Cardiac sympathoexcitation in heart failure

Abstract

Heart failure (HF) is a serious debilitating condition with poor survival rates and an increasing level of prevalence. The excessive sympatho-excitation that is a hallmark of heart failure has long-term effects that contribute to disease progression. The mechanisms causing the increase in renal sympathetic nerve activity (RSNA) have been extensively investigated in experimental models of heart failure, but there is less information on the factors causing the increase in cardiac SNA (CSNA). This review focuses on our recent investigations of the mechanisms driving the increased CSNA in an ovine rapid ventricular pacing model of HF. In conscious sheep with mild heart failure (ejection fraction 35-40%) the arterial baroreflex control of CSNA was normal. In contrast, the normal inhibition of CSNA with volume expansion was abolished in HF, indicating desensitisation of the cardiopulmonary mechano-reflex. Antagonism of central angiotensin AT1 receptors with losartan substantially reduced CSNA, demonstrating a critical role for the central renin-angiotensin system. Investigation of the role of the paraventricular nucleus of the hypothalamus (PVN), which plays a critical role in setting the increased RSNA in HF, demonstrated that the PVN did not maintain the increased CSNA in HF or the resting level of CSNA in normal animals. Furthermore, inhibition of the PVN in normal animals reversed the reduction in RSNA, but not CSNA, induced by volume expansion. These studies emphasise that the mechanisms controlling CSNA in the normal state, and causing the increase in HF, are different to those controlling sympathetic activity to the kidney.