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Cardiac Changes Associated With Growth Hormone Therapy Among Children Treated With Anthracyclines
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     Department of Pediatrics, Miller School of Medicine at the University of Miami, Holtz Children's Hospital of the University of Miami-Jackson Memorial Medical Center, and the Sylvester Comprehensive Cancer Center, Miami, Florida

    Department of Cardiology and Division of Hematology-Oncology, Children's Hospital, Boston, Massachusetts

    Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, South Carolina

    Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts

    ABSTRACT

    Objective. The objective was to assess the cardiac effects of growth hormone (GH) therapy. Anthracycline-treated childhood cancer survivors frequently have reduced left ventricular (LV) wall thickness and contractility, and GH therapy may affect these factors.

    Methods. We examined serial cardiac findings for 34 anthracycline-treated childhood cancer survivors with several years of GH therapy and baseline cardiac z scores similar to those of a comparison group (86 similar cancer survivors without GH therapy).

    Results. LV contractility was decreased among GH-treated patients before, during, and after GH therapy (–1.08 SD below the age-adjusted population mean before therapy and –1.88 SD 4 years after therapy ceased, with each value depressed below normal). Contractility was higher in the control group than in the GH-treated group, with this difference being nearly significant. The GH-treated children had thinner LV walls before GH therapy (–1.38 SD). Wall thickness increased during GH therapy (from –1.38 SD to –1.09 SD after 3 years of GH therapy), but the effect was lost shortly after GH therapy ended and thickness diminished over time (–1.50 SD at 1 year after therapy and –1.96 SD at 4 years). During GH therapy, the wall thickness for the GH-treated group was greater than that for the control group; however, by 4 years after therapy, there was no difference between the GH-treated group and the control group.

    Conclusions. GH therapy among anthracycline-treated survivors of childhood cancer increased LV wall thickness, but the effect was lost after therapy was discontinued. The therapy did not affect the progressive LV dysfunction.

    Key Words: growth hormone anthracyclines cardiac changes cardiomyopathy pediatric cancer congestive heart failure

    Abbreviations: LV, left ventricular GH, growth hormone

    Progressive abnormalities of left ventricular (LV) structure and function often develop among long-term survivors of childhood cancer who have been treated with anthracyclines.1–3 We reported previously that 65% of children who had been treated for acute lymphoblastic leukemia with an anthracycline had increased LV afterload, decreased contractility, or both at a mean of 6.4 years after the completion of chemotherapy. Excess afterload was attributable to reduced LV wall thickness. LV wall thickness and mass z scores decreased over time,1–3 most rapidly among patients who had substantial somatic growth induced by growth hormone (GH) therapy for radiation- or chemotherapy-induced GH insufficiency,4 a common endocrine late effect of oncology therapy among long-term survivors of childhood cancer.5 We originally hypothesized that the rapid somatic growth induced by GH might impair LV structure and function in some children.4

    However, GH has been proposed as a possible therapy for some types of LV dysfunction.6–10 GH may enhance contractility.11,12 GH, either directly or through insulin-like growth factor-1, also appears to induce LV hypertrophy13–15 and may thereby improve LV performance by decreasing systolic wall stress.16 Adults with GH insufficiency have impaired LV structure and function, which improve with GH replacement therapy.17–20 Studies of short-term GH therapy (3 months) among adults with cardiomyopathy have had conflicting results, with small pilot studies finding increased myocardial mass and improved hemodynamics and clinical status6–8 but 3 randomized trials showing variable increases in LV mass and no clinical benefit.15,21,22

    To determine the long-term effects of GH therapy among anthracycline-treated children with LV dysfunction, we performed a 10-year longitudinal study of cardiac structure and function before, during, and after GH therapy. We compared the patients with both a healthy pediatric population and a control group of anthracycline-treated children who did not receive GH therapy. This study was not a prospective trial of GH therapy for potential cardiomyopathy.

    METHODS

    Study Groups

    The eligible population consisted of all pediatric oncology patients who were treated with GH therapy after receiving anthracycline chemotherapy who underwent at least 1 echocardiogram at Children's Hospital, Boston, between 1988 and 1991. Thirty-four eligible patients were identified from lists provided by the cardiology and endocrinology departments of Children's Hospital, Boston, and by the Dana Farber Cancer Institute. This study was approved by the Committee on Clinical Investigation at Children's Hospital, Boston.

    A single researcher abstracted data from the medical records. A diagnosis suggesting GH insufficiency, necessitating GH therapy, was based on a maximal stimulated serum GH level of 10 ng/mL in response to 1 or 2 provocative stimuli; the stimuli included insulin (28 patients), glucagon (26 patients), L-dopa (3 patients), and clonidine (4 patients). The patients were also evaluated and treated for any other pituitary hormone deficiencies. GH was administered either subcutaneously or intramuscularly 2 to 7 times per week, at doses ranging from 0.2 to 0.4 mg/kg per week.

    The control group consisted of 86 survivors of acute lymphoblastic leukemia who did not receive GH therapy and who were monitored with serial echocardiography after anthracycline treatment. This group included 115 children whose characteristics were described previously1 minus 11 who received GH therapy minus another 18 who had very different baseline z scores for the LV parameters. In particular, the 86 control subjects were chosen to have baseline z scores similar to those of the GH group. The control subjects were chosen in this way to ensure comparability at baseline, so that later differences could not necessarily be considered a progression of baseline differences.

    Echocardiography

    The echocardiographic evaluations consisted of 2-dimensional echocardiographic and Doppler evaluations. To improve the reliability of echocardiographic measurements,23 all available original echocardiographic tracings were reanalyzed by a single pediatric cardiologist, who was blinded with respect to the patient's GH status.

    We determined LV contractility from the relationship between LV end systolic wall stress and the rate-adjusted velocity of fiber shortening, a validated index of contractility that incorporates afterload and is independent of preload.24 Contractility was defined as the standardized difference between the observed and expected values of the rate-adjusted velocity of fiber shortening.24 Afterload was measured as meridional end systolic LV wall stress. Peak systolic wall stress, a determinant of hypertrophy, was measured as defined previously.24 LV mass was calculated from the M-mode measurements with the method described by Devereux et al.25

    Statistical Analyses

    All cardiac data (except ratios of thickness to internal dimension) were converted to z scores relative to the distribution according to age or body surface area, to adjust for somatic growth.24 The normal predicted value was calculated from a generalized, nonlinear, exponential, growth model24 with data for 285 healthy children, eliminating assumptions of linearity or zero-intercepts in the regression model. The z scores for mass, afterload, dimension, and wall thickness were obtained relative to a function of body surface area. The z scores for fractional shortening, blood pressure, and peak systolic wall stress were adjusted for age. The heights and weights of the children were also converted to z scores.26

    To compare patient characteristics in the GH-treated and control groups, the Wilcoxon rank-sum test and Fisher's exact test were used. The plots of z scores over time were obtained with repeated-measures regression models in SAS Proc Mixed (SAS/STAT 6.12; SAS Institute, Cary, NC), in which we specified a model for the z score at a given time after diagnosis and a model for the correlation between z scores measured at 2 times for the same subject. The z score was modeled as a linear and quadratic function of time after diagnosis, with different linear and quadratic effects before, during, and after GH therapy. This allowed the curves in the plots to have different patterns before, during, and after GH therapy. Furthermore, the repeated-measures regression models were adjusted for age at diagnosis (because the median ages at diagnosis were slightly different for the GH and control groups), so that differences in z scores over time between the GH and control groups were not attributable to differences in age at diagnosis for the 2 groups. The results given in the tables and figures are the predicted values from the repeated-measures regression models for a typical patient starting GH therapy 7.5 years after diagnosis and ending it 10.5 years after diagnosis, ie, the approximate average start and end times for the GH-treated patients.

    To adjust for nonrandomly missing data and for the longer follow-up period for sicker patients, we used the mixed-model formulation in SAS Proc Mixed.27 In particular, the use of SAS Proc Mixed ensured that the patients with poor cardiac function who came back most often for repeat testing were not given too much weight. It also ensured that patients with poor cardiac function who were monitored more intensively did not have a disproportionate influence on the tails of the plots. Because this was an exploratory, hypothesis-generating analysis, we did not adjust for multiple testing. Therefore, the P values should be interpreted cautiously. Each test was 2-tailed and was performed at the .05 level of significance.

    RESULTS

    Patient Groups

    The GH-treated children and the control subjects received similar cumulative doses of anthracycline, but the GH-treated children were younger at diagnosis and at completion of anthracycline therapy (Tables 1 and 2). However, a subset analysis of control patients (N = 70) matched for age at diagnosis and at completion of anthracycline therapy produced no significant differences (data not shown). Furthermore, adjustment for gender and other covariates in the repeated-measures regression analysis did not alter the results substantially (data not shown). All of the control children and most of the GH-treated children had experienced acute lymphoblastic leukemia. Data for the 26 survivors of acute lymphoblastic leukemia in the GH-treated group were not significantly different from those for the whole group (analysis not shown). Some GH-treated children received cardiac medications, including digoxin (N = 2), diuretics (N = 2), and angiotensin-converting enzyme inhibitors (N = 5). Data on cardiac medications were not available for the control subjects. GH therapy was stopped for several patients because of deteriorating heart function or in preparation for heart transplantation (N = 4). Therapy was stopped for other patients when the treating physicians, in conjunction with the families, thought that height was sufficient (N = 13).

    Anthropometric Measurements for GH-Treated Children

    Echocardiographic Measurements

    Studies Performed

    One hundred sixty-four echocardiograms for the GH-treated patients and 207 echocardiograms for the control group were analyzed (Tables 1 and 2). The median follow-up period after the completion of anthracycline therapy was 9.3 years for the study patients and 9.2 years for the control subjects.

    GH-Treated Children

    Before initiation of GH therapy, the study patients had subnormal LV wall thickness, with normal LV end diastolic dimension (Table 4). This reduced the LV thickness/dimension ratio, with increased LV afterload and depressed LV fractional shortening, a result that is typical of late pediatric anthracycline cardiotoxicity. GH therapy increased transiently LV wall thickness and mass but did not decrease afterload. Peak systolic wall stress, a mediator of hypertrophy, was elevated at the initiation of GH therapy, increased slightly during therapy, and continued to increase after the end of therapy.

    Systolic performance did not improve during GH therapy (Table 4). Load-independent and preload-dependent contractility, fractional shortening, and velocity of fiber shortening each progressively deteriorated before, during, and after GH therapy.

    Systolic blood pressure was significantly depressed for age at the start of GH therapy (Table 3), remained stable but depressed during therapy, and then progressively decreased after therapy was discontinued. Tachycardia and elevated preload were present before and during GH therapy. Preload normalized after GH therapy ended.

    Comparison Between Children Treated and Not Treated With GH Therapy

    Contractility was more depressed (although not quite significantly) among the GH-treated patients than among the control subjects during and after therapy and decreased progressively among the GH-treated patients. Both groups showed slight LV dilation over time. LV mass and wall thickness progressively decreased in the control group but increased transiently in the GH-treated group during therapy. Fractional shortening was depressed and worsened over time in both groups. Afterload was elevated in both groups before the study children started GH therapy. Systolic blood pressure was significantly lower among the GH-treated children than among the control patients during therapy and remained stable but depressed during the treatment interval; systolic blood pressure decreased progressively for both groups after GH therapy ended. Diastolic blood pressure was not significantly different between the 2 groups at any time point, although diastolic blood pressure trended downward among the GH-treated children after therapy.

    A separate analysis controlling for gender and baseline contractility produced similar results (data not shown). In addition, the trends for the raw values were similar to those for the z scores (data not shown).

    Serial changes in end systolic wall thickness, dimension, pressure, and wall stress are demonstrated in Figure 3. Despite a lower end systolic pressure and an increase in the end diastolic thickness/dimension ratio, the adverse effect that the progressive decrease in contractility had on ventricular mechanics resulted in an increase in end systolic wall stress.

    DISCUSSION

    Among children with a history of anthracycline treatment for cancer, a diagnosis of probable GH deficiency, and LV dysfunction, prolonged GH therapy had significant cardiac effects. Notably, LV wall thickness and mass were lower than normal before GH therapy and increased significantly with GH therapy. The gains were lost after GH therapy was stopped. Cancer survivors with or without GH therapy had depressed LV function. LV function was worse among the GH-treated patients before, during, and after therapy. LV function decreased progressively in both groups.

    Significant increases in LV wall thickness and mass in response to GH therapy have also been reported for adult patients with dilated cardiomyopathy.6,21 Some of the size increase might have been caused by fluid retention,13 as supported by the increased preload observed during GH therapy in this study. However, pig studies suggested that GH treatment induces real myocardial growth by increasing capillary density, reducing the rate of apoptosis, and increasing myocardial cell number and size.28 Although GH therapy induces substantial LV growth in both young and old rats, the mechanism differs according to age.29,30 An increase in cardiac myocyte number with GH therapy occurs only in young rats, whereas an increase in myocardial cell size predominates as the mechanism of GH-induced LV growth in older rats.29,30

    Increasing myocardial cell size in itself may not be beneficial. Our past work showed that anthracycline-treated, long-term survivors of childhood cancer have enlarged cardiac myocytes but LV wall thickness and mass are still inadequate because the number of cardiac myocytes is reduced.1 Patients with acromegaly caused by GH excess have increased interstitial fibrosis, proliferation of intramural vessels, and inadequate remodeling, all caused by disarray in hypertrophied fibers.13 Such problems might explain why some adults with dilated cardiomyopathy who were given GH experienced a significant increase in LV mass without clinical improvement.21

    Among our patients, the excess afterload (elevated end systolic stress) did not improve during GH therapy, despite increases in wall thickness and LV mass and in contrast to the results of at least 1 previous study.16 This finding is particularly surprising because end systolic blood pressure decreased during GH therapy. Wall stress is related directly to LV pressure and dimension and is related inversely to wall thickness. Therefore, the increase in end systolic stress during GH therapy indicates that the increase in end systolic dimension was in excess of the combined influence of lower pressure and greater wall thickness. This is an illustration of the direct adverse effect of depressed contractility on afterload, as predicted by the end systolic pressure-volume relationship (Emax).17 That is, if end systolic pressure is held constant, then a decrease in contractility leads to an increase in end systolic volume. Among our patients, the increase in end systolic dimension despite a decrease in end systolic pressure during therapy was another indication of the progressive decrease in contractility. The Emax relationship also indicates that any acute decrease in contractility leads to a lower thickness/dimension ratio, with a secondary increase in afterload, unless there is a compensatory decrease in pressure. The progressive decrease in contractility among these patients resulted similarly in an increase in afterload, because the increase in wall thickness was insufficient to keep the end systolic thickness/dimension ratio constant.

    GH therapy for adults with dilated cardiomyopathy also failed to reduce afterload, although it increased LV mass.21 Our data demonstrated that chronic GH administration to our study population did not reduce LV afterload or increase contractility. In contrast, a 3-month administration of GH to adults with chronic heart failure was associated with improved vascular function and maximal oxygen uptake.31 A meta-analysis of 16 trials of the cardiac effects of GH among 468 adults with GH deficiency, who had received different GH dosages, had different durations of GH treatment, represented different study populations, and were not anthracycline-treated, long-term survivors of childhood cancer, as in our report, reached conclusions similar to ours.32 That is, there was a significant increase in LV mass and wall thickness with GH therapy but not a significant improvement in LV fractional shortening.

    The effects of GH therapy on LV wall thickness and mass were transient. These transient GH effects might indicate that hypertrophy had regressed, that GH-induced fluid retention had ended,17 or that the cardiac autonomic effects of GH had changed.6 Similar effects followed GH therapy among adults treated for dilated cardiomyopathy.6 The rates of increase in LV mass and height in response to GH therapy appeared similar. This is in contrast to findings for children with classic GH deficiency,33,34 for whom only height was retained after GH discontinuation. This suggests that GH is a required trophic factor for the hearts of these patients.

    Recently we highlighted the differences between anthracycline-associated cardiomyopathy among long-term survivors of childhood cancer and dilated cardiomyopathy among adults who had not been treated for cancer.35 Anthracycline cardiomyopathy over time has characteristics more like those of restrictive cardiomyopathy, with a more prolonged time course until the onset of congestive heart failure, than dilated cardiomyopathy among adults. In addition, anthracycline-treated, long-term survivors of childhood cancer who also received cardiac irradiation had different late cardiovascular effects, including restrictive cardiomyopathy, than did patients treated with anthracyclines alone.36 The effects of GH therapy on radiation-associated cardiovascular changes may differ from the results of this study. Therefore, even recent studies of the effects of GH therapy for idiopathic dilated cardiomyopathy37 and advanced heart failure38 among adults are quite variable and may not be relevant to the patients in this study. The cause of the cardiomyopathy is likely to influence the subsequent course and success of therapy.

    The 86 control subjects were chosen to have baseline cardiac z scores similar to those of the GH group. We chose the control subjects in this way to ensure comparability at baseline, so that later differences could not necessarily be considered a progression of baseline differences. However, the GH-treated and control groups differed at baseline with respect to age and some other variables. In addition, within the GH group, gender affected outcomes. The girls' LV mass was much lower and their LV volume decreased over time, whereas the boys' LV volume became enlarged (data not shown). Repeating the SAS Proc Mixed analyses to control for age, gender, and other variables did not affect the results, but it is possible that other factors had effects. We controlled statistically for some differences, but there are certainly other variables that were not available and thus were not controlled for; furthermore, there may be other variables that affect the difference but are unrecognized. Because our main concern was the difference between GH-treated patients and control subjects and controlling for these other factors did not affect the results presented in this article, we chose not to present the other results here.

    Our study did not address whether GH therapy may be helpful for other children who have received anthracyclines. This study also did not address the timing, use of physiologic dosages for replacement or pharmacologic dosages for therapy, or duration of GH therapy. These are all issues that have been raised as being important for severely GH-deficient adolescents, in attempts to optimize outcomes for impaired lipid profiles and cardiac morphologic features and performance.39 Adult survivors of childhood cancer, particularly those treated for brain tumors, had reduced final heights40 and an increased relative risk of 277 for GH deficiency, compared with their siblings.41 The desire for height to be more normal42,43 was the reason why patients in this study received a time-limited course of GH therapy. Our study demonstrated the transience of the GH therapy-related changes toward more normal LV mass, wall thickness, and blood pressure. There was a rapid return to pre-GH therapy levels after discontinuation. If the goal of GH therapy is to maintain these changes, then more chronic GH therapy is necessary. Whether GH therapy reduces the global risk of premature, symptomatic, cardiovascular disease (because of its other effects, such as a reduction in adverse lipid profiles, improved insulin sensitivity, reduced body fat, and improvements in skeletal muscle mass, strength, and exercise tolerance, in addition to the cardiac parameters mentioned in this report) or improves the overall quality of life44 was not assessed. GH replacement among adults with childhood-onset GH deficiency seems to reduce cardiovascular risks45 and increase LV mass.46 We have raised concerns about premature atherosclerosis among long-term survivors of childhood cancer, in addition to cardiomyopathy.47 This makes it important to assess the effects of GH therapy to reduce the global risk of premature cardiovascular disease.47 Increased mortality rates48 and the incidence of malignancy were raised as concerns related to GH therapy49–51 or GH excess in acromegaly52 in some studies but not others53 and were not measured.

    What prompted this longitudinal study was our initial observation that some anthracycline-treated, long-term survivors of childhood cancer with late cardiotoxicity exhibited clinically significant deterioration in cardiac status in the setting of rapid GH-induced somatic growth. For those patients, cardiac transplantation attributable to a failure of medical management of congestive heart failure resulted.4 More recent data on the substantial, and possibly progressive, cardiac morbidity and death in this population continue to make this a topic of great concern.54–58 The group data presented in this article demonstrate that GH therapy in this population not only is associated with increased somatic growth but also has significant cardiac effects. Our early concern regarding an inability to tolerate GH therapy was correct for some patients. For other patients, however, a variety of cardiac outcomes were observed, including less dramatic cardiac deterioration, no deterioration, or actual improvement. Because factors predictive of these different outcomes were not identified, it is prudent to assess cardiac status frequently during GH replacement therapy in this population. One of the authors (S.E.L.) routinely assesses cardiac status comprehensively before the initiation of GH therapy for these patients. He then reviews findings with patients, families, and providers before GH therapy. Follow-up echocardiography is performed initially after 3 to 6 months of GH therapy and less frequently thereafter, if possible. Rapid deterioration in LV structure or function has resulted in a decision to stop GH replacement therapy for some patients, after assessment of risks and benefits.

    Prolonged GH therapy for anthracycline-treated children with probable GH deficiency and LV dysfunction produced some short-term improvements in LV structure and function, but these effects diminished after therapy ended. LV dysfunction progressed regardless of GH therapy. Because neither GH therapy nor enalapril therapy59 results in long-term benefits in LV contractility among anthracycline-treated, long-term survivors of childhood cancer with LV dysfunction, strategies to prevent anthracycline cardiotoxicity during therapy are essential.60

    ACKNOWLEDGMENTS

    This work was supported in part by National Institutes of Health (Bethesda, MD) grants CA68484, CA79060, HL69800, HL59837, and HL53392.

    FOOTNOTES

    Accepted Oct 6, 2004.

    No conflict of interest declared.

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