Muscle wasting in cardiac cachexia.

Cardiac cachexia is a serious complication of chronic heart failure which is characterized by complex changes that overall lead to a catabolic/anabolic imbalance resulting in body wasting and a poor prognosis. The wasting process affects all body components, but particularly the skeletal musculature, causing extreme fatigue and weakness, especially in cachectic heart failure patients. Available evidence suggests that several pathophysiologic pathways play a role in the muscle wasting process. Metabolic, neurohormonal, and immune abnormalities lead to an altered regulation of proliferation, differentiation, apoptosis, and metabolism in skeletal muscle, finally resulting in deterioration of the underlying cause with symptomatic exercise intolerance. Possible treatment strategies against muscle wasting and cachexia in chronic heart failure are also described here. As there is no validated therapy for cardiac cachexia yet, further research is necessary to find more therapeutic options for the wasting process.

Furosemide induces mortality in a rat model of chronic heart failure.

OBJECTIVES: In an experimental heart failure model, we tested the hypothesis that furosemide causes excess mortality. BACKGROUND: Post-hoc analysis of large clinical heart failure trails revealed that furosemide treatment might be associated with worsening of morbidity and even mortality in heart failure patients. METHODS AND RESULTS: Myocardial infarction was induced in 7 ± 1 week old male Wistar rats by ligation of the left coronary artery. In study 1, animals were randomly assigned to treatment with furosemide (10mg/kg/d via drinking water, n=33) or placebo (n=33) starting 18 days after surgery. In study 2, animals received furosemide from day 18 and were then randomized to ongoing treatment with either furosemide only (n=38) or furosemide plus ACE-inhibitor Ramipril (1mg/kg/d, n=38) starting on day 42. In study 1 survival rate in the furosemide group was lower than in the placebo group (hazard ratio {HR} 3.39, 95% confidence interval {CI} 1.14 to 10.09, p=0.028). The furosemide group had a lower body weight (-6%, p=0.028) at the end of the study and a higher sclerosis index of the glomeruli (+9%, p=0.026) than the placebo group. Wet lung weight, infarct size, and cardiac function were similar between the groups. In study 2, the furosemide group had a higher mortality rate than the furosemide+ramipril group (HR 4.55, 95% CI 2.0 to 10.0, p=0.0003). CONCLUSION: In our rat model of heart failure furosemide, provided at a standard dose, was associated with increased mortality. This increased mortality could be prevented by additional administration of an ACE-inhibitor.

Ghrelin, peptide YY and their hypothalamic targets differentially regulate spontaneous physical activity.

Recent studies suggest that spontaneous physical activity (SPA) may be under the non-conscious control of neuroendocrine circuits that are known to control food intake. To further elucidate endocrine gut-brain communication as a component of such circuitry, we here analyzed long-term and acute effects of the gastrointestinal hormones ghrelin and PYY 3-36 as well as their hypothalamic neuropeptide targets NPY, AgRP and POMC (alpha-MSH), on locomotor activity and home cage behaviors in rats. For the analysis of SPA, we used an automated infrared beam break activity measuring system, combined with a novel automated video-based behavior analysis system (HomeCageScan (HCS)). Chronic (one-month) peripheral infusion of ghrelin potently increased body weight and fat mass in rats. Such positive energy balance was intriguingly not due to an overall increased caloric ingestion, but was predominantly associated with a decrease in SPA. Chronic intracerebroventricular infusion (7 days) of ghrelin corroborated the decrease in SPA and suggested a centrally mediated mechanism. Central administration of AgRP and NPY increased food intake as expected. AgRP administration led to a delayed decrease in SPA, while NPY acutely (but transiently) increased SPA. Behavioral dissection using HCS corroborated the observed acute and transient increases of food intake and SPA by central NPY infusion. Acute central administration of alpha-MSH rapidly decreased food intake but did not change SPA. Central administration of the NPY receptor agonist PYY 3-36 transiently increased SPA. Our data suggest that the control of spontaneous physical activity by gut hormones or their neuropeptide targets may represent an important mechanistic component of energy balance regulation.

Action profile of the antiobesity drug candidate oleoyl-estrone in rats.

Oleoyl-estrone (OE) has been presented as a potential antiobesity therapeutic, but the published series of studies from one laboratory has not yet been independently confirmed, and the exact mechanism of action is unknown. Based on the hypothesis that OE has potential for the treatment of obesity, male and female rats were chronically treated with several doses of OE to evaluate the impact of this compound on energy metabolism. Body weight, body composition, energy balance parameters and the expression of hypothalamic neuropeptides regulating food intake as well as key markers of the reproductive system were examined. OE impressively reduced food consumption and body weight gain in both sexes. Although a major part of the loss in body weight could be explained by decreased fat mass, a substantial loss of lean mass also occurred after OE administration. The loss of weight can be sufficiently explained by the suppression of food consumption, as there were no major changes in energy expenditure, locomotor activity or respiratory quotient. In situ hybridization data showed no significant change in the expression of key neuropeptides and hormone receptors regulating feeding behavior after OE treatment. Cocaine-amphetamine-regulated transcript (CART) mRNA levels were decreased in the arcuate nucleus of OE-treated rats. Hypogonadism and low plasma testosterone levels were found in OE-treated males, whereas females showed substantially increased liver size. The present data suggest that OE decreases food intake and body weight but also appears to cause a significant impact on the hypothalamus-pituitary-reproductive axis.

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats.

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol x kg(-1) x day(-1) using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

Metabolic and immunologic derangements in cardiac cachexia: where to from here?

The onset of cardiac cachexia is characterized by a defined severe weight loss in patients with advanced chronic heart failure and it predicts an increased mortality in these patients. Recent studies with potential therapeutics investigated the effects and efficiency of beta-blockers, ghrelin, or ghrelin-agonists in cachexia. These and other new studies, like the influence of heart transplantation on cardiac cachexia, give prospect into potential therapeutic options in the future. General aim of the treatment strategy is to prevent the onset and retard the progress of cachexia. This could be achieved by modifying the metabolic, neurohormonal and immune system abnormalities, e.g. with beta-blockers and angiotensin-converting enzyme inhibitors. However, these alterations interact in a complex pathophysiological process, which is supposed to end in a vicious circle and thereby the wasting process is further promoted. To interrupt this, an early start of therapy is important to decelerate the development of cardiac cachexia. Many further investigations are needed to find out more about the pathophysiological pathways, to confirm the previous results, and to evaluate new therapeutics.

Cardiac cachexia.

Chronic heart failure (CHF) remains an important and increasing public health care problem. It is a complex syndrome affecting many body systems. Body wasting (i.e., cardiac cachexia) has long been recognised as a serious complication of CHF. Cardiac cachexia is associated with poor prognosis, independently of functional disease severity, age, and measures of exercise capacity and cardiac function. Patients with cardiac cachexia suffer from a general loss of fat tissue, lean tissue, and bone tissue. Cachectic CHF patients are weaker and fatigue earlier, which is due to both reduced skeletal muscle mass and impaired muscle quality. The pathophysiologic alterations leading to cardiac cachexia remain unclear, but there is increasing evidence that metabolic, neurohormonal and immune abnormalities may play an important role. Cachectic CHF patients show raised plasma levels of epinephrine, norepinephrine, and cortisol, and they show high plasma renin activity and increased plasma aldosterone level. Several studies have also shown that cardiac cachexia is linked to raised plasma levels of tumour necrosis factor alpha and other inflammatory cytokines. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. The available evidence suggests that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder with a poor prognosis. A complex imbalance of different body systems may cause the development of body wasting.