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(Circulation. 2004;110:3674-3679.)
© 2004 American Heart Association, Inc.

Heart Failure

Effects of Ghrelin Administration on Left Ventricular Function, Exercise Capacity, and Muscle Wasting in Patients With Chronic Heart Failure

Noritoshi Nagaya, MD; Junji Moriya, MD; Yoshio Yasumura, MD; Masaaki Uematsu, MD; Fumiaki Ono, MD; Wataru Shimizu, MD; Kazuyuki Ueno, PhD; Masafumi Kitakaze, MD; Kunio Miyatake, MD; Kenji Kangawa, PhD

From the Department of Internal Medicine, National Cardiovascular Center, Osaka (N.N., J.M., Y.Y., F.O., W.S., M.K., K.M.); Cardiovascular Division, Kansai Rosai Hospital, Hyogo (M.U.); and Departments of Pharmacy (K.U.) and Biochemistry (K.K.), National Cardiovascular Center Research Institute, Osaka, Japan.

Reprint requests to Noritoshi Nagaya, MD, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail nagayann{at}hsp.ncvc.go.jp

Received April 30, 2004; revision received July 6, 2004; accepted August 23, 2004.

	Abstract

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Background— Ghrelin is a novel growth hormone–releasing peptide that also induces vasodilation, inhibits sympathetic nerve activity, and stimulates feeding through growth hormone–independent mechanisms. We investigated the effects of ghrelin on left ventricular (LV) function, exercise capacity, and muscle wasting in patients with chronic heart failure (CHF).

Methods and Results— Human synthetic ghrelin (2 µg/kg twice a day) was intravenously administered to 10 patients with CHF for 3 weeks. Echocardiography, cardiopulmonary exercise testing, dual x-ray absorptiometry, and blood sampling were performed before and after ghrelin therapy. A single administration of ghrelin elicited a marked increase in serum GH (25-fold). Three-week administration of ghrelin resulted in a significant decrease in plasma norepinephrine (1132±188 to 655±134 pg/mL; P<0.001). Ghrelin increased LV ejection fraction (27±2% to 31±2%; P<0.05) in association with an increase in LV mass and a decrease in LV end-systolic volume. Treatment with ghrelin increased peak workload and peak oxygen consumption during exercise. Ghrelin improved muscle wasting, as indicated by increases in muscle strength and lean body mass. These parameters remained unchanged in 8 patients with CHF who did not receive ghrelin therapy.

Conclusions— These preliminary results suggest that repeated administration of ghrelin improves LV function, exercise capacity, and muscle wasting in patients with CHF.

Key Words: growth substances • heart failure • hormones • nutrition

	Introduction

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Left ventricular (LV) remodeling (dilatation and wall thinning) and cardiac cachexia (body weight loss and muscle wasting) often are observed in patients with end-stage chronic heart failure (CHF).^1,2 Growth hormone (GH) and its mediator, insulinlike growth factor-1 (IGF-1), are anabolic hormones that are essential for skeletal and myocardial growth and metabolic homeostasis.^3,4 Earlier studies have shown that GH supplementation may have beneficial effects on LV myocardial structure and function in some patients with CHF,⁵ although the importance of GH resistance⁶ and neutral results of randomized trials also have been reported.^7,8

Ghrelin is a novel GH-releasing peptide that was isolated from the stomach and has been identified as an endogenous ligand for the growth hormone secretagogue receptor.⁹ Therefore, we believed that administration of ghrelin may induce beneficial changes in LV function and energy metabolism in patients with CHF via a GH-dependent mechanism. On the other hand, growth hormone secretagogue receptor mRNA is detected not only in the hypothalamus and pituitary but also in the heart and blood vessels,¹⁰ implying direct cardiovascular effects of ghrelin. Wiley and Davenport¹¹ have demonstrated that ghrelin is an endothelium-independent vasodilator in isolated human arteries. We have shown that intravenous administration of ghrelin decreases systemic vascular resistance and increases cardiac output in patients with CHF.¹² Furthermore, ghrelin induces a positive energy balance by stimulating food intake^13,14 and adiposity¹⁵ through GH-independent mechanisms. These findings raise the possibility that ghrelin administration may have beneficial effects in cachectic patients with CHF. In fact, we recently have demonstrated that treatment with ghrelin improves not only LV function but also cardiac cachexia in rats with CHF.¹⁶ In humans, however, the potential effects of ghrelin as a therapeutic agent for CHF remain unknown.

Thus, the purposes of this study were as follows: (1) to investigate whether repeated administration of ghrelin improves LV myocardial structure and function in patients with CHF, (2) to examine whether ghrelin improves exercise capacity in such patients, and (3) to examine whether ghrelin induces anabolic effects in patients with CHF.

	Methods

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Study Subjects
Eighteen patients with CHF (13 men, 5 women; mean age, 75 years; range, 63 to 80 years) were included in this study. Inclusion criteria were as follows: (1) LV ejection fraction <35% as assessed by cardiac catheterization, (2) a stable clinical condition, and (3) clinical evidence of heart failure despite conventional therapy. Exclusion criteria were the presence of any of the following: (1) chronic renal impairment (serum creatinine level 2.0 mg/dL), (2) significant liver dysfunction, (3) evidence of malignant diseases, (4) active infection, (5) hematologic abnormalities, or (6) systolic blood pressure <90 mm Hg. Ten patients with CHF (ghrelin group) received repeated administrations of ghrelin. Although this study was neither randomized nor placebo controlled, 8 patients with CHF who did not receive ghrelin (control group) were studied to exclude time-course effects during hospitalization. Patients in the ghrelin group were admitted only for the study. Those in the control group had been in hospital for diagnostic examination and stayed for 3 weeks for the study. There was no significant difference in demographic, clinical, or hemodynamic data at baseline between the ghrelin and control groups (Table 1). Eight patients in the ghrelin group and 6 patients in the control group were defined as exhibiting cardiac cachexia, as reported previously.¹⁷ The weight loss in cachectic patients amounted to 6.4±0.4 kg or 11.8±0.7% loss of previous body weight during 14±2 months. The ethics committee of the National Cardiovascular Center approved the study, and all patients gave written informed consent.

View this table: [in this window] [in a new window]   TABLE 1. Patient Characteristics

Preparation of Human Ghrelin
Human synthetic ghrelin was obtained from the Peptide Institute Inc. This peptide is not commercially available. Ghrelin was dissolved in distilled water with 4% D-mannitol and sterilized by passage through a 0.22-µm filter (Millipore Co). Ghrelin was stored in 2-mL volumes, each containing 200 µg ghrelin. The chemical nature and content of the human ghrelin in vials were verified by high-performance liquid chromatography and radioimmunoassay. All vials were stored frozen at –80°C from the time of dispensing until the time of preparation for administration.

Study Protocol
This study was performed while patients were in a stable clinical condition during hospitalization. Ghrelin (2 µg/kg, 10 mL solution) was administered intravenously over 30 minutes at a constant rate. The infusion was repeated twice a day (before breakfast and before dinner) for 3 weeks. Study patients in both groups remained hospitalized for 3 weeks. Echocardiography, cardiopulmonary exercise testing, dual x-ray absorptiometry, hand-grip test, and blood sampling were performed at baseline and after 3 weeks of treatment with ghrelin (ghrelin group) or without ghrelin (control group). Long-term medication, including digitalis, diuretics, ACE inhibitors, and ß-blockers, was kept constant during this study protocol.

Echocardiographic Studies
Echocardiography was performed by an investigator blinded to treatment allocation. Two-dimensional targeted M-mode tracings were obtained at the level of the papillary muscles with an echocardiographic system equipped with a 3.5-MHz sector scan probe (SONOS 2000, Hewlett Packard). LV wall thickness, dimensions, and fractional shortening were measured according to the recommendations of the American Society of Echocardiology from at least 3 consecutive cardiac cycles. LV end-diastolic volume, end-systolic volume, and ejection fraction were calculated with a modified version of Simpson’s method.¹⁸

Cardiopulmonary Exercise Testing
Cardiopulmonary exercise testing was performed in all patients except 1, who underwent a 6-minute walk test as recommended by attending physicians. The patients exercised seated on a cycle ergometer. The work rate was then increased by 15 W/min up to their symptom-limited maximum. Breath-by-breath gas analysis was performed with an AE280 (Minato Medical Science).¹⁹ Exercise capacity was evaluated by peak oxygen consumption (peak O). Ventilatory efficiency during exercise was represented by the E–CO₂ slope.¹⁹

Food Intake and Body Mass Analyses
Food intake for 3 consecutive days was assessed before ghrelin administration and during the last week of ghrelin therapy. Food intake was semiquantitatively assessed by a calorie count based on a 10-point scale method (0=null intake, 10=full intake or 1800 kcal), which was averaged for 3 days. Dual x-ray absorptiometry (DPX-L, Lunar Radiation) was repeated in all patients to examine changes in lean body mass, fat mass, and bone mineral content. Hand-grip strength was determined with a dynamometer.

Blood Sampling and Assay
Blood samples were taken from the antecubital vein the morning after an overnight fast. Serum GH and IGF-1 were measured by immunoradiometric assay (Ab Bead HGH Eiken, Eiken Chemical Co, Ltd, sensitivity=0.1 ng/mL; Somatomedin CII Bayer, Bayer Medical Ltd, sensitivity=0.3 ng/mL). Plasma norepinephrine and epinephrine were measured by high-performance liquid chromatography (HLC8030, Tosoh Co, sensitivity=6 pg/mL). Serum cortisol and insulin were measured by enzyme immunoassay (AIA-PACK CORT, sensitivity=0.2 µg/dL; AIA-PACK IRI, sensitivity=2.0 µU/mL, Tosoh Co). Serum tumor necrosis factor (TNF-) and interleukin-6 (IL-6) were measured by enzyme immunoassay (Quantikine HS, R&D Systems Inc, sensitivity=0.18 pg/mL; TFB kit, TFB Co, Ltd, sensitivity=0.3 pg/mL). Plasma renin and aldosterone were measured with radioimmunoassay kits (RENIN RIABEAD, sensitivity=0.1 ng/mL; ALDOSTERONE RIAKIT II, sensitivity=2.0 ng/dL, DAINABOT Co). Plasma brain natriuretic peptide (BNP) was measured by immunoradiometric assay (SHIONORIA BNP, sensitivity=4.0 pg/mL).

Statistical Analysis
Numerical values are expressed as mean±SEM. Comparisons of parameters between the 2 groups were made by unpaired Student’s t test. Comparisons of the time course of serum GH and IGF-1 between the 2 groups were made by 2-way ANOVA for repeated measures, followed by the Newman-Keuls test. Comparisons of changes in parameters during the 3-week follow-up between the 2 groups were also made by 2-way ANOVA for repeated measures, followed by the Newman-Keuls test. A value of P<0.05 was considered significant.

	Results

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Administration of ghrelin transiently caused stomach rumbles in 6 patients and a slight feeling of being warm and sleepy in 4 subjects. Two patients felt slightly thirsty during ghrelin infusion. Other than these minor complaints, all subjects tolerated 3-week administration of ghrelin without incident. After 3-week administration of ghrelin, NYHA functional class improved in 4 patients and was unchanged in 6 patients. No change in NYHA functional class was observed in patients who did not receive ghrelin.

Effects of Ghrelin on Somatotropic Function
A single administration of ghrelin markedly increased serum GH level (baseline, 1.4±0.4; peak, 35.0±5.0 ng/mL; P<0.001; Figure 1). This elevation lasted >60 minutes after the start of ghrelin infusion. Serum IGF-1 level tended to increase 3 hours after the start of ghrelin infusion (101±12 to 110±12 ng/mL; P=0.08). Three-week administration of ghrelin tended to increase basal serum IGF-1 level (99±13 to 116±13 ng/mL; P=0.07). There was no significant difference in basal serum GH level between before and after 3 weeks of ghrelin therapy (2.0±0.8 to 1.2±0.3 ng/mL; P=NS).

View larger version (36K): [in this window] [in a new window]   Figure 1. Changes in serum GH and IGF-1 after single administration of ghrelin. Solid line indicates cachectic patients; dotted line, noncachectic patients.

Effects of Ghrelin on Food Intake, Body Weight, and Lean Body Mass
Administration of ghrelin significantly increased food intake (Figure 2). Three-week administration of ghrelin tended to increase body weight (49.6±2.7 to 50.4±2.7 kg; P=0.09). No development of edema was observed during ghrelin therapy. Dual x-ray absorptiometry demonstrated that treatment with ghrelin significantly increased lean body mass in patients with CHF (38.3±2.1 to 39.1±2.1 kg; P<0.05). Ghrelin did not significantly alter bone mineral content (2243±191 to 2265±189 g; P=NS) or fat mass (8877±1353 to 8748±1311 g; P=NS). Hand-grip strength was increased significantly by ghrelin therapy (20.5±1.7 to 22.7±2.0 kg; P<0.01). All of these parameters remained unchanged in patients who did not receive ghrelin.

View larger version (21K): [in this window] [in a new window]   Figure 2. Food intake, body weight, and lean body mass before and after 3-week administration of ghrelin. Food intake was described semiquantitatively with 10-point scale method (0=null intake, 10=full intake). Data are mean±SEM. Solid line indicates cachectic patients; dotted line, noncachectic patients. *P<0.05 vs before; P<0.05 vs respective control group.

Effects of Ghrelin on Cardiac Structure and Function
Neither heart rate nor blood pressure was significantly changed by 3-week administration of ghrelin (Table 2). Ghrelin increased LV ejection fraction (27±2% to 31±2%; P<0.05) in association with a decrease in LV end-systolic volume and an increase in LV mass (Figure 3), although ghrelin did not significantly alter LV end-diastolic volume. All of these parameters remained unchanged in patients who did not receive ghrelin.

View this table: [in this window] [in a new window]   TABLE 2. Physiological and Echocardiographic Measurements

View larger version (21K): [in this window] [in a new window]   Figure 3. LV geometry and function before and after ghrelin therapy. Data are mean±SEM. Solid line indicates cachectic patients; dotted line, noncachectic patients. *P<0.05 vs before; P<0.05 vs respective control group.

Effects of Ghrelin on Exercise Capacity and Ventilatory Efficiency
Three-week administration of ghrelin significantly increased peak workload and peak O during exercise (739±127 to 801±126 mL/min; P<0.05; Figure 4). Treatment with ghrelin did not significantly alter the E–CO₂ slope. In 1 patient who did not undergo cardiopulmonary exercise testing, the distance walked in 6 minutes increased from 300 m to 410 m with ghrelin treatment. Exercise parameters remained unchanged without ghrelin.

View larger version (19K): [in this window] [in a new window]   Figure 4. Exercise capacity and ventilatory efficiency before and after ghrelin therapy. Data are mean±SEM. Solid line indicates cachectic patients; dotted line, noncachectic patients. *P<0.05 vs before; P<0.05 vs respective control group.

Effects of Ghrelin on Sympathetic Nerve Activity
Three-week administration of ghrelin significantly decreased plasma norepinephrine and epinephrine (Figure 5). Treatment with ghrelin significantly decreased plasma BNP level (Table 3). Ghrelin did not significantly alter circulating glucose, insulin, cortisol, TNF-, or IL-6. Neither plasma renin activity nor plasma aldosterone level was changed significantly. All of these parameters remained unchanged in patients who did not receive ghrelin.

View larger version (21K): [in this window] [in a new window]   Figure 5. Plasma levels of norepinephrine and epinephrine before and after ghrelin therapy. Data are mean±SEM. Solid line indicates cachectic patients; dotted line, noncachectic patients. *P<0.05 vs before; P<0.05 vs respective control group.

View this table: [in this window] [in a new window]   TABLE 3. Hormone Analysis in Patients With CHF

	Discussion

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Ghrelin is a novel GH-releasing peptide that acts through a mechanism independent of that of hypothalamic GH-releasing hormone.⁹ The GH-releasing effect of ghrelin has been shown to be more potent than that of GH-releasing hormone.²⁰ In fact, in the present study, ghrelin infusion elicited potent GH release in patients with CHF. Three-week administration of ghrelin increased LV ejection fraction in association with an increase in LV mass, which is consistent with findings from a previous experimental study in rats.¹⁶ Plasma BNP level, a marker for LV function and wall stress, was decreased by ghrelin therapy. GH and its mediator, IGF-1, have been shown to enhance physiological compensatory hypertrophy in rats with CHF, resulting in a decrease in LV wall stress, leading to improvement in cardiac function.²¹ Thus, ghrelin may also improve cardiac function partly through GH-dependent mechanisms. On the other hand, Baldanzi et al²² have shown that ghrelin inhibits apoptosis of cardiomyocytes and endothelial cells through activation of extracellular signal-regulated kinase-1/2 and Akt serine kinases. Furthermore, stimulation of GHS-R by hexarelin has been shown to prevent cardiac damage after ischemia-reperfusion in hypophysectomized rats.²³ When these results are considered together, improvement in cardiac function by ghrelin therapy may be related to direct effects of ghrelin on myocardium. Importantly, ghrelin significantly decreased plasma norepinephrine levels in the present study. It is possible that improvement in cardiac function may lead to attenuation of sympathetic nerve activity. Interestingly, a recent study has demonstrated that ghrelin acts directly on the central nerve system to decrease sympathetic nerve activity.²⁴ Thus, inhibitory effects of ghrelin on sympathetic nerve activity may contribute to a decrease in plasma norepinephrine, which may have beneficial effects on cardiac performance in patients with CHF.

In the present study, 3-week administration of ghrelin improved exercise capacity in patients with CHF, as indicated by an increase in peak workload and peak O. A decrease in peak O in patients with CHF is attributable not only to an inadequate increase in cardiac output during exercise, which is a central effect, but also to muscle wasting, a peripheral effect. Recently, we have shown that infusion of ghrelin increases cardiac output in patients with CHF.¹² In the present study, ghrelin increased lean body mass and muscle strength. These results suggest that ghrelin may improve exercise capacity through both central and peripheral effects.

Cardiac cachexia, a catabolic state characterized by weight loss and muscle wasting, occurs frequently in patients with end-stage CHF²⁵ and is a strong independent risk factor for mortality in such patients.²⁶ Recently, we have shown that plasma ghrelin level is increased in cachectic patients with CHF as a compensatory mechanism in response to anabolic-catabolic imbalance.¹⁷ In the present study, 3-week administration of ghrelin tended to increase body weight and significantly increased lean body mass and muscle strength. These results suggest that treatment with ghrelin improves muscle wasting in patients with CHF. These effects may be mediated, at least in part, by GH/IGF-1, which is considered essential for skeletal muscle. Earlier studies have shown that ghrelin induces orexigenic effects via activation of neuropeptide Y neurons in the hypothalamic arcuate nucleus.^13,14 In the present study, intravenous administration of ghrelin increased food intake in patients with CHF, which may contribute to anabolic effects of ghrelin. Tschop et al¹⁵ have shown that administration of ghrelin induces adiposity through a GH-independent mechanism. In the present study, however, ghrelin did not significantly increase fat mass. This difference may be explained by the high dose of ghrelin (>2000-fold) used by Tschop et al. Ghrelin itself decreases fat utilization and increases fat, whereas GH decreases fat tissue and increases lean tissue. Thus, in the present study, ghrelin-induced GH may have attenuated an increase in fat and enhanced an increase in lean tissue.

The major limitation of this pilot trial relates to the lack of a randomized, placebo-controlled group. Patients in the control group were not treated identically because a placebo infusion was not performed. Nonetheless, this study was performed while patients were in a stable clinical condition during hospitalization. In addition, 8 patients in the control group were studied to exclude time-course effects during hospitalization. On the basis of the results of this study, a double-blind, randomized, and placebo-controlled study should be conducted. Second, this clinical study did not clarify mechanisms of increased LV ejection fraction by ghrelin therapy. Further studies are necessary to examine which mechanism predominantly contributes to improvement in LV ejection fraction.

Except for a few minor complications, long-term treatment with ghrelin was tolerated well in patients with CHF. Although a preliminary study documented the beneficial effects of GH,⁵ controlled studies in humans have been predominantly negative.^7,8 Nevertheless, ghrelin has been shown to have GH-independent effects, stimulating vasodilation,^10–12 reversing cachexia,^13–15 and inhibiting sympathetic nerve activity²⁴ and myocyte apoptosis.²² Thus, ghrelin may have additional therapeutic potential compared with GH supplementation. Ghrelin improved cardiac function and exercise capacity in not only cachectic CHF patients but also noncachectic ones. Nevertheless, the best candidates may be cachectic CHF patients because ghrelin stimulates feeding and improves muscle wasting.

	Conclusions

Top Abstract Introduction Methods Results Discussion Conclusions References

 
These preliminary results suggest that repeated administration of ghrelin improves LV structure and function, exercise capacity, and muscle wasting in patients with CHF. Thus, administration of ghrelin may be a new therapeutic approach for the treatment of CHF.

	Acknowledgments

 
This work was supported by Research Grant for Cardiovascular Disease 16C-6 from the Ministry of Health, Labor and Welfare; Industrial Technology Research Grant Program in 2003 from the New Energy and Industrial Technology Development Organization of Japan; Health and Labor Sciences Research Grants–Genome 005, Mochida Memorial Foundation for Medical and Pharmaceutical Research; and the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research of Japan.

	References

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