Inducible Nitric Oxide Synthase and Tumor Necrosis Factor-Alph in Myocardium in Human Dilated Cardiomyopathy

Objectives. We examined the mRN expression and protein localization of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alph (TNF-alpha) in myocardial tissue obtained from patients with dilated cardiomyopathy (DCM). Background. The etiology of DCM is unknown, but viral infection or autoimmune abnormalities that induce cytokine expression have been proposed as pathogenetic factors. Nitric oxide (NO), synthesized by nitric oxide synthase (NOS), has negative inotropic and cytotoxic effects on cardiomyocytes. Cytokines such as TNF-alph are potent stimulators of iNOS expression. Expression of iNOS leads to excessive production of NO in the myocardium and may modulate cardiac contractility and ventricular morphology. Methods. We examined the mRN expression and protein localization of iNOS and TNF-alph in myocardial tissue obtained from 24 patients with DCM, 20 patients with hypertrophic cardiomyopathy (HCM) and 15 control subjects, using the reverse transcriptase-polymerase chain reaction method and immunohistochemical studies. We then compared the differences in clinical characteristics between DCM patient subgroups with and without myocardial iNOS expression. Results. Messenger RN expression of iNOS and TNF-alph was observed, respectively, in 13 (54%) and 18 (75%) patients with DCM. Gene expression of TNF-alph was consistently detected in endomyocardial tissue from patients with DCM and INOS expression. Inducible NOS protein was evident only in cardiomyocytes, whereas TNF-alph was apparent in both cardiomyocytes and endomyocardial endothelium. Neither mRN expression nor protein localization of iNOS or TNF-alph was observed in cardiac tissue obtained from patients with HCM or control subjects. Patients with DCM and iNOS mRN showed lower left ventricular ejection fraction (p < 0.01) and higher left ventricular volume (p < 0.05) than the negative DCM group. Conclusions. Inducible NOS was consistently coexpressed with TNF-alph in myocardial tissue obtained from subgroup of patients with DCM and advanced left ventricular dysfunction.