR-356 reduces myocardial stress associated with metabolic inflammation in HFpEF. Thus, GHRH-agonists may be an effective therapeutic strategy for the treatment of the cardiometabolic HFpEF phenotype.