Evidence for female specific changes in the sympathetic nervous system in post‐infarction heart failure

Abstract

The development and progression of post‐myocardial infarction (MI) heart failure is, in part, driven by adverse changes in the sympathetic nervous system (SNS). Clinically, females, compared to males, typically have a worse outcome post‐MI. The aim of these experiments was to characterize changes in the SNS in females and males. All experiments were performed in ovary‐intact female and male Wistar rats. Following MI or sham‐MI surgery, heart failure developed over a 6–8 week period at which time left ventricular (LV) function was assessed before and following the acute infusion of metoprolol, under chloralose‐urethane anesthesia. Following the terminal experiment, brain and heart tissue were collected and processed for histochemical and molecular analyses. Post‐MI, LV function was significantly reduced in both males and females which was associated with cardiomyocyte hypertrophy and increased collagen deposition. The acute infusion of metoprolol decreased arterial pressure significantly less in females with MI (−9±2 mmHg) compared to female sham‐MI group (−21±8 mmHg, P<0.05) and male MI group (−23±3 mmHg, P<0.05). In animals with post‐infarction heart failure, metoprolol decreased cardiac output similarly in males (−33±8 ml/min) and females (−31±7 ml/min); however females responded by significantly increasing total peripheral resistance (TPR) whereas TPR was unchanged in males. In a subset of animals with post‐infarction heart failure, renal sympathetic nerve activity responses to a decrease in arterial pressure were augmented in females but not in males and arterial baroreceptor denervation abolished this response. Compared to sham MI group, LV noradrenaline (NA) tissue content was decreased in males with MI (4.6±0.2 vs. 2.7±0.4 pmol/mg, P<0.05) but was unaltered in females with MI (4.3±0.4 pmol/mg). Post‐infarction heart failure resulted in reduced nNOS levels in the paraventricular nucleus (PVN) in both males and females with MI whereas super oxide dismutase levels were decreased only in males, not females. cFOS levels in the PVN were increased in females with post‐infarction heart failure but decreased in males, possibly related to an augmented baroreflex response in female MI group following the metoprolol mediated decrease in cardiac output. The current findings show that ovary‐intact female rats have similar changes in cardiac function and remodelling in post‐infarction heart failure as males; however there are sex differences in the regulation of the SNS. In particular, these findings suggest sex differences in post‐infarction heart failure particularly in relation to the autonomic regulation of arterial pressure.Support or Funding InformationThis work was supported by grants from the University of Auckland Research and Development Fund and The National Heart Foundation of New Zealand