CLINICAL STUDY
Growth hormone corrects vascular dysfunction in patients with chronic heart failure
Raffaele Napoli, MD*,
Vincenzo Guardasole, MD*,
Margherita Matarazzo, MD*,
Emiliano A. Palmieri, MD*,
Ugo Oliviero, MD*,
Serafino Fazio, MD* and
Luigi Saccà, MD*,*
* Department of Internal Medicine and Cardiovascular Sciences, University Federico II School of Medicine, Naples, Italy
Manuscript received June 12, 2001;
revised manuscript received September 4, 2001,
accepted September 7, 2001.
* Reprint requests and correspondence: Dr. Luigi Saccà, Medicina Interna, Via Pansini 5, 80131 Napoli, Italy.
sacca{at}unina.it
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Abstract
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OBJECTIVES: The goal of this study was to test the hypothesis that growth hormone (GH) administration to patients with chronic heart failure (CHF) corrects their vascular dysfunction.
BACKGROUND: Endothelial dysfunction is a prominent feature of CHF. Recent evidence indicates that GH plays a role in vascular reactivity.
METHODS: We studied vascular reactivity in 16 patients with CHF (New York Heart Association class II to III) before and after three months of GH (4 IU subcutaneously every other day) or placebo administration in a randomized, double-blind trial. We measured forearm blood flow (FBF) by strain-gauge plethysmography during intrabrachial, graded infusion of acetylcholine (ACh) and sodium nitroprusside (NP). We also measured the forearm balance of nitrite and cyclic guanosine monophosphate (cGMP) before and during ACh infusion. Maximal oxygen uptake (VO2max) was measured by breath-to-breath respiratory gas analysis.
RESULTS: Before treatment, the response of FBF to ACh was flat (p = NS). Growth hormone, but not placebo, greatly improved this response (p = 0.03) and, concomitantly, increased the forearm release of nitrite and cGMP (p < 0.05). Growth hormone also potentiated the FBF response to NP (p = 0.013). Growth hormone interacted with ACh response (p = 0.01) but not with the response to NP (p = NS). Accordingly, GH enhanced the slope of the dose-response curve to ACh (p < 0.05) but not to NP. The VO2max increased significantly after GH treatment (20 ± 2 and 26 ± 2 ml ·Kg–1· min–1 before and after GH treatment, respectively, p < 0.05) but not after placebo.
CONCLUSIONS: A three-month treatment with GH corrected endothelial dysfunction and improved non-endothelium-dependent vasodilation in patients with CHF. The data highlight the potential role of GH in the progression of congestive heart failure.
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Abbreviations and Acronyms
| | ACh | | acetylcholine | | cGMP | | cyclic guanosine monophosphate | | CHF | | chronic heart failure | | FBF | | forearm blood flow | | GH | | growth hormone | | IGF-I | | insulin-like growth factor I | | L-NMMA | | L-N-monomethylarginine | | LV | | left ventricular | | NYHA | | New York Heart Association | | NO | | nitric oxide | | NP | | sodium nitroprusside | | PVR | | peripheral vascular resistance | | VO2max | | maximal oxygen uptake |
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The vascular endothelium plays a relevant role in the control of many functions, including fibrinolysis, thrombosis, inflammation, vascular growth and vascular tone (1,2). To regulate the vascular tone, the endothelium releases several vasoactive substances, which exert either vasoconstrictive (i.e., endothelin) or vasodilating action (i.e., nitric oxide [NO]). Nitric oxide is synthesized from L-arginine and oxygen by the endothelial isoform of NO synthase. Once produced in the endothelial cells, NO diffuses into the subadjacent smooth muscle cells where it stimulates the conversion of GTP to cyclic guanosine monophosphate (cGMP) (1). This induces vascular relaxation by reducing the intracellular concentration of calcium (1).
A distinct feature of patients affected by chronic heart failure (CHF) is the impaired vascular reactivity (3,4). This consists of attenuated vasodilation in response to acetylcholine (ACh), pointing to an endothelium-dependent defect. On the other hand, the response to nitroprusside (NP), a direct NO donor and endothelium-independent vasodilator, appears to be largely preserved (5,6), suggesting that in CHF a loss of bioactive endothelial NO is responsible for the vascular dysfunction.
The impaired endothelium-dependent vasodilation in CHF contributes to the elevated peripheral vascular resistance (PVR), which further aggravates left ventricular (LV) afterload and impairs physical exercise capacity. For these reasons, endothelial dysfunction is relevant to heart failure progression, and consequently, it is regarded as one of the therapeutic targets. Indeed, there have been several attempts to correct the endothelium dysfunction of CHF, including oral arginine supplementation, administration of antioxidants and physical exercise (7–9).
Recent evidence indicates that growth hormone (GH) plays a role in the regulation of PVR and vascular reactivity. Patients with GH deficiency show increased PVR and reduced systemic generation of NO and cGMP (10,11). These abnormalities are reversed by specific replacement therapy with GH (11). Growth hormone deficiency is also associated with impaired vascular reactivity due to a complex defect that involves the entire pathway of NO-mediated vasodilation (12).
Given the role of GH in the regulation of PVR and vascular reactivity, the present study was designed to test the hypothesis that GH administration to patients with CHF, as an addition to their background therapy, is able to correct their abnormal vascular reactivity.
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Methods
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Patients and experimental design.
The study was performed on 16 patients with CHF due to idiopathic (n = 11) or ischemic (n = 5) dilated cardiomyopathy (Table 1). The inclusion criteria were: 1) echocardiographic evidence of LV ejection fraction <40% and LV internal diameter >58 mm; 2) clinical evidence of CHF despite conventional therapy; and 3) stable clinical conditions for the previous three months. Twelve patients were in New York Heart Association (NYHA) class II and four in NYHA class III. Exclusion criteria were myocardial infarction or treatment of coronary artery disease by interventional procedures for the previous six months, unstable angina, major arrhythmias (Lown class >IV), systemic hypertension, significant valvular heart disease, hypertrophic cardiomyopathy and chronic alcoholism. Eight patients were treated for three months with recombinant human GH at a dose of 4 IU given subcutaneously every other day, whereas eight patients received placebo, according to a randomized, double-blind design. Any other cardiovascular medication remained unchanged throughout the study period. Growth hormone (Humatrope), placebo and the injection system (Humatro-Pen II) were provided by Eli Lilly, Florence, Italy. Written informed consent was obtained from each patient, and the study was approved by the Ethics Committee of the University Federico II.
Procedures.
Each patient attended for two vascular studies, performed before and at the end of the three-month treatment period. All patients were studied in the morning, after a 12 to 15 h overnight fast, in a quiet room kept at 22°C to 24°C, as previously described (12). Briefly, a plastic cannula (20G) was inserted into the brachial artery of the nondominant arm under local anesthesia and used for the infusion of the test substances, the monitoring of arterial blood pressure and heart rate and arterial blood sampling. In the same arm, a second plastic cannula was introduced into a large antecubital vein to obtain venous blood samples. Forearm blood flow (FBF) was measured in both forearms by strain gauge plethysmography, with a calibrated mercury-in-silastic strain gauge applied around the forearm and connected to a plethysmography (Hokanson 045 EC4, P.M.S. Instruments, Berks, United Kingdom) associated with a MacLab computer. Both arms were supported slightly above the heart level. Each subject underwent the following stepwise infusions into the brachial artery: 1) ACh, at the rate of 30, 45 and 60 µg ·l of forearm–1·min–1, to assess endothelial-mediated vasodilation; 2) NP, a direct NO donor, at the rate of 1, and 3 µg ·l–1·min–1, to assess non-endothelial-mediated vasodilation; and 3) L-N-monomethylarginine (L-NMMA), a competitive analog of L-arginine, at the rate of 1 mg·l–1·min–1. Each dose of the test substances was infused for 5.5 min, and FBF was measured during the last 1.5 min of infusion. A 30-min washout was allowed between each substance infusion. Blood samples were simultaneously taken from the arterial and venous cannulas in the basal state and at the end of the maximal dose of ACh to measure nitrate/nitrite and cGMP concentrations. Forearm blood flow was measured simultaneously in both arms to ensure that no systemic effects occurred during the experiment. Each FBF value represents the mean of six consecutive measurements performed at 8-s intervals.
Symptom-limited exercise test was performed according to the Cornell-modified treadmill protocol (2-min step increments), and maximal oxygen uptake (VO2max) was measured by breath-to-breath respiratory gas analysis (Benchmark Exercise Test System, Morgan, Bologna, Italy).
Analytical methods.
Serum insulin-like growth factor I (IGF-I) concentration was measured by radioimmunoassay. Nitrite concentration was measured in plasma samples using EDTA as an anticoagulant. After collection, blood samples were immediately centrifuged at 2,000 rpm at 4°C and plasma stored at –20°C. Before assay, plasma was ultrafiltered through a 10kDa molecular weight cut-off filter (Centricon 10, Millipore, Bedford, Massachusetts). Total plasma nitrite and nitrate were measured using a colorimetric kit (Cayman Chemical Co., Ann Arbor, Michigan). Nitrate was converted to nitrite by nitrate reductase, and then nitrite was assayed by the standard Greiss diazo-reaction. All determinations were done in triplicate. The data are referred to as nitrite concentration, but they reflect the sum of nitrate and nitrite. For the determination of cGMP, plasma samples were centrifuged at 4°C after the addition of cold 6% trichloroacetic acid. Supernatants were washed with five volumes of water-saturated diethyl ether and dried under a stream of nitrogen at 60°C. The dried extracts were dissolved in 0.5 mol/l acetate buffer, pH 5.8, and acetylated by a mixture of acetic acid anhydride/triethylamine. The cGMP content was measured in duplicate with radioimmunoassay (Amersham International, UK).
Calculations.
The net forearm balance of nitrite and cGMP was calculated by multiplying the plasma arterial-venous concentration difference of each substrate by the plasma flow. Therefore, a negative balance indicates substrate release, whereas a positive balance indicates uptake. Results are expressed as mean ± SEM. The differences in clinical and metabolic characteristics between the two patient groups and the effect of treatment within groups were analyzed using the unpaired and the paired Student t test, respectively. The data on vascular reactivity were analyzed by a two-way repeated measures analysis of variance (ANOVA) (SPSS, version 10.0, Chicago, Illinois), which tested the effect of the vasodilating agent (ACh or NP), the treatment effect (GH or placebo) and the interaction between them. Vascular reactivity data are expressed as absolute values of FBF.
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Results
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Table 1 shows the patients’ clinical and biochemical data. No differences were observed between the two groups before treatment. As expected, at the end of the treatment period, IGF-I concentration was significantly higher in the GH-treated group compared with the basal values and the placebo group (p < 0.01). Both systolic and diastolic blood pressures were lowered by GH (p < 0.05).
The results of the repeated-measures ANOVA for the vascular reactivity data are summarized in Table 2. Before treatment, the FBF response to ACh was flat in both groups (Fig. 1). Treatment with placebo did not affect this response (at the highest ACh dose, FBF was 4.7 ± 0.9 and 5.9 ± 1.3 ml·dl of forearm–1·min–1 before and after placebo, respectively). In contrast, GH treatment greatly improved ACh-mediated, endothelium-dependent vasodilation (p = 0.03). In response to the highest dose of ACh, FBF rose to 4.6 ± 1.9 and 14.7 ± 4.2 ml·dl–1·min–1 before and after GH, respectively.
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Figure 1 Forearm blood flow response to acetylcholine (Ach) infusion in placebo- and growth hormone (GH)-treated patients at baseline and at the end of treatment. Data were analyzed by analysis of variance for repeated measures. p = NS for the basal response to Ach; p = 0.03 for the effect of GH treatment; p = 0.01 for the interaction between GH and ACh.
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Growth hormone also modified the pattern of the dose-response curve to ACh, as shown by the significant interaction between GH and ACh (p = 0.01). Accordingly, the slope of the dose-response curve to ACh was enhanced by GH (0.06 ± 0.02 and 0.16 ± 0.04 ml·dl–1·min–1 ·µg–1 before and after GH treatment, respectively; p < 0.05).
Figure 2 illustrates forearm nitrite and cGMP balances during ACh infusion. Before treatment, both groups of patients were characterized by lack of forearm nitrite production in response to ACh. After treatment, ACh did not induce any change in forearm nitrite release in the placebo group. In contrast, in the GH-treated patients ACh caused significant increase in forearm nitrite release (p < 0.05). Similarly, before treatment CHF patients were characterized by no response in forearm cGMP production to ACh. In the GH-treated patients, but not in the placebo group, ACh induced cGMP release by the forearm. This change was of borderline significance (p = 0.07).
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Figure 2 Forearm nitrite (upper panel) and cyclic guanosine monophosphate (cGMP) (lower panel) balance during intrabrachial acetlycholine infusion in placebo- and growth hormone (GH)-treated patients at baseline and at the end of treatment. *p < 0.05 versus the corresponding basal value; #0.1 > p > 0.05 versus the corresponding basal value. The signs (+) and (–) indicate uptake and release, respectively.
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As shown in Figure 3 and Table 2, in both groups of patients NP elicited a vasodilatory response before treatment. However, whereas in the placebo group this response was similar before and after treatment, in the GH-treated patients the increase of FBF was markedly potentiated (p = 0.013). At the highest dose of NP, FBF was 8.5 ± 1.0 and 12.8 ± 1.4 ml·dl–1·min–1 before and after GH treatment, respectively.
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Figure 3 Forearm blood flow response to sodium nitroprusside (NP) infusion in the placebo- and growth hormone (GH)-treated patients at baseline and at the end of treatment. Data were analyzed by analysis of variance for repeated measures. p < 0.005 for the basal response to NP; p = 0.013 for the effect of GH treatment; p = NS for the interaction between GH and NP.
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Despite the significant treatment effect, GH had no effect on the pattern of the response to NP, as indicated by the lack of significant interaction between GH and NP. In accordance, GH did not affect the slope of the dose-response curve (2.1 ± 0.32 and 3.0 ± 0.41 ml·dl–1·min–1 ·µg–1 before and after GH treatment, respectively; p = NS).
In Figure 4 the slopes of the dose-response curves to ACh are plotted against the baseline IGF-I levels of each patient. The data show a positive significant correlation between the serum IGF-I level and the endothelial response (p < 0.0001).
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Figure 4 Relation between the slopes of the dose response curves to acetylcholine and the basal serum insulin-like growth factor I (IGF-I) concentrations.
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The basal FBF was not different in the two study groups and was unchanged by both placebo and GH treatment (Fig. 1). The decrease of FBF after intrabrachial L-NMMA infusion was 1.0 ± 0.2 and 1.3 ± 0.3 ml·dl–1·min–1 before and after GH treatment, respectively (p = NS). A similar response was observed in the placebo group (0.6 ± 0.3 and 0.8 ± 0.2 ml·dl–1·min–1 before and after placebo, respectively (p = NS).
The VO2max increased significantly after GH treatment (20 ± 2 and 26 ± 2 ml ·Kg–1·min–1 before and after GH treatment, respectively, p < 0.05). No significant change was observed with placebo (22 ± 2 and 24 ± 2 ml ·Kg–1·min–1 before and after placebo, respectively, p = NS).
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Discussion
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Our patients with CHF showed a flat response of FBF to ACh infusion, attesting to their endothelial dysfunction, in agreement with previous studies (3–5). This defect was associated with the inability of ACh to induce the release of nitrite and cGMP from the forearm vascular bed. Three months of therapy with human recombinant GH corrected endothelial dysfunction, whereas no improvement was observed in the placebo group. The restored endothelial function was associated with significant release of nitrite and cGMP from the forearm during ACh infusion. It is noteworthy that normalization of vascular function by GH was paralleled by improvement of VO2max during physical exercise.
Vascular dysfunction in CHF.
Previous studies have shown that CHF is characterized by impairment of ACh-mediated endothelial response, suggesting that a defect in NO production by the endothelium is the mechanism responsible for vascular dysfunction (3–5). However, direct measurement of nitrite balance during ACh infusion in patients with CHF was not performed. This study shows that the forearm vasculature of patients with CHF does not produce nitrite in response to ACh, thus providing direct evidence that the defective endothelial function in CHF is due to reduced bioactive NO. Our data also suggest that GH corrects vascular reactivity by restoring one of the key functions of endothelial cells, that is, NO production. The fact that the restored response to ACh occurred in conjunction with simultaneous production of both NO and cGMP supports a central role of NO in mediating the vascular defect in CHF and its recovery after GH therapy. Interestingly, in this study the improved vascular reactivity by GH was associated with enhancement of exercise capacity, as shown by the VO2max data. Given the key role of shear-stress in the adaptive response of the vascular bed to physical exercise, one may speculate that GH is likely to interfere with the mechanism activated by shear-stress (13,14).
The improved vascular reactivity observed in our patients after GH treatment was not due solely to an endothelial component, but it also involved a non-endothelium-mediated mechanism. Although the response to NP was largely preserved in our patients before treatment, GH therapy induced a substantial change in the vasodilating response to NP. The mechanism by which GH affected this response remains speculative. Insulin-like growth factor I may act directly on the vascular smooth muscle cells by influencing the intracellular Ca2+ concentration (15) or regulating the Na+-K+-ATPase activity (16). In addition, it is well known that IGF-I stimulates smooth muscle cell proliferation and angiogenesis (17–19). Interestingly, GH was reported to increase the capillary density in patients with GH deficiency and in animal models of heart failure (20,21). Based on these findings, there is a temptation to think that GH may improve vascular reactivity also by inducing structural changes in the vascular bed.
Previous studies.
Our findings are in line with previous observations regarding the role of GH in the physiology of the resistance vessels and vascular reactivity. In patients with GH deficiency, the systemic generation of NO and cGMP is reduced, whereas vascular reactivity is impaired and vascular resistance is increased (11,12). After GH replacement therapy, vascular homeostasis is normalized, and concomitantly, the production of NO and cGMP is restored, systemically and at the forearm level (11,12). Consistent with our findings, a recent study of patients with CHF showed low urinary nitrate and cGMP excretion that was markedly increased by a three-month treatment with GH (22). In that study and in the current one, the basal IGF-I level was in the low physiologic range, in agreement with the documented reduced activity of the GH/IGF-I axis in patients with CHF (23). This observation raises the question whether the impaired endothelial function observed in CHF is, in part, accounted for by the low GH activity. Support for this interpretation would be provided by the striking similarity between CHF and GH deficiency with regard to the altered vascular homeostasis and its substantial correction after GH treatment. Consistent with this line of reasoning is the striking positive correlation between the IGF-I level and the slope of the dose response curve to ACh (p < 0.0001; Fig. 4). This correlation remained significant as well when the patients treated with GH were excluded from the analysis (p < 0.02), which supports the concept that the GH/IGF-I axis is likely to play a role in the pathogenesis of endothelial dysfunction and, consequently, in the progression of CHF, as previously suggested (11,12,22,23).
Clinical implications.
The present finding, that GH corrects the abnormal vascular reactivity in CHF, may have relevant clinical implications. Vascular dysfunction is one of the factors involved in the progression of CHF by the intervention of multiple mechanisms: 1) increased ventricular afterload; 2) reduced coronary perfusion; 3) progression of atherosclerotic lesions; 4) peripheral vascular remodelling; 5) limited vascular reserve in the skeletal muscle and consequent impaired exercise capacity; and 6) potential interference with myocardial structure and function (24–27). For these reasons, the endothelium is regarded as a primary therapeutic target in heart failure (28). The present finding that GH normalizes vascular reactivity by a complex action on the entire NO-mediated pathway and improves VO2max offers an additional mechanism in support of its potentially beneficial effect in patients with CHF (29,30).
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Footnotes
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Supported by grants from the National Research Council (# 99.02588CT04 and MURST-PRIN-EF98).
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L. D. Monti, E. Setola, G. Fragasso, R. P. Camisasca, P. Lucotti, E. Galluccio, A. Origgi, A. Margonato, and P. Piatti
Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy
Am J Physiol Endocrinol Metab,
January 1, 2006;
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[Abstract]
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S. Marleau, M. Mulumba, D. Lamontagne, and H. Ong
Cardiac and peripheral actions of growth hormone and its releasing peptides: Relevance for the treatment of cardiomyopathies
Cardiovasc Res,
January 1, 2006;
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M. J. Kleinz, J. J. Maguire, J. N. Skepper, and A. P. Davenport
Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man
Cardiovasc Res,
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S. E. Lipshultz, S. A. Vlach, S. R. Lipsitz, S. E. Sallan, M. L. Schwartz, and S. D. Colan
Cardiac Changes Associated With Growth Hormone Therapy Among Children Treated With Anthracyclines
Pediatrics,
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[Abstract]
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K. C Wollert and H. Drexler
Growth hormone and proinflammatory cytokine activation in heart failure: Just a new verse to an old sirens' song?
Eur. Heart J.,
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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.,
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[Abstract]
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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;
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[Abstract]
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Can Growth Hormone Restore Vascular Function in Heart Failure?
Journal Watch Cardiology,
March 15, 2002;
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