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Cardiovascular Research 2000 45(2):447-453; doi:10.1016/S0008-6363(99)00345-4
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Copyright © 2000, European Society of Cardiology

Role of nitric oxide in the vasodilator effect of recombinant human growth hormone in patients with dilated cardiomyopathy

Karl Josef Osterziela,*, Stefanie M Bode-Bögerc, Oliver Strohma, Annette E Ellmera, Nana Bit-Avragima, Dankward Hänleina, Michael B Rankeb, Rainer Dietza and Rainer H Bögerc

aCharité/Franz-Volhard-Klinik, Humboldt Universität Berlin, Berlin, Germany
bKinderklinik der Universität Tübingen, Tübingen, Germany
cKlinische Pharmakologie, Medizinische Hochschule Hannover, Hannover, Germany

* Corresponding author. Tel.: +30-94-17-2221; fax: +30-94-17-2279 osterziel{at}fvk-berlin.de

Received 7 July 1999; accepted 16 September 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusion
 References
 
Objective: Dilated cardiomyopathy is characterized by elevated arterial vascular resistance and impaired nitric oxide (NO)-dependent vasodilation. Insulin-like growth factor-I (IGF-I) has been shown to stimulate endothelial NO-synthase resulting in endothelium-dependent vasodilation. Growth hormone (GH) substitution therapy leads in GH-deficient patients to significant increases of IGF-I which may alter systemic vascular resistance by stimulating NO production. This study was designed to evaluate the effects of treatment with recombinant human growth hormone (GH) on NO production and NO-dependent vascular effects in patients with dilated cardiomyopathy. Methods: 50 patients with dilated cardiomyopathy were randomly assigned to double-blind treatment with 2 I.U. of GH or placebo for 3 months. Central hemodynamics were determined by Swan-Ganz catheter and cardiac output was obtained by the thermodilution method. Serum GH and IGF-I levels were measured and systemic NO production was determined from urinary nitrate and cyclic GMP excretion rates in 42 patients. Results: GH treatment caused in comparison to the placebo group a significant increase of IGF-I by 91 ng/ml (P=0.0001). Urinary excretion rates of nitrate and cyclic GMP increased also significantly by 38 µmol/mmol creatinine (P=0.027) and 65 nmol/mmol creatinine (P=0.003), respectively. The parallel increase of both marker molecules indicates increased systemic NO production during GH treatment. Conclusion: GH treatment induces a significant, but moderate increase of systemic NO production in patients with dilated cardiomyopathy. This effect may be mediated by IGF-I stimulating endothelial NO synthase.

KEYWORDS Cardiomyopathy; Endothelial factors; Growth factors; Hemodynamics; Nitric oxide


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 5 Conclusion
 References
 
Endothelium-dependent vasodilation is impaired in patients with chronic heart failure [1]. Impaired endothelium-dependent vasodilation leads to elevated peripheral vascular resistance which further increases left ventricular afterload at rest or during exercise [2,3]. This may contribute to the progressive deterioration of left ventricular function. The mechanism by which NO-dependent vasodilation is impaired in heart failure is unclear. Reduced NO-formation or increased oxidative inactivation may be involved [4]. Treatment with oral L-arginine, the substrate of NO synthase, improves endothelium-dependent vasodilation [5] and increases arterial compliance in patients with heart failure [6].

Reduced stimulation of endothelial NO synthase (NOS) by growth hormone and/or insulin-like growth factor-I (IGF-I) may be one of the mechanisms contributing to reduced NO elaboration in chronic heart failure. There is evidence for reduced activity of the GH-IGF-I axis in patients with chronic heart failure [7,8].Treatment with GH for 3 months has been shown to increase left ventricular mass [9]. Although no significant overall hemodynamic improvement was found during this relatively short-term treatment, a tendency towards decreased peripheral arterial resistance was observed [9]. In two small uncontrolled studies, however, a significant decrease of vascular resistance was reported in patients with ischemic or dilated cardiomyopathy during chronic treatment with GH [10,11].

Endothelial cells possess high affinity binding sites for IGF-I [12]. Haylor et al. [13] were the first to demonstrate that the vasodilator effect of IGF-I in the isolated perfused rat kidney is abrogated by the NO-synthase inhibitor L-NMMA. In healthy humans, IGF-I induces forearm vasodilation upon intra-arterial infusion into the brachial artery, which is completely reversed by addition of the NO-synthase inhibitor L-NMMA [14].

GH treatment increases IGF-I levels which might stimulate NO production in heart failure patients, and by this mechanism reduce arterial resistance and improve cardiovascular function. In the present study, we investigated whether systemic NO production is increased in patients with dilated cardiomyopathy during treatment with recombinant human growth hormone. Urinary nitrate and cyclic GMP excretion rates were measured as indices of systemic NO production rate and related to hemodynamic alterations.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 5 Conclusion
 References
 
2.1 Patients
Patients with dilated cardiomyopathy (DCM), who fulfilled all of the inclusion criteria were randomised for the study. The inclusion critieria were: 1) age between 25 and 70 years, 2) a previously documented left ventricular ejection fraction below 45% measured either by echocardiography or by LV-angiography, 3) exclusion of coronary artery disease by selective coronary angiography, 4) optimized and stable medical therapy with ACE-inhibitors (or in case of intolerance with angiotensin II receptor antagonists), digitalis, nitrates and β-blockers as well as stable clinical status for at least four weeks. Exclusion criteria were active myocarditis, significant valvular disease, previous cardiac or cerebral surgery, arterial hypertension, pregnancy, known alcohol or drug abuse, mental disease and presence of contraindications for magnetic resonance imaging. Recruitment was stopped after randomisation of 50 patients. Urine at baseline and after 3 months of therapy was obtained. Urine sampling was incomplete at one time-point in eight patients. Therefore, only the 42 patients with two urine samples were analysed further. The study was approved by the Ethics Committee of the Max Delbrück Centre for Molecular Medicine, Berlin. Written informed consent was obtained from all patients.

2.2 Protocol
Eligible patients were hospitalised for baseline measurements which included a physical examination, 12 lead ECG, right heart catheterisation and magnetic resonance imaging (MRI) of the heart. Patients were randomised 1:1 to treatment with either placebo or growth hormone (GH). The randomisation was balanced in groups of 10 patients, and together with the labelling of the vials, was undertaken by the independent pharmacy department of the community hospital Berlin-Buch. One vial of growth hormone (Genotropin) contained 16 I.U. of recombinant human GH dry powder which was mixed with 0.3% m-cresol solution upon insertion of the vial into the Kabi-pen (provided by Pharmacia & Upjohn, Erlangen, Germany). Visually identical vials containing placebo were also provided by Pharmacia & Upjohn. All patients were carefully trained in the use of the injection pen. The treatment phase started after completion of all baseline studies with subcutaneous injections of 0.5 I.U. GH in the evening. The dose was increased every second day by 0.5 I.U. until a final dose of 2 I.U./d was reached. The placebo group injected identical volumes of fluid. All patients were treated for a minimum of 12 weeks. As soon as possible thereafter patients were hospitalised again and all measurements were repeated.

2.3 Cardiac magnetic resonance imaging
LV ejection fraction was determined by a standard 1.0 Tesla whole-body imaging system (Siemens Expert Magnetom, Siemens AG, Erlangen, Germany) using an FISP (Fast Imaging with Steady State Precession) gradient echo sequence for gradient-echo-imaging (TR=RR–interval; flip angle 30°, echotime 13 ms). After identification of the true long axis, 8 to 12 perpendicular 10 mm slices were positioned from the apex to the mitral valve along the long axis with no intersection gap [15]. The surface areas of the endocardial tracings in end-diastole and in end-systole were multiplied by section thickness and summed up to determine LV end-diastolic and end-systolic volume. LV ejection fraction was calculated from enddiastolic and endsystolic volumes.

2.4 Central hemodynamics
Right heart catheterization was performed in the fasting state without the morning medication between 9.00 and 11.00 h. After positioning the catheter in the pulmonary artery the patient was brought to a quiet room where measurements were taken after 30, 90 and 150 min. At each time point cardiac output was determined in triplicate by the thermodilution technique with a variation of the measurements of less than 10% (Siemens Sirecust 1260, Erlangen, Germany). There were no time dependent hemodynamic changes and the last set of measurements were used as baseline data. Blood pressure was determined automatically using a cuff (Siemens, Erlangen, Germany) and the average heart rate was taken from the ECG.

2.5 Laboratory tests
At baseline and at the end of double-blind GH/placebo treatment urinary nitrate concentration was determined as its pentafluorobenzyl derivate by gas chromatography–mass spectrometry (GC–MS) as described previously [16]. Briefly, aliquots of urine were spiked with [15N]-NO3- (MSD Isotopes Merck Frosst, Montreal, Canada) as internal standard. Reduction of nitrate to nitrite was performed prior to derivatization under alkaline conditions (5 wt% ammonium chloride buffer adjusted to pH 8.8 by sodium borate) by incubating samples or standard with 5 mg of cadmium (10 min, 20°C). One hundred µl of these samples were treated with 400 µl of acetone and 5 µl of PFB bromide, and the mixture was allowed to react for 60 min at 50°C. Acetone was then removed under nitrogen, and reactants were extracted by vortexing with 1000 µl of toluene. 1 µl aliquots thereof were injected into the GC-MS instrument (Hewlett Packard MS Engine 5989 series II, Waldbronn, Germany). A fused-silica capillary column DB-5 MS (30 mmx25 mm I.D:, 0.25 µm film thickness) from J&W Scientific (Rancho Cordova, CA) was used with helium as the carrier gas (70 kPa). Negative ions were produced by chemical ionization using methane as the reactant gas (200 Pa) at an electron energy of 230 eV and an electron current of 300 µA. Quantitation was performed by selected ion monitoring at m/z 46 for endogenous NO2–/NO3– and m/z 47 for the internal standard. The detection limit was 20 fmol of nitrate; intra- and interassay variabilities were below 3.8%.

Urinary cGMP levels were measured by radioimmunoassay (RIA) (Amersham Pharmacia Biotech, Freiburg, Germany). Serum and urinary creatinine was determined spectrophotometrically with the alkaline picric acid method in an automatic analyzer (Beckman, Galway, Ireland). Urinary excretion rates of nitrate and cyclic GMP were corrected by urinary creatinine concentration to limit variability due to differences in renal function [17].

After completion of the hemodynamic measurements blood was drawn to determine plasma adrenaline and noradrenaline by high-performance liquid chromatography (Chromosystems, Munich, Germany). The reference ranges are 30–85 pg/ml and 185–275 pg/ml, respectively.

Serum levels of GH, IGF-I and IGFBP-3 were determined at rest in the morning of two subsequent days at baseline and after readmission and the average of both values was used for further analysis. Serum levels of growth hormone (GH) [18] and IGF-I were measured with specific RIAs [19]. The IGF-I assay (RIA; Mediagnost, Tübingen, Germany) uses an excess of IGF-II to eliminate interferences with IGFBPs [19]. Intra-assay variability was 8.5% at 69 ng/ml and 6.5% at 140 ng/ml. IGF-binding protein-3 (IGFBP-3) was measured using a specific RIA with an intra-assay variability of 7.3% at 2772 ng/ml and 6.9% at 3545 ng/ml [19]. All samples for GH, IGF-I or IGFBP-3 determinations were measured in one assay.

2.6 Statistics
All data are presented as mean±standard error of the mean (SEM). Differences between the two treatment groups were evaluated by Student’s t-test. Treatment effects within groups were evaluated by paired t-test. Data for catecholamines were not normally distributed, and, therefore, were analysed after logarithmic transformation. Categorial variables were evaluated by the chi-square test. Univariate regression analysis was employed to analyse the relation between variables (StatView 4.5 for Macintosh). A P<0.05 was considered significant.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 5 Conclusion
 References
 
3.1 Baseline measurements
At baseline 4 patients were in New York Heart Association (NYHA) functional class I, 25 in class II, 2 in class II–III, 10 in class III and 1 in class IV. The patients had a mean age of 54±2 years and mean LV ejection fraction of 25±2%. The baseline clinical characteristics did not differ significantly between the patients assigned to placebo and GH with respect to height, weight, NYHA classification, ejection fraction, medication (Table 1), renal function, and baseline hemodynamic variables (Table 2).


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  		Table 1 Baseline characteristics of the placebo and growth hormone treated (GH) groupa

 

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  		Table 2 Hemodynamics, growth hormone axis, serum creatinine, and urinary nitrate and cyclic GMP excretion rates at baseline and their changes by treatmenta

 
3.2 Clinical effects of growth hormone therapy
Body weight and NYHA classification had not changed significantly in either of the groups after 98±1 days of therapy. Minimal adjustments of drug therapy were made in 11 patients (GH: 4, placebo: 7).

3.3 Hemodynamic effects of growth hormone therapy
The baseline resting hemodynamic variables were not different between groups and the hemodynamic changes in the GH group did not differ significantly from the changes in the placebo group (Fig. 1, Table 2). Baseline plasma levels of adrenaline and noradrenaline and their changes were also not significantly different between both groups (data not shown).


Figure 1
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  		Fig. 1 Changes of mean blood pressure, stroke volume and systemic vascular resistance in the placebo and GH group. Comparison of the changes between both groups result in the P values given in the figure. When the changes from baseline were calculated seperately for each group there were significant decreases of blood pressure (P<0.001) and systemic vascular resistance (P<0.05) and a trend towards an increase of stroke volume (P=0.06) in the GH but not in the placebo group.

 
However, when changes from baseline within the GH group were calculated mean blood pressure (–5±1 mm Hg, P<0.001) and systemic vascular resistance (–97±46 dynes sec/cm, P<0.05) fell significantly and stroke volume showed a trend to increase (+7±4 ml, P=0.06) whereas pulmonary capillary pressure and heart rate remained unchanged (Fig. 1). The placebo group showed no significant changes in these variables from their respective baseline values.

3.4 Urinary nitrate and cGMP excretion rates
Serum creatinine, urinary nitrate and cGMP excretion rates at baseline were not different in the two groups (Table 2). Serum creatinine did not change in both groups but there were significant increases of urinary nitrate and of cGMP excretion rates in the GH group (Fig. 2).


Figure 2
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  		Fig. 2 Alterations of serum IGF-I, urinary nitrate and cyclic GMP excretion rates by GH or placebo treatment. Compared are the changes between both groups.

 
3.5 Growth hormone/IGF-I axis
Serum concentrations of GH and IGF-I were not significantly different between the groups. Morning serum levels of GH did not significantly increase during GH treatment whereas IGF-I (Fig. 2) and IGFBP-3 increased significantly (Table 2).

The changes of arterial vascular resistance during GH treatment were weakly related to the changes of nitrate excretion (r=0.36, P=0.098) and to the changes of serum IGF-I (r=0.364, P=0.095) but not to changes in cGMP excretion rates.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
5 Conclusion
 References
 
Our present study suggests that therapy with human recombinant growth hormone increases systemic NO formation in patients with dilated cardiomyopathy. In addition to medical treatment, the increase in systemic NO formation may contribute to a further, small decrease of arterial vascular resistance.

4.1 Endothelial NO production in heart failure
Reduced endothelial NO-formation or increased oxidative inactivation may contribute to the impaired NO-dependent vasodilation in heart failure [20]. Nitrate is the oxidative metabolite of NO which is formed irrespectively of whether NO is biologically active or inactivated early, and therefore is a marker of systemic NO production. Cyclic GMP is formed by soluble guanylyl cyclase due to the action of biologically active NO, and therefore is a biochemical marker of NO's biological function [21]. It is known that inhibition of the renin–angiotensin system increases endothelial NO production [22]. Although inhibition of the renin–angiotensin system may have increased NO production baseline excretion rates of nitrate and cGMP in our patients with moderate to severe heart failure were still lower than those reported for healthy subjects [23]. This indicates reduced whole-body NO production.

The mechanisms leading to reduced NO elaboration in chronic heart failure is not fully understood. Endothelial NO synthase gene expression is reduced in failing human hearts [24]. Further, protein expression of endothelial NO synthase is also diminished in dogs with pacing-induced heart failure [25]. In addition, relative deficiency of L-arginine, the substrate for NO synthase, may be another cause of reduced NO synthesis [5].

4.2 GH/IGF-I axis and endothelial NO production
There is evidence for reduced activity of the GH-IGF-I axis in patients with heart failure [8]. Several studies support the hypothesis that low levels of IGF-I may contribute to decreased NO synthase activity in heart failure. Firstly, endothelium-dependent vasodilation is induced by IGF-I in isolated arteries [13,26]. IGF-I induced vasodilation is completely blocked by the NO-synthase inhibitor, L-NMMA, in isolated perfused rat kidneys [13]. A direct NO-releasing effect of IGF-I has been demonstrated in cultured human endothelial cells by the use of an NO-sensitive microelectrode [27]. Secondly, IGF-I induced vasodilation in the human forearm is completely reversed upon addition of L-NMMA, suggesting that the vasodilator effect of IGF-I is also mediated via NO in humans [14]. Thirdly, systemic NO production is increased upon treatment with GH and subsequent elevation of IGF-I levels in adult patients with acquired growth hormone deficiency [28]. Additional supportive edvidence came from a clinical trial showing impaired endothelium-dependent vasodilation in adult patients with growth hormone deficiency, which was normalized during supplementation with GH [29].

In our patients, baseline urinary nitrate and cGMP excretion rates were in a similar range like those we have previously determined in adult patients with acquired growth hormone deficiency [28]. GH treatment caused a substantial increase in serum IGF-I concentration by a mean of 57%. Urinary excretion rates of nitrate and cyclic GMP increased by 37% and 61% of baseline, respectively. The parallel increase in both marker molecules indicates increased systemic NO production during GH treatment. As baseline left ventricular filling pressures and systemic arteriolar resistances were low additional vasodilation could hardly be achieved. Nonetheless, when changes from baseline values were calculated there were small but significant decreases of arterial resistance of 7% (P<0.05) in the patients receiving GH. The decrease in systemic vascular resistance in the GH group correlated weakly with the increase in serum IGF-I levels and in nitrate excretion.

4.3 Study limitations
Inducible NO synthase (iNOS) is expressed in myocytes and in skeletal muscle cells of patients with chronic heart failure [30,31]. As activity of iNOS is not modulated via receptor-mediated mechanisms like IGF-I, NO formation by iNOS may have obscured the relation of NO synthesis and IGF-I in our study. Besides stimulating NO-mediated vasodilation, IGF-I has been shown to induce endothelium-independent vasodilation in vitro [32]. This effect may also have obscured the relation between IGF-I increase and NO formation. Finally, some of the patients have been treated with NO donor drugs. Although the doses of these medications remained unchanged the drugs may have contributed to urinary nitrate excretion to an unknown but constant amount.

Cyclic GMP is a second messenger not only for NO which acts via stimulation of soluble guanylyl cyclase, but its formation is also triggered via the particulate guanylyl cyclase by atrial natriuretic peptides (ANP and BNP, respectively) [33]. Both peptide hormones are increased in relation to the severity of heart failure but their action is blunted [34]. Their plasma levels correlate significantly to left atrial pressure and left ventricular wall tension [35]. It is unlikely that GH treatment increased natriuretic peptides and, subsequently, cyclic GMP excretion, because GH did not significantly alter pulmonary capillary wedge pressure, a measure of left ventricular filling pressure [9]. By contrast, the increase in myocardial mass during GH treatment may have even decreased ventricular ANP/BNP secretion, as ventricular wall stretch had a tendency to decrease during GH treatment [9].


   5 Conclusion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusion
References
 
Our data suggest that GH treatment induces a moderate increase in NO production in patients with dilated cardiomyopathy. This effect may be mediated by elevated serum IGF-I, subsequently stimulating endothelial NO synthase. Enhanced NO formation results in vasodilation, and this may be one contributing factor that determines vascular resistance in heart failure.

Time for primary review 27 days.


   Acknowledgements
 
We thank Pharmacia & Upjohn, Germany, for kindly providing support and the pharmacy department of the Klinikum Buch (Dr. Möller) for blinding and randomisation. We thank the participating patients and all those who helped with the running of the study, particularly Ingrid Jackwerth, Anke Heiser, Elke Szczech, Matthias Friedrich, Udo Kuhnert, and Rainer Stein. The excellent technical assistance of M.-T. Suchy, B. Schubert, and K. Weber is gratefully acknowledged.

This study was supported in part by grants from the Dr.-Karl-Wilder Stiftung, Bonn, Germany and from the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusion
 References
 

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S. Adamopoulos, J. T. Parissis, I. Paraskevaidis, D. Karatzas, E. Livanis, M. Georgiadis, G. Karavolias, D. Mitropoulos, D. Degiannis, and D. Th. Kremastinos
Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy
Eur. Heart J., December 2, 2003; 24(24): 2186 - 2196.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
R. Napoli, V. Guardasole, V. Angelini, F. D'Amico, E. Zarra, M. Matarazzo, and L. Sacca
Acute Effects of Growth Hormone on Vascular Function in Human Subjects
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2817 - 2820.
[Abstract] [Full Text] [PDF]

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