GH TO TREAT Heart Failure/Injxn sites better

[ArmstrongJones]

I have posted before that I am using GH to treat Heart Failure
(for related journal articles, check PubMed, Fazio et al, or

http://www.medscape.com/viewarticle/452247_1 ).

I am not yet allowed to PM anyone here . I was wondering if anyone else with CHF/DCM has experienced improved heart function after using GH.

Also, I have stayed with Fitropin and the swollen injection sites seem to be getting better.

Now doing 4IUs every other day.

Thanks for any input,
Armstrong

Feel free to email me for privacy.

[MMA]

welcome aboard. BTW - why the EOD? the study that showed it was more effective actually shows exactly the opposite if you read it correctly.

unless this is a special medical protocol for your condition - your link doesn't work, can u cut and paste it for us, sounds interesting.

[ArmstrongJones]

The Fazio article:

http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=8596546

The medscape article is 7 pages and references both randomized and nonrandomized studies of rGH. You are correct that the low dosage, short term randomized studies didn't show improvements in heart function. Note the comparisons of the two types of studies and the reasons given for the reported benefits in the nonrandomized studies (Should I paste the entire article?):

http://www.medscape.com/viewarticle/452247_1

Forgive my dullness-bad flue/out of it. What is "EOD"?

Thanks for at least taking a look.
A

[ArmstrongJones]

Following is one article which attempts to summarize GH studies with respect to treating Heart Failure:

In This Article
Abstract and Introduction
GH and the Heart
The Cardiovascular System in States of GH Deficiency and Excess
Effects of GH Therapy in Animal Models of HF
Nonrandomized Human Studies Evaluating the Role of GH for the Treatment of HF
Randomized, Controlled, Clinical Trials Evaluating the Role of GH in HF
Conclusion

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Tables
References

Growth Hormone Therapy in Heart Failure: Where Are We Now?


from Congestive Heart Failure
Posted 04/21/2003
Catherine Demers, MD, MSc, Robert S. McKelvie, MD, PhD



Abstract and Introduction
Abstract
Despite improvement in survival with angiotensin-converting enzyme inhibitors and blockers, clinical events for patients with heart failure remain elevated. New therapies for heart failure are needed to improve functional capacity, quality of life, and prognosis. Growth hormone exerts direct and indirect effects on cardiac structure and function. Experimental models of heart failure and small studies have demonstrated significant improvements in cardiac function, hemodynamic parameters, functional capacity, and quality of life. Despite the lack of benefit demonstrated in small, short-term, randomized clinical trials, further studies are needed to assess the potential role of this adjuvant therapy in heart failure patients.

Introduction
Angiotensin-converting enzyme inhibitors and blockers have significantly decreased mortality and morbidity in heart failure (HF) patients and are considered the cornerstone of HF treatment.[1-6] Although mortality has decreased, clinical event rates remain at an unacceptable level. Potential novel therapies need to be investigated to determine if they may be of benefit to further improve quality of life, functional capacity, and prognosis in HF patients. HF is characterized by cell loss, decreased myocardial contractility, left ventricular dilatation, and increased systolic wall stress. Growth factors, such as growth hormone (GH) and insulin growth factor I (IGF-I), may potentially affect left ventricular remodeling by increasing myocardial cell hypertrophy, improving myocardial contractility, increasing cardiac output, providing additional peripheral vasodilatation, and decreasing afterload.[7,8] In this paper, we will review the role of GH in cardiac function, data on the cardiovascular effects of GH in patients with GH deficiency and excess, the effects of GH in experimental animal HF models, nonrandomized clinical studies, and randomized, controlled clinical trials of HF patients in terms of cardiac function, hemodynamic parameters, exercise performance, and quality of life.



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Section 1 of 7



GH and the Heart
GH is a small peptide secreted by the somatotropic cells of the anterior pituitary gland[9,10] (Figure). GH receptors are present on a number of organs, and stimulation of the GH receptor results in skeletal muscle growth, regulation of lipolysis, and anti-insulin effects.[10] GH may affect the heart and vessels directly or indirectly through circulating IGF-I, and IGF-I may have a central role in the hypertrophic growth response.[9] Most of the IGF-I is synthesized by the liver and circulates in the blood, bound to proteins (IGFBP) (IGFBP-3 is the main binding protein) that increase the circulating half-life of IGF-I; GH and IGF-I receptors are expressed in cardiac tissue. In addition, cardiac myocytes may produce local IGF-I, with stimulation of tissue growth, through paracrine and autocrine mechanisms promoting cardiac hypertrophy and increased mRNA production in the myocardium, more so in areas of mechanical stress.[10] Conditions of pressure and volume overload associated with increased systolic wall stress trigger gene expression of the IGF-I/GH receptors, suggesting a potential role of the GH/IGF-I axis in HF.

Figure. (click image to zoom) Possible sites of action of growth hormone on the cardiovascular system



Administration of GH stimulates molecular changes in the heart, with increased expression and concentration of IGF-I acting as a mediator of cardiac growth.[11-13] Myocardial mass is increased with conversion of myocardial contractile protein to the more efficient, forceful phenotype, low adenosine triphosphatase V3 myosin isoform.[14,15] GH may promote growth through mechanisms other than IGF-I with induction of the c-myc proto-oncogene and via platelet-derived growth factor. Finally, calcium-dependent contractile reserve in blood vessels and myocardium may be influenced through direct effects of GH.[16] In the post-myocardial infarction (MI) hearts of rats treated with GH, levels of sarcoplasmic reticulum calcium adenosine triphosphatase 2 (SERCA2) mRNA and protein were increased, suggesting restoration of contractile reserve in this animal model.[16] In summary, GH may increase contractility, increase ventricular mass through anabolic effects on cardiac myocytes, with a reduction in left ventricular wall stress, and reduce systemic vascular resistance by potentially increasing nitric oxide production.[17]



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Section 2 of 7



Tables
References

Growth Hormone Therapy in Heart Failure: Where Are We Now?
from Congestive Heart Failure

The Cardiovascular System in States of GH Deficiency and Excess
Studies in patients with GH deficiency have provided further knowledge of the interaction between GH and the cardiovascular system. Patients with GH deficiency present with decreased left ventricular wall thickness, left ventricular dilatation, increased left ventricular systolic wall stress, decreased exercise capacity, and decreased skeletal muscle mass and strength.[18-23] Administration of GH to these patients improves cardiac volumes and skeletal muscle mass, with resulting improvements in muscle strength as well as exercise performance.[21,24] In patients with GH deficiency presenting with HF due to dilated cardiomyopathy and unresponsive to digitalis, diuretics, and vasodilators, GH therapy administered for several months led to marked improvements in cardiac dimension, left ventricular ejection fraction, and symptoms.[22,25] These changes suggest that GH not only plays an important role in the development and growth of the human myocardium but also maintains normal left ventricular size and function in adults, with improvement in skeletal muscle mass and strength.

In contrast, acromegaly, the clinical manifestation of prolonged GH excess, is associated with concentric biventricular hypertrophy, hypertension, increased incidence of congestive heart failure, and increased mortality.[10] Cardiac changes associated with acromegaly include increased left and right ventricular mass -- the degree of hypertrophy related to duration of disease rather than circulating levels of GH and IGF-I -- and preserved systolic function with associated diastolic dysfunction.[10] The cardiac manifestations of sustained GH levels lead to nonfunctional hypertrophy with associated interstitial fibrosis. The potential role of physiologic replacement of GH in patients with GH deficiency with associated dilated cardiomyopathy, left ventricular chamber dilatation, and increased wall stress provides some rationale to evaluate the use of GH in the treatment of patients with HF. Proper dosage and length of GH administration is of great importance due to the deleterious effect of prolonged supraphysiologic levels observed in acromegaly, and we should be alerted to early signs of GH excess.



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Section 3 of 7



Effects of GH Therapy in Animal Models of HF
Administration of GH and/or IGF-I has been assessed in different experimental animal models of HF, with most studies demonstrating beneficial effects, with improvements in myocardial contractility, cardiac output, and stroke volume, a decrease in peripheral vascular resistance, and possible prevention of apoptosis.[26-34] In the rat postinfarction model, administration of GH resulted in an increase in left ventricular stroke volume, cardiac index, and left ventricular ejection fraction, with an increase in left ventricular weight.[26] In the pig HF model of rapid ventricular pacing, GH induced myocyte hypertrophy with an increase in the cross-sectional cardiomyocyte area.[35] Furthermore, following implantation of GH-secreting tumors in rats, maximum isometric force of the left ventricular papillary muscle was increased.[36] In a study using the rapid pacing model in pigs, an orally administered GH secretagogue administered for 3 weeks increased the production of IGF-I, which resulted in significant improvements of left ventricular fractional shortening and left ventricular peak wall stress.[37]



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Section 4 of 7


Nonrandomized Human Studies Evaluating the Role of GH for the Treatment of HF
Small, short-term, nonrandomized studies have disclosed beneficial effects of recombinant human GH (rhGH) treatment, in addition to angiotensin-converting enzyme inhibitors, in HF patients with idiopathic dilated cardiomyopathy and ischemic cardiomyopathy (Table I).[38-44] Fazio et al.[38] were the first to demonstrate significant improvements in cardiac function, functional capacity, and hemodynamic parameters in seven patients with dilated cardiomyopathy in an uncontrolled setting. In most studies, cardiac function improved significantly, with decreases in left ventricular end-diastolic and end-systolic dimensions, improvement in left ventricular ejection fraction, and decreased left ventricular wall stress, with increased wall thickness and mass.[25,38,41,43] Changes in cardiac function persisted at 3 months following discontinuation of the drug.[38,41] In these studies, New York Heart Association (NYHA) functional classification, exercise capacity, and quality of life were also improved at 3 months of rhGH therapy.[25,38,41,43,44] A study of 10 patients with ischemic cardiomyopathy treated with rhGH for 6 months showed that wall thickness, left ventricular dimensions, and left ventricular ejection fraction remained unchanged.[44]

Short-term (24-hour) continuous intravenous infusion of rhGH in patients with ischemic and idiopathic dilated cardiomyopathy have demonstrated similar hemodynamic benefits, with an increase in cardiac index and decreased systemic vascular resistance, pulmonary artery pressure, wedge pressure, and pulmonary vascular resistance, without an increase in heart rate.[42,45] GH may act partly as an inotropic agent in combination with vasodilatory effects in the acute administration of this agent. Myocardial norepinephrine release and plasma aldosterone concentration in response to exercise were significantly decreased in a small group of patients with idiopathic dilated cardiomyopathy.[46] Following discontinuation of rhGH treatment, the plasma aldosterone concentration returned to normal.

In most studies, rhGH was well tolerated, with no significant side effects reported. Worsening of ventricular arrhythmias was reported in one study evaluating five patients with idiopathic dilated cardiomyopathy (mean left ventricular ejection fraction of 22%), which returned to baseline following the discontinuation of rhGH therapy.[25] In a study evaluating rhGH administration in 10 patients with ischemic cardiomyopathy compared to a control group, mean blood glucose and insulin levels were slightly elevated following treatment with GH, but this was not statistically significant.[44] GH therapy was discontinued in one patient because of episodes of sustained and nonsustained ventricular tachycardia, and in one due to worsening HF leading to heart transplantation.[44]



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Section 5 of 7


Randomized, Controlled, Clinical Trials Evaluating the Role of GH in HF
Only three randomized, controlled clinical trials evaluating the effect of GH in patients with HF have been published (Table II).[47-49] In 50 patients with idiopathic dilated cardiomyopathy treated for 12 weeks, despite a significant increase in IGF-I and IGFBP-3, there were no changes in systolic wall stress, left ventricular cavity dimensions, or left ventricular ejection fraction, although there was a significant increase in left ventricular mass.[47] Another study evaluated 22 patients with dilated, ischemic, or valvular cardiomyopathies randomized to receive GH or placebo for 12 weeks.[48] IGF-I was significantly increased, but left ventricular ejection fraction at rest or with exercise, end-systolic diameter, end-diastolic diameter, left ventricular wall thickness, and left ventricular mass were not improved with rhGH, compared to placebo. Furthermore, cardiac index, stroke volume index, systemic vascular resistance, pulmonary artery pressure, and wedge pressure also remained unchanged after 3 months of therapy.[47] In an unblinded, randomized clinical trial, 22 patients with ischemic cardiomyopathy were randomized to GH or placebo for a duration of 6 months.[49] GH had no effect on the total perfusion score in the GH-treated group, as measured by gated single-photon emission-computed tomography imaging, or on left ventricular mass and left ventricular ejection compared to the placebo group, despite significant increases in IGF-I and IGFBP-3 levels. These studies involved a smaller daily dose of rhGH than the study by Fazio et al.,[38] where a doubled dose was administered every second day. The administration of GH every other day may be more optimal for the induction of IGF-I mRNA in the periphery.[48]

Osterziel et al.[47] reported that one patient with NYHA class IV symptoms at baseline treated with rhGH was withdrawn from treatment due to progressive left ventricular failure. One patient with known ventricular arrhythmia (Lown IV B) taking rhGH received an implantable cardioverter/defibrillator following hospital admission for sustained ventricular tachycardia, and another patient allocated to rhGH also received a defibrillator prior to active treatment for a syncopal episode that occurred during baseline testing. There were no significant adverse events reported for patients in the placebo group. Isgaard et al.[48] reported no serious side effects for patients treated with rhGH and placebo during the study. Finally, Smit et al.[49] reported that one patient was admitted with chest pain without evidence of myocardial infarction and two patients experienced a congestive heart failure exacerbation relieved by increased dosage of diuretics.

In these three studies, there were no significant improvements in exercise capacity, NYHA functional classification, plasma epinephrine, norepinephrine, aldosterone, renin activity, or angiotensin II. The lack of positive findings in these randomized clinical trials could be due to the small sample sizes, short duration of treatment, and the dose administered to patients with HF. Levels of plasma GH measured in cachectic heart failure patients are elevated, as well as other markers of catabolic state, such as cortisol and tumor necrosis factor levels, compared to noncachectic patients.[50] Patients with cachexia and HF present with characteristics suggestive of GH resistance, with increased levels of GH and a tendency to lower levels of IGF-I. GH resistance is also seen in states of malnutrition and critical illness.[51] Lack of response to GH therapy in cachectic HF patients with more severe disease may be associated with GH resistance.[51] This may suggest some "uncoupling" of the GH/IGF-I axis in some HF patients, but further study of this mechanism is needed in this population of patients.



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Section 6 of 7



Conclusion
Results from small, nonrandomized studies have demonstrated improvements in cardiac chamber dimensions, cardiac function, quality of life, and functional capacity in patients with mild to moderate symptoms of HF. Although these data are encouraging, results from short-term, randomized, placebo-controlled trials did not confirm the earlier reports of significant benefits on cardiovascular function from uncontrolled studies. However, the randomized, controlled studies were underpowered to detect significant differences in cardiac function, hemodynamic parameters, and functional capacity. The duration of treatment and dosage regimen of rhGH in patients with HF may also partially explain the lack of effectiveness seen in these three randomized clinical trials. The current level of evidence for GH replacement in HF does not support the use of GH as adjuvant therapy.

GH and IGF-I are clearly important in maintaining normal structure and function of the heart. GH may potentially be beneficial in HF patients by increasing left ventricular mass, decreasing left ventricular wall stress, and affecting left ventricular remodeling. GH may further unload the ventricle through left ventricular geometric changes combined with a reduction in peripheral vascular resistance. Compared to other inotropic treatments tested in HF patients, GH may potentially increase contractility and act on peripheral resistance without causing activation of the sympathetic nervous system. Additional benefit may be mediated through an increase in skeletal muscle mass and improvement of strength. In contrast, supraphysiologic levels of GH for prolonged durations, seen in acromegaly, are associated with left ventricular hypertrophy, hypertension, and congestive heart failure, all of which are associated with increased mortality. The administration of high doses of GH to critically ill patients in the intensive care unit setting has also been associated with increased mortality, prolonged intensive care unit stay, increased length of hospitalization, and increased duration of mechanical ventilation.[52] As there is only a small amount of data currently available on the therapeutic use of GH in patients with HF, further dose-ranging studies of longer duration are needed to elucidate the role of GH therapy in addition to standard therapy in improving cardiac function, functional capacity, and survival of HF patients.

Reprint Address

Address for correspondence: Robert S. McKelvie, MD, PhD, HHS-General Division, 237 Barton Street East, Hamilton, Ontario, L8L 2X2 Canada E-mail: [email protected]


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Section 7 of 7


CHF 9(2):84-90, 2003. © 2003 Le Jacq Communications, Inc.

[MMA]

The Fazio article:

http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=8596546

The medscape article is 7 pages and references both randomized and nonrandomized studies of rGH. You are correct that the low dosage, short term randomized studies didn't show improvements in heart function. Note the comparisons of the two types of studies and the reasons given for the reported benefits in the nonrandomized studies (Should I paste the entire article?):

http://www.medscape.com/viewarticle/452247_1

Forgive my dullness-bad flue/out of it. What is "EOD"?


Thanks for at least taking a look.
A

EOD - every other day

[ArmstrongJones]

Duh. My bad.

EOD is recomended in the protocol that I am following. I'll dig it up.

[ArmstrongJones]

Missunderstood.

You were refering to study re EOD not the GH/CHF article(s). Must cut back on my flue meds.

I was planning on a three month GH cycle, 5 on 2 off. Then evaluate heart function and decide whether to continue for six months. I recently saw two articles recomending 1/1 for longer term GH use for heart treatment.

In addition to improved heart function, I'll be looking for the same benefits I would as an athlete; strength, stamina, muscle mass, etc.

I'll come back with specific info re protocol.

Thanks