Growth Hormone in Chronic Heart Failure
To the Editor:
Anker et al1 2 reported on the hormonal changes in chronic heart failure (CHF) and their importance for cardiac cachexia. The authors found a trend for increased human growth hormone (hGH) in cachectic patients but similar levels of hGH in noncachectic patients compared with control subjects. No significant differences between patients and the control group were seen for insulin-like growth factor-1 (IGF-1). Nevertheless, the IGF-1/hGH ratio was approximately four times higher in noncachectic CHF patients and control subjects than in cachectic subjects. The authors suggest the presence of hGH-resistance in CHF because the increase in hGH in the cachectic patients was not accompanied by an increase in IGF-1.
With respect to the metabolic hGH–IGF-1-status in CHF, the published data so far are controversial. An exploratory pilot research in nine patients with CHF caused by dilated cardiomyopathy (DCM) and New York Heart Association functional class of dyspnea III-IV investigated hGH metabolism in severe CHF.3 The study group was compared with a control group matched for age, sex, and body mass index. Patients with CHF had markedly depressed levels of IGF-1, whereas hGH had not been measured. Another metabolic study by Giustina et al4 in patients with severe CHF caused by DCM (NYHA functional class of dyspnea III-IV) showed an impaired spontaneous hGH secretion, but Anand et al5 found hGH to be greatly increased in untreated patients with severe CHF.
Therefore CHF appears to be associated with a perturbation of the hGH/IGF-1 axis, leading to a state of functional IGF-1 deficiency.6 This can be viewed as a state of maladaptation, with the consequence that falling IGF-1 levels either systemic, or locally generated within the myocardium, cause a deleterious effect on myocardial function. The mechanism of the perturbation in the hGH/IGF-1 axis (systemic/local) is unclear; possible mechanisms include reduced hGH secretion from the pituitary or hGH resistance. Perturbation of this axis−either primary, as a result of hGH deficiency, or secondary, as a maladaptive response to CHF−may be responsible for the exacerbation of myocardial dysfunction.
Furthermore, it must be mentioned that DCM is the cause of CHF in which subcutaneous recombinant hGH (r-hGH) is likely to effectively counteract the pathogenetic defect of the disease.7 8 9 That is why subcutaneous r-hGH in conjunction with the widely accepted drugs for CHF, for example, angiotensin-converting enzyme inhibitors, diuretics, nitrates, calcium antagonists, and digoxin, could become an alternative to cardiac transplantation, as there is a worldwide shortage of donor organs.10 Further in vivo and in vitro studies with r-hGH in failing myocardial tissue are necessary and awaited.
- Copyright © 1998 by American Heart Association
Anker S, Chua T, Ponikowski P, Harrington D, Swan J, Kox W, Poole-Wilson P, Coats A. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation. 1997;96:526–534.
Farrell T, Jepson N, Evans T, Lipkin D, Bouloux P. Growth hormone abnormalities in severe heart failure. Br Heart J. 1995;73:(suppl):13. Abstract.
Anand I, Ferrari R, Kalra G, Wahi P, Poole-Wilson P, Harris P. Edema of cardiac origin: studies on body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive heart failure. Circulation. 1989;80:299–305.
Jonkman F, De Jong G, Fioretti P. Growth hormone in the treatment of heart failure: a new tool for the future? Eur Heart J. 1997;18:181–185. Editorial.
Fazio S, Cittadini A, Sabatini D, Merola B, Colao A, Biondi B, Longobardi S, Lombardi G, Saccà L. Growth hormone and heart performance: a novel mechanism of cardiac wall stress regulation in humans. Eur Heart J. 1997;18:340–347.
Dr Dreifuss raises some interesting issues about growth hormone (GH) and insulin-like growth factor-1 (IGF-1), quoting some previous studies of the GH–IGF-1 axis in patients with chronic heart failure (CHF). Acquired GH resistance is known to occur in patients with severe catabolism and malnutrition after surgery and in critical illnesses such as sepsis (see References 1 and 2 for review). Biochemically it is defined as the presence of high GH but low IGF-1 levels. Additionally, it is important to know about GH and IGF-binding proteins and possibly about the actual bioactive hormone levels. Our studyR3 did not aim to study these pathways; it is correct that further detailed studies are needed. The other studies mentioned by Dr Dreifuss did not report the cachectic state of the patients, and therefore it is difficult to compare the results. In any case we would like to emphasize that the possible presence of GH resistance in these patients would not be the first metabolic hormone resistance syndrome in CHF (we have recently shown that insulin resistance is also presentR4 ) and that the metabolic abnormalities of these patients can only be viewed in conjunction with functional and hemodynamic abnormalities.R5
We believe that it is important to state that previous studies of GH therapy in patients with dilated cardiomyopathy were small and not placebo controlled. It is far from clear that all patients would benefit from GH therapy and that GH in conjunction with other well-established drugs could become an alternative for cardiac transplantation. There is good reason to predict that patients with GH resistance, that is, patients with an inadequate hormone response on GH administration, are less likely to respond positively to GH administration. As Dr Dreifuss mentioned, recently Fazio et alR6 have shown in a pilot study of GH treatment of patients with CHF caused by dilated cardiomyopathy (n=7) favorable effects on cardiac function and exercise capacity that corresponded with a positive response of the IGF-1 levels. Frustaci et alR7 reported contrary results in five patients with dilated cardiomyopathy. Possibly these patients had more severe CHF, but it could well have been the case that these patients were resistant to the action of GH (unfortunately, the change of IGF-1 levels was not reported). The first prospective randomized trials are now coming through and have failed to demonstrate substantial benefits of GH treatment in patients with CHF due to dilated cardiomyopathy.R8
We agree with Dr Dreifuss entirely−more in vivo and in vitro studies must be performed.
Ross RJM, Chew SL. Acquired growth hormone resistance. Eur J Endocrinol. 1995;132:655–660.
Anker SD, Chua TP, Swan JW, Ponikowski P, Harrington D, Kox WJ, Poole-Wilson PA, Coats AJS. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure: the importance for cardiac cachexia. Circulation. 1997;96:526–534.
Fazio S, Sabatini D, Capaldo B, Vigorito C, Giordano A, Guida R, Pardo F, Biondi B, Sacca L. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996;334:809–814.
Osterziel KJ, Strohm O, Schuler J, Friedrich M, Hänlein D, Willenbrock R, Anker SD, Poole-Wilson PA, Ranke M, Dietz R. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. In press.