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Cardiomyocyte apoptosis is reported to be involved in the pathogenesis of human chronic Chagas cardiomyopathy (CCC). Members of the tumour necrosis factor (TNF) superfamily (TNF-α, FasLigand/CD95L, and TNF-related apoptosis-inducing ligand) are known to activate the death receptor pathway. We therefore investigated whether levels of TNF-α, FasLigand/CD95L, and TRAIL correlated with changes in heart function of patients with Chagas disease (n=31).Concentrations of TNF-α and TRAIL were clearly augmented in individuals with severe form CCC (n=16). Levels of FasLigand/CD95L were greater in chagasic patients than in non-infected individuals (n=15) but did not differentiate between clinical forms of Chagas disease. There was a good correlation between TNF-α (r=0.85 and r=0.68, P < 0.0001) or TRAIL (r=0.68 and r=0.60, P < 0.001) and left ventricular ejection fraction (LVEF) and left ventricular diastolic diameter (LVDD), respectively. In addition, TNF-α (r=0.57, P=0.0001), TRAIL (r=0.56, P=0.001), and FasLigand/CD95L (r=0.51, P=0.001) showed a good correlation with brain natriuretic peptide, a well-known parameter of ventricular dysfunction in CCC. There was a weak correlation between levels of FasLigand/CD95L (r=0.50, P < 0.004) and both LVEF and LVDD. There was no correlation between levels of TNF superfamily ligands and chronotropic incompetence, maximal heart rate, or number of ventricular premature beats in 24 h.Plasma levels of TNF superfamily ligands are elevated in patients with functional but not arrhythmogenic disturbances, and these death receptor ligands may be potential markers of ventricular dysfunction in CCC.