Abstract
Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired relaxation, ventricular stiffening and fibrosis. We previously showed that activation of GHRH receptor markedly reduces fibrosis in rat and swine models of ischemic myocardial injury. Therefore, we hypothesized that activation of GHRH receptor signaling can improve diastolic dysfunction in a mouse model of HFpEF. C57BL6N mice (n=4-5) were implanted with a mini-osmotic pump to deliver angiotensin-II (Ang-II: 0.8 mg/kg/day) for 4 weeks and randomly assigned to receive daily injections of GHRH-Agonist (GHRH-A [MR-409]: 100 μg/kg) or vehicle (DMSO+propylene-glycol). Cardiac performance was assessed by serial echocardiography and hemodynamic analysis. Chronic administration of Ang-II resulted in increased end-diastolic pressure (EDP, p=0.0186) with no changes in EF (p=ns) or end-systolic pressure (ESP, p=ns) in comparison to control mice. Isovolumetric relaxation time (IVRT, p<0.05) and end-diastolic pressure-volume relationship (EDPVR, p=0.0229) were markedly increased in the Ang-II group consistent with increased ventricular stiffness and poor myocardial relaxation. MR-409 treatment reset these parameters to normal levels (table 1). Our findings demonstrate that chronic administration of Ang-II mediates structural and functional changes that mimic HFpEF. Importantly, MR-409 treatment reduces Ang-II-induced elevation of EDP, EDPVR and IVRT; thus preventing HFpEF–like effects, suggesting that activation of the GHRH receptor signaling pathways represents a potential new therapeutic approach for HFpEF.
Published Version
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