(Circulation. 1998;97:1650-1651.)
© 1998 American Heart Association, Inc.
Growth Hormone in Chronic Heart Failure
Philipp Dreifuss, MD
Former Research Fellow,,
University Hospital,
Basel, Switzerland
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.
References
1.
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.[Abstract/Free Full Text]
2.
Anker S, Ponikowski P, Varney S, Chua T, Clark A, Webb-Peploe
K, Harrington D, Kox W, Poole-Wilson P, Coats A. Wasting as independent
risk factor for mortality in chronic heart failure. Lancet. 1997;349:1050–1053.[Medline]
[Order article via Infotrieve]
3.
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.
4.
Giustina A, Lorusso R, Borghetti V, Bugari G, Misitano V,
Alfieri O. Impaired spontaneous growth hormone secretion in patients
with severe dilated cardiomyopathy. Am
Heart J. 1996;131:620–622.[Medline]
[Order article via Infotrieve]
5.
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.[Abstract/Free Full Text]
6.
Dreifuss P. Wachstumshormon: ein pathogenetischer Faktor bei
chronisch-kongestiver Herzinsuffizienz? Dtsch Med
Wochenschr. 1996;121:492–496.[Medline]
[Order article via Infotrieve]
7.
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.[Free Full Text]
8.
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.[Abstract/Free Full Text]
9.
Fazio S, Sabatini D, Capaldo B, Vigorito C, Giordano A, Guida
R, Pardo F, Biondi B, Saccà L. A preliminary study of growth
hormone in the treatment of dilated cardiomyopathy.
N Engl J Med. 1996;334:809–814.[Abstract/Free Full Text]
10.
Dreifuss P. Growth hormone in end-stage heart failure.
Lancet. 1997;349:1841–1842.
Response
Stefan D. Anker, MD;
; Andrew J.S. Coats, DM
Cardiac Medicine,
National Heart and Lung Institute,
London, UK
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
study3 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
present4 ) and that the metabolic
abnormalities of these patients can only be viewed in conjunction with
functional and hemodynamic
abnormalities.5
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
al6 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 al7
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.8
We agree with Dr Dreifuss entirely-more in vivo and in vitro studies
must be performed.
References
1.
Bentham J, Rodriguez-Arnao J, Ross RJM. Acquired growth
hormone resistance in patients with hypercatabolism. Horm
Res. 1993;40:87–91.[Medline]
[Order article via Infotrieve]
2.
Ross RJM, Chew SL. Acquired growth hormone resistance.
Eur J Endocrinol. 1995;132:655–660.[Abstract/Free Full Text]
3.
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.
4.
Swan JW, Anker SD, Walton C, Godsland IF, Clark AL, Leyva F,
Stevenson JC, Coats AJS. Insulin resistance in chronic heart failure:
relationship to severity and etiology of heart failure. J Am
Coll Cardiol. 1997;30:527–532.[Abstract]
5.
Anker SD, Coats AJS. Metabolic, functional, and
haemodynamic staging for CHF? Lancet.. 1996;348:1530–1531.[Medline]
[Order article via Infotrieve]
6.
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.
7.
Frustaci A, Gentiloni N, Russo MA. Growth hormone in the
treatment of dilated cardiomyopathy. N
Engl J Med. 1996;335:672–673.[Free Full Text]
8.
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.
