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

Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Circulation (Impact Factor: 14.43). 12/2004; 110(24):3674-9. DOI: 10.1161/01.CIR.0000149746.62908.BB
Source: PubMed


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).
Human synthetic ghrelin (2 microg/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.
These preliminary results suggest that repeated administration of ghrelin improves LV function, exercise capacity, and muscle wasting in patients with CHF.

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    • "Apart from the ability to stimulate growth hormone secretion and to exert regulatory effects on appetite and metabolism, there is an increasing evidence that ghrelin has cardiovascular effects [6]. Previous studies have demonstrated that ghrelin inhibited cardiomyocyte apoptosis [7], improved left ventricular function and attenuates the development of cardiac cachexia in rats and humans with chronic heart failure (CHF) [8] [9]. We also reported that ghrelin modulated sympathetic innervation and improved cardiac function after myocardial infarction through anti-inflammation and antiapoptosis [10] [11]. "
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    ABSTRACT: Ghrelin is a novel growth hormone-releasing peptide, which has been shown to exert beneficial effects on cardiac function and ventricular remodeling. The present study aimed to investigate the expression of ghrelin and the growth hormone (GH) secretagogue receptor 1a (GHSR-1a), and the association with cardiac remodeling in rats with myocardial infarction (MI). Twenty-four hours after ligation of the anterior descending artery (LAD), adult male Sprague-Dawley rats were randomized to 3 d, 7 d and 28 d group. Sham animals underwent thoracotomy and pericardiotomy, but not LAD ligation. Expression of both ghrelin and GHSR-1a was assessed by means of immunohistochemistry and real-time PCR. Plasma ghrelin levels were measured by ELISA kit. In addition, cardiac remodeling was assessed by Echocardiographic and haemodynamic measurements. Plasma and cardiac expression of ghrelin decreased on days 3, 7 and 28 compared with the sham group (P < 0.05). In contrast the GHSR-1a mRNA levels increased during the same days (P < 0.05). Decreased positive immunoreaction for ghrelin and increased positive GHSR-1a was also observed in infarcted heart. Interestingly, plasma ghrelin correlated negatively with left ventricular end-diastolic pressure(r = -0.59, P = 0.002) and left ventricular end-diastloic dimension (r = -0.73, P < 0.01). The ghrelin system may play an important role regulating cardiac remodeling after MI and present as a potential significant target for pharmacological modulation and treating cardiac remodeling.
    Preview · Article · Jun 2014 · Regulatory Peptides
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    • "Ghrelin expression by T cells is also reduced in ageing mice and ghrelin infusion in this model has been shown to reduce levels of IL-6, TNF-a and IL-1b (Dixit et al., 2009). Ghrelin infusion to improve lean body mass and appetite and decrease circulating inflammatory cytokines has had positive outcomes in patient populations with inflammation–related cachexia including cachetic cancer, cardiovascular disease, chronic obstructive pulmonary disease and chronic kidney disease (DeBoer, 2011; DeBoer et al., 2008; Nagaya et al., 2004, 2005; Strasser et al., 2008). Our finding of increased GHS-R1a availability after exercise and a higher circulating proportion and concentration of GHS-R1a+ lymphocytes in active compared with sedentary individuals suggests that exercise prescription should be explored further as a tool to enhance the effectiveness of ghrelin therapy. "
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    ABSTRACT: The orexigenic peptide hormone ghrelin exerts potent inhibitory effects on pro-inflammatory cytokine release via the growth hormone secretagogue receptor-1a (GHS-R1a) on T cells and monocytes. As such, ghrelin is a promising therapeutic agent for the treatment of inflammatory conditions, but these effects depend on the availability of GHS-R1a. The aim of this study was to determine the effect of acute exercise on GHS-R1a expression on circulating CD14+ monocytes, total lymphocytes and CD3+ T cells. Nine male club-standard cyclists cycled for 1 h at 75% V̇ O2peak (EX) or rested (REST) in a randomised cross-over design. Compared with the equivalent times in REST, the concentration of circulating GHS-R1a+ lymphocytes and monocytes was higher in EX at immediately and 1 and 2 h post-exercise (all p < .05). The concentration of CD3+GHS-R1a+ cells was higher in EX than in REST immediately post-exercise only (258 (203) cells.μl(-1) vs. 62 (42) cells.μl(-1), p < .05). Density of GHS-R1a receptor expression was unaffected by trial or time. Comparison of active participants at rest with 7 age-, sex- and BMI-matched sedentary controls revealed a higher concentration of GHS-R1a+ lymphocytes in active males (p < .05). These findings suggest a preferential recruitment of specific cell subpopulations expressing GHS-R1a into the peripheral circulation with acute and regular exercise. Given that the anti-inflammatory effects of ghrelin depend on the availability of GHS-R1a, the preferential recruitment of subpopulations with high anti-inflammatory potential found here add a novel aspect to the potential mechanisms by which exercise acts to reduce pro-inflammatory cytokine levels.
    Preview · Article · Oct 2013 · Brain Behavior and Immunity
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    • "Treatment of catabolic states and cachexia with ghrelin has demonstrated promising results [15–18]. Human clinical trials conducted with native ghrelin in patients with cardiac cachexia demonstrate increases in appetite, weight, and cardiac output without apparent toxicity [15]. In a previous study, it could be shown that ghrelin and the related analogues BIM-28125 and BIM-28131 (now known as RM-131) induced weight gain in an animal model of CHF. "
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    ABSTRACT: Background In chronic heart failure (CHF), cachexia is a hallmark of the terminal stage of this disease and is associated with a severely reduced quality of life and poor prognosis. Therapeutic options are currently not available. Ghrelin and its analogues BIM-28125 and BIM-28131 (now known as RM-131) have been shown to increase weight in a rat model of CHF. It has been further demonstrated that the expression of myostatin, a negative regulator of skeletal muscle mass, is increased in CHF. The aim of the study was to investigate the influence of ghrelin or its analogues on myostatin in CHF. Methods In an animal model of CHF, Sprague–Dawley rats received either ghrelin or two ghrelin analogues BIM-28125 and BIM-28131 in two different concentrations (50 and 500 nmol/kg/day) compared to placebo. The compounds were delivered using osmotic mini pumps. The expression of myostatin was analyzed in skeletal muscle by RT-PCR and Western blot, and muscle mass of gastrocnemius muscle was measured. The plasma levels of tumor necrosis factor alpha (TNF-α) were measured. Results The relative weight of the gastrocnemius muscle of the sham-operated group was significantly increased compared to placebo-treated CHF rats. The application of ghrelin analogue BIM-28125 and BIM-28131 in their higher concentrations led to a significant reduction in myostatin mRNA expression in comparison to placebo. Myostatin protein expression was significantly reduced in both concentrations of ghrelin and BIM-28131 and in the lower concentration of BIM-28125. The increase of TNF-α plasma concentration in the CHF-animals could be abolished by all used substances. Conclusions In an animal model of CHF, the expression of myostatin is significantly reduced in the skeletal muscle after application of ghrelin and most concentrations of its analogues BIM-28125 and BIM-28131 possibly due to anti-inflammatory effects.
    Full-text · Article · Sep 2012
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