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Abstract

Heart failure (HF) is an important health concern with almost a quarter million deaths each year despite advances in medical therapy. Improvement of cardiac function has been shown to reduce morbidity and mortality in patients with HF. There has been recent interest in the growth hormone (GH) / insulin-like growth factor (IGF) pathway as a potential therapeutic target for patients with HF. Insulin-like growth factor 1 has been shown to augment cardiac function ex vivo and in animals. It was hypothesized that IGF-1/IGF-binding protein 3 levels might be able to provide prognostic benefits in patients with heart disease. Initial observational studies have shown significant benefits from GH supplementation including improved ejection fraction, increased exercise tolerance, and decreased New York Heart Association functional class. These results, however, were not replicated in randomized, controlled trials. Patients with advanced stages of HF might develop cachexia associated with a state of significant GH resistance. The lack of response to GH supplementation may be secondary to a deficiency in IGF-1, the effector hormone. Hypothetically, this group of patients could benefit from direct IGF-1 supplementation. Combined therapy with GH and IGF-1 is appealing; however, future trials in patients with advanced HF are warranted to prove this concept.

Keywords

congestive heart failure cardiomyopathy heart disease experimental and clinical heart failure heart failure

Introduction

Heart failure (HF) affects 5.7 million people in the United States and results in a staggering 250 000 deaths per year.¹ Heart failure is a syndrome of multiple neurohormonal imbalances. While there have been major advances in the medical management of HF, there remains significant morbidity and mortality. As such, there is a need for identifying alternate pathways in which therapeutic intervention may improve outcomes.

There has been recent interest in the growth hormone (GH)/IGF-1 pathway because patients with HF have been shown to have significantly lower GH and insulin growth factor 1 (IGF-1) levels compared to controls.^2,3 In the Framingham Heart Study, lower IGF-1 levels were independently associated with increased all-cause mortality after multivariate analysis.⁴ Previous trials of GH therapy have shown equivocal results,^5–8 that have been correlated with increasing levels of GH resistance in HF.⁹ Furthermore, GH resistance has been shown to be associated with cachexia.¹⁰ In patients with cardiac cachexia, GH supplementation may lack therapeutic benefits due to a failure to increase IGF-1 levels secondary to GH resistance. Theoretically, direct supplementation with IGF-1 should provide the therapeutic benefit sought in GH supplementation. This paper will evaluate the mechanisms of growth hormone resistance and will suggest IGF-1 as a possible therapeutic choice.

Growth Hormone and IGF-1

GH production in the anterior pituitary is stimulated by GH-releasing hormone and inhibited by somatostatin. Additional GH secretagogues help induce pulsatile GH secretion by inhibiting somatostatin. Growth hormone induces the production of IGF-1 in the liver, which is the anabolic effector hormone of pituitary GH. Once secreted by the liver, IGF-1 acts systemically as an endocrine hormone. Ninety-nine percent of IGF-1 remains bound to binding proteins (BP), 80% of which is bound to IGF-BP3.¹¹ Insulin growth factor 1 (IGF-1) at the cellular level promotes cell survival and cell growth. On the other hand, cell apoptosis is initiated by the p53 pathway. This pathway leads to increased production of IGF-BP3 which sequesters the active form of IGF-1. In cells, the increased production of IGF-BP3 that is induced by the p53 apoptotic pathway will decrease cellular levels of IGF-1 and decrease the effects of IGF-1.¹² Exogenous administration of IGF-1 has been shown to attenuate the p53 apoptotic process.¹³ Insulin growth factor 1 also has been shown to specifically affect cardiac cells as well. Ito et al evaluated the effects of IGF-1 administration on cardiac myocytes in rats. After administration of IGF-1, cardiac myocytes were enlarged and expressed increased mRNA levels of actin, myosin light chain 2 and troponin I.¹⁴ In addition, IGF-1 was shown to protect against cardiac senescence including attenuation of cardiac contractile dysfunction through increasing the maximal velocity of contraction and relaxation in a rat model.¹⁵ Insulin growth factor 1 promotes cell survival and enhances cardiac function and IGF-BP3 inhibits the function of IGF-1 (Figure 1).

Figure 1.

Pathophysiologic pathways of growth hormone and insulin growth factors.

Insulin Growth Factors as Markers for Disease

Insulin growth factor 1 and IGF-BP3 have been investigated as markers for disease and mortality. There has been significant interest in IGF-1 and IGF-BP3 levels related to standard cardiovascular risk factors such as blood pressure, lipids, and diabetes (Table 1). Insulin growth factor 1 has been shown to have a negative association and IGF-BP3 a positive association with low-density lipoprotein (LDL) cholesterol, triglycerides, diabetes, and waist circumference.^16,17 Low IGF-1 levels are associated with endothelial dysfunction.^18–20 A study of 122 patients undergoing coronary angiography reported significantly reduced IGF-1 levels in patients with significant coronary disease (126 ± 7 ng/mL) compared to those without coronary disease 162 ± 15 ng/mL).²¹ In acute myocardial infarction, there is a significant decrease in IGF-1 levels compared with controls (115 ± 112 vs 615 ± 300 ng/mL P < .0001).²² The relative risk of ischemic heart disease (IHD) is increased with low IGF-1 levels and high IGF-BP3 levels. Juul et al. measured IGF-1 and IGF-BP3 levels in 231 patients with ischemic heart disease and 374 controls and stratified the patients into quartiles based upon IGF-1 and IGF-BP3 levels.²³ The study exhibited a negative association between IGF-1 and IHD and a positive association between IGF-BP3 and IHD. In the low IGF-1 quartile range, the relative risk of IHD was 2.17 (95% CI, 1.20 to 3.94); compared to the high IGF-1 quartile range. In the high IGF-BP3 range, the relative risk of IHD was 2.00 (95% CI, 1.09 to 3.68) compared to the low IGF-BP3 group range.²³ The results seen in patients after myocardial infarction and in ischemic heart disease exhibit a strong association between low levels of IGF-1, high levels of IGF-BP3, and increased ischemic heart disease and myocardial infarction. In Japanese patients with HF, there was an association with HF and low IGF-1 levels.²⁴ IGF-1 and IGF-BP3 have also been associated with overall health and mortality. Insulin-like growth factor 1 levels were significantly lower in patients who experienced worse health compared with their peers.²⁵ Higher IGF-1 levels were protective for survival with a mortality hazard ratio of 0.41 (CI: 0.24 to 0.70 P < .0005) per log₁₀ difference in IGF-1 levels.⁴ These studies showed significantly lower IGF-1 levels in patients with HF and heart disease in general as compared with controls. IGF-BP3 levels were increased in patients with HF, but this result was not corroborated in all studies. In general, low IGF-1 levels and high IGF-BP3 levels were associated with increased cardiovascular disease, worse overall health, and mortality in general.

Table 1.

Hormone Levels as Related to Heart Failure

Study	Sample	Design	Comparative Factors	Stratified Groups	Results
Saydah et al.¹⁷	5,903 patients over 20 years old	Cross-sectional	IGF-1, IGF-BP3 levels, abdominal obesity, triglycerides, HDL, BP, Fasting glucose	Metabolic syndrome components: 0 components, 1-2 components, 3-5 components	IGF-1 levels significantly lower in group 3-5 (235 ng/mL), to group 1-2 (266.2 ng/mL) to group 0 (296.2 ng/mL) P < .0001
Sesmilo et al.¹⁹	40 patients with growth hormone deficiency	Randomized-controlled trial	IGF-1, insulin levels, lipids anthropometric, hemoglobin A1c, glucose	2 groups: 20 received GH replacement, 20 received placebo	GH group showed decreases in total cholesterol (−33.2 ± 6.6 mg/dL, P < .001), LDL (−24.5 ± 5.9 mg/dL, P < .001)
Conti et. al.²²	23 patients with acute MI and 11 matched controls	Case-control trial	IGF-1 levels within 24 hours of symptom onset	Patients after acute MI and matched controls	AMI patients versus controls showed markedly reduced IGF-1 (115 ± 112 vs. 615 ± 300 ng/mL, P < .0001)
Juul et al.²³	271 IHD patients and 374 controls	Case control trial	IGF-1, IGF-BP3 levels and ischemic heart disease prevalence	Patients stratified into quartiles by IGF-1 and IGF-BP3 levels	Low IGF-1 quartile had RR of IHD 1.95 (CI 1.03-3.66), High IGF-BP3 quartile had RR of IHD 4.07 (CI 1.48-11.22)
Watanabe et al.²⁴	142 HF patients	Case-control trial	IGF-1, IGF-BP3 levels and HF	HF patients were stratified into NYHA Class I-II and Class III-IV	Class I-II had higher IGF-1 levels 66.6 ng/mL (46.3-99.6) than Class III-IV 54.6 ng/mL (29.9-74.1), P < .0028. IGF-BP3 levels were comparable
Janssen et al.²⁵	218 healthy elderly patients	Cross-sectional trial	IGF-1, and IGF-BP3 levels and health questionnaire	Stratified by response to question if they judged their health to be better, same or worse compared to their peers	21 patients with ‘worse’ health had IGF-1 levels 0.068 nmol/L compared to ‘same’ or better 0.093 nmol/L, IGF-BP3 levels were comparable

Growth Hormone Supplementation in Heart Failure

Observational Studies

Growth hormone and IGF-1 both have been shown to have inotropic actions with acute administration. In a rat model, IGF-1 has been shown to improve contractility with an increase in force of contraction by 22% to 24%.²⁶ In a study of 12 patients with acutely decompensated HF, receiving a continuous intravenous administration of GH over 24 hours, cardiac indices significantly increased from 2.1 to 3.3 L/min per m² P < .01. There was also a trend in acute reduction in pulmonary artery pressures with a 25% decrease in mean pulmonary artery pressures from 40 mm Hg to 30 mm Hg (P = NS).²⁷ In a small study of 7 patients with dilated cardiomyopathy receiving daily supplementation of 2IU of GH, patients reported a feeling of well-being and improved quality of life after 3 months. Left ventricular ejection fraction (LVEF) increased from 34% ± 1.5% to 47% ± 1.9% (P < .001) immediately after therapy and 3 months later the improvement in LVEF was preserved at 40% ± 2.4%. Exercise capacity on upright bicycle was increased in duration from 6.5 ± 0.5 to 8.9 ± 0.9 minutes (P < .001).³

Randomized Control Trials

Data from randomized control trials have been less promising. Isgaard et al performed a randomized placebo-control trial in 22 patients with 0.1 IU/kg per week of GH supplementation. All patients responded with a significant increase in IGF-I levels from 175 ± 10 µg/L to 425 ± 20 µg/L. There was no significant effect on ejection fraction at rest or during exercise and there was no increase in left ventricular mass.⁵ Osterziel et al randomized 50 patients to daily 2 IU GH administration versus placebo with no significant difference in NYHA class (P = .27) or 6-minute walk test (P = .11). Interestingly, left ventricular mass increased in the GH-treated group (P = .0001), with a significant positive correlation between serum IGF-1 concentration and left ventricular mass.⁶ Acevedo et al performed a randomized controlled trial of 19 patients with daily GH administration. After 8 weeks of treatment, there was no significant effect on LVEF or peak oxygen consumption; however, left ventricular mass appeared to be increased.⁷

Meta-Analyses

The small randomized controlled studies were underpowered to detect differences. A meta-analysis of 14 trials of GH administration in patients with HF demonstrated a significant increase in exercise duration by 1.9 minutes [1.1-2.7 minutes], NYHA class was decreased by 0.9, and maximal oxygen consumption (VO₂ max) was increased by 2.1 mL/kg per minute. There was a negative correlation between an increase in serum IGF-1 levels and decrease in NYHA class (beta coefficient 5.77 [0.39-11.14] P = .035) as well as a positive correlation between increased serum IGF-1 levels and left ventricular mass (P = .01).⁸ Growth hormone supplementation did provide benefits with regard to left ventricular size, ejection fraction, exercise duration, and maximal O₂ consumption, which all correlated with increases in serum IGF-1 levels.

Observational trials and meta-analysis showed a significant benefit from GH supplementation in patients with DCM in terms of symptomatology, functional capacity, and ejection fraction (Table 2). Since these results have not been confirmed by randomized controlled clinical trials, no general recommendations can be made to date with regard to GH therapy for HF.

Table 2.

Growth Hormone Trials

Study	Sample	Design	Dosage, Duration	Variables tested	Results
Volterrani et al.²⁷	12 male patients with HF	Observational trial	0.1 IU/kg of GH given over 24 hours	GH serum levels, Cardiac index (CI), Pulmonary artery pressures (PAP)	CI increased 2.1 to 3.3L/min/m² P < .01, PAP decreased 40 to 30 mm Hg (P = NS)
Fazio et al.³	7 patients with HF	Observational trial	14 IU GH given weekly for 3 months	Wall thickness (WT) Left ventricular end diastolic dimension (LVEDD), Ejection fraction (EF), Exercise capacity (EC)	WT 10 to 12.9 mm P < .001, LVEDD 65 to 61 mm P < .001; EF 34 to 47% P < .001, 3 months later EF 40% P < .001, (EC) 6.5 to 8.9 min P < .001
Isgaard et al.⁵	22 patients with HF	Randomized-control trial	0.1 IU/kg weekly vs. placebo treated for 3 months	Ejection fraction, Wall thickness, LVEDD, Left ventricular mass	There was no significant difference between placebo and treated group with EF, WT, LVEDD or LV mass.
Osterziel et al.⁶	50 patients with HF	Randomized-control trial	2 IU GH daily vs. placebo × 12 weeks	LV mass, EF, wall thickness, NYHA class, 6 min walk test	LV mass increased by 27% P < .0001. There was no significant difference with EF, WT, NYHA, or 6-min walk.
Acevedo et al.⁷	19 patients with HF	Randomized- control trial	0.03 IU/kg daily vs. placebo × 8 weeks	EF, Oxygen consumption (VO₂ max), Exercise capacity, Norepinephrine levels	There was no significant difference with EF, VO₂ max, EC or neurohormonal status.
Tritos et al.⁸	212 patients with HF	Meta-analysis	Variable dosing based upon individual trials	Exercise capacity (EC), NYHA class, VO2 max, LV mass	EC increased by 1.9 (1.1-2.7) min, NYHA decreased by beta coefficient 5.77 P = .035, VO₂ max increased by 2.1 (1.2-3.1) mL/kg per min, LV mass increased by beta coefficient, 32.12 P = .010

Cachexia and GH Resistance

Cachexia, or muscle wasting, is characterized by fatigue, weakness, and the progressive loss of skeletal muscle and adipose tissue. Cachexia is defined as a nonintentional weight loss of >7.5% from previous nonedematous weight and is present in multiple chronic disease states including chronic heart failure.²⁸ Cachexia in HF carries 50% mortality at 18 months; which is 3 times higher than noncachectic HF patients.^28,29 Cachexia is characterized by a propensity toward catabolism due to the action of numerous cytokines in a pro-inflammatory state including tumor necrosis factor alpha (TNF-α). TNF-α is thought to mediate its actions through stimulation of caspases leading to cell death by apoptosis. The caspases induce reorganization of the cytoskeleton, destroy DNA, inhibit DNA replication, and disintegrate the cell into apoptotic bodies.³⁰ TNF-α interferes with the normal IGF-1 signaling pathway by decreasing IGF-1 gene and protein expression as well as receptor sensitivity.³¹ TNF-α inhibition has been investigated as a therapeutic target in patients with HF.³² Two randomized-control trials were performed with Etanercept and they found no decrease in mortality or frequency of hospitalizations.³³ Infliximab therapy in HF resulted in increased mortality as compared with placebo.³⁴ There has been decreased interest in therapy TNF-α inhibitors since the failure of these trials.

Although treatment with direct TNF-alpha inhibitors has not been shown to be clinically beneficial, cachexia is an important factor to consider in trials of patients with HF. In the clinical trials of GH supplementation in HF, patients were not stratified according to cachexia as a risk factor.⁹ The cytokine milieu in cachexia involves pathways that are directly opposed to the IGF-1 pathways. GH therapy can significantly reduce plasma TNF-α levels, in one trial levels decreased from 7.8 ± 1.1 to 5.5 ± 0.9 pg/mL, P < .02.³⁵ In addition, those patients with HF and cachexia have been shown to have 342% higher levels of serum GH than noncachectic HF patients. Interestingly, cachectic HF patients had a GH/IGF-1 ratio that was 12-fold higher compared to non-cachectic HF patients.¹⁰ Alteration in the GH-IGF axis has been implicated in the development of cachexia in patients with HF. Decreases in the level of IGF-1 with increasing levels of GH have been shown to precede the clinical development of cachexia in patients with HF .³⁶ In addition, cachexia as an independent risk factor carries a higher mortality for patients with HF.²⁸ In summary, cachexia causes GH resistance resulting in increasing levels of GH without increased levels of IGF-1, which may contribute to the lack of response to GH supplementation in this group of patients.

Direct IGF-1 Supplementation

Direct IGF-1 supplementation may be beneficial in patients with HF, cachexia, and subsequent GH resistance. To our knowledge, no studies have investigated the actions of direct IGF-1 supplementation in cachectic HF patients. Carroll et al showed that concomitant administration of both IGF-1 and GH in a population of critically ill cachectic patients reversed the negative protein balance that is usually seen.³⁷ There is another medical condition that simulates the hormonal profile of GH resistance seen in cachexia: Laron syndrome is a genetic disorder of GH resistance and secondary IGF-1 deficiency. By echocardiogram, untreated patients with Laron syndrome have significantly diminished left ventricular mass compared with age-matched controls.³⁸ Chernausek et al studied IGF-1 supplementation in 76 children with Laron syndrome. Although this group is quite different from patients with chronic HF, the study provided some valuable insight in dosing, safety, and monitoring of IGF-1 administration. Because of the insulin-like effects of IGF-1, the most common side effect of IGF-1 administration was hypoglycemia, with 49% of patients experiencing these episodes during the first month of treatment.³⁹ Simultaneous coadministration of GH with IGF-1 appears to prevent hypoglycemia (Figure 2).⁴⁰ Although GH and IGF-1 act synergistically to promote anabolism and growth, they act antagonistically in terms of glucose metabolism.^9,40,41

Figure 2.

Theoretical therapeutic effects of direct IGF-1 supplementation.

Conclusions

Heart failure remains a significant cause of morbidity and mortality, and novel therapies are warranted. Interventions that augment cardiac myocyte function have a potential to provide long-term benefits. The development of cachexia in a patient with heart failure portends significantly increased mortality.²⁸ The cytokine milieu in cachexia interferes with the normal function of the GH/IGF-1 pathway. Low levels of IGF-1 and high levels of IGF-BP3 are associated with increasing risk of heart disease and mortality in general. Substitution of IGF-1, however, has been shown to promote cell survival and enhance myocyte contractility. Initial observational studies of GH supplementation in HF showed significant benefit but these results have not been replicated in randomized controlled trials. These trials were not controlled for either cachexia or GH resistance. Patients with the coincidence of HF and cachexia have the highest mortality, and this group may not have benefited from GH supplementation because of GH resistance and insufficient IGF-1 production. This group of patients could potentially benefit from direct IGF-1 supplementation. Due to safety concerns of hypoglycemia, it is recommended to coadminister GH with IGF-1. Potentially, IGF-1 supplementation would provide the therapeutic benefit. Coadministration of GH would increase IGF-1 levels in a varying degree but also decrease the risk of hypoglycemia caused by IGF-1. At this time there are no ongoing clinical trials of direct supplementation with IGF-1 in patients with HF, but this could be a potential target in patients with HF and cachexia. The potential clinical benefits from direct IGF-1 supplementation include decreased NYHA class, increased exercise capacity, increased ejection fraction, increased left ventricular mass, improved quality of life, less frequent hospitalizations, and decreased morbidity and mortality. These clinical endpoints should be included in future trials of direct IGF-1 supplementation in patients with HF and cachexia. Future investigation in direct IGF-1 supplementation can potentially provide significant clinical benefit in this prevalent disease.

Footnotes

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ES is a consultant for the Cenegenics Research Foundation.

The author(s) received no financial support for the research and/or authorship of this article.

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The Potential Effects of IGF-1 and GH on Patients With Chronic Heart Failure

Abstract

Keywords

Introduction

Growth Hormone and IGF-1

Insulin Growth Factors as Markers for Disease

Growth Hormone Supplementation in Heart Failure

Observational Studies

Randomized Control Trials

Meta-Analyses

Cachexia and GH Resistance

Direct IGF-1 Supplementation

Conclusions

Footnotes

References