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.

Introduction

Heart failure (HF) is a major public health epidemic and is one of the few health conditions with increasing prevalence in developed countries. It is a major burden on society because of the poor quality of life and premature death of affected individuals, and the high costs of medical care with HF being the main cause of hospital admission for those over 65 years of age. An estimated 5.7 million Americans have heart failure, and it is predicted that a further 3 million will have heart failure by 2030 (Roger et al., 2012). Despite advances in therapies, the mortality and morbidity of HF remains at unacceptably high levels. The five year mortality rates for subjects with HF in the Framingham Heart Study were 59% for men and 45% for women (Levy et al., 2002), this rate being worse than for most cancers (Stewart et al., 2001). The increased frequency of HF is due to ageing of the population and a decrease in fatality associated with improved treatment of acute coronary syndromes.

A hallmark of HF is activation of many neurohumoral systems in response to decreased cardiac output and subsequent under-perfusion of tissues. Although these compensatory mechanisms help maintain homeostasis in the short term, chronically the increased activity of these systems leads to further deterioration and progression of HF, and a worse prognosis. Thus inhibition of the effects of the sympathetic nervous system and renin–angiotensin system (RAS) is a major focus of current therapy (CIBIS Investigators, 1994; Swedberg and Kjekshus, 1988, Pfeffer et al., 1992). It is important to note that activation of the sympathetic nervous system occurs not only in classical HF with reduced systolic ejection fraction, but also in HF with preserved ejection fraction (Kitzman et al., 2002), which is estimated to encompass 50% of the patients with clinical features of HF.