Recombinant Growth Hormone Therapy in Patients With Ischemic Cardiomyopathy
Effects on Hemodynamics, Left Ventricular Function, and Cardiopulmonary Exercise Capacity
Background—We studied the effects of recombinant growth hormone (rhGH) on exercise capacity and cardiac function in patients with ischemic cardiomyopathy.
Methods and Results—Seven patients (aged 55±9 years) with mild to moderate congestive heart failure (ejection fraction 31±4%) who were on standard therapy were included. The patients were studied at baseline, after 3 months of rhGH treatment, and 3 months after rhGH discontinuation. Cardiac function was assessed by exercise capacity, right heart catheterization at rest and after submaximal exercise, MRI, echocardiography, and Holter monitoring. When administered at a dose of 2 IU/d, rhGH doubled the serum concentration of insulin-like growth factor-I. rhGH improved clinical symptoms and exercise capacity significantly (New York Heart Association class 2.4±0.5 initially versus 1.4±0.5 at 3 months [mean±SD], P<0.05; V̇o2max 13.6±3.8 versus 17.4±5.4 mL · kg−1 · min−1, P<0.05). Additionally, pulmonary capillary wedge pressures at rest and after submaximal exercise were reduced significantly. Cardiac output increased, particularly at rest (5.0±1.1 versus 5.8±1.3 L/min; P<0.05). Posterior wall thickness was increased (1.08±0.1 versus 1.24±0.3 cm; P<0.05), and the end-diastolic and end-systolic volume indexes decreased significantly after rhGH treatment. There was no significant increase in left ventricular ejection fraction. The improvements were partially reversed 3 months after rhGH discontinuation.
Conclusions—The administration of rhGH for 3 months in patients with ischemic cardiomyopathy results in significant improvement in hemodynamics and clinical function. The attenuation of left ventricular remodeling persisted 3 months after discontinuation of treatment.
Prolonged growth hormone deficiency may contribute to the development of dilated cardiomyopathy.1 Fazio et al2 reported an increase in myocardial muscle mass and reduced dimensions of the left ventricle in patients with idiopathic dilated cardiomyopathy after 3 months of treatment with recombinant growth hormone (rhGH). Studies in rats with experimental heart failure demonstrated an increase in myocardial contractility, cardiac output, and stroke volume, with a decrease in diastolic pressure and peripheral resistance,3 4 after treatment with rhGH. The aim of the present study was to investigate the effects of rhGH in addition to conventional therapy on hemodynamic parameters (at rest and during exercise), left ventricular function, and cardiopulmonary exercise capacity during a 3-month period in patients with ischemic cardiomyopathy.
The study involved 7 male patients (age, 55±9 years) with chronic heart failure due to ischemic heart disease (ejection fraction 31±4%). All patients had experienced an anterior myocardial infarction; CABG and PTCA had been performed in 4 and 3 patients, respectively. All patients were treated with digitalis (0.2 mg/d digoxin), diuretics (mean dose, 80 mg/d furosemide), ACE inhibitors (10 mg/d enalapril), and β-blockers (100 mg/d metoprolol tartrate). Medical therapy was administered unaltered for ≥2 months. Entry criteria were clinical evidence of congestive heart failure (CHF) despite optimal medical therapy and revascularization procedures, as well as an ejection fraction ≤40%, as assessed by echocardiography. Furthermore, a stable hemodynamic condition for ≥2 months before randomization and sinus rhythm were required. Exclusion criteria included myocardial infarction, CABG or PTCA within the last 6 months, significant valvular heart disease, and malignancies. Four patients were in New York Heart Association class II, and 3 were in class III. Written informed consent was obtained from each patient, and the study was approved by the ethics committee of the University of Mainz.
All patients were studied at baseline, after 3 months of rhGH treatment, and 3 months after discontinuation of rhGH treatment. All patients were treated with Genotropin (Pharmacia & Upjohn) 2 IU/d SC. Standard therapy for CHF was continued throughout the study. If necessary, medication doses could be adjusted. Patients were observed closely during the first weeks to detect the sodium-retaining property of rhGH. Exercise tolerance was assessed by symptom-limiting cardiopulmonary exercise testing on a bicycle starting with 20 W, which was then increased by 10 W/min. The test was terminated when severe dyspnea or fatigue occurred. Left ventricular systolic and diastolic function were evaluated with an ultrasonic system. The measurements were performed according to the recommendations of the American Society of Echocardiography. MRI was performed on a Philips ACS 1.5-T Gyroscan system. Left ventricular volumes were determined by use of serial short-axis cine MRI and Simpson’s rule.5 Right heart catheterization at rest and after submaximal exercise was performed in the morning after the patients had fasted overnight. Standard medication was administered. rhGH was not given within 24 hours of catheterization. All measurements were performed in triplicate with 2 mechanoelectrical transducers used simultaneously. Cardiac output was determined by thermodilution. After a stabilization period, baseline measurements were taken, and the patients performed a submaximal exercise test (3 minutes at 50 W) with the bicycle attached to the catheterization table. Hemodynamic measurements were repeated immediately after termination of exercise and again after a 3-minute rest period. Holter monitoring was performed at baseline and after 3 months of rhGH treatment. Serum growth hormone, insulin-like growth factor-1 (IGF-1), and thyroid hormone were measured at baseline, after 3 months of treatment, and 3 months after rhGH discontinuation with commercially available radioimmunoassay kits.
For each variable and individual patient, the relative alterations of values over time were calculated as follows: For all patients, the mean and CI of the above term were calculated and graphed. Significance was anticipated if the CI did not include zero.
All patients completed the 3-month treatment phase without any adverse side effects. Dose adjustment of concomitant medications was not necessary. During rhGH treatment, all patients improved clinically, as indicated by a decreased NYHA functional class. This improvement had deteriorated 3 months after discontinuation of rhGH. Exercise capacity increased in all patients; maximal oxygen uptake (V̇o2max) rose from 13.6±3.8 to 17.4±5.4 mL · kg−1 · min−1 and fell to 17.1±3.9 mL · kg−1 · min−1 3 months after rhGH was discontinued (Figure⇓ and Table⇓). Exercise duration increased significantly after 3 months compared with baseline measurements, without significant alterations in heart rate at rest and during maximal exercise. MRI showed a significant reduction in end-systolic and end-diastolic volume indexes (86.4±27.6 mL/m2 at baseline versus 74.9±8.1 mL/m2 after 3 months of treatment versus 72.2±18.7 mL/m2 3 months after discontinuation of treatment) and an increase in posterior wall thickness (1.10±0.10 versus 1.24±0.13 versus 1.25±0.15 cm). Left ventricular ejection fraction did not change significantly. There was an increase of early diastolic filling velocity (V̇max E) and a decrease of the deceleration time of early diastolic filling. Holter monitoring did not show any malignant ventricular arrhythmia.
After treatment, the mean pulmonary capillary wedge pressure (PCWP) significantly decreased at rest (18.9±4.2 versus 13.7±4.3 versus 15.2±5.1 mm Hg) and after exercise (37.1±13.0 versus 29.8±10.9 versus 34.1±4.2 mm Hg). After 3 months of discontinuation, PCWP at rest was still lower than at baseline. Pulmonary artery pressure at rest and after exercise tended to decrease, but this did not achieve statistical significance. rhGH therapy significantly increased cardiac output at rest and in response to physical exercise and significantly decreased systemic vascular resistance. Serum concentrations of rhGH determined at baseline (0.46±0.8 ng/mL) increased the day after injection to 0.74±0.4 ng/mL (normal range, <8 ng/mL), and the concentrations of IGF-1 were 0.69±0.34 at baseline versus 1.45±0.17 U/mL after 3 months of rhGH treatment (normal range, 0.32 to 2.2 U/mL). Serum thyroid hormone and thyrotropin concentrations did not change significantly after rhGH therapy.
Over the past years, remarkable advances have been made in understanding the cellular and molecular mechanisms involved in the action of growth hormone, including its effects on cardiac tissue.6 There is now solid evidence implicating rhGH and/or its local effector, IGF-1, in the intricate cascade of events connected with the regulation of heart development and hypertrophy. In the present study, a 3-month period of rhGH treatment in addition to conventional therapy resulted in significant improvement in functional status, exercise capacity, and hemodynamic parameters and a reduction in left ventricular systolic and diastolic volume indexes in patients with ischemic cardiomyopathy. However, there was no significant improvement in left ventricular systolic function. These effects tended to decrease 3 months after rhGH was discontinued. Despite that, significant improvements in functional class and V̇o2max, a reduction in PCWP at rest, and an increase in posterior wall thickness were still detectable, but these effects were diminished compared with values after 3 months of treatment. Our results are comparable to observations published for patients with dilated cardiomyopathy.2 The observed lack of a significant increase in heart rate at rest and after exercise can be explained by the fact that all patients had been undergoing stable therapy with metoprolol (100 mg/d) for ≥2 months. In our opinion, the marked improvement of exercise capacity despite unaltered simultaneous β-blockade can be attributed to the rhGH treatment. The same applies for ACE inhibition with regard to growth response and ventricular remodeling, because therapy with enalapril had been unaltered for ≥2 months before the start of the study. In retrospect, a maximal exercise test might have been an alternative to investigate the hemodynamic changes after rhGH treatment. This is supported by the finding that cardiac output did not increase significantly after submaximal exercise, whereas V̇o2max rose significantly during maximal symptom-limiting exercise. However, the supine position of the patients while undergoing right heart catheterization prevented a maximal test and might have resulted in false-negative values. Therefore, we decided to use this submaximal test, which patients in functional classes II and III were able to perform alike. The decrease in left ventricular chamber size and reduced systemic vascular resistance were induced by rhGH treatment. Those changes resulted in a reduction in systolic wall stress. Reduced systolic wall stress, which is an important determinant for oxygen consumption, could be responsible for these changes. On the other hand, changes in molecular gene expression that result in an increase in actin-myosin cross bridges, without an alteration of ATP demand, could explain the positive effects of rhGH.7 Another possible mechanism by which rhGH could be exerting its positive contractile effects may involve regulation at the level of the adrenergic receptor–G-protein complex.7
A limitation of our study is the lack of a placebo-control group. A placebo effect cannot be entirely ruled out. However, given the consistency of the hemodynamic improvements and decrease in left ventricular size after 3 months of treatment with rhGH and its partial reversibility after discontinuation of treatment, it is unlikely that the overall clinical improvement was spontaneous.
In conclusion, the administration of rhGH in addition to conventional therapy is safe and results in an attenuation of left ventricular remodeling and an improvement in hemodynamics and exercise performance. Thus, rhGH seems to be effective in the treatment of patients with CHF independently of its pathophysiological cause. Although these results were obtained in a small group of patients without a placebo group, they are encouraging and point to the need for a randomized, double-blind trial to study several doses of rhGH and possibly a longer duration of treatment, because the effects we observed partially disappeared 3 months after termination of therapy.
- Received May 27, 1998.
- Revision received October 28, 1998.
- Accepted November 5, 1998.
- Copyright © 1999 by American Heart Association
Cuocolo A, Nicolai E, Colao A, Longobardi S, Cardei S, Fazio S, Merola B, Lombardi G, Sacca L, Salvatore M. Improved left ventricular function after growth hormone replacement in patients with hypopituitarism: assessment with radionuclide angiography. Eur J Nucl Med. 1996;23:390–394.
Yang R, Bunting S, Gillett N, Clark R, Jin H. Growth hormone improves cardiac performance in experimental heart failure. Circulation. 1995;92:262–267.