Ghrelin improves left ventricular dysfunction and cardiac cachexia in heart failure
Introduction
Heart failure is a major public health problem. Currently, there are five million Americans with congestive heart failure, with nearly 500 000 new cases every year [1]. In the past 10 years, several large-scale, randomized clinical trials have shown that angiotensin-converting enzyme inhibitors and β-blockers reduce the risk of death in patients with chronic heart failure (CHF) 2., 3., 4., 5., 6., 7., 8., 9.. Nevertheless, heart failure contributes to more than 250 000 deaths every year.
In patients with end-stage CHF, left ventricular (LV) dysfunction and cardiac cachexia are observed 10., 11.. Cardiac cachexia, which is a catabolic state characterized by weight loss and muscle wasting, is associated with hormonal changes and cytokine activation 10., 11., 12., 13., 14.. Importantly, the presence of cardiac cachexia is a strong independent risk factor for mortality in patients with CHF [15] and, therefore, is a therapeutic target for the treatment of CHF, together with LV dysfunction.
Growth-hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), are anabolic hormones that are essential for skeletal and myocardial growth and metabolic homeostasis 16., 17.. Elevated serum GH levels with normal or low IGF-1 levels were observed in cachectic patients with CHF 18., 19., suggesting that the GH/IGF-1 axis may be related to LV dysfunction and the resultant cachexia.
Ghrelin is a novel GH-releasing peptide and is the endogenous ligand for the growth-hormone secretagogue receptor (GHS-R) [20]. Ghrelin stimulates GH secretion through a mechanism independent from that of hypothalamic GH-releasing hormone (GHRH). Considering the haemodynamic and anabolic effects of GH/IGF-1, ghrelin might have beneficial effects on LV function and energy metabolism in CHF through GH-dependent mechanisms. Conversely, ghrelin might have direct cardiovascular and metabolic effects through GH-independent mechanisms. GHS-R mRNA is detected not only in the hypothalamus and pituitary but also in the heart and blood vessels [21], and stimulation of GHS-R has been shown to prevent cardiac damage after ischemia-reperfusion in hypophysectomized rats [22]. In addition, intravenous injection of ghrelin decreases arterial pressure and increases cardiac output in healthy humans [21], and can cause a positive energy balance by stimulating food intake [23•] and inducing adiposity [24]. These findings raise the possibility that administration of ghrelin may be beneficial in cachectic patients with CHF (Figure 1). This article summarizes data from preclinical and clinical trials for the treatment of CHF.
Section snippets
Discovery of ghrelin
In addition to physiological stimulation by GHRH, the release of GH from the pituitary is stimulated by small synthetic molecules called growth-hormone secretagogues 25., 26., 27.. They act through GHS-R, a G-protein-coupled receptor [28] for which the ligand was unknown until the discovery of ghrelin. Using GHS-R-expressed cells to monitor intracellular Ca2+ concentrations, Kojima et al. [20] found that GHS-R was activated by stomach extracts. Thus, an endogenous ligand specific for GHS-R,
GH-releasing activity of ghrelin
Ghrelin stimulates GH release both in vitro and in vivo. Ghrelin was shown to increase GH release from cultured pituitary cells in a dose-dependent manner 20., 33.. Intravenous injection of ghrelin markedly increased circulating GH in rats and humans, with greater potency than GHRH [33]. The peak level of GH occurred 15–20 min after a bolus injection of ghrelin, with the elevation in GH levels lasting longer than 60 min [21]. These results suggest that ghrelin causes potent, long-lasting GH
Stimulation of feeding by ghrelin
Ghrelin is the first appetite-stimulatory peptide derived from the stomach. Ghrelin peptide and mRNA levels in the blood and stomach, respectively, are increased by fasting and decreased by feeding [35]. In addition, hyperglycaemia suppresses circulating ghrelin levels [36]. These results confirm that ghrelin serves as an appetite-stimulatory peptide. Indeed, peripheral and intracerebroventricular administration of ghrelin stimulated food intake and increased body weight in both normal and
Increased plasma ghrelin levels in cardiac cachexia
Ghrelin is secreted from the stomach and circulates in the bloodstream [31]. To examine the pathophysiological significance of ghrelin in CHF, we examined circulating ghrelin levels in 74 patients with CHF (LV ejection fraction=28±1%) [40]. Plasma ghrelin levels did not significantly differ between CHF patients and control subjects, and also did not significantly correlate with LV ejection fraction. When cardiac cachexia was defined as non-edematous and a non-intentional weight loss of more
Acute cardiovascular effects of ghrelin in heart failure
GHS-R mRNA is detectable in blood vessels as well as in cardiac ventricles in rats and humans 21., 41.. To clarify whether ghrelin has direct vasodilatory effects in humans, we examined the response of forearm blood flow to intra-arterial infusion of ghrelin in eight healthy volunteers using a plethysmograph. Ghrelin increased forearm blood flow in a dose-dependent manner [42]. A single injection of ghrelin significantly decreased mean arterial pressure in both sham-operated and CHF rats [43].
Chronic cardiovascular effects of ghrelin in heart failure
LV dysfunction, remodeling and cardiac cachexia (body weight loss and muscle wasting) are often observed in patients with end-stage CHF 10., 46.. GH and IGF-1 are essential for skeletal and myocardial growth and metabolic homeostasis 16., 17.. Earlier studies have shown that GH supplementation could have beneficial effects on myocardial structure and function in some patients with CHF 47., 48., 49.. As a result, we investigated whether chronic treatment with ghrelin improved LV remodeling and
Therapeutic potential in cardiac cachexia
Increasingly, cardiac cachexia is being seen as a therapeutic target for the treatment of heart failure. CHF rats (with cardiac cachexia) given placebo showed an impaired increase in body weight and a significant decrease in the muscle/bone ratio whereas, when treated with ghrelin, these rats revealed an appropriate increase in body weight and a preserved muscle/bone ratio similar to those observed in sham-operated rats [50••]. The gastrocnemius muscle weight/body weight and the protein
Conclusions
Plasma ghrelin levels are elevated in cachectic patients with CHF possibly through a compensatory mechanism to catabolic/anabolic imbalance. Exogenously administered ghrelin has been shown to improve LV dysfunction and attenuate the development of cardiac cachexia in rats with CHF. Thus, supplementation of ghrelin could be a new therapeutic approach in the treatment of CHF.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
This work was supported by KANAE FOUNDATION FOR LIFE & SOCIO-MEDICAL SCIENCE, the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (OPSR) of Japan, and HLSRG H14 genome-005.
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