(Circulation. 1999;99:3260-3265.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Tumor Necrosis Factor-
–Converting Enzyme and Tumor Necrosis Factor- in Human Dilated Cardiomyopathy
From the Second Department of Internal Medicine (M.S., M.N., H. Saito, H. Satoh, I.S., A.T., K.H.) and the Second Department of Pathology (C.M.), Iwate Medical University School of Medicine, Iwate, Japan.
Correspondence to Mamoru Satoh, MD, Second Department of Internal Medicine, Iwate Medical University School of Medicine, Uchimaru 19-1, Morioka 020-8505, Iwate, Japan. E-mail satohm{at}iwate-med.ac.jp
Background—Tumor necrosis
factor-
(TNF-) has been implicated in the pathogenesis of dilated
cardiomyopathy (DCM). TNF-–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- in the mature form. The aim of this
study was to determine whether TACE is expressed with TNF- in
myocardium and whether levels of TACE and TNF- are
related to clinical severity of DCM.
Methods and Results—Endomyocardial tissues
were obtained from 30 patients with DCM and 5 control subjects. TNF-
and TACE mRNA levels were measured by a novel real-time quantitative
reverse transcriptase–polymerase chain reaction method. Expression of
TNF- and TACE proteins was determined by immunohistochemical
analysis. TNF- mRNA was expressed in DCM patients
(TNF-/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- and TACE mRNA levels (r=0.779,
P<0.001). TACE and TNF-
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- (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-
(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- expression in
both mRNA and protein levels in clinically advanced DCM.
Key Words: cytokine • heart failure • polymerase chain reaction • immunohistochemistry • myocardium
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