Growth Hormone Releasing Hormone Agonist Improves Cardiometabolic Parameters In A Murine Model Of Heart Failure With Preserved Ejection Fraction

The incidence of heart failure (HF) with preserved ejection fraction (HFpEF) is steadily rising, becoming the predominant form of HF. To date, no effective therapies reverse HFpEF symptoms. Several preclinical and clinical studies demonstrate that GHRH plays a role in the cardiovascular system, aging and obesity. We hypothesized that a GHRH-agonist (GHRH-A) can mitigate/reverse the HFpEF phenotype. Methods C57BL6N mice received a high fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks (HFD+L-NAME). After 5 weeks of the HFD+L-NAME regimen, animals were randomized to receive daily subcutaneous injections of GHRH-A (200 μg/Kg/day) or placebo (DMSO+ propylene glycol) for 4-weeks. Control animals received neither HFD+L-NAME nor treatment. Evaluation of cardiac performance was assessed by serial echocardiography. Blood pressure, glucose tolerance and exercise exhaustion were also evaluated. Results After 9 weeks of HFD+L-NAME there was no difference in EF, but the E/E’ ratio, global longitudinal strain (GLS), and exercise tolerance test revealed significantly impaired cardiac performance in HFpEF mice compared to control (Fig. 1A-D). Increased glucose levels were seen in the placebo group compared to control, suggesting glucose intolerance (Fig 1 E-F). GHRH-A administration improved most of these parameters (one-way ANOVA with Tukey's multiple comparisons test, *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001. Unpaired Student's t-test, *p<0.05). Conclusions Our results reveal that GHRH-A treatment reduces HFpEF-like effects associated with HFD+ L-NAME treatment, suggesting that activation of GHRH receptor signaling as an effective therapeutic strategy for the treatment of cardiometabolic HFpEF phenotype. The incidence of heart failure (HF) with preserved ejection fraction (HFpEF) is steadily rising, becoming the predominant form of HF. To date, no effective therapies reverse HFpEF symptoms. Several preclinical and clinical studies demonstrate that GHRH plays a role in the cardiovascular system, aging and obesity. We hypothesized that a GHRH-agonist (GHRH-A) can mitigate/reverse the HFpEF phenotype. C57BL6N mice received a high fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks (HFD+L-NAME). After 5 weeks of the HFD+L-NAME regimen, animals were randomized to receive daily subcutaneous injections of GHRH-A (200 μg/Kg/day) or placebo (DMSO+ propylene glycol) for 4-weeks. Control animals received neither HFD+L-NAME nor treatment. Evaluation of cardiac performance was assessed by serial echocardiography. Blood pressure, glucose tolerance and exercise exhaustion were also evaluated. After 9 weeks of HFD+L-NAME there was no difference in EF, but the E/E’ ratio, global longitudinal strain (GLS), and exercise tolerance test revealed significantly impaired cardiac performance in HFpEF mice compared to control (Fig. 1A-D). Increased glucose levels were seen in the placebo group compared to control, suggesting glucose intolerance (Fig 1 E-F). GHRH-A administration improved most of these parameters (one-way ANOVA with Tukey's multiple comparisons test, *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001. Unpaired Student's t-test, *p<0.05). Our results reveal that GHRH-A treatment reduces HFpEF-like effects associated with HFD+ L-NAME treatment, suggesting that activation of GHRH receptor signaling as an effective therapeutic strategy for the treatment of cardiometabolic HFpEF phenotype.