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Title: The nature of cachexia in patients with heart failure and stable coronary artery disease
Author: McEntegart, Margaret B.
ISNI:       0000 0004 2671 2129
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2007
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Cachexia is a prognostically important development in patients with heart failure. The most commonly used definition of cardiac cachexia is loss of a percentage of body weight over time. Muscle wasting has been assumed to be the major contributor to this weight loss, and cytokine activation is postulated to be central to the pathogenesis. We hypothesised that elevated circulating cytokines in cachectic heart failure patients would be associated with muscle inflammation, injury and impaired ability to repair. The aim of this doctoral work was to characterise the nature of cachexia in patients with heart failure (HF) and stable coronary artery disease (CAD), to quantify the loss of muscle mass, and test the hypothesis that muscle wasting is mediated by the activation of tissue cytokines and cell cycle inhibitors. We studied five subject groups. Three were groups of patients with stable coronary artery disease: 1) HF-cachexia - patients with HF, reduced left ventricular systolic function and cachexia, n=10; 2) HF-no cachexia - those with HF, reduced systolic function but no cachexia, n=20; and 3) CAD - those with CAD, no symptoms of HF and preserved systolic function, n=10. The other subject groups were: 4) IDCM - patients with idiopathic dilated cardiomyopathy, n=7; and 5) HC - healthy controls, n=9. Subjects were characterised by New York Heart Association (NYHA) classification, left ventricular ejection fraction (LVEF), peak oxygen consumption (VO2), weight history and body composition analysis. Circulating levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), leptin, adiponectin, and Btype natriuretic peptide (BNP) were measured. Skeletal muscle biopsies were analysed for the expression of messenger ribonucleic acid (mRNA) for TNF-α, IL-6, interleukin-1β (IL-1β), interleukin-18 (IL-18) and the cell cycle inhibitors (cyclin dependent kinase (CDK) inhibitors) p21, p27 and p57. We found that the HF-cachexia group had significantly lower body mass index (BMI) and percentage body fat than all the other subject groups. In contrast, there was no significant reduction in fat free mass index (FFMI). In addition, the HF-cachexia group had higher rates of fat oxidation than all other groups. While the HF-cachexia group had elevated circulating levels of TNF-α and IL-6, there was no increased expression of cytokines or CDK inhibitors in the skeletal muscle. Circulating adiponectin and BNP levels were elevated in the HF-cachexia group. There was a positive association between adiponectin and BNP, and a negative relationship of each with BMI and percentage body fat. In addition, adiponectin positively correlated with rate of fat oxidation and TNF-α concentration. A possible causal relationship between adiponectin and increased rate of fat oxidation was further investigated in an additional study of young healthy male subjects performing an exercise program specifically designed to maximise fat metabolism (n=11). Despite inducing significantly increased rates of fat oxidation and adiponectin concentrations no relationship was observed between them. In conclusion, cachexia in patients with heart failure and stable coronary artery disease predominantly involves the loss of adipose tissue, with no evidence of muscle wasting or inflammation. The presence of increased circulating levels of adiponectin and BNP, their association with each other, and the relationship of each with body composition, energy metabolism and TNF-α suggests these peptides may play an important role in the pathogenesis of cardiac cachexia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine ; QP Physiology