The Effect of Oestrogen on Ca2+ and Na+ Regulation in Heart Failure

Abstract

In this work, we show that long-term absence of oestrogen impairs cardiac function and produces detrimental changes to Ca2+ and Na+ regulation in cardiomyocytes following pressure-overload heart failure (HF). Oestrogen supplementation reverses the negative effects of ovariectomy following HF. Pressure-overload HF was induced by aortic constriction (AC) in female guinea pigs. To examine the effects of long-term absence of oestrogen on HF progression, selected ovariectomy (OV) animals underwent AC (ACOV). Pellets containing 17β-oestradiol (1mg, 60-day release) were placed subcutaneously in selected ACOV animals (ACOV+E). Electrophysiological and fluorescence techniques were used to assess Ca2+ and Na+ regulation 150 days post-operatively. ACOV animals heart weight/body weight ratios increased by 11% and in vivo fractional shortening decreased by 14% compared with the AC group, suggesting greater impairment of cardiac function following pressure-overload in the absence of oestrogen. Action potential duration increased in all three interventions but the changes were oestrogen-independent. While ICa and fractional SR Ca2+ release were unaltered, myocytes from ACOV animals typically had reduced Ca2+ transient amplitudes, slower transient decay kinetics, decreased SR Ca2+ contents and increased Ca2+ spark frequencies and spark mediated SR Ca2+ leak compared with the AC and ACOV+E groups. The Na+/K+ ATPase current densities and Na+ extrusion rates were reduced by 13% and 19%, respectively, in parallel with a 17% increased INa,L current densities following ACOV compared with the AC group. Interestingly, myocytes isolated from ACOV animals supplemented with 17β-oestradiol (ACOV+E) typically had similar Ca2+ and Na+ regulation compared with the gonad-intact AC group. Here we present that long-term deprivation of oestrogen, in an animal model whose electrophysiological and hormonal status is akin to human, exacerbates the detrimental effects of pressure-overload HF. Oestrogen supplementation reverses the negative effects of ovariectomy following AC.