Abstract
Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth hormone releasing hormone (GHRH) agonists reduce fibrosis in rat and swine models of ischemic myocardial injury. However, their effect on cardiomyocytes is not known. We hypothesized that activation of GHRH receptor signaling improves impaired cardiomyocyte relaxation 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 received daily injections of GHRH-Agonist (GHRH-A [MR-409]: 100 μg/kg) or vehicle (DMSO+propylene-glycol). Cardiomyocytes were isolated and calcium and sarcomere shortening assessed. Ang-II-treated cardiomyocytes exhibited reduced sarcomere length, indicating an inability to completely relax, despite lower resting calcium. These cardiomyocytes also exhibited impaired ability to contract with no changes in calcium transient amplitude, deficient relaxation and delayed calcium decay. MR-409 treatment restored resting calcium and resting sarcomere length; improved sarcomere shortening and completely abrogated Ang-II-induced delay in calcium decline and relaxation (see figure 1). Our findings demonstrate that chronic administration of Ang-II mediates structural and functional changes consistent with HFpEF and suggest that activation of the GHRH receptor signaling pathways prevents HFpEF-associated cardiomyocyte performance alterations.