This Research Topic focuses on autonomic dysfunction, both central and peripheral, in the clinical settings of heart failure and renal disease, with papers extending from molecular to clinical investigations. There is growing interest in the mechanisms driving autonomic dysfunction in heart failure and renal disease because of the recognition that this activity has direct detrimental effects, and that there is a need for novel treatments targeting both hypertension and target end organ damage.   Recent developments in renal denervation are an example of this. Further, heart disease, renal disease and autonomic dysfunction can be linked under the umbrella of a number of different disease states including obesity, diabetes and depression.

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Frontiers in Physiology

Integrative Physiology

Autonomic dysfunction in heart failure and renal disease

In the clinical settings of heart failure and chronic kidney disease, autonomic dysfunction is increasingly being recognized as having direct detrimental effects (<a href="#B5">Klein et al., 2003</a>; <a href="#B8">May et al., 2010</a>; <a href="#B13">Schwartz and De Ferrari, 2011</a>). More broadly across the fields of cardiovascular and renal disease, research efforts are being directed toward understanding the mechanisms that bind complex interactions between the autonomic, cardiovascular, and renal systems. The ultimate goal being the identification of innovative diagnostic and treatment approaches that limit hypertension and target end organ damage. Our increasing knowledge of the role of the central renin angiotensin system (RAS) in mediating autonomic function (<a href="#B19">Zucker et al., 2009</a>) and current developments in renal denervation as a treatment for resistant hypertension are examples of this (<a href="#B6">Krum et al., 2009</a>; <a href="#B2">Esler et al., 2010</a>). This Frontiers Research Topic brings together original research, methods, and review articles to provide an overall perspective on this interaction. These manuscripts serve to highlight not only the critical role of the autonomic nervous system, but also the potential usage of non-invasive measures of sympathetic and parasympathetic outflow as diagnostic and predictive tools.As reviewed by <a href="#B4">Hildreth (2011)</a>, in patients with renal disease, sympatho-vagal imbalance (namely increased sympathetic and decreased parasympathetic function) is a prognostic indicator of cardiovascular mortality, as measured using the autonomic indices of heart rate variability (HRV), baroreflex sensitivity (BRS), and baroreceptor reflex effectiveness index (BEI). A comparison of studies utilizing various measures of HRV and baroreflex function in end stage renal disease patients show that a progressive decline in renal function can be correlated with a reduction in these parameters. <a href="#B4">Hildreth (2011)</a> hypothesizes that this may be due to peripheral changes, such as vascular stiffness, or alternatively, abnormal central processing or an inability of the cardiac autonomic efferents to effectively control heart rate. The major role of the kidneys in driving autonomic dysfunction and subsequent cardiovascular disease is highlighted by studies that show renal transplantation results in an improvement in HRV parameters (<a href="#B18">Yang et al., 2010</a>).The association between autonomic dysfunction, as determined using HRV parameters, and increased risk of mortality and morbidity in cardiovascular disease is further demonstrated in the original research article by <a href="#B9">Norman et al. (2012)</a>. Using a model of acute cardiac arrest in the mouse, the authors demonstrate an inverse linear relationship between HRV and measures of neuronal cell damage and microglial activation in the hippocampus. While further work in this area is required to establish causality, this study raises the exciting possibility that HRV can be used as a non-invasive measure to determine and monitor neuronal damage after cardiac arrest and global cerebral ischemia.In the methods paper presented by <a href="#B10">Reulecke et al. (2012)</a>, autonomic function is examined in healthy preterm neonates, applying HRV to cardiorespiratory data using non-linear methods. Reference HRV data is currently only available for adults (<a href="#B14">Taskforce, 1996</a>), but through a complex series of analyses, <a href="#B10">Reulecke et al. (2012)</a> show that while the relationship between heart rate and respiration in preterm infants is not fully developed, there is a difference in the degree of control during quiet and active sleep states, with the quiet state demonstrating an increased degree of vagal modulation or activity. This study provides a clear step forward in our knowledge of the development of autonomic function in humans. It further highlights the potential application of HRV as a way of monitoring this critical subgroup of patients for disorders of the cardiovascular and respiratory systems, and as used in adults, predicting cardiovascular risk (<a href="#B16">Voss et al., 2006</a>).The central mechanisms that may drive autonomic dysfunction in heart failure, and specifically increased sympathetic outflow, are reviewed in the paper by <a href="#B1">Campos et al. (2011)</a>. The role of the brain RAS is examined, with an extensive review of the authors previous studies using the [TGR(AsrAOGEN)] transgenic rat, where just brain angiotensinogen is inhibited (<a href="#B11">Schinke et al., 1999</a>). These animals show a number of differences to control animals under baseline conditions, including low blood pressure and diabetes, but most notably, under imposed cardiovascular disease such as myocardial infarction, sympathetic hyperactivity is markedly attenuated in the transgenic animals, alongside reduced left ventricular remodeling (<a href="#B17">Wang et al., 2004</a>). This body of work supports pharmacological targeting of brain RAS as a treatment option for disorders characterized by autonomic dysfunction.In the review provided by <a href="#B12">Schlaich et al. (2012)</a>, the topical issue of renal denervation is reviewed by the pioneers of this approach. This treatment is receiving marked scientific and community interest, and has opened up not only an exciting therapeutic option but also consolidated our appreciation of the critical role renal afferents play as drivers of central sympathetic outflow. The review article looks further into the links between sympathetic outflow and glucose metabolism, with data presented from a group of patients who, after renal denervation, show improved fasting glucose, insulin, and C-peptide levels, in addition to reduced insulin resistance (<a href="#B7">Mahfoud et al., 2011</a>; <a href="#B12">Schlaich et al., 2012</a>). The benefits of renal denervation are therefore not limited to blood pressure control alone, and in line with the theme of this Frontiers Research Topic, the authors conclude that patients with chronic kidney disease or heart failure may also be suitable candidates for this approach. Indeed, a recent pilot study assessing renal denervation in patients with moderate to severe renal disease indicates not only a reduction in blood pressure in these patients, but indications of improvement in other clinical markers including hemoglobin levels and peripheral augmentation index (<a href="#B3">Hering et al., 2012</a>).The broader implications of renal denervation as a therapeutic option are still under consideration, and this is addressed in the review by <a href="#B15">Vink and Blankestijn (2012)</a>, who raise questions regarding the wide range of responses amongst patients after renal denervation and the mechanism(s) responsible for non-responders (<a href="#B2">Esler et al., 2010</a>). Questions are also posed as to how best monitor the intervention. As highlighted in their review (<a href="#B15">Vink and Blankestijn, 2012</a>), the kidney is both a generator and recipient of sympathetic activity, with increased sympathetic activity being an early event in the pathophysiology of renal failure that correlates with disease severity. Autonomic dysfunction is a key feature therefore, and as described by <a href="#B4">Hildreth (2011)</a>, measures such as HRV or BRS/BEI may prove to be clinically viable approaches by which to not only assess autonomic function after renal denervation, but also be a valuable long term measure for monitoring outcomes.In conclusion, this Frontiers Review Topic will hopefully serve to provide an comprehensive overview of the critical role played by the autonomic nervous system in heart failure and renal disease, and stimulate interest in how determination of autonomic dysfunction can be applied both as a measure of risk and a specific target for treatment options.

Autonomic Dysfunction in Heart Failure and Renal Disease

This study examines the relationship between autonomic functioning and neuropathology following cardiac arrest (CA) in mice. Within 24 h of CA, parasympathetic cardiac control, as indexed by high frequency (HF) heart rate variability, rapidly decreases. By day 7 after CA, HF heart rate variability was inversely correlated with neuronal damage and microglial activation in the hippocampus. Thus, by virtue of its sensitivity to central insult, HF heart rate variability may offer an inexpensive, non-invasive method of monitoring neuropathological processes following CA. The inverse linear relationships between heart rate variability and brain damage after CA also may partially explain why low heart rate variability is associated with increased morbidity and mortality in myocardial infarction patients.

This study examines the relationship between autonomic functioning and neuropathology following cardiac arrest (CA) in mice. Within 24 h of CA, parasympathetic cardiac control, as indexed by high frequency (HF) heart rate variability, rapidly decreases. By day 7 after CA, HF heart rate variability was inversely correlated with neuronal damage and microglial activation in the hippocampus. Thus, by virtue of its sensitivity to central insult, HF heart rate variability may offer an inexpensive, non-invasive method of monitoring neuropathological processes following CA. The inverse linear relationships between heart rate variability and brain damage after CA also may partially explain why low heart rate variability is associated with increased morbidity and mortality in myocardial infarction patients.

Heart Rate Variability Predicts Cell Death and Inflammatory Responses to Global Cerebral Ischemia

The immature autonomic nervous system (ANS) in premature infants regulates heart rate (HR) and respiration different during quiet sleep (QS) and active sleep (AS). Little information is available about ANS regulation in these subjects. The aim of this study was to investigate changes in autonomic regulation and cardiorespiratory coupling during AS and QS in five very preterm neonates with gestational age (GA) 26–31 weeks, applying univariate and bivariate linear and non-linear dynamics methods to the recorded cardiorespiratory signals. During QS univariate linear indices revealed lower standard deviations and entropies, indicating decreased heart rate (HR) variability. More balanced sympatho-vagal behavior of the ANS was revealed by decreased low frequency (LF), increased high frequency (HF), and a trend toward lower ratio LF/HF in QS. Applied non-linear indices (probabilities, entropies, and fractal measures) quantifying the complexity and scaling behavior of HR regulation processes were significantly altered in QS in comparison to AS. This reflects a lower short-term variability, less complexity, and a loss of fractal-like correlation properties of HR dynamics in QS. One major finding is that cardiorespiratory coupling is not yet completely developed in very preterm neonates with 26–31 weeks GA. Significantly different regulation patterns in bivariate oscillations of HR and respiration during AS and QS could be recognized. These patterns were characterized on the one hand by predominant monotonous regulating sequences originating from respiration independently from HR time series in AS, and to a minor degree in QS, and on the other hand by some prominent HR regulation sequences in QS independent of respiratory regulation. We speculate that these findings might be suitable for monitoring preterm neonates and for detecting disorders in the developing cardiorespiratory system.

The immature autonomic nervous system (ANS) in premature infants regulates heart rate (HR) and respiration different during quiet sleep (QS) and active sleep (AS). Little information is available about ANS regulation in these subjects. The aim of this study was to investigate changes in autonomic regulation and cardiorespiratory coupling during AS and QS in five very preterm neonates with gestational age (GA) 26&#x2013;31 weeks, applying univariate and bivariate linear and non-linear dynamics methods to the recorded cardiorespiratory signals. During QS univariate linear indices revealed lower standard deviations and entropies, indicating decreased heart rate (HR) variability. More balanced sympatho-vagal behavior of the ANS was revealed by decreased low frequency (LF), increased high frequency (HF), and a trend toward lower ratio LF/HF in QS. Applied non-linear indices (probabilities, entropies, and fractal measures) quantifying the complexity and scaling behavior of HR regulation processes were significantly altered in QS in comparison to AS. This reflects a lower short-term variability, less complexity, and a loss of fractal-like correlation properties of HR dynamics in QS. One major finding is that cardiorespiratory coupling is not yet completely developed in very preterm neonates with 26&#x2013;31 weeks GA. Significantly different regulation patterns in bivariate oscillations of HR and respiration during AS and QS could be recognized. These patterns were characterized on the one hand by predominant monotonous regulating sequences originating from respiration independently from HR time series in AS, and to a minor degree in QS, and on the other hand by some prominent HR regulation sequences in QS independent of respiratory regulation. We speculate that these findings might be suitable for monitoring preterm neonates and for detecting disorders in the developing cardiorespiratory system.

Autonomic Regulation during Quiet and Active Sleep States in Very Preterm Neonates

Chronic elevation of the sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload – such as heart failure – and progressive kidney disease. It is also a strong determinant for clinical outcome. This review focuses on the central role of the kidneys in the pathogenesis of sympathetic hyperactivity. As a consequence, renal denervation may be an attractive option to treat sympathetic hyperactivity. The review will also focus on first results and the still remaining questions of this new treatment option.

Chronic elevation of the sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload &#x2013; such as heart failure &#x2013; and progressive kidney disease. It is also a strong determinant for clinical outcome. This review focuses on the central role of the kidneys in the pathogenesis of sympathetic hyperactivity. As a consequence, renal denervation may be an attractive option to treat sympathetic hyperactivity. The review will also focus on first results and the still remaining questions of this new treatment option.

Evidence and Consequences of the Central Role of the Kidneys in the Pathophysiology of Sympathetic Hyperactivity

Increased central sympathetic drive is a hallmark of several important clinical conditions including essential hypertension, heart failure, chronic kidney disease, and insulin resistance. Afferent signaling from the kidneys has been identified as an important contributor to elevated central sympathetic drive and increased sympathetic outflow to the kidney and other organs is crucially involved in cardiovascular control. While the resultant effects on renal hemodynamic parameters, sodium and water retention, and renin release are particularly relevant for both acute and long term regulation of blood pressure, increased sympathetic outflow to other vascular beds may facilitate further adverse consequences of sustained sympathetic activation such as insulin resistance, which is commonly associated with hypertension. Recent clinical studies using catheter-based radiofrequency ablation technology to achieve functional renal denervation in patients with resistant hypertension have identified the renal nerves as therapeutic target and have helped to further expose the sympathetic link between hypertension and insulin resistance. Initial data from two clinical trials and several smaller mechanistic clinical studies indicate that this novel approach may indeed provide a safe and effective treatment alternative for resistant hypertension and some of its adverse consequences.

Increased central sympathetic drive is a hallmark of several important clinical conditions including essential hypertension, heart failure, chronic kidney disease, and insulin resistance. Afferent signaling from the kidneys has been identified as an important contributor to elevated central sympathetic drive and increased sympathetic outflow to the kidney and other organs is crucially involved in cardiovascular control. While the resultant effects on renal hemodynamic parameters, sodium and water retention, and renin release are particularly relevant for both acute and long term regulation of blood pressure, increased sympathetic outflow to other vascular beds may facilitate further adverse consequences of sustained sympathetic activation such as insulin resistance, which is commonly associated with hypertension. Recent clinical studies using catheter-based radiofrequency ablation technology to achieve functional renal denervation in patients with resistant hypertension have identified the renal nerves as therapeutic target and have helped to further expose the sympathetic link between hypertension and insulin resistance. Initial data from two clinical trials and several smaller mechanistic clinical studies indicate that this novel approach may indeed provide a safe and effective treatment alternative for resistant hypertension and some of its adverse consequences.

Effects of Renal Denervation on Sympathetic Activation, Blood Pressure, and Glucose Metabolism in Patients with Resistant Hypertension

Although the annual mortality rate for end-stage renal disease (ESRD) is decreasing, likely due to an increase in kidney transplantation rate, the survival probability for ESRD patients from day one of dialysis has not changed, and is still poor with a 5-year survival rate of approximately 34%. This is contributed to by a high prevalence of cardiovascular disease, which is the leading cause of death in ESRD patients. In order to improve survival outcomes, patients at high risk of cardiovascular related mortality need to be identified. Heart rate variability (HRV), baroreceptor sensitivity, and baroreceptor reflex effectiveness index can be used to assess heart rate control and may predict cardiovascular mortality. This paper will discuss how HRV, baroreceptor sensitivity, and baroreceptor reflex effectiveness index are altered in renal disease and the utility of these indices as markers of cardiac risk in this patient population.

Although the annual mortality rate for end-stage renal disease (ESRD) is decreasing, likely due to an increase in kidney transplantation rate, the survival probability for ESRD patients from day one of dialysis has not changed, and is still poor with a 5-year survival rate of approximately 34%. This is contributed to by a high prevalence of cardiovascular disease, which is the leading cause of death in ESRD patients. In order to improve survival outcomes, patients at high risk of cardiovascular related mortality need to be identified. Heart rate variability (HRV), baroreceptor sensitivity, and baroreceptor reflex effectiveness index can be used to assess heart rate control and may predict cardiovascular mortality. This paper will discuss how HRV, baroreceptor sensitivity, and baroreceptor reflex effectiveness index are altered in renal disease and the utility of these indices as markers of cardiac risk in this patient population.

Prognostic Indicators of Cardiovascular Risk in Renal Disease

Brain renin–angiotensin system (RAS) is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the development of cardiac hypertrophy and fibrosis through sympathetic activation. Inhibition of sympathetic hyperactivity after myocardial infarction through suppression of the brain RAS appears beneficial. Furthermore, the brain RAS modulates the cardiovascular and fluid–electrolyte homeostasis not only by interacting with the autonomic nervous system but also by modulating hypothalamic–pituitary axis and vasopressin release. The brain RAS is also involved in the modulation of circadian rhythms of arterial pressure, contributing to non-dipping hypertension. We conclude that the brain RAS in pathophysiological states interacts synergistically with the chronically overactive RAS through a positive biofeedback in order to maintain a state of alert in diseased conditions, such as cardiac hypertrophy and failure. Therefore, targeting brain RAS with drugs such as renin or angiotensin converting enzyme inhibitors or receptor blockers having increased brain penetrability could be of advantage.

Brain renin&#x2013;angiotensin system (RAS) is significantly involved in the roles of the endocrine RAS in cardiovascular regulation. Our studies indicate that the brain RAS participates in the development of cardiac hypertrophy and fibrosis through sympathetic activation. Inhibition of sympathetic hyperactivity after myocardial infarction through suppression of the brain RAS appears beneficial. Furthermore, the brain RAS modulates the cardiovascular and fluid&#x2013;electrolyte homeostasis not only by interacting with the autonomic nervous system but also by modulating hypothalamic&#x2013;pituitary axis and vasopressin release. The brain RAS is also involved in the modulation of circadian rhythms of arterial pressure, contributing to non-dipping hypertension. We conclude that the brain RAS in pathophysiological states interacts synergistically with the chronically overactive RAS through a positive biofeedback in order to maintain a state of alert in diseased conditions, such as cardiac hypertrophy and failure. Therefore, targeting brain RAS with drugs such as renin or angiotensin converting enzyme inhibitors or receptor blockers having increased brain penetrability could be of advantage.