Cachexia Research Research Articles

Myostatin

Cachexia in chronic heart failure (HF) is a major clinical problem that is still underestimated for its impact on morbidity, mortality, and healthcare expenditures. The pathophysiology of cardiac cachexia is characterized by a catabolic/anabolic imbalance. An important player in the development of muscle wasting and cachexia in HF may be myostatin. Article see p 419 Myostatin, also known as growth differentiation factor-8 (GDF-8), is a member of the transforming growth factor-β superfamily and was identified in 1997.1 In humans, myostatin is expressed almost exclusively in skeletal muscle and is essential for normal regulation of muscle mass through its actions as a negative regulator of muscle bulk.2 Gene disruption, either natural or by targeted mutation, leads to a marked increase in muscle mass due to hypertrophy and hyperplasia.1 This was clearly evident in a child with a mutation in the myostatin gene who had the ability to hold two 3-kg dumbbells at the age of 4 years.3 Myostatin has been shown to be upregulated in human immunodeficiency virus– and cancer-associated cachexia,4 with advanced age,5 and in chronic HF.6 In each of these conditions, a loss of skeletal muscle mass occurs that leads to a disproportionate loss of exercise tolerance and an early increase in muscle fatigue. Human cardiovascular studies concerning myostatin are generally lacking. Before the report by Heineke et al7 in this issue of Circulation , 2 animal studies reported increased myostatin expression in the peri-infarct zone in sheep8 and in a rat model of volume overload induced by an aortocaval shunt.9 Importantly, the expression remained increased after 4 weeks in the shunt model. In 2008, Hoenig10 presented a hypothesis that myostatin acts as a mediator of cardiac cachexia, insulin resistance, and osteoporosis in chronic HF. To date, it …

The obesity paradox: weighing the benefit

Obesity has become a medical and socioeconomic burden of epidemic proportions and the World Health Organization (WHO) has marked obesity as one of the most blatantly visible but most neglected public health problems. Indeed, being overweight is an established risk factor for the development of many different diseases including cardiovascular, metabolic, and orthopaedic illnesses. In contrast, obesity has not been associated with a worse outcome in all patient populations. In fact, substantial data have accumulated suggesting a survival benefit in patients with existing chronic cardiovascular diseases for patients who are overweight and moderately obese. In chronic heart failure (CHF), convincing evidence has accumulated from studies including >30 000 patients over a broad spectrum of disease severity, that being overweight is associated with decreased mortality.1–4 Similarly, in patients with acutely decompensated heart failure, higher body mass index (BMI) is associated with lower in-hospital mortality.5 Despite the known role of obesity as a major risk factor for cardiovascular events,6–8 the mortality risk after an acute myocardial infarction is no higher in overweight and obese patients compared with lighter patients.9 In a systematic review of 40 studies including a total of >250 000 patients with coronary artery disease, a better outcome for cardiovascular and total mortality was seen in the overweight and mildly obese groups … *Corresponding author. Applied Cachexia Research, Department of Cardiology, Charite Medical School, Campus Virchow-Medical Center, Augustenburger Platz 1, D-13353 Berlin, Germany. Tel: +49 30 450 553 507, Fax: +49 450 553 951, Email: wolfram.doehner{at}charite.de

Systematic review of research trends in cancer cachexia: Insights from the literature and funding agencies

e17540 Background: Cancer cachexia affects about 250,000 patients in the US worsening treatment outcome and quality of life. To evaluate the scholar contribution to cancer cachexia, we analyzed the cachexia literature and funding support. Methods: In May 2008, we conducted a search of the major databases Medline, Web of Sciences, and Scopus of all publications with MeSH heading “cachexia” or keywords “cachexia, cachectic, cachexic” since 1982, distinguishing “original research” from “review” articles. To examine the trend over time, we compared the publication rate in the field of cachexia to that of published manuscripts in reference fields (cancer, AIDS, Alzheimer's disease, and CHF). To study the federal funding for cachexia research, we examined the Computer Retrieval of Information on Scientific Projects database. Only descriptive statistical analysis was adopted because of the heterogeneity of methods. Results: We identified 1990 published manuscripts, 677 (34%) of which are “reviews”. Out of the 2,890 country of origin affiliations, the US is the lead contributor (N = 1,105; 38%). In the last 5 years, the ratio of “review” articles in cachexia increased significantly (49%), compared to cancer (17%), and science publications (8%). Unlike the of publications in reference fields, the increase in cachexia has been mostly due to the dominance of “review” articles (ratio of original/review of 0.928 in cachexia, versus 0.417 in CHF, 0.337 in Alzheimer and 0.206 in AIDS). Nevertheless, published cachexia articles in journals with high impact factors (IF ≥ 4.0) remains similar (8.49%) to that of science research (8.63%) with a predominance of “review’ articles. Only one in four published manuscripts (24%) acknowledged federal support. Cachexia research support by US federal agencies declined significantly in the last decade (with a peak of 161 awards in 1999 down to 40 in 2006), the NCI remains the leading funding agency (17%). Only 275 out of the total of 121,997 NCI- awards over 25 years (0.22%) were awarded to cachexia research, with a clear decline in the latest decade by 50% (0.14% vs. 0.29%). Conclusions: Advances in the field of original cancer cachexia research have been very limited, perhaps related to the lack of federal research funding support, which is on the decline. No significant financial relationships to disclose.

Cancer cachexia

Cancer cachexia is a severe debilitating disorder for which there are currently few therapeutic options. It is driven by the release of pro-inflammatory cytokines and cachectic factors by both host and tumour. Over the past few years, basic science advances have begun to reveal the breadth and complexity of the immunological mechanisms involved, and in the process have uncovered some novel potential therapeutic targets. The effectiveness of thalidomide and eicosapentaenoic acid at attenuating weight loss in clinical trials also provides a further rationale for modulating the immune response. We are now entering an exciting period in cachexia research, and it is likely that the next few years will see effective new biological therapies reach clinical practice.

Report of a Joint Cancer Research UK/Medical Research Council workshop on cancer cachexia research at the Royal College of Physicians, Tuesday, 2 December 2003

A joint workshop held by Cancer Research UK and the Medical Research Council aimed to stimulate interest in further research into the area of cancer cachexia. The workshop was divided into four sessions: an overview of cancer cachexia, potential mechanisms involved and methodologies that might be used to understand cachexia, and also the experience of cachexia from other disease areas. The workshop identified a need to develop a multimodal therapeutic approach to cancer cachexia and a need to undertake more multidisciplinary research.