Recombinant Human Growth Hormone Treatment for Dilated Cardiomyopathy in Children

Subjects

Patients 1 to 19 years of age with DCM and echocardiographic evidence of sustained cardiac dysfunction for at least 6 months were identified by searching departmental databases and announcing the study to pediatric cardiologists in New England and New York State. DCM was defined according to the following echocardiographic parameters, which are based on normative data derived at our institution: 1) LV end diastolic (ED) dimension ≥2 SD above the mean for body surface area (z score ≥ 2) and 2) LV shortening fraction (SF) or ejection fraction (EF) ≤3 SD below the mean for age (z score ≤ −3). Patients meeting any of the following criteria were excluded: 1) associated cardiovascular anomalies, including aortic coarctation, coronary artery anomalies, and hemodynamically significant LV outflow tract obstruction; 2) prior cardiac surgery; 3) a known cause of DCM (eg, doxorubicin toxicity, metabolic disorders, or muscular dystrophies); 4) associated untreated endocrine abnormalities, including diabetes mellitus and hypothyroidism; 5) Turner’s syndrome; 6) systemic hypertension; or 7) symptoms of heart failure at rest. With the permission of the primary cardiologist, an attempt was made to contact the parents of qualifying patients. Written informed consent for study participation was obtained for all patients enrolled, in accordance with a protocol approved by the institutional review board of Children’s Hospital (Boston, MA).

Treatment Arms

After enrollment, patients were randomly assigned to receive treatment for 6 months with either conventional therapy plus recombinant human GH (Humatrope; Eli Lilly and Co, Indianapolis, IN), administered as daily subcutaneous injections (group 1), or conventional therapy alone (group 2). Patients were then crossed over to the other treatment strategy for 6 months. For prepubertal patients, the dose of GH was 0.04 mg/kg per day; for pubertal patients, GH was initiated at a dose of 0.025 mg/kg per day and then adjusted as necessary to maintain serum IGF-1 levels of 250 to 500 ng/mL. Group 2 patients were monitored for an additional 6 months after discontinuation of GH therapy. Conventional therapy was administered to each patient according to the preference of his or her primary cardiologist.

Evaluation of Outcome Measures

Adverse Event Monitoring

Adverse events were recorded and classified according to their relationship to GH therapy (ie, not related, probably not related, possibly related, or probably related) and severity (ie, not serious, moderately serious, or serious).

Data Analyses

Data are presented as median and range or mean ± SD. Paired t test analyses were used to assess rates of change of continuous outcome measures. To determine whether changes in outcome measures were attributable to trends with time, between-subject comparisons of rates of change of outcome measures during the first and second 6-month periods were performed with unpaired t test analyses. Generalized estimating equations, which adjust for the effects of repeated observations, were used to compare mean values at the measured times with the baseline mean values, to assess changes in outcome measures during GH therapy. To assess carryover or deterioration of treatment effects beyond the period of GH administration, mean values measured 6 months after discontinuation of GH were compared with mean values at baseline. The primary outcome measure was change in LV SF. On the basis of power calculations with a 2-sided significance level of .05, enrollment of 15 subjects was estimated to provide 82% power to detect an absolute change of 3% in LV SF (eg, from 10% to 13%) and 99% power to detect an absolute change of 5% in LV SF.

Patients

With review of departmental databases, 119 patients between the ages of 1 and 19 years with DCM were identified. Of these 119 patients, 96 were ineligible because of death (n = 7), cardiac transplantation (n = 8), improvement in LV function (n = 48), form of cardiomyopathy other than DCM (n = 15), metabolic disease (n = 6), hypertensive cardiomyopathy (n = 3), other known cause of DCM (n = 4), congenital heart disease and/or prior history of cardiac surgery (n = 3), or symptoms of heart failure at rest (n = 2). Of the 23 eligible patients, 5 were living overseas and 3 could not be located. The remaining 15 patients and their parents were invited to participate in the study, but 7 (47%) declined. Therefore, 8 patients were ultimately enrolled and randomized between November 1999 and October 2000. Baseline demographic and clinical data for these 8 study patients are summarized in Table 1. Seven of the patients were prepubertal at the time of study entry and throughout the study period and accordingly received a GH dose of 0.04 mg/kg per day; 1 patient was pubertal at the time of study entry and continued to receive the starting GH dose of 0.025 mg/kg per day, without adjustment, for the duration of the treatment phase.

Outcome Measures

Somatic Growth Indices and Bone Age Analysis

Somatic growth indices are summarized in Table 3. During GH treatment, height percentile for age increased by a median of 23.7 percentile points (range: 4.7–29.1 percentile points) (Fig 1). During the 6 months after discontinuation of GH treatment, height percentile for age decreased for 4 of the 6 patients with available data, by a median of −12.1 percentile points (range: −21.2 to 21.0 percentile points). The annualized height velocity during GH treatment was 13.7 ± 3.3 cm/year, which was well above the 97th percentile for age and gender during this period.²⁷ During the 6 months after discontinuation of GH treatment, in contrast, the annualized height velocity was 3.2 ± 3.5 cm/year. Weight percentile for age also increased substantially during GH treatment and plateaued thereafter. Bone age increased in accordance with chronological age.

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Fig 1.

Effects of GH therapy on height among children with DCM. Curves for each patient depict height percentile for age for 6 months before the initiation of GH treatment (group 2 only), at the initiation of GH treatment, at the cessation of GH treatment, and 6 months after the cessation of GH treatment. Curves for patients in groups 1 and 2 are staggered to overlap the periods during GH treatment and after cessation of GH treatment. Group 1 and group 2 patients are indicated by solid and open symbols, respectively. Mean ± SD changes in height percentile during the 6-month periods before (group 2 only, n = 3), during (n = 7), and after (n = 6) GH treatment are also indicated.

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TABLE 3.

Somatic Growth Data

Endocrine Laboratory Studies

Baseline laboratory results are summarized in Table 4. All baseline laboratory values were normal, except for a low IGFBP-3 level for 1 patient, high total T₃ levels for 3 patients, and a high total T₄ level for 1 patient. All abnormal levels normalized after GH treatment or discontinuation of GH. IGF-1 and IGFBP-3 levels increased during the period of GH administration for all patients and then decreased, stabilized, or increased slightly after discontinuation of GH (Figs 2 and 3). After 6 months of GH treatment and 6 months after discontinuation of GH treatment, serum IGF-1 (P = .006 and P = .02, respectively) and IGFBP-3 (P = .03 and P = .007, respectively) levels were significantly higher than at baseline. For 1 patient, IGFBP-3 levels increased above the upper limit of normal for age during GH treatment. Total T₃ levels were significantly lower 6 months after discontinuation of GH than at baseline (P = .02), and TBGI levels were higher (P = .02). GH treatment did not cause glucose intolerance, inasmuch as blood glucose and hemoglobin A1c levels were normal at entry and for the duration of the study.

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Fig 2.

Serum levels of IGF-1 for each patient 6 months before the initiation of GH treatment (group 2 only), at the initiation of GH treatment, at the cessation of GH treatment, and 6 months after the cessation of GH treatment. Curves for patients in groups 1 and 2 are staggered to overlap the periods during GH treatment and after cessation of GH treatment. Group 1 and group 2 patients are indicated by solid and open symbols, respectively. Mean ± SD changes in IGF-1 levels during the 6-month periods before (group 2 only, n = 3), during (n = 7), and after (n = 6) GH treatment are also indicated.

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Fig 3.

Serum levels of IGFBP-3 for each patient 6 months before the initiation of GH treatment (group 2 only), at the initiation of GH treatment, at the cessation of GH treatment, and 6 months after the cessation of GH treatment. Curves for patients in groups 1 and 2 are staggered to overlap the periods during GH treatment and after cessation of GH treatment. Group 1 and group 2 patients are indicated by solid and open symbols, respectively. Mean ± SD changes in IGFBP-3 levels during the 6-month periods before (group 2 only, n = 3), during (n = 7), and after (n = 6) GH treatment are also indicated.

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TABLE 4.

Baseline Laboratory Data

Adverse Events

There were no deaths during the study period. Two patients in group 2 developed progressive heart failure and underwent cardiac transplantation, 1 just after starting GH treatment and the other after completing 6 months of GH treatment, in the context of a viral illness. One other patient reported possible side effects, which were considered not serious and probably not related to GH therapy, including headache, arthralgia, chest pain, and axillary swelling.

GH/IGF-1 Axis in Cardiac Failure

The rationale for administration of GH among children with heart failure attributable to DCM is based on the emerging understanding of the myocardial effects of GH and IGF-1, its primary effector in the cardiovascular system, which have been studied in a variety of experimental and clinical investigations. GH is thought to exert most of its effects on myocardial growth and function via GH receptor binding and JAK/STAT-mediated transcription of IGF-1, which in turn acts on cardiac myocytes through several different intracellular signaling pathways to alter Ca²⁺ trafficking, regulate expression of contractile and cytoskeletal proteins, and modify the activation of intrinsic neurohormonal networks.⁵, ^16,28–30 Patients with heart failure exhibit a number of abnormalities in the GH/IGF-1 axis, including decreased serum GH and IGF-1 levels.^4,31 Decreased serum IGF-1 levels among individuals with DCM may be attributable to both decreased GH secretion in response to GH-releasing hormone and peripheral GH resistance.^32,33

Potential Cardioprotective Mechanisms of GH

There are several potential mechanisms by which GH therapy may ameliorate cardiac dysfunction among patients with DCM, most of which are mediated through induction of IGF-1. GH/IGF-1 signaling augments the force-generating machinery of myocytes by down-regulating cytoskeletal proteins, thus facilitating myofibril assembly and growth, and up-regulating certain contractile proteins.^13,28 Expansion of the contractile apparatus causes myocyte hypertrophy, which leads to increased wall thickness and consequent attenuation of LV wall stress (assuming that wall thickness increases more than the chamber radius) and thus myocardial oxygen consumption. Indeed, we observed decreased wall stress and fiber stress in response to GH treatment.

Effects of GH in Human Cardiac Failure

Studies examining the effects of exogenous GH among adults with DCM have yielded equivocal findings.^17–20 With a series of 7 patients with DCM, Fazio et al¹⁷ observed significant improvement in most measures of cardiac geometry and systolic function in response to GH therapy. Other investigators, however, noted only increased LV mass in response to GH, without significant changes in cardiac function or exercise capacity.^18–20 Findings among adults with cardiac failure attributable to other causes, primarily myocardial ischemia, are similarly equivocal.^21,22 In several of those studies, increased LV mass was correlated with the magnitude of elevation of IGF-1 levels after initiation of GH treatment,^19–21 whereas others found that patients with low baseline IGF-1 levels were less likely to benefit from GH.³⁴ These findings are consistent with the results of a study in which direct administration of IGF-1 improved LV function,³⁵ and they suggest that GH therapy among patients with cardiac failure may lead to increased LV mass and improved LV function to the extent that serum IGF-1 levels are augmented. Patients with heart failure who manifest a blunted IGF-1 response to exogenous GH, presumably because of peripheral GH resistance, are less likely to benefit from GH treatment.

Cardiovascular Effects of GH Among Children

Although case reports have suggested that GH may be of benefit for children with DCM,³⁶, ³⁷ no systematic studies had been performed among pediatric patients with heart failure before this investigation. However, limited data on the effects of exogenous GH on the myocardium of children without GH deficiency can be derived from studies of children with constitutional short stature, which found increased LV wall thickness and mass commensurate with somatic growth after GH therapy, with no adverse effects on cardiac function.³⁸

Somatic Growth

Among non-GH-deficient patients receiving GH because of idiopathic short stature, GH treatment leads to accelerated height velocity without markedly altering ultimate height.³⁹ In our small population of children with chronic heart failure attributable to DCM, GH therapy also resulted in significantly increased somatic growth, which did not continue beyond the cessation of GH treatment. These findings raise the possibility that GH treatment of chronic heart failure among children may also aid somatic growth, which is frequently impaired among children with heart failure.

Limitations of the Study

There are several important limitations of this study, most significantly the small number of patients. Our intention was to enroll 15 subjects, but only 23 of 119 patients with DCM were eligible and only 8 of the 23 eligible patients were enrolled, in part because of a high refusal rate, which was based primarily on patient or parental discomfort with administration of daily subcutaneous injections, the major drawback of GH therapy. The low enrollment rate limits the statistical power of our study. It also highlights one of the important difficulties of conducting controlled studies with an invasive component among pediatric patients, as well as the rarity of stable chronic heart failure attributable to DCM among children. Another limitation of the study was its non-placebo-controlled design, which was chosen to avoid administration of subcutaneous placebo injections among pediatric patients. Because of this design, patients and their primary physicians were not blinded with respect to treatment phase, although outcome variables were assessed by individuals who were blinded with respect to patient and treatment phase.