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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 180-185
Copyright © 2007 by The Endocrine Society

Cardiac Effects of Growth Hormone Treatment in Chronic Heart Failure: A Meta-Analysis

Philippe Le Corvoisier, Luc Hittinger, Philippe Chanson, Olivier Montagne, Isabelle Macquin-Mavier and Patrick Maison

Service de Pharmacologie Clinique (I.M.-M., P.M.), Fédération de Cardiologie (P.L.C., L.H.), Centre d’Investigation Clinique (O.M., P.L.C.), Unité de Recherche Clinique (P.M.), Assistance Publique-Hôpitaux de Paris, Université Paris XII, Faculté de Médecine, Centre Hospitalier Universitaire (CHU) Henri Mondor, 94010 Créteil, France; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 421 (P.M.), 94000 Créteil, France; INSERM Unité 660 (P.L.C., L.H.), 94000 Créteil, France; Service d’Endocrinologie et des Maladies de la Reproduction (P.C.), Assistance Publique-Hôpitaux de Paris, and INSERM Unité 693, CHU Bicêtre, and Faculté de Médecine Paris-Sud, Université Paris XI, 94270 Le Kremlin-Bicêtre, France

Address all correspondence and requests for reprints to: Dr. P. Maison, Service de Pharmacologie Clinique, Centre Hospitalier Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, F-94010 Créteil, France. E-mail: patrick.maison{at}hmn.ap-hop-paris.fr.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Context: Experimental studies suggest that GH treatment may improve cardiovascular parameters in chronic heart failure (CHF). However, clinical trials involved small numbers of patients and did not allow a conclusion to be drawn on the effect of this treatment in humans.

Objective: We systematically reviewed and analyzed all randomized controlled trials and open studies of sustained GH treatment in CHF.

Study Selection: Twelve trials were identified in three databases. We conducted a combined analysis of GH effects on cardiovascular parameters using the overall effect size to evaluate significance and computing the weighted mean differences with and without treatment to assess effect size.

Data Synthesis: GH treatment significantly modified morphological cardiovascular parameters [interventricular septum thickness, +0.55 (SD, 0.43) mm (P < 0.001); posterior wall thickness, +1.01 (0.44) mm (P < 0.01); left ventricle (LV) end-diastolic diameter, –2.02 (1.22) mm (P < 0.01); and LV end-systolic diameter, –5.30 (2.33) mm (P < 0.05)]; LV and systemic hemodynamics [LV end-systolic wall stress, –38.9 (13.3) dynes/cm2 (P < 0.001); LV ejection fraction, +5.10 (1.74)% (P < 0.05); and systemic vascular resistance, +195.0 (204.5) dyn·sec–1·cm–5 (P < 0.01)]; and functional parameters [New York Heart Association class, –0.97 (0.23) (P < 0.01); exercise duration, +103.7 (37.6) sec (P < 0.001); and maximal oxygen uptake, +2.48 (1.76) ml/kg·min (P < 0.01)]. Subgroup analysis and meta-regression showed significant relationships between the IGF-I response and GH treatment effects.

Conclusion: Our meta-analysis suggests that GH treatment improves several relevant cardiovascular parameters in patients with CHF. However, these results must be confirmed by a large randomized placebo-controlled trial on hemodynamic, morphological, and functional parameters during long-term high-dose GH treatment of patients with CHF.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CHRONIC HEART FAILURE (CHF) is characterized by a deleterious activation of several neurohormonal systems, and drugs blocking the sympathetic or renin-angiotensin-aldosterone system improve survival in patients with CHF (1, 2, 3). Nevertheless, the prognosis of CHF remains poor, most notably in New York Heart Association (NYHA) class III–IV patients. Clearly, new treatment strategies are needed (4).

Epidemiological studies have shown that GH deficiency is associated with increased cardiovascular mortality (5, 6, 7). A recent review of clinical trials of GH treatment in patients with GH deficiency suggests beneficial effects of GH on reduced left ventricular (LV) mass (LVM) and LV systolic function (8). In addition, GH treatment reduces cardiovascular risk factors in these patients (9). In contrast, GH excess contributes to increase cardiovascular mortality in acromegaly (10).

Numerous experimental and clinical studies suggest that GH and its effector IGF-I may contribute to regulate the cardiovascular system (11, 12, 13, 14, 15, 16, 17). In experimental studies, GH or a GH-releasing peptide had beneficial effects on cardiac function, peripheral resistance, and survival in animals with postischemic heart failure (12, 15, 16, 17). In addition, the anabolic effects of IGF-I are well established, together with its role in regulating heart function. IGF-I directly causes cardiomyocyte hypertrophy (14), augmented myocardial contractility via myofilament sensitization to Ca2+ (13), and retardation of cardiomyocyte apoptosis (11). Taken in concert, these data suggest that GH administration may have marked trophic and contractile effects on the heart.

Based on these experimental observations, several clinical studies have been performed to evaluate the effects of GH given to patients with CHF in addition to conventional therapy (18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). However, the results are inconclusive. For instance, LV ejection fraction (LVEF) improved significantly in some studies (21, 22, 25, 28) but not in others (18, 20, 23, 24, 29, 30). Similarly, only some of these studies showed increases in the thickness of the interventricular septum (IVS) (20, 21, 25, 27) or LV posterior wall (LVPW) (19, 20, 21, 23, 25). Conflicting results were obtained for other cardiac parameters such as LV end-diastolic diameter (LVEDD), systemic vascular resistance, and LV end-systolic wall stress (LVESWS). However, most of these trials included small numbers of patients, raising the possibility that nonsignificant results were related in part to inadequate statistical power. We therefore conducted a meta-analysis to obtain a more reliable picture of the effect of sustained GH administration in patients with CHF.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Identification of relevant trials

The medical literature was searched for reports on the effect of sustained GH administration to adults with CHF in the absence of GH deficiency. We searched three electronic databases—MEDLINE (Ovid), BIOSIS, and Experta Medica (EMBASE)—from their years of inception to June 2005. We used the following keywords: growth hormone, GH, somatotropin, IGF-I, cardiac function, heart failure, cardiac failure, cardiomyopathy, vascular function, and vasodilatation. The search strategy was not limited by study design or language. GH manufacturers and authors of published studies were contacted, and abstracts from major cardiology meetings were reviewed, in an attempt to identify unpublished trials and to reduce the risk of publication bias.

Inclusion criteria

We included all open studies and randomized, blind, placebo-controlled trials of sustained (treatment duration >1 month) GH administration to adults with CHF but without GH deficiency. The selected publications reported at least one of the following outcome measures: heart rate (HR), IVS, LVPW, LVEDD, LV end-systolic diameter (LVESD), LVM, LVESWS, LVEF, ratio of early to late mitral diastolic flow, isovolumic relaxation time, systemic vascular resistance (SVR), NYHA class, exercise duration, and maximal oxygen uptake (VO2max).

Data extraction

Data were extracted from published reports onto standardized forms by two meta-analysts (P.L.C. and P.M.). Discrepancies were resolved by discussion among the authors of the present paper. The following data were extracted: mean age, sex, number of patients included, etiology of heart failure, conventional heart failure therapy, target GH dose, treatment duration, increase in IGF-I concentration, study quality (design, blindness, statistical methods), losses to follow-up for each outcome measure, and baseline and follow-up values in both groups (means and SD or SEM). The authors of selected reports were contacted to obtain unpublished data and to verify extracted data when necessary.

Statistical methods

For primary analyses of continuous outcome measures, we calculated standardized effect sizes for each trial and global effect sizes for each outcome. In the study by Acevedo et al. (18), the values had to be estimated from the figures. The effect size was calculated differently for parallel-group, cross-over, and open study designs, to reflect the intergroup and intragroup variances (31). For parallel groups, the effect size was computed using the mean difference (GH minus placebo) in the changes (follow-up minus baseline) for each outcome measure divided by the estimated variance of changes in the two groups. Effect sizes in crossover trials were calculated using the mean difference between the ends of each period divided by the variance in the placebo group at follow-up. For open studies, effect sizes were calculated using the mean difference between baseline and follow-up divided by the variance. A positive effect size is an increase with GH treatment and a negative effect size is a decrease. To calculate the global effect size, each study was weighted by the reciprocal of its variance. When the variance of changes was not stated, it was calculated from the confidence intervals (variances, SEM) (31). We report the overall effect sizes with their 95% confidence intervals.

We explored heterogeneity across studies using the Q test. When the effect size was significant in a fixed model but the Q test was significant, causes were investigated and the analyses were repeated using a random-effects model. In these cases, the effect sizes according to the random-effects model are reported.

Funnel plots were drawn, and their asymmetry was measured to assess the possible influence of publication and location biases (32). The intercept of linear regression, where the effect size divided by the SE is regressed against the reciprocal of the SE, provides a measure of asymmetry. To assess sensitivity, when the effect size was dependent on one or two trials (e.g. a large trial), these trials were dropped from the analysis.

To quantify effect size, we calculated the weighted mean (and SD) of the change between the groups or periods, for each outcome measure, when data were available.

The effects of the GH dose, IGF-I increase, treatment duration, age of patients, etiology of heart failure, and degree of LV dysfunction on the overall estimates were assessed by stratification or meta-regression. Weighted least squares regression was used for meta-regression, with individual study effects weighted by the inverse of the estimated variance. The ß coefficient and its significance are reported, along with the adjusted R2 to show the overall variability explained by the model.

Analyses were conducted using the SPSS 12.0 (SPSS Inc., Chicago, IL) package for Windows.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The combined search strategy identified 12 publications, four open studies, and eight blinded, randomized, placebo-controlled trials, including a total of 195 patients (Table 1Go). Patient characteristics (age, sex), treatment (dose, duration), and baseline parameters were not different between randomized controlled trials and open studies (data not shown). Most of the patients included in these studies were treated with conventional drugs: diuretics (88.1%), angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists (94.3%), and ß-blockers (42.4%). Mean baseline NYHA (n = 5 studies) and LVEF (n = 10) were, respectively, 2.8% (0.3) and 25.1% (9.5). The studies were generally of good quality, estimated with: lost to follow-up, intention-to-treat analysis, adequate statistical methods. Subjects were lost in only four trials (24, 27, 29, 30) (Table 1Go).


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  		TABLE 1. Characteristics of studies included in the meta-analysis

 
A search for potential bias in the meta-analysis showed significant heterogeneity for LVPW, LVM, and LVEF (Table 2Go). Funnel plot and linear regression did not suggest selection bias (data not shown), except for LVEF and exercise duration (ß = 5.3, P = 0.003; and ß = 17.3, P = 0.022, respectively).


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  		TABLE 2. Global effect sizes by outcomes

 
A significant overall effect size was found with GH treatment (Table 2Go) for IVS (0.47 [0.18; 0.77]), LVPW (0.58 [0.20; 0.96]), LVEDD (–0.43 [–0.71; –0.16]), LVESD (–0.48 [-0.93; –0.04]), LVESWS (–0.80 [–1.43; –0.17]), LVEF (0.57 [0.18; 0.97]), SVR (–0.45 [–0.77; –0.13]), NYHA class (–0.93 [–1.75; –0.12]), exercise duration (0.79 [0.35; 1.23]), and VO2max (0.68 [0.27; 1.09]). A trend was noted for isovolemic relaxation time (–0.52 [–1.05; 0.01]), which was measured in only three studies. Overall effect sizes were not significant for HR (0.02 [–0.24; 0.29]), LVM (0.65 [–0.40; 1.7]), or ratio of early to late mitral diastolic flow (E/A ratio) (0.15 [–0.31; 0.61]) (Table 2Go). When the analysis was confined to randomized controlled trials, the significant effect sizes were confirmed for IVS (0.43 [0.08; 0.77]), LVESWS (–0.69 [–1.37; –0.02]), and VO2max (0.62 [0.16; 1.09]). Because selection bias was suspected for LVEF and exercise duration, effect sizes were recalculated after exclusion of studies responsible for asymmetry (Osterziel et al. (27) for LVEF and Spallarossa et al. (30) for exercise duration). The effect sizes remained significant for both parameters (0.59 [0.25; 0.93] and 0.67 [0.22; 1.14], respectively).

The mean difference (and SD) between the GH treatment and control groups weighted were determined for each outcome to quantify the size of the effect (Table 2Go).

In the subgroup analysis according to the target dose, high-dose GH therapy (14 IU/wk) was associated with significant overall effect sizes for IVS (0.43 [0.12; 0.74]), LVPW (0.65 [0.22; 1.08]), LVEDD (–0.46 [–0.77, –0.16], LVESWS (–0.80 [–1.43; –0.17]), SVR (–0.45 [–0.77; –0.13]), exercise duration (0.64 [0.16; 1.12]), and VO2max (0.68 [0.27; 1.09]). With low-dose therapy (7 IU/week, n = 2 studies), effect sizes were significant only for exercise duration (1.32 [0.52; 2.13]) and NYHA (–2.06 [–1.13; –3.00]). Although these results suggest a dose/effect relationship, definitive conclusions cannot be drawn because of the small number of studies using the low dose. The analysis of subgroups defined by GH treatment duration led to similar conclusions, because short studies (2 or 3 months) used high-dose GH, whereas two of the three 6-month studies used low-dose GH. Therefore, our results suggest that GH may induce an effect as early as 3 months after treatment initiation, but they cannot be used to determine whether the effect is increased after 6 months.

When enough studies were available, trials were separated in two groups according to the median of IGF-I increase (89%) observed for all studies. In trials with large IGF-I increases (>89%), a significant overall effect size was found for LVPW (0.78 [0.02; 1.55]), LVEDD (–0.49 [–0.95; –0.04]), NYHA (–1.22 [–2.24; –0.20]), and exercise duration (0.67 [0.19; 1.14]) (all parameters were evaluated except VO2max). By contrast, trials with smaller IGF-I increases (<89%) showed no effect; the following parameters were evaluated: HR (n = 3), FE (n = 3), LVM (n = 2), VO2max (n = 2), and ESWS (n = 2). The meta-regression model confirmed a relationship between the change in IGF-I concentration and the treatment effects, with significant results on NYHA (ß = 0.96, P = 0.04, R2 = 0.89) and VO2max (ß = 1.0, P = 0.008, R2 = 1.0). No significant relationship was found with patient age or HF treatment. A significant relationship between sex and PW (ß = –0.96, P = 0.003, R2 = 0.92) independently to the cause suggests a more favorable effect in men. A significant relationship between the cause and LVEF (ß = 0.73, P = 0.04, R2 = 0.53) independent of sex suggests a more favorable effect in ischemic etiology.

No difference was observed in the frequency of major adverse events between GH and placebo treatments: deaths (2.8 vs. 2.1%, not significant), worsening of heart failure (6.1 vs. 9.3%, not significant), or ventricular arrhythmias (2.0 vs. 0.0%, not significant).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Experimental studies showed potentially beneficial effects of GH treatment in different heart failure models (12, 15, 16, 17). However, the small clinical trials performed to date produced conflicting results (18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30). The present systematic review demonstrates that sustained GH treatment improves several cardiovascular parameters in patients with CHF.

As with all systematic reviews, the possibility of publication bias is of major concern, because trials with positive and significant results are more likely to be published than those with neutral or negative results (32). However, in the present meta-analysis, an effect of publication bias is unlikely because statistically significant parameters were rarely identical across the selected trials and because results for nonsignificant parameters were reported also. Meta-analysis is also limited by study quality. One third of the studies are open, but the results were confirmed in sub-group analysis of randomized controlled trials.

Our meta-analysis shows that sustained GH treatment in CHF patients leads to an increase in LVEF and a reduction in SVR, suggesting an improvement in systemic hemodynamics. This last effect may be ascribable to an improvement in endothelium-dependent vasodilatation (33) that occurs within hours after treatment onset, as shown by reports of similar results after short-term (<24 h) iv GH infusion in healthy individuals or patients with heart failure (34, 35, 36). The improvement in LV systolic function may be related to GH-induced modifications in loading conditions (12, 21, 34, 36) or, as suggested by experimental studies, to a direct positive effect of GH on intrinsic myocardial contractility mediated by a shift in sarcolemmal calcium affinity (13) and/or by preservation of cardiac sarcoplasmic reticulum Ca2+ release channels (37). In addition, sustained GH treatment induces long-term modifications in cardiac morphology, i.e. a reduction in LVEDD and an increase in left ventricular wall thickness (IVS and LVPW), resulting in reduced LVESWS. These cardiovascular effects of GH may explain the improvement in functional capacity of patients with CHF, which manifested as improvements in NYHA class, exercise duration, or VO2max, although an effect of GH on peripheral muscle wasting cannot be excluded (38). It is interesting to note that, recently, similar results on LVEF, LVM, and exercise capacity were reported after treatment with the growth hormone-releasing factor ghrelin in patients with CHF (38).

Beneficial effects of GH treatment on cardiac parameters in patients with GH deficiency caused by hypopituitarism have been shown in several clinical trials and in recent a meta-analysis by our group (8). Interestingly, striking similarities exist between patients with GH deficiency and those with CHF regarding abnormalities in cardiac parameters, as well as the effects of GH treatment on cardiovascular parameters. GH deficiency is characterized by a specific cardiac phenotype that includes alterations in endothelium-dependent vasodilatation (39), diminished LV wall thickness (40, 41) resulting in increased LVESWS (42), and a reduction in LVEF correlated with the severity of GH deficiency (40, 41, 43). Similar to patients with CHF, patients with GH deficiency respond to GH treatment by increases in LV wall thickness and stroke volume (8) and by improvement in endothelium-dependent vasodilatation that cause a reduction in SVR (39, 44).

CHF occurred mainly in the elderly, and functional GH deficiency (somatopause) is generally reported in this population (45). In CHF patients, modification of the GH-IGF-I axis has been reported only in patients with cachexia with a relative increase in GH plasma concentration associated with an unchanged (46) or even decreased IGF-I level (47), suggesting an acquired endogenous GH resistance in these patients (46, 47). In addition, the magnitude of the IGF-I increase in response to GH in patients with CHF is inversely correlated with disease severity (48). Conceivably, differences in the degree of GH resistance across patients or studies may explain the variability of the results obtained with GH treatment. Interestingly, the Osterziel’s study (28) has been reanalyzed and the authors reported that increase in IGF-I (expressed as a relative change during GH treatment) determined the magnitude of increases in LVEF and LVM. Our meta-analysis supports these results and suggests a dose/effect relationship and a correlation between the IGF-I response and the improvements in cardiovascular parameters in patients with CHF. Failure to use high doses to overcome GH resistance might explain the lack of efficacy in some studies.

Finally, our meta-analysis suggests that the effect of GH treatment could be more favorable in men. This gender effect could be related to differences in IGF-I release sensibility (49).

Conclusion

Our meta-analysis suggests that GH treatment improves several relevant cardiovascular parameters in patients with CHF. However these results must be confirmed by a large randomized placebo-controlled trial on hemodynamic, morphological, and functional parameters during long-term high-dose GH treatment of patients with CHF.


   Footnotes
 
Conflict of Interest Statement: Pr. P. Chanson has been an investigator in clinical trials sponsored by manufacturers (Pfizer, Serono, Novo Nordisk), has received funds for organizing education, and is a member of the International Advisory Board of HYPOCCS (Hypopituitary Control and Complication Study), which is sponsored by Eli Lilly.

Financial Disclosure Statement: The authors have nothing to disclose.

First Published Online October 24, 2006

Abbreviations: CHF, Chronic heart failure; HR, heart rate; IVS, interventricular septum; LV, left ventricular; LVEDD, LV end-diastolic diameter; LVEF, LV ejection fraction; LVESD, LV end-systolic diameter; LVESWS, LV end-systolic wall stress; LVM, LV mass; LVPW, left ventricular posterior wall; NYHA, New York Heart Association; SVR, systemic vascular resistance; VO2max, maximal oxygen uptake.

Received June 20, 2006.

Accepted October 17, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Doughty RN, Rodgers A, Sharpe N, MacMahon S 1997 Effects of beta-blocker therapy on mortality in patients with heart failure. A systematic overview of randomized controlled trials. Eur Heart J 18:560–565[Abstract/Free Full Text]
  2. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, Torp-Pedersen C, Ball S, Pogue J, Moye L, Braunwald E 2000 Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 355:1575–1581[CrossRef][Medline]
  3. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J 1999 The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341:709–717[Abstract/Free Full Text]
  4. MacIntyre K, Capewell S, Stewart S, Chalmers JW, Boyd J, Finlayson A, Redpath A, Pell JP, McMurray JJ 2000 Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995. Circulation 102:1126–1131
  5. Bates AS, Van’t Hoff W, Jones PJ, Clayton RN 1996 The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 81:1169–1172[Abstract]
  6. Rosen T, Bengtsson BA 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336:285–288[CrossRef][Medline]
  7. Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM 2001 Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357:425–431[CrossRef][Medline]
  8. Maison P, Chanson P 2003 Cardiac effects of growth hormone in adults with growth hormone deficiency: a meta-analysis. Circulation 108:2648–2652
  9. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P 2004 Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a meta-analysis of blinded, randomized, placebo-controlled trials. J Clin Endocrinol Metab 89:2192–2199[Abstract/Free Full Text]
  10. Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B 1988 Epidemiology and long-term survival in acromegaly. A study of 166 cases diagnosed between 1955 and 1984. Acta Med Scand 223:327–335[Medline]
  11. Chen DB, Wang L, Wang PH 2000 Insulin-like growth factor I retards apoptotic signaling induced by ethanol in cardiomyocytes. Life Sci 67:1683–1693[CrossRef][Medline]
  12. Cittadini A, Grossman JD, Napoli R, Katz SE, Stromer H, Smith RJ, Clark R, Morgan JP, Douglas PS 1997 Growth hormone attenuates early left ventricular remodeling and improves cardiac function in rats with large myocardial infarction. J Am Coll Cardiol 29:1109–1116[Abstract]
  13. Cittadini A, Ishiguro Y, Stromer H, Spindler M, Moses AC, Clark R, Douglas PS, Ingwall JS, Morgan JP 1998 Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated muscles. Circ Res 83:50–59[Abstract/Free Full Text]
  14. Ito H, Hiroe M, Hirata Y, Tsujino M, Adachi S, Shichiri M, Koike A, Nogami A, Marumo F 1993 Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytes. Circulation 87:1715–1721
  15. Yang R, Bunting S, Gillett N, Clark R, Jin H 1995 Growth hormone improves cardiac performance in experimental heart failure. Circulation 92:262–267
  16. Duerr RL, McKirnan MD, Gim RD, Clark RG, Chien KR, Ross Jr J 1996 Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat. Circulation 93:2188–2196
  17. Ryoke T, Gu Y, Mao L, Hongo M, Clark RG, Peterson KL, Ross Jr J 1999 Progressive cardiac dysfunction and fibrosis in the cardiomyopathic hamster and effects of growth hormone and angiotensin-converting enzyme inhibition. Circulation 100:1734–1743
  18. Acevedo M, Corbalan R, Chamorro G, Jalil J, Nazzal C, Campusano C, Castro P 2003 Administration of growth hormone to patients with advanced cardiac heart failure: effects upon left ventricular function, exercise capacity, and neurohormonal status. Int J Cardiol 87:185–191[CrossRef][Medline]
  19. Adamopoulos S, Parissis JT, Paraskevaidis I, Karatzas D, Livanis E, Georgiadis M, Karavolias G, Mitropoulos D, Degiannis D, Kremastinos DT 2003 Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy. Eur Heart J 24:2186–2196[Abstract/Free Full Text]
  20. Cittadini A, Ines Comi L, Longobardi S, Rocco Petretta V, Casaburi C, Passamano L, Merola B, Durante-Mangoni E, Sacca L, Politano L 2003 A preliminary randomized study of growth hormone administration in Becker and Duchenne muscular dystrophies. Eur Heart J 24:664–672[Abstract/Free Full Text]
  21. Fazio S, Sabatini D, Capaldo B, Vigorito C, Giordano A, Guida R, Pardo F, Biondi B, Sacca L 1996 A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med 334:809–814[Abstract/Free Full Text]
  22. Frustaci A, Gentiloni N, Russo MA 1996 Growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med 335:672–673; author reply 673–4[Free Full Text]
  23. Genth-Zotz S, Zotz R, Geil S, Voigtlander T, Meyer J, Darius H 1999 Recombinant growth hormone therapy in patients with ischemic cardiomyopathy: effects on hemodynamics, left ventricular function, and cardiopulmonary exercise capacity. Circulation 99:18–21[Medline]
  24. Isgaard J, Bergh CH, Caidahl K, Lomsky M, Hjalmarson A, Bengtsson BA 1998 A placebo-controlled study of growth hormone in patients with congestive heart failure. Eur Heart J 19:1704–1711[Abstract/Free Full Text]
  25. Jose VJ, Zechariah TU, George P, Jonathan V 1999 Growth hormone therapy in patients with dilated cardiomyopathy: preliminary observations of a pilot study. Indian Heart J 51:183–185[Medline]
  26. Napoli R, Guardasole V, Matarazzo M, Palmieri EA, Oliviero U, Fazio S, Sacca L 2002 Growth hormone corrects vascular dysfunction in patients with chronic heart failure. J Am Coll Cardiol 39:90–95[Abstract/Free Full Text]
  27. Osterziel KJ, Strohm O, Schuler J, Friedrich M, Hanlein D, Willenbrock R, Anker SD, Poole-Wilson PA, Ranke MB, Dietz R 1998 Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet 351:1233–1237[CrossRef][Medline]
  28. Perrot A, Ranke MB, Dietz R, Osterziel KJ 2001 Growth hormone treatment in dilated cardiomyopathy. J Card Surg 16:127–131[Medline]
  29. Smit JW, Janssen YJ, Lamb HJ, van der Wall EE, Stokkel MP, Viergever E, Biermasz NR, Bax JJ, Vliegen HW, de Roos A, Romijn JA, Roelfsema F 2001 Six months of recombinant human GH therapy in patients with ischemic cardiac failure does not influence left ventricular function and mass. J Clin Endocrinol Metab 86:4638–4643[Abstract/Free Full Text]
  30. Spallarossa P, Rossettin P, Minuto F, Caruso D, Cordera R, Battistini M, Barreca A, Masperone MA, Brunelli C 1999 Evaluation of growth hormone administration in patients with chronic heart failure secondary to coronary artery disease. Am J Cardiol 84:430–433[CrossRef][Medline]
  31. Follmann D, Elliott P, Suh I, Cutler J 1992 Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 45:769–773[CrossRef][Medline]
  32. Egger M, Davey Smith G, Schneider M, Minder C 1997 Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634[Abstract/Free Full Text]
  33. Drexler H, Hayoz D, Munzel T, Hornig B, Just H, Brunner HR, Zelis R 1992 Endothelial function in chronic congestive heart failure. Am J Cardiol 69:1596–1601[CrossRef][Medline]
  34. Giustina A, Volterrani M, Manelli F, Desenzani P, Poiesi C, Lorusso R, Giordano A 1999 Endocrine predictors of acute hemodynamic effects of growth hormone in congestive heart failure. Am Heart J 137:1035–1043[CrossRef][Medline]
  35. Napoli R, Guardasole V, Angelini V, D’Amico F, Zarra E, Matarazzo M, Sacca L 2003 Acute effects of growth hormone on vascular function in human subjects. J Clin Endocrinol Metab 88:2817–2820[Abstract/Free Full Text]
  36. Volterrani M, Desenzani P, Lorusso R, d’Aloia A, Manelli F, Giustina A 1997 Haemodynamic effects of intravenous growth hormone in congestive heart failure. Lancet 349:1067–1068[CrossRef][Medline]
  37. Ueyama T, Ohkusa T, Yano M, Matsuzaki M 1998 Growth hormone preserves cardiac sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors) and enhances cardiac function in cardiomyopathic hamsters. Cardiovasc Res 40:64–73[Abstract/Free Full Text]
  38. Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, Ueno K, Kitakaze M, Miyatake K, Kangawa K 2004 Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 110:3674–3679
  39. Capaldo B, Guardasole V, Pardo F, Matarazzo M, Di Rella F, Numis F, Merola B, Longobardi S, Sacca L 2001 Abnormal vascular reactivity in growth hormone deficiency. Circulation 103:520–524
  40. Amato G, Carella C, Fazio S, La Montagna G, Cittadini A, Sabatini D, Marciano-Mone C, Sacca L, Bellastella A 1993 Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab 77:1671–1676[Abstract]
  41. Merola B, Cittadini A, Colao A, Longobardi S, Fazio S, Sabatini D, Sacca L, Lombardi G 1993 Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. J Clin Endocrinol Metab 77:1658–1661[Abstract]
  42. Fazio S, Cittadini A, Sabatini D, Merola B, Colao A, Biondi B, Longobardi S, Lombardi G, Sacca L 1997 Growth hormone and heart performance. A novel mechanism of cardiac wall stress regulation in humans. Eur Heart J 18:340–347[Abstract/Free Full Text]
  43. Longobardi S, Cuocolo A, Merola B, Di Rella F, Colao A, Nicolai E, Cardei S, Salvatore M, Lombardi G 1998 Left ventricular function in young adults with childhood and adulthood onset growth hormone deficiency. Clin Endocrinol (Oxf) 48:137–143[CrossRef][Medline]
  44. Pincelli AI, Bragato R, Scacchi M, Branzi G, Osculati G, Viarengo R, Leonetti G, Cavagnini F 2003 Three weekly injections (TWI) of low-dose growth hormone (GH) restore low normal circulating IGF-I concentrations and reverse cardiac abnormalities associated with adult onset GH deficiency (GHD). J Endocrinol Invest 26:420–428[Medline]
  45. Giordano R, Lanfranco F, Bo M, Pellegrino M, Picu A, Baldi M, Balbo M, Bonelli L, Grottoli S, Ghigo E, Arvat E 2005 Somatopause reflects age-related changes in the neural control of GH/IGF-I axis. J Endocrinol Invest 28:94–98[Medline]
  46. Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, Hosoda H, Shimizu W, Yamagishi M, Oya H, Koh H, Yutani C, Kangawa K 2001 Elevated circulating level of ghrelin in cachexia associated with chronic heart failure. Circulation 104:2034–2038
  47. Anker SD, Volterrani M, Pflaum CD, Strasburger CJ, Osterziel KJ, Doehner W, Ranke MB, Poole-Wilson PA, Giustina A, Dietz R, Coats AJ 2001 Acquired growth hormone resistance in patients with chronic heart failure: implications for therapy with growth hormone. J Am Coll Cardiol 38:443–452[Abstract/Free Full Text]
  48. Osterziel KJ, Blum WF, Strohm O, Dietz R 2000 The severity of chronic heart failure due to coronary artery disease predicts the endocrine effects of short-term growth hormone administration. J Clin Endocrinol Metab 85:1533–1539[Abstract/Free Full Text]
  49. Span JP, Pieters GF, Sweep CG, Hermus AR, Smals AG 2000 Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: role of sex hormone replacement. J Clin Endocrinol Metab 85:1121–1125[Abstract/Free Full Text]



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