Correspondence

Growth Hormone in the Treatment of Dilated Cardiomyopathy

N Engl J Med 1996; 335:672-674August 29, 1996

Article

To the Editor:

In their study of the use of growth hormone to treat dilated cardiomyopathy (March 28 issue),1 Fazio et al. describe the beneficial effects of administering recombinant human growth hormone for three months and urge the planning of longer clinical trials to assess the effects of growth hormone in patients with this condition. We are concerned, however, that the levels of insulin-like growth factor I in the patients they describe were doubled and considerably above the normal range. This means that the patients had biochemical acromegaly, and it seems clear that in this instance growth hormone is being used pharmacologically rather than as physiologic replacement therapy.

The effects of an excess of growth hormone on mortality are well known, and several studies show increases in mortality from cardiovascular and respiratory disease.2,3 The incidence of cancer is almost certainly increased, and patients with acromegaly are at increased risk for colon cancer and premalignant colonic polyps.4,5 Insulin resistance is seen, and eventually frank diabetes develops in about a third of patients.6 Undoubtedly, growth hormone will have an important part to play in a number of catabolic and other conditions, but the possibility of iatrogenic biochemical acromegaly means that a careful watch for the early development of these potential complications of growth hormone therapy will be needed.

Helen Turner, M.R.C.P.
J.A.H. Wass, M.D.
Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom

6 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med 1970;39:1-16
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3. 3

   Alexander L, Appleton D, Hall R, Ross WM, Wilkinson R. Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol (Oxf) 1980;12:71-79
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   Ezzat S, Melmed S. Are patients with acromegaly at increased risk for neoplasia? J Clin Endocrinol Metab 1991;72:245-249
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   Ezzat S, Strom C, Melmed S. Colon polyps in acromegaly. Ann Intern Med 1991;114:754-755
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   Wass JA, Cudworth AG, Bottazzo GF, Woodrow JC, Besser GM. An assessment of glucose intolerance in acromegaly and its response to medical treatment. Clin Endocrinol (Oxf) 1980;12:53-59
   CrossRef | Web of Science | Medline

To the Editor:

Since our report of a woman with hypopituitarism and severe dilated cardiomyopathy whose cardiac volume, function, and myofibrillar content improved dramatically after the administration of growth hormone,1 we have studied the potential therapeutic role of growth hormone in patients with idiopathic dilated cardiomyopathy and normal growth hormone values. We enrolled five patients (two men and three women; mean age, 28 years) (Table 1Table 1Echocardiographic, Hemodynamic, and Morphologic Characteristics of Five Patients with Idiopathic Dilated Cardiomyopathy, before and after Therapy with Growth Hormone.) who had idiopathic dilated cardiomyopathy with severely reduced left ventricular ejection fractions (<30 percent), reduced myocardial mass (low electrocardiographic voltages; interventricular septal and left ventricular free-wall thickness on two-dimensional echocardiography, <8 mm), and reduced myofibrillar content of cardiocytes on light and electron microscopy (myofibrillar area, <40 percent of cell area as assessed by quantitative morphometry with a control value of >60 percent).

Growth hormone was administered at a dose of 4 IU intramuscularly daily for three months in addition to conventional therapy with diuretics, digitalis, and angiotensin-converting–enzyme inhibitors. The patients were followed with electrocardiography, Holter monitoring, and two-dimensional echocardiography every two weeks, and cardiac catheterization and biopsy were repeated at the end of the study. The patients had mild reductions in left ventricular end-diastolic diameter and mild improvement in the left ventricular ejection fraction (Table 1). However, ventricular arrhythmias increased from Lown class 2 or 3 to class 4A or 4B, and electrocardiographic voltages, cardiac wall thickness, and myofibrillar content as determined by the control biopsy did not change significantly (Table 1). The mild improvement in left ventricular function and the worsening of arrhythmias during growth hormone therapy may have been due to the known growth hormone–induced enhancement of sympathetic activity2; conversely, treatment with growth hormone did not affect myocyte diameter or myofibrillar content. Because of the worsening of ventricular arrhythmias and the high cost of recombinant growth hormone, we discontinued this therapy. Two weeks after its withdrawal, noninvasive measures of cardiac function returned to the base-line values, and the arrhythmias improved.

Andrea Frustaci, M.D.
Nicola Gentiloni, M.D.
Catholic University, 00168 Rome, Italy

Matteo A. Russo, M.D.
Università La Sapienza, 00100 Rome, Italy

2 References

1. 1

   Frustaci A, Perrone GA, Gentiloni N, Russo MA. Reversible dilated cardiomyopathy due to growth hormone deficiency. Am J Clin Pathol 1992;97:503-511
   Web of Science | Medline

2. 2

   Loh E, Swain JL. Growth hormone for heart failure -- cause for cautious optimism. N Engl J Med 1996;334:856-857
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The concern of Drs. Turner and Wass that long-term treatment with growth hormone may induce insulin resistance or overt diabetes is certainly well founded. Attempts are under way to minimize this risk with a treatment combining growth hormone and insulin-like growth factor I. In view of the increased risk of colonic neoplasia associated with acromegaly, long-term treatment with growth hormone, given for whatever reason, requires periodic colonoscopy. It is also true that a long-term excess of growth hormone such as occurs in untreated acromegaly may eventually lead to specific cardiomyopathy characterized by interstitial remodeling and impairment of function, first diastolic and then systolic.1 To prevent such possible untoward effects, long-term growth hormone treatment might be given in intermittent bursts and maintenance doses. Moreover, it is reassuring that in patients with acromegaly, diastolic function is preserved for at least five years of disease, despite cardiac hypertrophy.2

Although Frustaci et al. do not mention the clinical status of their patients, in all likelihood they had end-stage heart failure, as the hemodynamic measures show (for example, the mean cardiac index was as low as 1.6 liters per minute per square meter). Furthermore, the criteria for inclusion in the study required evidence of cardiac atrophy (the free-wall thickness was 7 mm), a condition found in only a tiny segment of the population with dilated cardiomyopathy. The data of Frustaci et al. suggest that in patients with apparently terminal heart failure the mechanisms of myocardial growth are no longer responsive to stimulation with growth hormone. In an analogous manner, resistance to growth hormone has been documented in catabolic states.3 Alternatively, the effect of growth hormone on growth may be blocked by concomitant, high-dose therapy with angiotensin-converting–enzyme inhibitors.4 Despite the lack of cardiac growth, growth hormone induced mild but significant increases in left ventricular ejection fraction (P = 0.02) and cardiac index (P = 0.004), suggesting that it had a growth-independent effect on ventricular performance.

The worsening of arrhythmias may be related to the very high dose of growth hormone used (twice as much as we used in our study) and the severe degree of heart failure. An increased incidence of arrhythmias has been described in patients with acromegaly.1 On the other hand, there is no evidence to support a growth hormone–induced enhancement of sympathetic activity. We did not observe an increase in arrhythmias during treatment with growth hormone in our study. Two of our patients were receiving low-dose amiodarone before the therapy with growth hormone began, and in one of them the dose was reduced further because of improvement in the patient's arrhythmias. Unfortunately, Frustaci et al. do not mention antiarrhythmic therapy. Doing so would have clarified whether growth hormone–induced arrhythmias were resistant to antiarrhythmic drugs and whether the beneficial effect of growth hormone on cardiac performance was attenuated by such drugs.

Luigi Saccà, M.D.
Serafino Fazio, M.D.
Federico II University, 80131 Naples, Italy

4 References

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   Sacca L, Cittadini A, Fazio S. Growth hormone and the heart. Endocr Rev 1994;15:555-573
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2. 2

   Fazio S, Colao A, Sabatini D, et al. Effects of short-term acromegaly on cardiac morphology and function. In: Abstracts of the International Congress of Endocrinology, San Francisco, June 12–15, 1996. Bethesda, Md.: Endocrine Society, 1996:P2-P272.
   

3. 3

   Ross RJ, Chew SL. Acquired growth hormone resistance. Eur J Endocrinol 1995;132:655-660
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4. 4

   Jin H, Yang R, Gillett N, Clark RG, Ko A, Paoni NF. Beneficial effects of growth hormone and insulin-like growth factor-1 in experimental heart failure in rats treated with chronic ACE inhibition. J Cardiovasc Pharmacol 1995;26:420-425
   CrossRef | Web of Science | Medline

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   Catherine Demers, Robert S McKelvie. (2005) Growth hormone therapy in heart failure: a novel therapy worthy of further consideration?. Expert Opinion on Investigational Drugs 14:8, 1009-1018
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   Catherine Demers, Robert S. McKelvie. (2003) Growth Hormone Therapy in Heart Failure: Where Are We Now?. Congestive Heart Failure 9:2, 84-90
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   Annamaria Colao, Carolina Di Somma, Giovanni Vitale, Mariagiovanna Filippella, Gaetano Lombardi. (2003) Influence of Growth Hormone on Cardiovascular Health and Disease. Treatments in Endocrinology 2:5, 347-356
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   Lindsay Brown, Sheila A Doggrell. (2002) Present and future pharmacotherapy for heart failure. Expert Opinion on Pharmacotherapy 3:7, 915-930
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    Annamaria Colao, Paolo Marzullo, Carolina Di Somma, Gaetano Lombardi. (2001) Growth hormone and the heart. Clinical Endocrinology 54:2, 137-154
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    Tien M. H. Ng, Julie K. Kenney, Mark A. Munger. (2000) Growth Hormone: A Promising Treatment for the Failing Heart?. Pharmacotherapy 20:9, 1096-1106
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    Karl Josef Osterziel, Michael B. Ranke, Oliver Strohm, Rainer Dietz. (2000) The somatotrophic system in patients with dilated cardiomyopathy: Relation of insulin-like growth factor-1 and its alterations during growth hormone therapy to cardiac function. Clinical Endocrinology 53:1, 61-68
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    Josef Niebauer, Claus-Dieter Pflaum, Andrew L Clark, Christian J Strasburger, James Hooper, Philip A Poole-Wilson, Andrew J.S Coats, Stefan D Anker. (1998) Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation. Journal of the American College of Cardiology 32:2, 393-397
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    BENGT-ÅKE BENGTSSON, GUDMUNDUR JOHANNSSON, JÖRGEN ISGAARD. (1998) Use of Growth Hormone for Treatment of Anatomic and Physiologic Decrements Associated with Aging. Journal of Anti-Aging Medicine 1:3, 197-205
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    Maurizio Volterrani, Paolo Desenzani, Roberto Lorusso, Antonio d'Aloia, Filippo Manelli, Andrea Giustina. (1997) Haemodynamic effects of intravenous growth hormone in congestive heart failure. The Lancet 349:9058, 1067-1068
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