Tumor necrosis factor-alpha-converting enzyme and tumor necrosis factor-alpha in human dilated cardiomyopathy

Background-Tumor necrosis factor-alpha (TNF-alpha) has been implicated in t he pathogenesis of dilated cardiomyopathy (DCM). TNF-alpha-converting enzym e (TACE) has recently been purified and its complementary DNA cloned. The e xpression of TACE results in the production of a functional enzyme that has precursor TNF-alpha in the mature form. The aim of this study was to deter mine whether TACE is expressed with TNF-alpha in myocardium and whether lev els of TACE and TNF-alpha are related to clinical severity of DCM. Methods and Results-Endomyocardial tissues were obtained from 30 patients w ith DCM and 5 control subjects. TNF-alpha and TACE mRNA levels were measure d by a novel real-time quantitative reverse transcriptase-polymerase chain reaction method. Expression of TNF-alpha and TACE proteins was determined b y immunohistochemical analysis. TNF-alpha mRNA was expressed in DCM patient s (TNF-alpha/GAPDH ratio 0.85+/-0.24) but not in control subjects. TACE mRN A expression was si,significantly greater in DCM patients than in control s ubjects (TACE/GAPDH ratio 2.52+/-0.59 vs 0.03+/-0.02, P<0.05). A positive c orrelation was found between TNF-alpha and TACE mRNA levels (r=0.779, P<0.0 01). TACE and TNF-alpha immunostaining was observed in myocytes in patients with DCM. When 2 subgroups of DCM were divided on the basis of left ventri cular end-systolic diameter (LVESD) of 45 mm and left ventricular ejection fraction (LVEF) of 40%, the DCM subgroup with high LVESD (greater than or e qual to 45 mm) showed significantly greater expression of TACE (P=0.02) and TNF-alpha (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-alpha (P=0.01) than did the subgroup with high LVEF (great er than or equal to 40%). Conclusions-This study has shown that increased myocardial TACE expression is associated with elevated myocardial TNF-alpha expression in both mRNA an d protein levels in clinically advanced DCM.