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Departments of Endocrinology (J.W.A.S., Y.J.H.J., N.R.B., J.A.R., F.R.), Radiology (H.J.L., A.d.R.), Cardiology (E.E.v.d.W., J.J.B., H.W.V.), Nuclear Medicine (M.P.M.S.), Leiden University Medical Center, Leiden, The Netherlands Department of Cardiology, Groene Hart Hospital (E.V.), Gouda, The Netherlands
Address all correspondence and requests for reprints to: Jan W. A. Smit, M.D. Ph.D., Department of Endocrinology, C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: j.w.a.smit.endo{at}lumc.nl
Abstract
Beneficial effects of recombinant human GH on cardiac function have been reported in humans with GH deficiency and in patients with idiopathic dilated cardiomyopathy. No randomized controlled trial has been performed on the effects of recombinant human GH on cardiac function in patients with ischemic cardiac failure. We therefore randomly assigned 22 patients with ischemic cardiac failure (left ventricular ejection fraction, <40%; 19 men and 3 women; mean age, 64 yr) to receive 6 months of unblinded therapy with recombinant human GH (2.0 IU/d) or no treatment. Primary end points were left ventricular ejection fraction and left ventricular mass. Left ventricular end-diastolic volume, left ventricular end-systolic volume, and myocardial perfusion, both at rest and during exercise, were assessed as well. Cardiac imaging techniques were electrocardiographically gated single photon emission computer tomography and magnetic resonance imaging. In addition, biochemical and biometric measurements were performed. Nineteen patients completed the study (10 controls and 9 GH-treated subjects). IGF-I and IGF-binding protein-3 increased significantly after recombinant human GH treatment (+24% and +58%, respectively) compared with control values (-14% and +5%; P < 0.05). Left ventricular ejection fraction, left ventricular end-diastolic volume, left ventricular end-systolic volume, left ventricular mass, and myocardial perfusion were not influenced by recombinant human GH therapy. We conclude that 6 months of recombinant human GH treatment in patients with ischemic cardiac failure had no beneficial effect on left ventricular function and mass.
THE EFFECTS OF GH on the cardiovascular
system have been well documented in disorders with excessive or
deficient GH production. GH excess in humans is accompanied by
myocardial hypertrophy, which initially enhances cardiac output
(1) but ultimately leads to diminished cardiac performance
(2). Conversely, GH deficiency leads to reduced cardiac
muscle mass (3) and consequently to impaired cardiac
function. Substitution with recombinant human GH in patients with GH
deficiency increases myocardial mass, cardiac function, and exercise
capacity, most prominently after prolonged (6-month) treatment
(3, 4, 5). Experimental data in rats revealed favorable
effects of GH and IGF-I on cardiomyocyte diameter and contractility,
probably through enhanced myofibrillar development and myosin isoenzyme
pattern (6, 7). In experimental myocardial infarction in
rats, GH therapy leads to improved or retained cardiac function
compared with that in nontreated rats (8, 9, 10). These
observations have resulted in the experimental treatment with
recombinant human GH in patients with cardiac failure of various
origins without underlying GH deficiency (Table 1
).
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In patients with ischemic cardiac failure, beneficial effects of recombinant human GH have been suggested as well. In a nonrandomized study, 3 months of GH therapy in 7 patients with ischemic cardiac failure increased left ventricular posterior wall thickness and improved hemodynamic parameters and exercise performance (15). The study by Isgaard and colleagues (13) included 8 patients with ischemic cardiac failure, but these patients were not analyzed separately. Another study of 15 patients with ischemic heart failure revealed no effect of recombinant human GH on cardiac dimensions compared with controls (16). However, this study was not randomized. In a recent study of patients with ischemic cardiac failure, 8 d of GH in different dosages produced correlations between IGF-I changes and left ventricular ejection fraction (17). We report a randomized study of the effects of 6 months of recombinant human GH treatment in patients with ischemic cardiac failure on left ventricular function, as assessed by magnetic resonance (MR) imaging and electrocardiographically gated myocardial perfusion, single photon emission, computed tomography (gated-SPECT).
Subjects and Methods
Patients
Patients with ischemic cardiac failure were selected from the Departments of Cardiology of Leiden University Medical Center (Leiden, The Netherlands), Groene Hart Hospital (Gouda, The Netherlands), and Rijnland Hospital (Leiderdorp, The Netherlands). Inclusion criteria for the study were the presence of ischemic heart disease proven by prior myocardial infarction and/or coronary angiography, a left ventricular ejection fraction less than 40% assessed by gated-SPECT myocardial imaging, a stable clinical condition for at least 3 months, and stable medical therapy with inhibitors of angiotensin-converting enzyme, cardiac glycosides, nitrates or ß-blocking agents for at least 3 months. Exclusion criteria were myocardial infarction within 3 months before the study, the presence of a pacemaker or implantable defibrillator, arrhythmias, chronic renal and liver disease, diabetes mellitus, and malignant disease. The protocol was approved by the ethical committee of the Leiden University Medical Center, and all patients gave written informed consent.
A total of 155 patients were screened for inclusion. Of these patients, 64 were not eligible because they had a pacemaker or cardiac arrythmias, 27 patients had renal dysfunction, 26 had impaired glucose tolerance or diabetes mellitus, 3 died, and 13 could not be included for other reasons. Twenty-two patients entered the study.
Protocol
Baseline measurements included a physical examination, a 12-lead electrocardiogram, cardiac MR imaging, gated-SPECT myocardial imaging, and biochemical tests. After baseline measurements, patients were randomly allocated to treatment with recombinant human GH (Zomacton, Ferring Pharmaceuticals Ltd., Hoofddorp, The Netherlands) or no treatment (control group) using 6 randomization blocks of 4 subjects each with a proportion of 1:1. The randomization schedule was prepared by the Department of Clinical Pharmacy of Leiden University Medical Center, which was not involved in the execution of assignment. Except for recombinant human GH treatment, the study protocol was identical for the 2 groups. GH treatment started with 0.5 IU recombinant human GH/d, self-administered sc around 2300 h. The dose was increased after 2 wk to 1.0 IU/d. Four weeks after entering the study, the final dose of 2.0 IU/d was initiated and continued until the end of the study at 26 wk. Safety visits were performed at 2, 4, 8, and 16 wk after randomization. At 26 wk, cardiac MR imaging and gated-SPECT myocardial imaging were performed again. At each visit, weight, waist/hip ratio, blood pressure, and heart rate were recorded, and recombinant human GH vials were collected to assess compliance.
Gated-SPECT myocardial imaging
Gated-SPECT myocardial imaging was performed as described previously (18) after a 1-d imaging protocol (19). In short, both at rest and after a symptom-limited exercise test with stepwise increased workload, 99mTc-tetrofosmin (Myoview, Nycomed-Amersham Pharmacia Biotech, Eindhoven, The Netherlands) was administered iv, and images were acquired using a GCA-9300 triple head camera (Toshiba, Tokyo, Japan) (19). Left ventricular end-diastolic volume and left ventricular end-systolic volume were calculated as described by Germano et al. (18). Myocardial perfusion at rest and during exercise was assessed in five left ventricular segments, i.e. anterior, septal, lateral, apical, and inferior wall, and scored on a four-point scale as normal (score of 3), mild defect (score of 2), severe defect (score of 1), or absent (score of 0) as described previously (20). For each patient, the scores for each segment were combined and expressed as a total score (maximum, 15) both at rest and during exercise. In addition, the number of segments per treatment group with perfusion scores of 0–3 were expressed as a percentage of the total segments examined at rest and after exercise. Segments with defective perfusion after exercise without improvement at rest were considered persistent defects (20). All scintigraphic studies were evaluated in consensus readings by two experienced observers who were unaware of the treatment modality.
Cardiac MR imaging
Cardiac MR imaging was performed using a standard Philips 1.5-T ACS-NT15 MR system (Philips Medical Systems International, Best, The Netherlands) as described previously (21, 22). Temporal resolution was 35–39 msec, the time between successive short-axis images of the cardiac cycle. Borders of the left ventricle were outlined manually using the MR analytical software system MASS (Medis, Leiden, The Netherlands) by an experienced observer (23, 24). The left ventricular ejection fraction was calculated as the summed difference between surface areas of endocardial tracings in end diastole and end systole, multiplied by section thickness and section factor. The difference between the summed end-systolic epicardial and endocardial borders multiplied by section thickness and section factor served as an estimate of wall volume, which was multiplied by the specific density of cardiac muscle (1.05 g/cm3) to obtain the left ventricular wall mass (24).
Laboratory tests
At baseline and at the end of the study, fasting blood samples were taken between 0800–0900 h for GH, IGF-I, and IGF binding protein-3 (IGFBP-3) measurements. Plasma GH was measured with the Delfia human GH assay (Wallac, Inc., Turku, Finland). IGF-I was measured by RIA (INCSTAR Corp., Stillwater, MN). Intraassay variability was less than 11%; the detection limit was 1.5 nmol/liter. Normal values range between 9–34 nmol/liter for subjects aged 30–50 yr and between 8–26 nmol/liter for those aged 50–70 yr. IGFBP-3 was measured by RIA (Nichols Institute Diagnostics, Wychen, The Netherlands). The detection limit was 0.03 mg/liter. The intraassay variability was less than 8%. Safety laboratory measurements included serum levels of urea, creatinine, glucose, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase and a hematological profile. Other measurements were performed using routine laboratory methods.
Statistics
Since this study was initiated in 1997, power calculation was
based on the results of the study by Fazio et al.
(11). For the primary end points of left ventricular mass
and left ventricle ejection fraction from the study of Fazio, estimated
SD values of the difference before and after GH
therapy in left ventricular mass of 29 g and left ventricular
ejection fraction of 5.9 U were calculated. Based on these data, it was
calculated that a sample size of 7 patients/group was needed to detect
a difference of 50 g in the change in left ventricular mass
between the recombinant human GH group and the control group and a
sample size of 10 patients/group was needed to detect a difference of 7
U in the change in the left ventricular ejection fraction between both
groups, with a power of 80% and a significance level of 0.05 for both.
Continuous variables are expressed as the mean ±
SE unless indicated otherwise. The distribution
of continuous variables was assessed by the Kolmogorov-Smirnov test.
Normally distributed variables were compared with unpaired t
test. Other data were analyzed with the Mann-Whitney test. To analyze
treatment effects, the differences in treatment response (posttherapy
minus pretherapy values) were compared between the groups. Categorical
variables were expressed as proportions and compared with the
2 test. Univariate and multivariate regression
analyses were performed to assess correlations between biochemical and
cardiac parameters. SPSS 9.0 (SPSS, Inc., Chicago, IL) was
used for all statistical calculations.
Results
Patients
Twenty-two patients fulfilled all inclusion criteria and entered
the trial. Three patients left the study prematurely. One patient from
the control group developed cardiac arrhythmias at 18 wk, for which a
pacemaker was implanted. One patient in the GH group presented with
severe anemia (hemoglobin, 5.6 mmol/liter) at baseline, caused by a
gastric ulcer. Another patient from the GH group died after 16 wk of
treatment, probably from sudden cardiac death. The exact cause of his
death could not be determined, as autopsy was not permitted. Data from
these 3 patients were not included in any analysis. The baseline
characteristics of the remaining 19 patients are shown in Table 2 and included in Tables 3 and 4. No
differences in baseline characteristics between the 2 groups were
present.
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The effects of recombinant human GH treatment on blood pressure,
heart rate, body mass, waist/hip ratio, and biochemical parameters are
given in Table 3
. Systolic blood pressure decreased slightly in the
treatment group (-15.8%) compared with controls (-5.8%;
P = 0.048). Serum IGF-I levels in all patients were
within the normal age-adjusted range (9–34 nmol/liter). There were no
significant effects of GH therapy on other biometric parameters. Serum
IGF-I and IGFBP-3 levels increased significantly in the treatment group
compared with the control group [IGF-I, +23.6% and -14.0%,
respectively (Fig. 1;
P = 0.048); serum IGFBP-3 levels, +58.2% and 4.6%,
respectively (P = 0.036)]. Serum free
T4 levels decreased slightly in the GH group
compared with the control group (-7.6% vs. 1.9%;
P = 0.010). No significant differences in changes in
lipid levels were found between the groups.
Cardiac parameters
Gated-SPECT myocardial imaging. Data from gated-SPECT
myocardial imaging are presented in Table 4 and Fig. 2. There were no effects of recombinant
human GH treatment on left ventricular end-diastolic or end-systolic
volumes or, consequently, on left ventricular ejection fraction. As
indicated in Table 4, nearly all perfusion defects were persistent in
both groups (96.6% in controls and 91.7% in the GH group). GH
treatment did not significantly influence the total perfusion scores
per patient, the proportion of segments within each perfusion category
per treatment group, or the proportion of persistent defects either at
rest or during exercise.
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Data from cardiac MR imaging are presented in Table 4. A
marked concordance was observed between the results of the left
ventricular ejection fraction as measured by MR imaging and
gated-SPECT. Recombinant human GH treatment had no effect on the left
ventricular ejection fraction. In addition, left ventricular mass was
not influenced by GH treatment. Although recombinant human GH did not
influence left ventricular mass, a positive correlation was observed
between changes in serum IGF-I levels and changes in left ventricular
mass in all patients combined (r = 0.502; P =
0.017) and in GH-treated patients (r = 0.870; P =
0.002). In multivariant regression analysis the change in serum IGF-I
was found to be an independent predictor of changes in left ventricular
mass, whereas GH treatment was not. In contrast, we did not discover a
correlation between baseline IGF-I levels and left ventricular mass at
baseline (r = 0.05) or left ventricular ejection fraction at
baseline (r = 0.18).
Adverse events
Three patients from the GH treatment group experienced adverse events. One patient was admitted for cardiac chest pain and was treated for 3 d with iv nitroglycerine. No signs of myocardial infarction were present. Two other patients experienced an exacerbation of congestive heart failure. Dosages of diuretics were increased, after which the symptoms subsided. Recombinant human GH treatment was continued in these patients. No adverse events were observed in the control group. GH treatment did not affect glucose tolerance (glucose levels and hemoglobin A1C), kidney function, or hepatic function.
Discussion
The present study was performed to assess the effects of 6 months of treatment with recombinant human GH on left ventricular function in patients with ischemic cardiac failure. The main outcome measures of the study, left ventricular ejection fraction and left ventricular mass, were not changed by recombinant human GH treatment. Left ventricular end-diastolic and end-systolic volumes and left ventricular myocardial perfusion were also not influenced.
Prior studies of treatment with recombinant human GH in ischemic cardiac failure suggested beneficial effects on clinical parameters and cardiac function. However, these studies were without a control group (15), without randomly assigned GH treatment (16), or included other patient categories (13). The subjects in our study were slightly older than those in the trial reported by Gent Zoth and colleagues (15), but their history of cardiac disease, the New York Heart Association class, and GH dosages were comparable, as was concomitant medication, although treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors and anticoagulant drugs was not indicated in that study (15). In the study by Spallarossa and colleagues (16), concomitant medication was not indicated. In our study advanced cardiac imaging techniques were applied (cardiac MR imaging and gated-SPECT myocardial imaging), which are regarded as more accurate than Doppler echocardiography, which was used in the study by Spallarossa et al. (16). A drawback of the present study could be the study size and, consequently, whether this study size was sufficient to detect clinical significant effects of GH treatment. We therefore performed a post-hoc power calculation and calculated from the results that the sample size was sufficient to detect with 80% power a change in left ventricular ejection fraction of 4 U and in left ventricular mass of 15 g, which is adequate. Moreover, we carefully selected the patients from 155 candidates to include a well characterized homogenous patient group.
Although GH therapy had effects on the biochemical parameters that are dependant on GH action (i.e. increase in IGF-I and decrease in free T4), the increase in IGF-I in our study was less than that observed in other studies of GH treatment in cardiac disease despite a comparable dosage (11, 12, 13, 15, 16). The duration of treatment in our study may not explain the moderate increase in IGF-I, as the treatment period was longer than that in most studies, and the effects of recombinant human GH on cardiac function in GH-deficient patients become apparent only after 6 months of therapy (3, 4, 5). A larger increase in IGFBP-3 than in IGF-I was observed. It may be hypothesized that in chronic cardiac failure, partial resistance to GH is present, as in many other chronic diseases (25). Indeed, in chronic cardiac failure, patients with decreased sensitivity to GH have been identified (26, 27). In contrast, IGF-I levels in the patients studied by Genth-Zotz et al. (15) were within the normal range. Baseline IGF-I levels in our patients were within the normal range as well. Osterziel et al. (14) observed a threshold for beneficial cardiac response to GH, dependent on the IGF-I response in patients with idiopathic dilated cardiomyopathy. Although baseline IGF-I levels in that patient group were decreased, we cannot exclude that such a phenomenon may play a role in ischemic cardiac failure as well and that higher dosages of GH might have resulted in higher IGF-I levels and, consequently, a more favorable response (17). Another hypothesis for the lack of beneficial effects of recombinant human GH on cardiac function is the chronic state of cardiac failure. Indeed, in animals with cardiac failure, GH improved cardiac function when given after 4 months (28), but not when started later (29), which may indicate that GH therapy is less effective in chronic ischemic cardiac failure. A significant correlation between changes in IGF-I concentrations and left ventricular mass was observed in the GH-treated group, which is in accordance with other studies in idiopathic dilated cardiac failure (12, 14) and in ischemic cardiac failure (17). This correlation has been explained by an increase in cardiomyocyte myofibrillar content during GH or IGF-I therapy, which leads to hypertrophy of cardiomyocytes and, consequently, left ventricular mass (7, 8, 9, 10). However, the correlation between changes in left ventricular mass and IGF-I in our study and in the study by Osterziel et al. (12) also existed in subjects with a decrease in IGF-I levels during therapy, which illustrates the complex relationship between circulating IGF-I and cardiac mass. The slight decrease in systolic blood pressure in the patients treated with recombinant human GH may be explained by the effects of GH on peripheral vascular resistance, although we did not measure this (3).
We conclude from our study that 6 months of treatment with 2.0 IU/d recombinant human GH has no beneficial effect on left ventricular function in patients with ischemic cardiac failure.
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Recombinant human GH was kindly supplied by Ferring Pharmaceuticals Ltd. (Hoofddorp, The Netherlands).
Footnotes
Abbreviations: gated-SPECT, Electrocardiographically gated myocardial perfusion, single photon emission, computed tomography; IGFBP-3, IGF binding protein-3; MR, magnetic resonance.
Received February 15, 2001.
Accepted May 11, 2001.
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