Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy

Background Two important features of dilated cardiomyopathy (DCM) are low myocardial contractility and risk of thromboembolism. Nitric oxide (NO) exerts a negative inotropic effect on the myocardium and is produced by NO-synthase, an inducible form of which (iNOS) is stimulated by tumour necrosis factor (TNF-α). Accordingly, we hypothesised that locally produced TNF-α might contribute to the pathogenesis and complications of DCM by inducing iNOS in the heart. Methods iNOS and TNF-α were quantified by histochemistry and computerised image analysis in explanted heart tissues or myocardial biopsy material from patients with DCM (n=21) or ischaemic heart disease (IHD; N=10) and from normal donor hearts (n=9). Findings Immunoreactivity for iNOS was strong in myocytes of DCM hearts, particularly in areas adjacent to the endocardium, and moderately intense in blood vessels of DCM and IHD hearts. The median optical density of the immunostaining for iNOS was greater in cardiac myocytes of patients with DCM (0·86, range 0·21 to 1·29) than in those from patients with IHD (0·20, range 0·095 to 0·26) (p<0·01) or controls (0·01, range 0·001 to 0·02) (p<0·001). Staining for TNF-α was observed in the vascular endothelium and smooth muscle cells of patients with DCM but not in IHD or control tissues. Interpretation The localisation of iNOS and TNF-α within cardiac tissues in DCM suggests that TNF-α contributes to both the low contractility and the tendency to thromboembolism in these patients.