The assessment of body composition for muscle mass, fat mass, bone mass and density as well as hydration status is an important measure in several clinical conditions. Assessing the complex pathophysiology of obesity and cachexia without information on body composition is not possible. Furthermore, it has been established that the sequelae of metabolic syndrome to diabetes mellitus is associated with important alterations in fat tissue mass and function. Combining the prospective patient-oriented assessments over time in WP03 and WP04 as well as WP06 and WP07 with body composition assessments in this WP will allow detailed analyses of the cause-effect interrelations that trigger deterioration processes in patients with CHF. When additionally the tissue based analyses at cellular and molecular level (WP07, WP08) are considered together with the absolute amount of fat or muscle tissue in which these alterations occur, for the first time a comprehensive and overall quantitative assessment of the contribution of the co-morbidities obesity, cachexia and diabetes on the CHF deterioration process will be possible.
Technology Background
The project will utilize two principal approaches to body composition analysis. First, body impedance assessment (BIA), and second dual energy x-ray absorptiometry (DEXA) scanning. BIA is easily applicable to large patient cohorts using inexpensive equipment and provides information on the whole body. Hence, it will be possible to use this technology in all recruited patients. DEXA scanning is more precise method that requires use of significantly more expensive machinery that can provide body composition results for the whole body as well as any region of interest. This method will only be applicable in patients recruited in centers where this technology is available (Berlin, Hull, Rome, Wroclaw, Bolnisnica Golnik).
BIA: The term bioimpedance refers to the response of a living organism to an externally applied electric current. It is a measure of the oppostion to the flow of that electric current through the tissues, the opposite of electrical conductivity. Since both extracellular and intracellular water contains ions, they are conducting, and the measurements of their volume is based on their resistance or their impedance as cell membranes may act as capacitors at low and intermediate frequencies (Jaffrin and Morel, 2008). Extracellular water resistance must be measured at very low frequency, <1 kHz and that of ICW and ECW combined at very high frequency (>5 MHz). Measurements of fat-free-mass and total body water permit to detect dehydration, which is frequent in elderly persons or athletes after heavy training (Jaffrin and Morel, 2008). It has been shown that an overhydratation may indicate the presence of oedema in patients with chronic heart failure (Thomas et al., 1998). It needs to be understood that BIA is an indirect method depending on the validity of the electrical model of the tissues used. Thomasset was the first to propose the use of two frequencies of 1 and 100 kHz to measure extracellular water and total body water, respectively (Thomasset, 1963). A more elaborate method, bioimpedance spectroscopy (BIS), was proposed in 1992 to measure both extracellular and intracellular water.
DEXA scanning: The basis of DEXA scanning is the fact that photon attenuation is a function of tissue composition. Therefore, rectilinear scanning of the supine body is performed. This divides the body into a series of pixels, within each of which the photon attenuation is measured at two different energies. The DEXA body composition approach assumes that the body consists of three components that are distinguishable by their X-ray attenuation properties: fat, bone mineral and fat-free or 'lean' soft tissue. As soft tissues consist largely of water and organic compounds, they reduce photon flux to a much lesser extent than bone mineral, and pixels containing bone are relatively easily distinguished from those with no bone present (Plank 2005). In areas where bone is not present suitable calibration allows fat and lean fractions to be resolved from soft tissue. The technique is attractive because it is non-invasive, is easily applied for both healthy individuals and patients, and the radiation dose is extremely small. Moreover, it provides the ability to analyze regional body composition. DEXA is increasingly being viewed as a laboratory reference method for the estimation of total body fat (Plank, 2005). DEXA is able to measure body fat, fat-free mass, and bone mineral density (Kiebzak et al., 2000, Lohman, 1996), which makes it a valuable tool for longitudinal studies in the clinical setting.
Body Composition Research in CHF
A limited number of cross-sectional body composition assessments have been published on CHF patients with obesity or cachexia compared to normal-weight patients. In non-cachectic patients, skeletal muscle wasting in legs occurs in 50% of patients (Mancini et al., 1992). This muscle wasting is associated with increased fat mass accumulation (Anker et al., 1999), and hence body weight remains stable. Whether this fat accumulation is causal for insulin resistance development that is known to occur in CHF patients (Doehner et al., 2005) has never been investigated. Once weight loss (i.e. cachexia) has developed, muscle wasting also affects arm muscles. In addition also lower fat tissue and bone tissue mass are found in cachectic CHF patients (Anker et al., 1999). The predictors and correlates of body composition changes have never been investigated in CHF. We have recently concluded a retrospective study including 498 CHF patients recruited in 3 centres (London/UK, Wroclaw/PL and Verona/IT) using DEXA scanning for detailed body composition analysis. We found that %fat mass was the strongest independent predictor amongst many body composition measures for survival in patients with CHF. The quartile with obesity (>30 %fat mass) had the best survival. These observations are similar to what we described for patients with chronic kidney disease treated with haemodyalysis (Kalantar-Zadeh et al., 2006). The relationship between changes in body composition and outcome has never been investigated. Adjustment of exercise test results for lean tissue mass rather than body weight makes more pathophysiologic sense (muscle but not fat tissue performs exercise) but also provides superior prognostic information (Cicoira et al., 2004). Again changes in body composition have never been investigated in the context of changes in exercise capacity.
Aims of WP
The aim of this work package is to investigate body composition and body composition alterations in patients with CHF in the context of assessments for the presence of type 2 diabetes, obesity, and cachexia. The planned analyses include assessments of the whole body and regions (limbs vs. trunk) and we aim to relate them to pathophysiological changes assessed in other WPs, as well as assessment of vascular and cellular status. Better understanding of the regulation of body composition may contribute to develop therapeutic strategies to delay or prevent weight loss and development of cachexia, may help to better understand the obesity paradox of CHF as well as the importance of diabetes as co-morbidity of CHF.
A second aim of this WP is to ensure (in close co-operation with other WP leaders and all involved centers) good test reproducibility for important pathophysiology tests in the consortium, including body composition analyses, exercise testing and metabolic testing.
WP5 aims to achieve the following objectives:
Workpackage Leader: Charité
Involved Partners: HULL, Wroclaw, Zabrze, IRCCS, Golnik
Body impedance measurement is available or will be made available in all participating centers of the consortium (objective 1). To improve the data quality, cross-center validity and comparability all centers will use the same machine (Bodystat Quadscan 4000; Bodystat Ltd, UK). At all study visits, all patients will be weighed using a scale with 50 g precision and then undergo BIA for assessment of whole body fat mass, lean mass and hydration status. All data will be documented in the electronic CRF for later analysis. The availability of DEXA is limited across European research units, but it is available in 5 centres of the consortium, namely in Berlin (Germany), Wroclaw (Poland), Rome (Italy), Bolnisnica Golnik (Slovenia) and Hull (UK). Only cardiology centers in Berlin and Rome own the DEXA device so that no subcontract charges will be incurred. Therefore, we plan to perform DEXA scanning at baseline and in follow-up visits in one third of recruited patients (objective 2). All body composition assessments will be performed at baseline and after a follow-up period of 4-6 months, 12-14 months, and 22-24 months. A detailed analysis will be performed of fat, bone mineral and fat-free or 'lean' soft tissue, particularly broken down into patients with the co-morbidities of interest: type 2 diabetes, obesity, and cachexia. Follow-up assessments will focus on the development of tissue wasting in the aforementioned body compartments in order to identify targets for therapeutic interventions and to relate observed changes to other pathophysiologic changes and clinical outcome measures (objectives 3 and 4).
Each centre will assess 12 patients with CHF at least twice (within 14 days or less) in order to assess and compare reproducibility of assessments with body impedance and DEXA. Also we will introduce a regular schedule of phantom assessments in the DEXA scanning centers (objective 5). In order to ensure test reproducibility and test standardization, this work package also aims to implement similar reproducibility tests for exercise testing and metabolic insulin sensitivity studies (objective 6).
Consortium
Rationale & Design Paper
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