Skip Navigation

European Heart Journal 2003 24(24):2164-2165; doi:10.1016/j.ehj.2003.10.016
Copyright © 2003 by the European Society of Cardiology.
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in EHJ
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Wollert, K. C
Right arrow Articles by Drexler, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wollert, K. C
Right arrow Articles by Drexler, H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Editorial

Growth hormone and proinflammatory cytokine activation in heart failure

Just a new verse to an old sirens’ song?

Kai C Wollert and Helmut Drexler*

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany

* Corresponding author: Prof. H. Drexler, Abt. Kardiologie und Angiologie Med. Hochschule Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany. Tel.: +49-511-532-3840; Fax: +49-511-532-5412
E-mail address: drexler.helmut{at}mh-hannover.de

Received 9 October 2003; accepted 23 October 2003

See doi:10.1016/S1095-668X(03)00480-9for thearticle to which this editorial refers

Despite recent advances in pharmacotherapy, patients living with heart failure carry a heavy burden in terms of morbidity and mortality. For example, in a recently completed large-scale clinical trial, 30% of patients with stable NYHA class II or III heart failure died during a mean follow-up period of less than 3 1/2 years; at the same time, 25% of these patients were hospitalized at least once for worsening heart failure, despite optimal combination treatment with an ACE-inhibitor, AT1-receptor antagonist, and ß-blocker.1Apparently, we have reached a therapeutic ceiling with traditional neurohormonal approaches for treating heart failure. Fortunately, however, additional therapeutic strategies are actively being explored. In this context, growth hormone (GH) has been proposed as a treatment modality for heart failure patients.2Remarkably, the scientific rationale that has stimulated research into growth hormone as an adjunctive therapy for heart failure appears to be diametrically opposed to the concept that gave rise to the aforementioned neurohormonal strategies for treating heart failure. The neurohormonal concept of heart failure predicts that persistent activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system promotes maladaptive cardiac hypertrophy that results in contractile dysfunction and progressive ventricular dilatation.3–5Neurohormonal antagonists halt or even reverse this deleterious hypertrophy/remodeling process.6Treatment with GH, by contrast, promotes cardiac hypertrophy in heart failure patients.7,8It has been argued that the concentric pattern of left ventricular (LV) hypertrophy induced by GH yields favourable effects on LV contractile function and remodelling by reducing LV wall stress according to Laplace’s law.9Moreover, experimental studies have demonstrated that treatment with GH enhances intrinsic cardiac myocyte contractile function, restores myocardial sarcoplasmic reticulum Ca2+-ATPase expression levels, and increases myocardial capillary density in the failing heart, suggesting that GH may promote an ‘adaptive’ form of cardiac hypertrophy.9,10In addition to these purported beneficial cardiac effects, GH treatment reportedly promotes favourable non-cardiac effects in chronic heart failure by reducing skeletal muscle atrophy and enhancing skeletal muscle strength, and by correcting peripheral vascular endothelial dysfunction.11,12

In this issue, Adamopoulos et al. propose yet another mechanism whereby treatment with GH might exert beneficial effects in heart failure. Using a randomized crossover design in 12 patients with idiopathic dilated cardiomyopathy, the authors show that a 3 month course of GH reduces circulating levels of proinflammatory cytokines and inflammatory markers, including tumor necrosis factor-{alpha} (TNF{alpha}), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor and its soluble receptor, macrophage chemoattractant protein-1, and soluble adhesion molecules.13Consistent with some earlier reports, GH treatment promotedincreases in LV wall thickness, LV contractile indices, and exercise capacity, and a decrease in LV wall stress.13Adamopoulos et al. propose that suppression of proinflammatory markers by GH is a desirable treatment effect. Considering that recent clinical trials evaluating the therapeutic efficacy of selective TNF{alpha}-antagonists have produced negative results,14that IL-6 related cytokines may actually promote beneficial effects in the failing heart,15and that we know little about the pathophysiological role in the setting of heart failure (if any) of the other ‘inflammatory markers’ suppressed by GH, such a conclusion is speculative at the present time. These caveats in mind, it is possible that suppression of inflammatory markers by GH is beneficial in heartfailure, given the substantial body of evidence that sustained activation of proinflammatory cytokines(especially TNF{alpha}) produces maladaptive effects in the failing heart.16As recently discussed by Douglas Mann,17previous targeted anti-TNF{alpha} therapies may have failed because the biological agents that were used in these trials had intrinsic toxicity. Therefore, the concept of cytokine-antagonism as a therapeutic strategy in heart failure may still be alive,16,17and GH may represent a novel and comprehensive anti-inflammatory approach in this regard.

As outlined above, the ode to GH as a therapeutic adjunct for heart failure patients has many verses already, and a new one has just been added. Unfortunately, we still do not know whether we are, in fact, listening to a Sirens’ song. Despite a wealth of experimental studies and early clinical reports, suggesting that GH improves cardiac function and functional capacity in heart failure, (small-scale) randomized studies have failed to confirm that GH promotes functional improvement in heart failure patients (reviewed in [2]). Will someone have the courage (and the financial support) to carry out a randomized, placebo-controlled clinical trial with sufficient statistical power to address the impact of growth hormone on morbidity and mortality in heart failure patients?

References

  1. McMurray JJ, Ostergren J, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767–771.[CrossRef][Web of Science][Medline]
  2. Demers C, McKelvie RS. Growth hormone therapy in heart failure: where are we now? Congest Heart Fail. 2003;9:84–90.[Medline]
  3. Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992;20:248–254.[Abstract]
  4. Braunwald E, Bristow MR. Congestive heart failure: fifty years of progress. Circulation. 2000;102:IV14–IV23.
  5. Dorn GW 2nd, Robbins J, Sugden PH. Phenotyping hypertrophy: eschew obfuscation. Circ Res. 2003;92:1171–1175.[Free Full Text]
  6. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000;35:569–582.[Abstract/Free Full Text]
  7. Fazio S, Sabatini D, Capaldo B et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996;334:809–814.[Abstract/Free Full Text]
  8. Osterziel KJ, Strohm O, Schuler J et al. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. 1998;351:1233–1237.[CrossRef][Web of Science][Medline]
  9. Houck WV, Pan LC, Kribbs SB et al. Effects of growth hormone supplementation on left ventricular morphology and myocyte function with the development of congestive heart failure. Circulation. 1999;100:2003–2009.[Abstract/Free Full Text]
  10. Tajima M, Weinberg EO, Bartunek J et al. Treatment with growth hormone enhances contractile reserve and intracellular calcium transients in myocytes from rats with postinfarction heart failure. Circulation. 1999;99:127–134.[Abstract/Free Full Text]
  11. Dalla Libera L, Ravara B, Volterrani M et al. Beneficial Effects of GH/IGF-1 on Skeletal Muscle Atrophy and Function in Experimental Heart Failure. Am J Physiol Cell Physiol. 2004;00:in press.
  12. Napoli R, Guardasole V, Matarazzo M et al. Growth hormone corrects vascular dysfunction in patients with chronic heart failure. J Am Coll Cardiol. 2002;39:90–95.[Abstract/Free Full Text]
  13. Adamopoulos S, Parissis JT, Paraskevaidis I et al. Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy. Eur Heart J. 2003;24:2186–2196.[Abstract/Free Full Text]
  14. Coletta AP, Clark AL, Banarjee P et al. Clinical trials update: RENEWAL (RENAISSANCE and RECOVER) and ATTACH. Eur J Heart Fail. 2002;4:559–561.[CrossRef][Web of Science][Medline]
  15. Wollert KC, Drexler H. The role of interleukin-6 in the failing heart. Heart Fail Rev. 2001;6:95–103.[CrossRef][Medline]
  16. Mann DL. Stress-activated cytokines and the heart: from adaptation to maladaptation. Annu Rev Physiol. 2003;65:81–101.[CrossRef][Web of Science][Medline]
  17. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res. 2002;91:988–998.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?

Related articles in EHJ:

Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy
Stamatis Adamopoulos, John T. Parissis, Ioannis Paraskevaidis, Dimitrios Karatzas, Efthimios Livanis, Michael Georgiadis, George Karavolias, Dimitrios Mitropoulos, Dimitrios Degiannis, and Dimitrios Th. Kremastinos
EHJ 2003 24: 2186-2196. [Abstract] [FREE Full Text]  



This article has been cited by other articles:


Home page
 BioinformaticsHome page
G. Gamberoni, E. Lamma, G. Lodo, J. Marchesini, N. Mascellani, S. Rossi, S. Storari, L. Tagliavini, and S. Volinia
Fun&Co: identification of key functional differences in transcriptomes
Bioinformatics, October 15, 2007; 23(20): 2725 - 2732.
[Abstract] [Full Text] [PDF]

This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in EHJ
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Wollert, K. C
Right arrow Articles by Drexler, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wollert, K. C
Right arrow Articles by Drexler, H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?