Epinephrine and Depletion of Female Sex Hormone Exacerbate the Pathology of Obesity-Induced Cardiac Phenotype

Abstract

Heart failure is associated with poor quality of life and mortality, and the prevalence of heart failure is increasing together with aging of the population. Approximately 50% of patients with heart failure present as HFpEF, and the survival of HFpEF patients is as poor as that of HFrEF patients. Furthermore, therapies for HFpEF are limited and are not proven to improve prognosis, except for SGLT2 inhibitors. HFpEF is more prevalent in women and the risk of HFpEF increases more drastically with aging in women than men. HFpEF is a syndrome with multiple comorbidities, and modeling HFpEF in animal models has been attempted by reproducing major comorbidities highly associated with human HFpEF. In order to elucidate the female-specific mechanisms of HFpEF, we established a new mouse model by applying additional stressors on the basis of obesity and post-menopausal model. Ovariectomy or epinephrine injection was added to a high-fat diet-induced obesity model. Ovariectomy exacerbates obesity and serial epinephrine injections ameliorate obesity. Exercise tolerance in treadmill testing was inversely correlated with body weight, and was reduced more than expected based on body weight in mice that underwent ovariectomy and epinephrine injection (OVX + Epi group). In a pressure-volume analysis, the end-diastolic pressure at afterload increase was significantly high in OVX + Epi mice, which is considered to reflect left ventricular diastolic dysfunction. In conclusion, this study demonstrated that epinephrine and depletion of female sex hormone by ovariectomy reproduce the pathology of obesity-induced cardiac phenotype, which might represent an early phase of HFpEF conditions.