Abstract 18614: Growth Hormone Releasing Hormone Agonists Reverse the Cardiometabolic Heart Failure With Preserved Ejection Fraction Phenotype via the Hypoxia-Inducible Factor 1 Alpha

Abstract

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) treatment is limited due in large part to lack of understanding of the underlying mechanisms involved. Recently, we showed that growth hormone-releasing hormone-agonist (GHRH-agonist) has cardioprotective effects in a cardiometabolic HFpEF model; however, the mechanism of these therapeutic effects is still unclear. Here, we hypothesize that the anti-HFpEF properties of GHRH-receptor activation are mediated by hypoxia-induced factor (HIF)-1α pathway. Methods: Wild-type (WT) and HIF-1α cardiomyocyte knockout (HIF-1α CM KO) mice received a high-fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of HFD+L-NAME regimen, animals receive daily injections of GHRH-agonist, MR-356, or placebo during a 4-week period. Control animals received no HFD+L-NAME or MR-356 treatment. Echocardiography, blood pressure, glucose tolerance test, and hemodynamic measurements were evaluated. Results: The HFD+L-NAME diet produced a HFpEF phenotype, which was reversed in mice with intact HIF-1α treated with MR-356 (Figure 1 A-E). In contrast, following cardiac-specific deletion of HIF-1α CM , MR-356 no longer reversed (A) the elevated isovolumetric relaxation time (IVRT), (B) increased E/E’ ratio and (C) reduced global longitudinal strain (GLS). EF was preserved (D) while the slope of the end-diastolic pressure-volume relationship (EDPVR, E) was increased in the placebo group and restored by MR-356 in WT mice but not HIF-1α CM KO mice. Figure 1F shows representative pressure-volume loops from WT placebo, HIF-1α CM treated with placebo or MR-356. Conclusions: Our findings show that cardiac-specific HIF-1α deletion blocks cardioprotective effects of MR-356 suggesting that HIF-1α is necessary for its anti-HFpEF effects.