Tumor Necrosis Factor-α–Converting Enzyme and Tumor Necrosis Factor-α in Human Dilated Cardiomyopathy

Abstract

Background —Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). TNF-α–converting enzyme (TACE) has recently been purified and its complementary DNA cloned. The expression of TACE results in the production of a functional enzyme that has precursor TNF-α in the mature form. The aim of this study was to determine whether TACE is expressed with TNF-α in myocardium and whether levels of TACE and TNF-α are related to clinical severity of DCM. Methods and Results —Endomyocardial tissues were obtained from 30 patients with DCM and 5 control subjects. TNF-α and TACE mRNA levels were measured by a novel real-time quantitative reverse transcriptase–polymerase chain reaction method. Expression of TNF-α and TACE proteins was determined by immunohistochemical analysis. TNF-α mRNA was expressed in DCM patients (TNF-α/GAPDH ratio 0.85±0.24) but not in control subjects. TACE mRNA expression was significantly greater in DCM patients than in control subjects (TACE/GAPDH ratio 2.52±0.59 vs 0.03±0.02, P <0.05). A positive correlation was found between TNF-α and TACE mRNA levels ( r =0.779, P <0.001). TACE and TNF-α immunostaining was observed in myocytes in patients with DCM. When 2 subgroups of DCM were divided on the basis of left ventricular end-systolic diameter (LVESD) of 45 mm and left ventricular ejection fraction (LVEF) of 40%, the DCM subgroup with high LVESD (≥45 mm) showed significantly greater expression of TACE ( P =0.02) and TNF-α ( P =0.001) than did the low LVESD subgroup (<45 mm). In addition, the DCM subgroup with lower LVEF (<40%) showed higher expression of TACE ( P =0.006) and TNF-α ( P =0.01) than did the subgroup with high LVEF (≥40%). Conclusions —This study has shown that increased myocardial TACE expression is associated with elevated myocardial TNF-α expression in both mRNA and protein levels in clinically advanced DCM.