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(Circulation. 2004;110:e34.)
© 2004 American Heart Association, Inc.

Correspondence

Vagal Nerve Stimulation in Chronic Heart Failure: An Antiinflammatory Intervention?

Jochen Springer, PhD

Division of Applied Cachexia Research, Department of Cardiology, Charité Campus Virchow-Klinikum, Berlin, Germany

Darlington O. Okonko, BSc, MRCP; Stefan D. Anker, MD, PhD

Clinical Cardiology, National Heart & Lung Institute, Imperial College, London, UK, s.anker{at}imperial.ac.uk

To the Editor:

Li et al¹ recently reported that vagal nerve stimulation improved survival in otherwise untreated rats with heart failure secondary to left coronary artery ligation. Although this finding is indeed intriguing and of potential therapeutic importance, the authors are understandably speculative about the possible mechanisms underlying this observation.

The authors discuss that the beneficial effects seen in their study cannot solely be ascribed to vagal inhibition of myocardial presynaptic norepinephrine release or to the attenuation of cardiomyocyte G-protein interactions that normally augment ß-adrenergic tone. Although the inhibition of sympathetic activity may partly account for the benefits observed, there are likely to be, we suggest, additional and important effects on the chronic inflammation seen in chronic heart failure (CHF).

It is increasingly appreciated that efferent vagal nerve stimulation can directly and rapidly regulate immune responses. Vagal nerve stimulation can inhibit the release of cytokines like tumor necrosis factor; interleukins-1, -6, and -18 (but not interleukin-10); and intracellular high-mobility group B1 protein. In particular, vagal nerve stimulation protects against endotoxemia² and ischemia-reperfusion injury.³ Tracey has termed this the "cholinergic anti-inflammatory pathway" or "the inflammatory reflex."³ Mechanistically, the process seems to depend on the nicotinic acetylcholine receptor -7 subunit.⁴

In edematous human CHF patients, increased levels of proinflammatory endotoxin (LPS) have been detected.⁵ Plausibly, we propose that increased levels of LPS may have been present in the studied rats with untreated CHF. These rats were treated from 2 weeks onward. At this time, >60% had died, and many were severely ill, as indicated by the subsequent 20-week mortality rate of 50% in the sham-treated CHF rats. Therefore, it can be considered that among other properties, vagal stimulation was a highly effective antiinflammatory treatment that was applied to animals with advanced CHF (likely equivalent to New York Heart Association class IV in humans). It is our contention that this study may have demonstrated the potential utility of antiinflammatory and particularly anti-LPS therapies in severe CHF.

References

1. Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation. 2004; 109: 120–124.Epub 2003 Dec 8.[Abstract/Free Full Text]
   
2. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000; 405: 458–462.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Tracey KJ. The inflammatory reflex. Nature. 2002; 420: 853–859.[CrossRef][Medline] [Order article via Infotrieve]
   
4. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003; 421: 384–388.[CrossRef][Medline] [Order article via Infotrieve]
   
5. Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, Rauchhaus M, Poole-Wilson PA, Coats AJ, Anker SD. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999; 353: 1838–1842.[CrossRef][Medline] [Order article via Infotrieve]
   

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Response

Meihua Li, PhD; Can Zheng, PhD; Toru Kawada, MD; Masaru Sugimachi, MD; Kenji Sunagawa, MD

Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Suita, Japan

Takayuki Sato, MD

Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan, tacsato-kochimed{at}umin.ac.jp

We, along with Drs Springer, Okonko, and Anker, speculate about the possibility that vagal stimulation improves survival in severe chronic heart failure (CHF) through the inhibition of the release of cytokines such as tumor necrosis factor- (TNF-).¹ In an earlier cohort study, they showed that the plasma levels of the endotoxins, cytokines, and C-reactive protein were higher in edematous CHF patients than in stable CHF patients, suggesting that altered gut permeability with bacterial translocation and endotoxemia triggers immune activation in CHF patients during edematous episodes.² A recent clinical trial shows that pentoxifylline, an inhibitor of TNF- synthesis at its transcriptional level, improved cardiac function and reduced the plasma level of TNF- and C-reactive protein in CHF patients.³ Although we did not measure the plasma concentration of endotoxins or cytokines, there was no significant difference between the treated and untreated CHF rats in the plasma level of C-reactive protein (Li et al, unpublished observation, 2003).

At this stage, there is no supporting evidence that the immunomodulating agents⁴ and the cholinergic antiinflammatory effects⁵ improve survival in CHF. Therefore, to clarify the mechanisms for beneficial effects of vagal stimulation on CHF, further studies, including immunological assay, are needed.

References

1. Li M, Zheng C, Sato T, et al. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation. 2004; 109: 120–124.[Abstract/Free Full Text]
   
2. Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999; 353: 1838–1842.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Sliwa K, Woodiwiss A, Kone VN, et al. Therapy of ischemic cardiomyopathy with the immunomodulating agent pentoxifylline: results of a randomized study. Circulation. 2004; 109: 750–755.[Abstract/Free Full Text]
   
4. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation. 2003; 107: 3133–3140.[Abstract/Free Full Text]
   
5. Tracey KJ. The inflammatory reflex. Nature. 2002; 420: 853–859.[CrossRef][Medline] [Order article via Infotrieve]
   

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