Sex differences in the progression from cardiac hypertrophy towards heart failure

Abstract

This thesis aims to investigate differential changes in Ca2+ and Na+ regulation during the development from cardiac hypertrophy to heart failure (HF) between sexes. Clinical evidences show females are more resistant to the development of cardiac hypertrophy and have better survival in HF than males. Oestrogen is postulated to provide cardioprotection although this is still under debate. This work used guinea pigs (GPs), a species with electrophysiology akin to human, that were subjected to aortic constriction (AC) to study the progression from pressure-overload cardiac hypertrophy to HF between sexes. Selected female animals underwent ovariectomy (OVx), mimicking postmenopausal status, to examine the effects of long-term deprivation of ovarian hormones. The effect of oestradiol supplementation was also investigated.

Ventricular myocytes isolated from hearts at cardiac hypertrophy had prolonged action potential duration (APD), increased Ca2+ transient amplitudes and SR Ca2+ content, reduced Na+/K+ ATPase (NKA) function and increased late sodium current (INa,L). Fractional shortening (FS) remained unchanged in these hearts. Compromised FS with detrimental Ca2+ handling, more reduced NKA function and enhanced INa,L were noted at HF. Males showed earlier declined NKA function, more compromised FS and more detrimental Ca2+ handling than females at HF.

Ventricular myocytes from OVx animals showed increased L-type Ca2+ channel current with gating shifts and larger window current, larger Ca2+ transient amplitudes, greater SR Ca2+ content, and increased Ca2+ sparks and waves. OVx myocytes showed more early and delayed afterdepolarisations (EADs and DADs) with DAD-induced extrasystoles following β-adrenergic stimulation. AC with OVx GPs showed more reduced FS, more dysregulated Ca2+ handling, more reduced NKA function and larger INa,L than AC females.

In conclusion, females were more resistant to pressure-overload. Long-term deprivation of ovarian hormones abolishes the slower onset of HF in females, and provides pro-arrhythmic substrates to females. Oestradiol supplementation offered protective effects on OVx GPs.