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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 9 4095-4099
Copyright © 2003 by The Endocrine Society

Effects of One Year of Recombinant Human Growth Hormone (GH) Therapy on Cardiac Mass and Function in Children with Classical GH Deficiency

Dorothy I. Shulman, Allen W. Root, Frank B. Diamond, Barry B. Bercu, Richard Martinez and Robert J. Boucek, Jr.

Department of Pediatrics, Divisions of Endocrinology and Cardiology, University of South Florida College of Medicine, Tampa 33612; and All Children’s Hospital, St. Petersburg, Florida 33701

Address all correspondence and requests for reprints to: Dorothy I. Shulman, M.D., Associate Professor of Pediatrics, All Children’s Hospital, 801 6th Street South, St. Petersburg, Florida 33701. E-mail: shulmand{at}allkids.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Cardiac mass and function were evaluated in 10 children with classical GH deficiency. Echocardiograms were performed at baseline, 3, 6, and 12 months after initiation of recombinant human (rh) GH therapy (0.3 mg/kg·wk). Before treatment, left ventricular (LV) mass indexed to body surface area (BSA) was low or low normal (<50 g/m2) in five children compared with reference control data. Height SD score (-3.2 ± 0.9 vs. -1.8 ± 1.3 yr; P < 0.01), growth velocity SD score (-2.7 ± 1.6 vs. 5.8 ± 3.1; P < 0.01), LV mass (36 ± 9 vs. 60 ± 30 g; P < 0.02), LV mass/BSA (51 ± 12 vs. 72 ± 11 g/m2; P < 0.01), LV mass/height (36 ± 9 vs. 54 ± 15 g/m; P < 0.02), and LV mass/m2.7 (36 ± 12 vs. 45 ± 8; P < 0.05) increased significantly with rhGH therapy. Pretreatment LV mass/BSA correlated inversely with fold increase in LV mass/BSA over the year (r = -0.83; P < 0.01). Load-dependent indices of diastolic performance were normal at baseline and did not change with rhGH therapy. Percentage increase of mean velocity of circumferential shortening, an index of systolic function, correlated with fold increase in LV mass/BSA (r = 0.88; P < 0.02) over the year of rhGH administration. LV mass can be lower than predicted for body size in some children with severe GH deficiency but is responsive to rhGH replacement. LV mass/BSA increases into the normal range during the first year of rhGH therapy. The rate of increase of LV mass is greater than the increase in BSA during rhGH treatment, suggesting that GH could also be a trophic factor for the heart.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH APPEARS TO BE a determinant of cardiac growth, but the confounding association of cardiac mass with body mass has made it difficult to determine whether GH is an independent trophic factor for the heart. The clinical syndrome of GH excess is associated with left ventricular (LV) hypertrophy and cardiac dysfunction (1, 2). Evidence suggests that GH deficiency can also adversely affect cardiac growth and function. Increased cardiovascular mortality has been reported in adults with hypopituitarism compared with the general population (3). Cardiomyopathy, decreased myocardial mass, and systolic and diastolic dysfunction at rest and with exercise have been reported in GH-deficient adults (1, 2, 4, 5, 6, 7, 8). Recombinant human (rh) GH therapy increases exercise capacity, LV mass, and cardiac output in some GH-deficient adults (2, 4, 5, 6, 7, 8).

There are little data assessing cardiac structure and function in GH-deficient children. Potential adverse cardiac effects of rhGH therapy in non-GH-deficient children have not been demonstrated (9, 10, 11). Cardiac mass and function in GH-deficient children after at least 1 yr of rhGH therapy were normal (12, 13). Lanes et al. (14) reported normal cardiac mass relative to body mass index in 10 GH-deficient adolescents, eight of whom had idiopathic GH deficiency. Six of these children had received rhGH treatment. Colao et al. (15) recently reported a decline in LV mass/body surface area (BSA), but not to subnormal values, in GH-deficient adolescents 6 months after discontinuing rhGH therapy, with return to prewithdrawal values after resuming rhGH treatment. These studies leave open the questions of whether cardiac mass or function are reduced in children with severe GH deficiency who have never received rhGH treatment, and to what degree these parameters change with rhGH replacement.

To determine the effects of GH deficiency and rhGH replacement therapy in children, we studied 10 children with classical GH deficiency. Indices of systolic and diastolic function, as well as LV mass, were assessed from comprehensive echocardiograms before and during the first year of rhGH therapy and correlated with linear growth response.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Ten children entered the study (Table 1Go). All had a peak GH response to either arginine-L-dopa, insulin-arginine, or arginine-glucagon of less than 7 µg/liter in a polyclonal GH RIA (Endocrine Sciences Laboratory, Calabasas Hills, CA), consistent with classical GH deficiency. Serum IGF-I and IGF binding protein (IGFBP)-3 concentrations (Quest Laboratories, San Juan Capistrano, CA) were generally low for age. All children were prepubertal throughout the study. Five of 10 had multiple pituitary hormone deficiencies and were receiving L-T4 with hydrocortisone, if cortisol response to insulin-induced hypoglycemia was subnormal, for at least 4 months before entering the study. One child was receiving desmopressin acetate for central diabetes insipidus. Seven of 10 had documented structural abnormalities of the hypothalamic-pituitary axis; in three, no cause could be determined (idiopathic). After diagnosis of GH deficiency, patients had a baseline complex echocardiogram. Echocardiograms were repeated at 3 months, 6 months, and 12 months after initiation of rhGH therapy, 0.3 mg/kg·wk divided into daily sc injections. The patients were examined and measured by an endocrinologist (D.I.S., A.W.R., B.B.B., or F.B.D.) on the day of each echocardiogram. Triceps skinfold thickness was assessed with skin calipers. One patient (patient 2; Table 1Go) completed only 6 months of the study; only his baseline data are included in the statistical analyses.


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  		TABLE 1. Clinical and biochemical characteristics of GH-deficient children at the start of the study

 
Comprehensive two-dimensional, Doppler, and two-dimensional-directed M-mode echocardiograms were performed by one technician. Quantitative analyses of M-mode echocardiograms were made off-line from strip chart recordings at 100 mm/sec of the echocardiogram on an XY digitizing board (Summagraphics, Seymour, CT) in accordance with the conventions of the American Society of Echocardiography (16). Calculations were based on a mean of three cardiac cycles that had complete endocardial definition throughout the entire cardiac cycle. LV mass was calculated using the formula: LV mass (g)= 1.04 x (interventricular septum + LV internal dimension + posterior wall thickness)3] (16). LV mass was normalized for both BSA, height, and height2.7 to index cardiac growth disproportionate to somatic growth (17, 18, 19). The velocity of circumferential shortening (VCF)-wall stress relationship was calculated as a load-independent, heart rate corrected measure of LV systolic performance (20). LV wall stress (LVWS) and mean VCF (mVCF) were calculated as follows: LVWS (g/cm2) = 0.334 (peak systolic blood pressure) (LV short axis diameter)/(LV posterior wall thickness) [1 + (LV posterior wall thickness/LV end diastolic dimension)]. mVCF (circ/sec) = (LV end diastolic dimension) - (LV systolic dimension)/(LV end diastolic dimension)(LV ejection time). LV diastolic performance was indexed both by LV filling and thinning characteristics. LV filling was determined by the peak early (E) and late (A) velocities obtained with pulse wave integration of mitral inflow from a standard apical four chamber view. Instantaneous thinning velocities of the LV posterior wall were determined by computer-assisted analyses of digitized M-mode tracings of the endocardial and epicardial/pericardial surfaces of at least three cardiac cycles as previously described (21, 22). Peak thinning velocity normalized for LV wall thickness at the point of maximal velocity was selected as the index of LV relaxation (diastolic function) for this study.

Height age was defined as the age for which the patient’s height was at the 50th percentile on the National Center for Health Statistics Growth Charts (23).

The t test for paired observations was used to compare baseline data with measurements obtained at 3, 6, and 12 months. Regression analyses were performed with the use of SigmaPlot 8.0 software (SPSS Inc., Chicago, IL). Baseline LV mass, LV mass/BSA, and LV mass/height2.7 were compared with the normal reference data of Vogel et al. and de Simone et al. (17, 18, 19). Baseline measurements of systolic and diastolic function were compared with published normative data (20, 22). Data are expressed as mean ± SD.

This study was approved by the Institutional Review Board of All Children’s Hospital (St. Petersburg, FL). Informed consent was obtained for all participants.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Growth velocity and height SD scores (SDS) increased significantly over the year of treatment in all patients (Table 2Go). The mean pretreatment LV mass indexed for BSA for the group was within the normal range (>=50 g/m2) (17). However, five patients (Table 3Go: patients 4, 6, 7, 8, and 10) had a baseline LV mass/BSA less than 50 g/m2, low or low normal for both chronological age and height age (see legend in Table 3Go for more detailed normative data). Patient 10 also had a baseline LV mass and LV mass/height2.7 measurement at least 1 SD below the mean for chronological age and height age reported by de Simone et al. (18, 19) (Table 3Go). LV mass increased significantly over baseline after 1 yr of rhGH treatment when indexed for BSA, height, or height2.7 (Fig. 1Go). LV mass/BSA assessed at three monthly intervals is shown in Fig. 2Go. In seven patients an increase in LV mass/BSA was apparent at 3 months; peak LV mass/BSA occurred at a mean of 8 months. In the group as a whole, change in LV mass was 26.8 ± 24.2 g/yr compared with 4.9–5.7 g/yr reported in normal prepubertal children (19). LV mass/BSA at baseline correlated inversely with fold increase in LV mass/BSA over the year of treatment (r = -0.83; P < 0.01) (Fig. 3Go). Triceps skinfold thickness decreased significantly with treatment (Table 2Go). There were no significant correlations between changes in LV mass/BSA and height SDS, growth velocity SDS, pretreatment IGF-I or IGFBP-3 levels, skin fold thickness, chronological age, or systolic blood pressure. Systolic blood pressure did not change significantly over the year of treatment (Table 2Go).


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  		TABLE 2. Growth parameters, cardiac mass, systolic blood pressure, and skin fold thickness before and after 1 yr of rhGH therapy

 

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  		TABLE 3. LV mass, LV mass/BSA, and LV mass/height2.7 at baseline in individual GH-deficient patients

 


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  		FIG. 1. Comparison of LV mass/BSA (P < 0.01), LV mass/height (P < 0.02), LV mass/height2.7 (P < 0.05) at baseline and after 1 yr of rhGH therapy in individual GH-deficient patients.

 


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  		FIG. 2. LV mass/BSA assessed at baseline and after 3, 6, and 12 months of rhGH treatment.

 


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  		FIG. 3. LV mass/BSA at baseline correlated inversely with fold increase in LV mass/BSA over the year of rhGH treatment.

 
Mean LVWS and mVCF for the cohort were normal at baseline and did not change significantly with rhGH therapy (Table 4Go). However, percent increase over baseline of mVCF at 1 yr did correlate with fold increase in LV mass/BSA (r = 0.88; P < 0.02) (Fig. 4Go) in a nonlinear manner. If patient 4, an outlier with a mVCF of 75% of the baseline measurement at 1 yr, was omitted this became a strong linear relationship (r = 0.84; P < 0.01). mVCF increased by more than 15% in six patients by 1 yr, five of whom had organic hypopituitarism. mVCF increased by more than 25% in three children (patients 5, 7, and 10) (Fig. 5Go), two of whom had low LV mass/BSA at baseline.


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  		TABLE 4. Measures of cardiac systolic and diastolic function before and after 1 yr of rhGH therapy

 


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  		FIG. 4. Fold increase in LV mass/BSA correlated with percentage increase in mVCF over the year of rhGH treatment. If patient 4, an outlier (percentage increase in mVCF 75%), is removed from the analysis, this becomes a significant linear relationship (r = 0.84; P < 0.02).

 


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  		FIG. 5. Percentage increase in mVCF over the year of rhGH treatment in individual patients (see Table 1Go for patient characteristics).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have demonstrated that, in children with classical GH deficiency, there is a significant increase in LV mass indexed by BSA, height or height2.7 in the first year of rhGH therapy. In the majority of studies examining GH effects on the heart assessment of LV mass has been normalized to BSA. In the cardiac literature, human LV mass has been indexed to a variety of body size measurements including weight, body surface area, height, and height2.7. De Simone et al. (18, 19) have argued that the variability in normal subjects and the impact of overweight are reduced when LV mass is normalized for height2.7. Therefore, we included this measure that increased significantly in our patients following 1 yr of rhGH therapy.

LV mass/BSA was low or low normal for chronological age and height age in five children (four with organic hypopituitarism) before rhGH treatment. The oldest of our patients (patient 10), who had presumably been GH deficient for the longest time, had relatively low LV mass when indexed for BSA or height2.7 (>1 SD below mean for chronological age and height age). The lower the LV mass/BSA pretreatment, the greater this index rose after 1 yr of rhGH treatment. The discrepancy between our findings of low LV mass/BSA in some individuals and normal values reported in the patients of Lanes et al. (14) likely reflects the severity of GH deficiency in our group. Also, six of their 10 patients had received GH treatment that may have increased cardiac mass. In support of our findings is a recent study by Colao et al. (15) reporting a decline within the normal range in LV mass/BSA and E/A ratio in GH-deficient adolescents 6 months after discontinuing rhGH therapy, with return to prewithdrawal levels after resuming rhGH therapy.

No abnormalities of LV systolic or diastolic function were identified in these GH-deficient children before or during rhGH therapy. A significant effect of rhGH on mVCF has been reported in GH-deficient adults who had childhood onset GH deficiency (6). This effect of rhGH therapy may require that the heart be GH deficient for a longer time.

GH appears to be a determinant of cardiac growth, but the confounding association of cardiac mass with body mass has made it difficult to determine whether GH is an independent trophic factor for the heart. Our data support a trophic effect of rhGH therapy on the myocardium that appears to be as robust as is its effect on linear growth. Demonstration of increased LV mass relative to BSA, height, and height2.7 suggests that GH may modulate cardiac growth, in part, independent of somatic growth. GH may be acting directly on the myocardium to stimulate local IGF-I production. The GH receptor gene is expressed in the myocardium to a greater extent than in many other tissues (24) and GH administration to hypophysectomized rats increases myocardial IGF-I mRNA expression and myocardial IGF-I content (25, 26). In rats GH and IGF-I induce myocyte growth and alter the distribution of myosin isoforms to favor the V3 isoform which is more energy efficient (27, 28). Cittadini et al. (29) studied cardiac performance and structure in GH-deficient dwarf rats. Compared with control rats GH-deficient rats showed reduced ventricular weight and myocyte cross-sectional area, and impaired in vivo performance not mediated though the ß adrenergic system. These abnormalities were reversed with GH treatment.

Our study has limitations. Other factors such as higher blood pressure, increase in lean body mass, or levels of physical activity with rhGH replacement could also contribute to increased LV mass relative to body mass. The changes in body composition (increased skeletal muscle) that accompany rhGH replacement therapy may increase peripheral arterial resistance and increase the workload of the LV. A significant change in blood pressure was not documented in our study. Triceps skinfold thickness declined, suggesting a relative increase in lean body mass. We did not otherwise assess body composition. We did not systematically question patients regarding their level of physical activity. In the five patients with multiple pituitary hormone deficiencies replacement therapy with hydrocortisone or T4 could also have influenced cardiac mass. These five patients had been on replacement therapy with one or both of these hormones for at least 4 months before starting rhGH therapy. Patient 10, whose LV mass/BSA at baseline was the lowest of the group relative to chronological age and height age, and who had the most dramatic change in LV mass/BSA with rhGH therapy, had been on stable doses of desmopressin acetate, T4, and hydrocortisone for over 1 yr before entering the study. Thus, it is unlikely that a deficiency or treatment effect of these hormones affected his LV mass/BSA assessment during the period of study. Doses of T4 and hydrocortisone did not change during the year of rhGH therapy.

We conclude from this study that cardiac growth may be impeded by childhood GH deficiency and that it is improved by rhGH therapy. While body size and cardiac mass both increase during the first year of rhGH treatment, there is an increase in LV mass normalized for changes in body size, implying a quantitatively more significant effect of rhGH on this organ.


   Acknowledgments
 
We acknowledge Joy McGarrah for her expertise in performing the echocardiograms.


   Footnotes
 
This work was supported by a grant from The Genentech Foundation.

Abbreviations: BSA, Body surface area; IGFBP, IGF binding protein; LV, left ventricular; mVCF, mean VCF; rh, recombinant human; SDS, SD score; VCF, velocity of circumferential shortening.

Received January 6, 2003.

Accepted May 18, 2003.


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 Introduction
 Subjects and Methods
 Results
 Discussion
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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals