Abstract 18489: Growth Hormone Releasing Hormone Agonist (GHRH-A) Restores Cardiac Function in a Rodent Model of Heart Failure With Preserved Ejection Fraction (HFpEF)

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Introduction: Roughly half of patients with heart failure (HF) have preserved EF (HFpEF) and this rate is increasing. The pathophysiology of HFpEF is unclear and treatment of HFpEF remains a critical unmet need.

Hypothesis: Growth hormone releasing hormone agonist (GHRH-A) restores cardiac function in a rodent model of HFpEF.

Methods: C57BL/6N mice (n=4-5) received angiotensin-II (Ang-II: 0.8 mg/kg/day) via mini-osmotic pump for 4 weeks with concurrent daily administration of GHRH-A (MR-356: 200 μg/kg) or vehicle (DMSO+propylene-glycol). Echocardiography was assessed at baseline and 4 weeks after Alzet pump placement. Hemodynamic studies were performed and the titin N2BA/N2B ratio measured.

Results: Ang-II administration 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 significantly increased in the Ang-II/vehicle group, consistent with increased ventricular stiffness and impaired relaxation. Importantly, GHRH-A treatment reset these parameters to normal conditions (table). HFpEF mice exhibited higher HW/BW ratios and lung weight. The titin N2BA/N2B ratio, which was increased (p<0.05) in the Ang-II group, was restored by GHRH-A treatment.

Conclusions: Chronic administration of Ang-II mediates structural and functional changes that mimic HFpEF. GHRH-A treatment improves diastolic dysfunction and impaired relaxation. Therefore, GHRH-A therapy may be beneficial in the treatment of HFpEF.

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