Phillips, Jacqueline Kathleen

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Jacqueline Kathleen Phillips

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Autonomic dysfunction in heart failure and renal disease

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Editorial
published: 26 June 2012
doi: 10.3389/fphys.2012.00219
Autonomic dysfunction in heart failure and renal disease
Jacqueline Kathleen Phillips*
Australian School of Advanced Medicine, Faculty of Human Sciences, Macquarie University, Sydney, NSW, Australia
*Correspondence: jacqueline.phillips@mq.edu.au
Edited by:
Geoffrey A. Head, BakerIDI Heart and Diabetes Institute, Australia
Reviewed by:
Geoffrey A. Head, BakerIDI Heart and Diabetes Institute, Australia
In the methods paper presented by Reulecke et al. (2012), auto-
nomic 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 (Taskforce, 1996), 
but through a complex series of analyses, Reulecke et al. (2012) 
show that while the relationship between heart rate and respira-
tion 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 modu-
lation 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 (Voss et al., 2006).
The central mechanisms that may drive autonomic dysfunction 
in heart failure, and specifically increased sympathetic outflow, are 
reviewed in the paper by Campos et al. (2011). 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 (Schinke et al., 1999). 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 ven-
tricular remodeling (Wang et al., 2004). 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 Schlaich et al. (2012), the topical issue 
of renal denervation is reviewed by the pioneers of this approach. 
This treatment is receiving marked scientific and community inter-
est, 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, insu-
lin, and C-peptide levels, in addition to reduced insulin resistance 
(Mahfoud et al., 2011; Schlaich et al., 2012). 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 the clinical settings of heart failure and chronic kidney disease, 
autonomic dysfunction is increasingly being recognized as hav-
ing direct detrimental effects (Klein et al., 2003; May et al., 2010; 
Schwartz and De Ferrari, 2011). More broadly across the fields of 
cardiovascular and renal disease, research efforts are being directed 
toward understanding the mechanisms that bind complex interac-
tions 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 
(Zucker et al., 2009) and current developments in renal denervation 
as a treatment for resistant hypertension are examples of this (Krum 
et al., 2009; Esler et al., 2010). 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 Hildreth (2011), 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 stud-
ies 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 param-
eters. Hildreth (2011) hypothesizes that this may be due to periph-
eral 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 (Yang et al., 2010).
The association between autonomic dysfunction, as determined 
using HRV parameters, and increased risk of mortality and morbid-
ity in cardiovascular disease is further demonstrated in the original 
research article by Norman et al. (2012). 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 fur-
ther 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.
www.frontiersin.org June 2012 | Volume 3 | Article 219 | 1
in blood pressure in these patients, but indications of improve-
ment in other clinical markers including hemoglobin levels and 
peripheral augmentation index (Hering et al., 2012).
The broader implications of renal denervation as a therapeu-
tic option are still under consideration, and this is addressed in 
the review by Vink and Blankestijn (2012), who raise questions 
 regarding the wide range of responses amongst patients after renal 
denervation and the mechanism(s) responsible for non-respond-
ers (Esler et al., 2010). Questions are also posed as to how best 
monitor the intervention. As highlighted in their review (Vink 
and Blankestijn, 2012), the kidney is both a generator and recipi-
ent 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 Hildreth (2011), meas-
ures 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 dysfunc-
tion can be applied both as a measure of risk and a specific target 
for treatment options.
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Received: 24 May 2012; accepted: 01 June 2012; published online: 26 June 2012.
Citation: Phillips JK (2012) Autonomic dysfunction in heart failure and renal disease. 
Front. Physio. 3:219. doi: 10.3389/fphys.2012.00219
This article was submitted to Frontiers in Integrative Physiology, a specialty of Frontiers 
in Physiology.
Copyright © 2012 Phillips. This is an open-access article distributed under the terms of the 
Creative Commons Attribution Non Commercial License, which permits non-commercial 
use, distribution, and reproduction in other forums, provided the original authors and 
source are credited. 
Phillips Cardiac, renal and autonomic function
Frontiers in Physiology | Integrative Physiology  June 2012 | Volume 3 | Article 219 | 2


Autonomic Dysfunction in Heart Failure and Renal Disease

Macquarie University ResearchOnline

Editorial : Autonomic dysfunction in heart failure and renal disease

Crossref

[Epub ahead of print].

accepted: 01

Autonomic dysfunction in heart failure and renal disease.

Brain renin-angiotensin system in hypertension, cardiac hypertrophy, and heart failure.

Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.

doi: 10.3389/fphys.2012.00219 This article was submitted to Frontiers in Integrative Physiology, a specialty of Frontiers

Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study.

Effects of renal denervation on sympathetic activation, blood pressure, and glucose metabolism in patients with resistant hypertension.

Evidence and consequences of the central role of the kidneys in the pathophysiology of sympathetic hyperactivity.

Heart rate variability during hemodialysis and following renal transplantation.

Heart rate variability predicts cell death and inflammatory responses to global cerebral ischemia.

Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the

Prevention of sympathetic and cardiac dysfunction after myocardial infarction in transgenic rats deficient in brain angiotensinogen.

Prognostic indicators of cardiovascular risk in renal disease.

Regulation of central angiotensin type 1 receptors and sympathetic outflow in heart failure.

renal and autonomic function Frontiers

Specific control of sympathetic nerve activity to the mammalian heart and kidney.

Sympathetic nerve activity is inappropriately increased in chronic renal disease.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3382733

Autonomic Dysfunction in Heart Failure and Renal Disease

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