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... Mark A. Clinical neurocardiol- ogy: role of the autonomic nervous system in clinical heart failure. In: Armour J, Ardell. J, eds. Neurocardiology. Oxford, England:.
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ORIGINAL PAPER

Aberrant Central Nervous System Responses to the Valsalva Maneuver in Heart Failure

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utonomic nervous system (ANS) abnormalities are common in all etiologies of heart failure (HF) and have been linked to loss of cardiac function and increased risk of ventricular dysrhythmia and sudden death.1,2 While the presence of ANS dysfunction in HF is well-known, the underlying mechanisms mediating such aberrations remain unclear. Disorders of peripheral control processes involved in ANS reactivity have been studied extensively; however, central regulation of ANS outflow is rarely examined in this patient population. A recent report of significant brain gray matter loss in HF patients, particularly in areas implicated in ANS control,3 suggests that deficient central neural function may underlie a portion of the ANS dysfunction found in the syndrome. Both parasympathetic and sympathetic branches of the ANS are affected in HF, with sympathetic outflow often exaggerated,4,5 parasympathetic activity lessened,6 and moment-tomoment reactivity in both systems often altered.7 These findings suggest that central mechanisms controlling both sustained and rapid responses to behaviors requiring adjustment of the cardiovascular system are altered in HF. The Valsalva maneuver is a noninvasive and nonpharmacologic procedure for examining both branches of the ANS.8 The test consists of a voluntary forced expiratory effort against a closed upper airway, which raises intrathoracic pressure and results in a sequence of hemodynamic changes and compensatory cardiovascular regulatory reflex activation. CNS response to Valsalva

Heart failure (HF) is associated with aberrant autonomic nervous system (ANS) activity, with altered responses to blood pressure and breathing challenges that appear to reflect abnormal central nervous system function. The authors used functional magnetic resonance imaging (fMRI) to determine whether the Valsalva maneuver, an ANS challenge, would show abnormal responses in ANS regulatory areas of the brain in HF. Brain fMRI signal changes in 5 HF patients (left ventricular ejection fraction, 0.15±0.08; age, 50±10 years) and 14 controls (age, 47±11 years) were assessed during 3 successive Valsalva maneuvers. The hypothalamus, hippocampus, putamen, amygdala, mid-cingulate, right insula, and cerebellar cortex showed exaggerated and phase-shifted fMRI responses in HF; other areas showed inverted signals from those found in controls. Central ANS control areas have altered phase, extent, and direction of responses to Valsalva maneuvers in a small sample of HF patients. These findings suggest that therapeutics that address neuroprotective aspects may be useful interventions for the condition. (CHF. 2007;13:29–35) ©2007 Le Jacq Mary A. Woo, DNSc, RN;1 Paul M. Macey, PhD;2 Peter T. Keens, BA;2 Rajesh Kumar, PhD;2 Gregg C. Fonarow, MD;3 Michele A. Hamilton, MD;3 Ronald M. Harper, PhD2 From the School of Nursing,1 the Department of Neurobiology,2 and the Division of Cardiology, David Geffen School of Medicine at UCLA,3 University of California at Los Angeles, Los Angeles, CA Address for correspondence: Mary A. Woo, DNSc, RN, UCLA School of Nursing, 700 Tiverton Avenue, Los Angeles, CA 90095-1702 E-mail: [email protected] Manuscript received July 5, 2006; revised November 9, 2006; accepted December 21, 2006

The challenge is simple to administer and can be readily performed by HF patients. The challenge also allows evaluation of the patterning of ANS responses, as timing of onset of ANS sequences (ie, sympathetic and parasympathetic activation) can be assessed. This last aspect is significant, since delayed reactivity of neural structures mediating autonomic regulation has identified ANS disturbances in another condition with chronic cardiovascular concerns, obstructive sleep apnea syndrome,9 and can aid in the identification of potential etiologies for such ANS alterations.

A noninvasive method to evaluate central neural responses to ANS stimuli is functional magnetic resonance imaging (fMRI). fMRI differs from clinical structural MRI procedures in that activity within brain areas responding to behaviors or stimuli can be visualized. Areas of the brain shown to be damaged in HF should show inappropriate fMRI responses (ie, greater, lesser, delayed, or advanced activity compared with controls) to stimuli which provoke ANS activity changes. We used the Valsalva maneuver to elicit sympathetic and parasympathetic january . february 2007

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Congestive Heart Failure® (ISSN 1527-5299) is published bimonthly (Feb., April, June, Aug., Oct., Dec.) by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright ©2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at [email protected] or 781-388-8470.

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from the community and were in good health. Exclusion criteria for all study participants were the presence of contraindications to MRI such as claustrophobia and metallic implants (implantable cardioverter-defibrillator, pacemaker, embolic coils) and weight more than 285 pounds (exceeding MRI bore size limitations). Exclusion criteria for controls included diagnosis of a cardiovascular disorder (including hypertension and heart failure, history of myocardial infarction) and neurologic diseases. The research protocol for this study was approved by the Institutional Review Board of the University of California at Los Angeles and complied with the Declaration of Helsinki. All subjects gave their written, informed consent for participation in this investigation.

Figure 1. Mean load pressure (A), breathing rate relative to baseline (B), and heart rate (C), with SE bars, during 3 Valsalva maneuvers. HF indicates heart failure patients; bpm, beats per minute.

central nervous system (CNS) outflow sequences in HF patients and evaluated fMRI signal changes throughout the brain to determine whether autonomic control areas differed from control subjects in response and whether patterns of aberrant responses emerged in brain regions that previously showed gray matter loss in HF.

Methods

Subjects. Patients with end-stage/ advanced HF, meeting HF diagnostic criteria,10 were recruited from a tertiary HF referral center. Inclusion criteria included systolic HF, left ventricular ejection fraction