Abstract 5902: Upregulation Of Stat-3, Socs-1, Pro-inflammatory And Antiinflammatory Circulating Cytokine mRNA Gene Expression In CHF Patients With And Without Cachexia Compared To Healthy Control Subjects
BACKGROUND: Chronic heart failure (CHF) is a state of chronic inflammation. The roles of pro-and anti-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL) 10 and transforming growth factor (TGF) beta are well established. Intracellular levels of the transcription factors like signal transducer and activator of transcription (STAT)-1, STAT-3, suppressor of cytokine signaling (SOCS)-1, and SOCS-3 that have been implicated in the wasting process of ageing have not been investigated in CHF. We sought to determine their mRNA levels in peripheral blood mononuclear cells.
METHODS: mRNA gene expression was assessed by real time polymerase chain reaction in 3 cohorts of subjects: cardiac cachexia (n=11, LVEF 28±4%, peak VO2 13.1±1.0 mL/kg/min, body fat 25±3%, >6% weight loss in the previous 6–24 months), non-cachectic (nc) CHF (n=19, LVEF 31±2%, peak VO2 14.7±1.1 mL/kg/min, body fat 32± 1%), and control subjects (n=17, LVEF 71±2%, peak VO2 25.1±1.7 mL/kg/min, body fat 33 ± 3%). Body composition was assessed by dual energy X-ray absorptiometry (DEXA).
RESULTS: TNF mRNA expression was higher in cardiac cachexia (0.39±0.10 relative units [RU] p=0.001) than in nc CHF (0.12±0.03 RU) and controls (0.11±0.02 RU, all p<0.004). This was also true for IL-10 mRNA (all p<0.01). TNF/IL-10 ratio was highest in cachectics (269±99 RU), and lower in both nc CHF patients (132±58 RU) and controls (101±37 RU, p=0.08 vs. cachectic patients). STAT-3 mRNA expression was higher in cachectic vs nc CHF patients (p<0.05). Cachectic patients showed higher SOCS-1 expression compared to nc patients and controls (ANOVA p=0.04). While SOCS-3 and TGF-b mRNA levels did not differ between groups (all p>0.2), there was a trend towards higher STAT-1 expression in cachectics compared to nc patients (p=0.07) or controls (p<0.08). Higher TNF-mRNA correlated with lower %fat mass and lower peak Vo2/lean mass as a measure of muscle quality in cachectic CHF patients (r=0.8, p=0.01).
CONCLUSION: Elevated intracellular levels of STAT-3 and SOCS-1 mRNA suggest an involvement of this system in inflammatory signaling cascades that may ultimately trigger body wasting. Proinflammatory cytokine upregulation in cardiac cachexia may be important for the pathophysiology of body wasting.