(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
 |
Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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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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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Tumor necrosis factor-
(TNF-) is a pleiotropic
cytokine that contributes to cellular immunity and inflammatory
reaction in a range of inflammatory diseases.1 Several
studies suggest that the expression of TNF- in
myocardium plays an important role in the progression of
dilated cardiomyopathy (DCM).2 3 4 Our
previous study demonstrated that cardiomyocytes expressed
excessive quantities of TNF- and nitric oxide in human
DCM.5 Kubota et al6 and Bryant et
al7 reported that cardiac-specific overexpressing TNF-
transgenic mice showed decreased ventricular function and
developed heart failure and increased mortality rates.
TNF-–converting enzyme (TACE) has recently been purified and cloned
as a metalloproteinase disintegrin that specifically cleaves precursor
TNF-.8 9 The enzyme also releases and activates
mature 17-kDa TNF- into the extracellular space. However, it is
unclear whether both TACE and TNF- are expressed in myocardial
tissue in DCM. In this study, we examined the expression of TACE and
TNF- in endomyocardial tissues of patients with
DCM and control subjects by using a novel real-time quantitative
reverse transcriptase–polymerase chain reaction (RT-PCR) method and
immunohistochemical analysis. We also explored the relation
between clinical characteristics and myocardial expression of TACE and
TNF-. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Subjects
Endomyocardial biopsies were obtained from 30 patients with DCM, and these tissues were examined. The DCM group included 23 men and 7 women with a mean age of 59±3 years (range 15 to 79 years). DCM was diagnosed according to the criteria of the World Health Organization and the International Society and Federation of Cardiology Task Force.10 Control myocardial tissue samples were obtained by endomyocardial biopsy from 5 subjects (4 men and 1 woman; mean age 46±13 years) suspected of cardiac disorder because of minor ECG and echocardiographic changes but showing no evidence of myocardial disease or other abnormality on morphological examination and cardiac catheterization. To confirm compatibility of expression of TACE and TNF-
between left and right
ventricles, we compared expression in 3 pairs of samples obtained by
biventricular endomyocardial biopsy.
Consistency of expression from sample to sample was
established by comparing 14 pairs of right ventricular
endomyocardial biopsy samples from DCM patients.
These study protocols were approved by our hospital ethics committee,
and written informed consent was obtained from all subjects.
Positive Control Cells for TACE and TNF- mRNA
Peripheral blood monocytes were prepared from normal
donors. The monocytes were washed and resuspended in AIM-R medium
(GIBCO BRL) supplemented with 2 mg of anti-human LeuTM-4 (CD3) (Becton
Dickinson). They were then allowed to adhere to tissue culture flasks
for 48 hours at 37°C.
Extraction of Total RNA
Total RNA was extracted by the acid guanidinium
thiocyanate-phenol-chloroform method from
endomyocardial tissues and cultured monocytes and
treated with RNase I (GIBCO BRL).11 The purity of
extracted total RNA was confirmed by determining the ratio of
absorbance at 260 nm to that at 280 nm. The extracted RNA was diluted
to 100 ng/µL with double-distilled water. TaqMan
glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
control reagents were used for fluorogenic detection of human GAPDH
transcript (Perkin-Elmer Applied Biosystems Division).
Oligonucleotides of Primers and Probes
Published cDNA sequences for human TNF-,12
TACE,8 and GAPDH13 were used for primer and
probe construction. The following primers and probes were used for
relative quantification of targeted gene expression: for TNF-:
forward primer 5'-CTT CTC CTT CCT GAT CGT GG-3', reverse primer 5'-GCT
GGT TAT CTC TCA GCT CCA-3', and probe 5'-CAG GCA GTC AGA TCA TCT TCT
CGA AC-3'; for TACE: forward primer 5'-ACC TGA AGA GCT TGT TCA TCG
AG-3', reverse primer 5'-CCA TGA AGT GTT CCG ATA GAT GTC-3', and probe
5'-TTG GTG GTA GCA GAT CAT CGC TTC T-3'; for GAPDH: forward primer
5'-GAA GGT GAA GGT CGG AGT-3', reverse primer 5'-GAA GAT GGT GAT GGG
ATT TC-3', and probe 5'-CAA GCT TCC CGT TCT CAG CC-3'. The PCR
products of TNF-, TACE, and GAPDH were amplified at 266, 190,
and 226 bp, respectively.
Real-Time Quantitative RT-PCR
cDNA was synthesized from 100 ng of total RNA and 10-fold serial
dilutions of human control RNA (Perkin-Elmer) by RT at 42°C for 30
minutes with the use of random hexamers and MuLV RT (Perkin-Elmer). PCR
was performed with a TaqMan PCR core kit (Perkin-Elmer). The cDNA
products were amplified with 40 cycles of PCR, with each cycle
consisting of first denaturation at 95°C for 10 minutes, denaturation
at 95°C for 15 seconds, annealing at 55°C for 15 seconds, and
extension at 72°C for 30 seconds. A novel quantitative PCR method was
developed with the use of real-time detection and 5' nuclease assay by
an ABI PRISM 7700 sequence detector (Perkin-Elmer).14 This
system was based on the use of the 5' nuclease activity of
Taq polymerase to cleave a nonextendable dual-labeled
fluorogenic hybridization probe during the extension phase of
PCR.14 The probe was labeled with reporter
fluorescent dye (6-carboxyfluorescein) at the 5'
end and a quencher fluorescent dye
(6-carboxy-tetramethyl-rhodamine) at the 3' end. When the probe is
intact, reporter dye emission is quenched by the physical proximity of
the reporter and quencher fluorescent dyes. However, during the
extension phase of the PCR cycle, the nucleolytic activity of the DNA
polymerase cleaves the hybridization probe and releases the
reporter dye from the probe. Nuclease degradation of the hybridization
probe quenched 6-carboxyfluorescein fluorescent
emission, resulting in an increase in peak fluorescent emission
at 518 nm.14 The ABI PRISM 7700 sequence detector measured
fluorescent emission synchronized with the thermal cycler
during each extension step. Relative quantification of GAPDH, TNF-,
and TACE mRNA was calculated by the comparative cycle threshold method
outlined in user bulletin No. 2 provided by Perkin-Elmer.
Immunohistochemical Analysis
Immunohistochemical analysis was performed on paraffin
sections to investigate the source of TACE and TNF-
production. Monoclonal antibody against TACE, TACE-M220 (1:100,
Immunex), and polyclonal rabbit anti-human TNF- (1:1000, Genzyme)
were used as primary antibodies. The tissue sections were
deparaffinized with xylene for 20 minutes and thoroughly dehydrated
with serial diluted ethanol. After inhibition of endogenous
peroxidase and blocking of nonspecific reactions, primary antibodies
were applied. Biotinylated goat immunoglobulin (Histofine, SAB-PO kit,
Nichiren Corp) was used as a secondary antibody. Peroxidase-labeled
streptavidin (Histofine, SAB-PO kit, Nichiren Corp) was applied and
visualized with the use of diaminobenzidine as a chromogen. The
specificity of the immunohistochemistry was confirmed by substituting
the primary antibodies with mouse IgG1 negative control (Dako) for TACE
and rabbit immunoglobulin fraction (Dako) for TNF- on control
sections from patients with DCM.
Statistical Analysis
All values are presented as mean±SE. Statistically, the
difference in TNF- and TACE expression levels between the DCM and
control groups was analyzed by unpaired t test.
Comparison between TNF- and TACE mRNA expression levels was
analyzed by Fisher's test. Pearson's correlation coefficients
were used to examine the relation between mRNA expression level and
clinical parameters. A value of P<0.05 was
considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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PCR Detection in Real Time
An amplification plot is shown in Figure 1a
. Amplification was performed on a
10-fold serial diluted human control RNA, and the target was human
GAPDH. The calculation of a value termed 
Rn used the following
equation: Rn=Rn+-Rn-,
where Rn+=emission intensity of reporter/emission
intensity of quencher at any given time in the reaction tube, and
Rn-=emission intensity of reporter/emission
intensity of quencher measured before PCR amplification in the same
reaction tube. During early cycles of PCR amplification, Rn values
remained at baseline. When sufficient hybridization probe had been
cleaved, intensity of reporter fluorescent emission increased.
Most PCR amplifications reached a plateau phase of reporter
fluorescent emission at high cycle numbers. The amplification
plot was examined at a point representing the log phase of
product accumulation. This was done by assigning an arbitrary
threshold based on the variability of baseline data. When the threshold
was chosen, the point at which the amplification plot crossed the
threshold was defined as threshold cycle (CT).
CT was shown as the cycle number at this point.
Figure 1b shows linearity of dilution determined by making
10-fold serial dilutions of control RNA. The CT
value was therefore predictive of the quantity of target sequence.
|
Expression of TACE and TNF- mRNA
RT-PCR of positive controls revealed a single band corresponding
to the size of TNF- (266 bp), GAPDH (226 bp), and TACE (190 bp)
(Figure 2). There was a statistically
significant rise in the level of TACE mRNA expression in right
ventricular myocardium in DCM compared with
control subjects (TACE/GAPDH ratio 2.52±0.59 vs 0.03±0.02,
P<0.05). The expression of TNF- mRNA was detected in
right ventricular myocardium of DCM
(TNF-/GAPDH ratio 0.85±0.24) but not in control subjects. Figure 3 shows the association between
TACE/GAPDH ratio and TNF-/GAPDH ratio in the DCM group. The plots
show a strong and significant correlation (r=0.779,
P<0.001). The mRNA expression of TACE and TNF- showed no
significant differences between right and left ventricular
myocardium obtained from DCM (TACE/GAPDH ratio 2.87±1.75
vs 2.91±0.82, TNF-/GAPDH ratio 1.80±1.55 vs 1.57±1.42,
respectively). When paired biopsy samples taken from 14 patients with
DCM were examined, no difference in TACE and TNF- mRNA expression
levels was found (TACE/GAPDH ratio 3.04±0.91 vs 3.30±1.10,
TNF-/GAPDH ratio 1.14±0.46 vs 1.21±0.47, respectively).
|
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Immunohistochemical Analysis
Immunohistochemical analysis was performed to identify the
source of TACE and TNF- protein in myocardial tissues. TACE
immunostaining was found in the cytoplasm of cardiac
myocytes in 16 patients with DCM (Figure 4A). TNF-
immunostaining was localized not only in cardiac
myocytes but also in endothelium (Figure 4C).
TNF- immunostaining was observed in 14 biopsy
tissues obtained from patients with DCM who showed positive myocardial
TACE protein. Both TACE and TNF- immunostaining were
also found in cardiac myocytes of left ventricular tissues
as well as in right ventricular samples. Figures 4B and 4D show an absence of nonspecific
immunostaining in the myocardial tissues obtained from
patients with DCM. The DCM subgroups with TACE and TNF- proteins
showed significantly higher expression of TACE and TNF- mRNA than
did subgroups without TACE and TNF- proteins (TACE/GAPDH ratio
4.07±0.94 vs 0.75±0.19, P<0.05, TNF-/GAPDH ratio
1.54±0.44 vs 0.24±0.11, P<0.05, respectively). Neither
TACE nor TNF- immunostaining was present in any
of the specimens from the control group.
|
Comparison of Clinical Data
The differences in myocardial expression of TACE and TNF-
mRNA between the 2 subgroups of DCM divided by clinical
parameters of left ventricular
end-systolic diameter (LVESD) (45 mm) and left
ventricular ejection fraction (LVEF) (40%) are shown in
the Table. The DCM subgroup with
LVESD45 mm yielded a significantly higher expression of TACE and
TNF- mRNA (TACE/GAPDH ratio 4.20±0.91 vs 0.59±0.13,
P=0.001; TNF-/GAPDH ratio 1.31±0.41 vs 0.32±0.10,
P=0.04) than did the subgroup with LVESD<45 mm. The
DCM subgroup with LVEF<40% showed a significantly higher expression
of TACE and TNF- mRNA (TACE/GAPDH ratio 4.98±1.16 vs 1.10±0.37,
P=0.006; TNF-/GAPDH ratio 1.82±0.53 vs 0.28±0.10,
P=0.01) than did the subgroup with LVEF40%. LVESD was
correlated positively with mRNA expression of TACE (r=0.61,
P<0.01; Figure 5a) and
TNF- (r=0.41, P<0.05; Figure 5b).
Similarly, LVEF was significantly negatively correlated with mRNA
expression of both TACE (r=-0.77, P<0.001;
Figure 5c) and TNF- (r=-0.49,
P<0.05; Figure 5d).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study has demonstrated that myocardial expression of TACE mRNA and protein was significantly increased in DCM patients, and these levels were associated with increased levels of TNF-
mRNA and
protein in advanced DCM. It has been suggested that inflammatory
cytokines such as interleukins and TNF- induced by viral
replication and autoimmune mechanisms may be pathogenetic factors
underlying DCM.15 16 If inflammatory processes do
contribute to the pathogenesis of DCM, then cytokine
production may be an important factor in the pathogenesis of
DCM. Our previous study showed that TNF- is expressed in
cardiomyocytes in patients with DCM, who usually have
advanced left ventricular dysfunction and large
ventricular volume.5 Yokoyama et
al17 reported that a negative inotropic effect was
directly mediated by TNF- expression in the adult mammalian
myocardium and that this might be caused by decreased
levels of intercellular calcium. Recently, Kubota et al6
and Bryant et al7 reported that a transgenic mouse model
with myocardial overexpression of TNF- developed a primary
phenotype consistent with DCM, displaying both cardiac
dilation and left ventricular dysfunction. These transgenic
mice also developed a failing heart with pulmonary and liver
congestion and increased mortality rates.6 7 These facts
strongly imply that TNF- production by cardiac myocytes in
vivo plays an important pathophysiological role not
only in the pathogenesis of DCM but also in its progression. There is a
further implication that an increase in cardiac expression of TNF-
may contribute to ventricular dysfunction and remodeling.
However, the mechanism for release and activation of TNF- in
cardiomyocyte in DCM has remained uncertain.
Recent studies report the purification and cloning of the
metalloproteinase disintegrin (called TACE), which specifically cleaves
precursor TNF- from membrane-bound precursor and releases mature
TNF-.8 9 Black et al8 also reported that
TACE allele–deficient mouse cells were required to determine the
extent to which TACE accounts for the production of soluble
TNF- in vivo. McGeehan et al18 and Mohler et
al19 reported that metalloproteinase
inhibitors suppress TACE processing of TNF- precursor
and lipopolysaccharide-induced TNF- production. TACE
may therefore regulate the processing of posttranslational
myristoylation promoting membrane insertion and interaction of TNF-.
In this study, myocardial expression of TACE mRNA was greater in DCM
than in control subjects. There was a positive correlation between TACE
and TNF- expression in myocardium in human DCM.
Immunohistochemical analysis demonstrated that the protein
biosynthesis of TACE and TNF- was predominantly in
cardiomyocytes. The DCM subgroup with TACE and TNF-
protein showed higher expression of TACE and TNF- mRNA than the
subgroup without TACE and TNF- protein. These findings suggest a
link between increased TACE and TNF- expression in
myocardium in this disorder.
DCM subgroups with higher left ventricular volume and lower
LVEF showed significantly higher mRNA expression of TACE and TNF-
than did the lower ventricular volume and higher ejection
fraction DCM subgroups. In addition, both TACE and TNF- expression
levels were positively correlated with left ventricular
volume and negatively correlated with left ventricular
systolic function. Although this study could not show whether
TNF- was a direct cause of myocytic injury, Bozkurt et
al20 have recently reported that continuous infusion of
TNF- led to a time-dependent depression of ventricular
function with ventricular dilatation in the intact
ventricle, possibly caused by TNF-–induced apoptotic cell
death in myocytes. Although we were unable to confirm that expression
of TACE came before that of TNF-, the present observations
suggest that increased TACE levels may be related to TNF- expression
in myocardium, making TACE a potentially important factor
in the establishment of a new pathological concept and therapeutic
challenge for human DCM.
In conclusion, the present study has shown that increased
myocardial TACE expression is associated with elevated myocardial
TNF- expression as reflected in both mRNA and protein levels in
clinically advanced DCM.
|
Acknowledgments |
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This study was supported by a grant-in-aid for general scientific research from the Japanese Ministry of Education, Science, Sports, and Culture (No. 09670742) and grants from the Keiryoukai Research Foundation (No. 57 and 65).
Received December 8, 1998; revision received March 17, 1999; accepted April 9, 1999.
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M. Satoh, J. Iwasaka, M. Nakamura, T. Akatsu, Y. Shimoda, and K. Hiramori Increased expression of tumor necrosis factor-{alpha} converting enzyme and tumor necrosis factor-{alpha} in peripheral blood mononuclear cells in patients with advanced congestive heart failure Eur J Heart Fail, December 1, 2004; 6(7): 869 - 875. [Abstract] [Full Text] [PDF]
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P. W.M. Fedak, D. S. Smookler, Z. Kassiri, N. Ohno, K. J. Leco, S. Verma, D. A.G. Mickle, K. L. Watson, C. V. Hojilla, W. Cruz, et al. TIMP-3 Deficiency Leads to Dilated Cardiomyopathy Circulation, October 19, 2004; 110(16): 2401 - 2409. [Abstract] [Full Text] [PDF]
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M. Bourraindeloup, C. Adamy, G. Candiani, M. Cailleret, M.-C. Bourin, T. Badoual, J. B. Su, S. Adubeiro, F. Roudot-Thoraval, J.-L. Dubois-Rande, et al. N-Acetylcysteine Treatment Normalizes Serum Tumor Necrosis Factor-{alpha} Level and Hinders the Progression of Cardiac Injury in Hypertensive Rats Circulation, October 5, 2004; 110(14): 2003 - 2009. [Abstract] [Full Text] [PDF]
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A. P. Patrianakos, F. I. Parthenakis, E. A. Papadimitriou, G. F. Diakakis, P. G. Tzerakis, D. Nikitovic, and P. E. Vardas Restrictive filling pattern is associated with increased humoral activation and impaired exercise capacity in dilated cardiomyopathy Eur J Heart Fail, October 1, 2004; 6(6): 735 - 743. [Abstract] [Full Text] [PDF]
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 K. Vidal, P. Serrant, B. Schlosser, P. van den Broek, F. Lorget, and A. Donnet-Hughes Osteoprotegerin production by human intestinal epithelial cells: a potential regulator of mucosal immune responses Am J Physiol Gastrointest Liver Physiol, October 1, 2004; 287(4): G836 - G844. [Abstract] [Full Text] [PDF]
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G. W. Moe, J. Marin-Garcia, A. Konig, M. Goldenthal, X. Lu, and Q. Feng In vivo TNF-{alpha} inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1813 - H1820. [Abstract] [Full Text] [PDF]
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Y. Ichikawa, T. Miura, A. Nakano, T. Miki, Y. Nakamura, K. Tsuchihashi, and K. Shimamoto The role of ADAM protease in the tyrosine kinase-mediated trigger mechanism of ischemic preconditioning Cardiovasc Res, April 1, 2004; 62(1): 167 - 175. [Abstract] [Full Text] [PDF]
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T. Tsutamoto, A. Wada, M. Ohnishi, T. Tsutsui, C. Ishii, K. Ohno, M. Fujii, T. Matsumoto, T. Yamamoto, T. Takayama, et al. Transcardiac increase in tumor necrosis factor-{alpha} and left ventricular end-diastolic volume in patients with dilated cardiomyopathy Eur J Heart Fail, March 1, 2004; 6(2): 173 - 180. [Abstract] [Full Text] [PDF]
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M. Cailleret, A. Amadou, N. Andrieu-Abadie, A. Nawrocki, C. Adamy, B. Ait-Mamar, F. Rocaries, M. Best-Belpomme, T. Levade, C. Pavoine, et al. N-Acetylcysteine Prevents the Deleterious Effect of Tumor Necrosis Factor-{alpha} on Calcium Transients and Contraction in Adult Rat Cardiomyocytes Circulation, January 27, 2004; 109(3): 406 - 411. [Abstract] [Full Text] [PDF]
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A. Diwan, Z. Dibbs, S. Nemoto, G. DeFreitas, B. A. Carabello, N. Sivasubramanian, E. M. Wilson, F. G. Spinale, and D. L. Mann Targeted Overexpression of Noncleavable and Secreted Forms of Tumor Necrosis Factor Provokes Disparate Cardiac Phenotypes Circulation, January 20, 2004; 109(2): 262 - 268. [Abstract] [Full Text] [PDF]
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Z. I. Dibbs, A. Diwan, S. Nemoto, G. DeFreitas, M. Abdellatif, B. A. Carabello, F. G. Spinale, G. Feuerstein, N. Sivasubramanian, and D. L. Mann Targeted Overexpression of Transmembrane Tumor Necrosis Factor Provokes a Concentric Cardiac Hypertrophic Phenotype Circulation, August 26, 2003; 108(8): 1002 - 1008. [Abstract] [Full Text] [PDF]
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D. R. Murray and G. L. Freeman Proinflammatory Cytokines: Predictors of a Failing Heart? Circulation, March 25, 2003; 107(11): 1460 - 1462. [Full Text] [PDF]
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P. W. M. Fedak, S. M. Altamentova, R. D. Weisel, N. Nili, N. Ohno, S. Verma, T.-Y. J. Lee, C. Kiani, D. A. G. Mickle, B. H. Strauss, et al. Matrix remodeling in experimental and human heart failure: a possible regulatory role for TIMP-3 Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H626 - H634. [Abstract] [Full Text] [PDF]
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T. P. Zwaka, D. Manolov, C. Ozdemir, N. Marx, Z. Kaya, M. Kochs, M. Hoher, V. Hombach, and J. Torzewski Complement and Dilated Cardiomyopathy: A Role of Sublytic Terminal Complement Complex-Induced Tumor Necrosis Factor-{alpha} Synthesis in Cardiac Myocytes Am. J. Pathol., August 1, 2002; 161(2): 449 - 457. [Abstract] [Full Text] [PDF]
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A. Deswal, N. J. Petersen, A. M. Feldman, J. B. Young, B. G. White, and D. L. Mann Cytokines and Cytokine Receptors in Advanced Heart Failure : An Analysis of the Cytokine Database from the Vesnarinone Trial (VEST) Circulation, April 24, 2001; 103(16): 2055 - 2059. [Abstract] [Full Text] [PDF]
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X. Li, M. R. Moody, D. Engel, S. Walker, F. J. Clubb Jr, N. Sivasubramanian, D. L. Mann, and M. B. Reid Cardiac-Specific Overexpression of Tumor Necrosis Factor-{alpha} Causes Oxidative Stress and Contractile Dysfunction in Mouse Diaphragm Circulation, October 3, 2000; 102(14): 1690 - 1696. [Abstract] [Full Text] [PDF]
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M. Satoh, M. Nakamura, H. Satoh, H. Saitoh, I. Segawa, and K. Hiramori Expression of tumor necrosis factor-alpha-converting enzyme and tumor necrosis factor-alpha in human myocarditis J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1288 - 1294. [Abstract] [Full Text] [PDF]
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E. J. Birks, V. J. Owen, P. B. J. Burton, A. E. Bishop, N. R. Banner, A. Khaghani, J. M. Polak, and M. H. Yacoub Tumor Necrosis Factor-{alpha} Is Expressed in Donor Heart and Predicts Right Ventricular Failure After Human Heart Transplantation Circulation, July 18, 2000; 102(3): 326 - 331. [Abstract] [Full Text] [PDF]
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D. MacKenna, S. R. Summerour, and F. J. Villarreal Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis Cardiovasc Res, May 1, 2000; 46(2): 257 - 263. [Abstract] [Full Text] [PDF]
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G. Z. Feuerstein and P. R. Young Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways Cardiovasc Res, February 1, 2000; 45(3): 560 - 569. [Abstract] [Full Text] [PDF]
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L. Tiret, C. Mallet, O. Poirier, V. Nicaud, A. Millaire, J.-B. Bouhour, G.e. Roizes, M. Desnos, R. Dorent, K. Schwartz, et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: The CARDIGENE study J. Am. Coll. Cardiol., January 1, 2000; 35(1): 29 - 35. [Abstract] [Full Text] [PDF]
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