JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2006; 47:2319-2325, doi:10.1016/j.jacc.2006.03.033 (Published online 3 May 2006).
© 2006 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
j.jacc.2006.03.033v1
47/11/2319    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sato, A.
Right arrow Articles by Hiroe, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sato, A.
Right arrow Articles by Hiroe, M.

EXPEDITED REVIEW

Serum Tenascin-C Might Be a Novel Predictor of Left Ventricular Remodeling and Prognosis After Acute Myocardial Infarction

Akira Sato, MD*, Kazutaka Aonuma, MD{dagger}, Kyoko Imanaka-Yoshida, MD{ddagger},*, Toshimichi Yoshida, MD{ddagger}, Mitsuaki Isobe, MD§, Daisuke Kawase||, Noriaki Kinoshita, PhD||, Yoshio Yazaki, MD and Michiaki Hiroe, MD#

* Department of Cardiology, Yokosuka Kyosai Hospital, Yokosuka, Japan
{dagger} Department of Cardiology, University of Tsukuba Graduate School of Comprehensive Human Science, Tsukuba, Japan
{ddagger} Departments of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan
§ Department of Cardiovascular Medicine, Tokyo Medical and Dental Postgraduate School of Medicine, Tokyo, Japan
|| IBL Co., Gunma, Japan
National Hospital Organization, Tokyo, Japan
# Department of Nephrology and Cardiology, International Medical Center of Japan, Tokyo, Japan

Manuscript received January 23, 2006; revised manuscript received March 7, 2006, accepted March 15, 2006.

* Reprint requests and correspondence: Dr. Kyoko Imanaka-Yoshida, Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan (Email: imanaka{at}doc.medic.mie-u.ac.jp).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We investigated clinical implications of serum tenascin-C (TN-C) levels in patients with acute myocardial infarction (AMI).

BACKGROUND: Tenascin-C, an extracellular matrix glycoprotein, is not normally expressed in the adult heart, but transiently appears during pathological conditions and plays important roles in tissue remodeling.

METHODS: Serum TN-C levels were measured by ELISA in 105 AMI patients at various time points, in 10 old myocardial infarction (OMI) patients, and 20 normal controls.

RESULTS: The mean serum TN-C level of AMI patients on admission (63.3 ± 30.1 ng/ml) was significantly higher than that of controls and OMI (30.9 ± 8.8 ng/ml and 27.4 ± 11.7 ng/ml, respectively, p < 0.01), and peaked at 5 days (83.2 ± 43.0 ng/ml). Follow-up examination (mean: 43.9 ± 19.6 months) revealed that 25 of 105 AMI (23.8%) patients showed left ventricular (LV) remodeling (≥20% end-diastolic volume increase), and in 15 (14.3%), major adverse cardiac events (MACE) were detected. The peak TN-C level was significantly higher in the remodeling group than the nonremodeling group (112 ± 37 ng/ml vs. 66 ± 29 ng/ml; p < 0.0001). By receiver-operating characteristic (ROC) analysis, TN-C levels clearly discriminated prediction of LV remodeling and MACE compared with other variables including plasma B-type natriuretic peptide, creatine kinase-MB, and LV function. Best predictive values of TN-C for remodeling and MACE were 84.8 and 92.8 ng/ml, respectively. Cox proportional hazards model analysis showed that TN-C was an important independent predictor of MACE.

CONCLUSIONS: The findings suggest that serum TN-C levels might be useful in predicting LV remodeling and prognosis after AMI.

Abbreviations and Acronyms
  AMI = acute myocardial infarction
  CHF = congestive heart failure
  LV = left ventricle
  LVEDV = left ventricular end-diastolic volume
  LVESV = left ventricular end-systolic volume
  MACE = major cardiac adverse events
  MMP = matrix metalloproteinase
  OMI = old myocardial infarction
  ROC = receiver-operating characteristic
  SPECT = single photon emission computerized tomography
  TDS = total defect score
  TN-C = tenascin-C

Left ventricular (LV) remodeling following acute myocardial infarction (AMI) is a major predictor of morbidity and mortality for overt congestive heart failure (CHF) and life-threatening arrhythmias (1). It occurs in an appreciable proportion of patients with AMI successfully treated with primary percutaneous transluminal coronary angioplasty despite sustained patency of the infarct-related artery and preservation of regional and global LV functions (2). Therefore, it may be important to identify patients at risk of LV remodeling to prevent LV dilation after AMI. It has been reported that infarct size, anterior infarct location, perfusion status of the culprit lesion, and CHF on admission are major predictors of LV dilation. Recently, several factors, including B-type natriuretic peptide (BNP), cardiac troponin I, and high-sensitivity C-reactive protein, have been examined as potential predicting biomarkers of LV remodeling (2).

Tenascin-C (TN-C) is an extracellular matrix protein specifically expressed at high levels during embryonic development, wound healing, and cancer invasion and involved in regulation of cell behavior during tissue remodeling in various tissues (3–6). In the heart, TN-C is normally expressed in early-stage embryos, playing important roles in development of the myocardium, valves, and coronary vessels; but is not detected in adults (7). However, it is re-expressed under pathologic conditions such as AMI (8,9), hibernation (10), and myocarditis (11–13) and is closely associated with tissue injury and inflammation. Based on these specific expression patterns, we recently revealed that immunostaining of myocardial tissues (11,13) and immunoscintigraphic imaging (12) for TN-C could be useful in diagnosis of active myocarditis. Furthermore, using an experimental model of myocardial infarction, we found that TN-C transiently appeared during acute stages, with several significant roles in myocardial tissue remodeling (8,14). Therefore, we hypothesized that TN-C expression levels might be useful for the diagnosis and determination of LV remodeling following AMI. In the present study, to clarify clinical implications of TN-C levels in patients with AMI, we assessed serum TN-C concentrations with reference to cardiac function and patient outcomes.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study population.   We prospectively studied 105 patients with AMI (73 men and 32 women, mean age 66 ± 12 years) admitted to Yokosuka Kyosai Hospital between January 2000 and March 2003, 10 patients with old myocardial infarction (OMI) (8 men and 2 women, mean age 66 ± 9 years), and 20 normal volunteers (14 men and 6 women, mean age 49 ± 15 years). Inclusion criteria for this study for AMI patients were as follows: 1) chest pain >30 min in duration and present within 12 h after onset of symptoms; 2) ST-segment elevation >0.1 mV with two contiguous electocardiographic leads; 3) total occlusion of the infarct-related artery; 4) elevated creatine kinase (CK)-MB isoenzymes within 12 h of chest pain; and 5) successful primary coronary angioplasty (defined as Thrombolysis In Myocardial Infarction flow grade 3 [15] and residual diameter stenosis <30%). Clinical characteristics of the AMI patients on hospital admission are described in Table 1. The drugs listed in Table 2 were administered at the time of admission according to the discretion of the treating physicians. Written informed consent was obtained from all patients and volunteers, and the study protocol was approved by our institutional review board.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical Characteristics of 105 Patients With Acute Myocardial Infarction Undergoing Successful Primary Percutaneous Coronary Intervention
 

View this table:
[in this window]
[in a new window]
  		Table 2. Clinical Characteristics of Patients in the Remodeling and Non-Remodeling Groups
 
Assay of serum TN-C levels by ELISA.   Blood samples were centrifuged at 15,000 g for 15 min, and resulting supernatants were stored at –80°C until analysis. Serum levels of TN-C with the large subunit containing the C domain of FNIII repeats were determined using an ELISA kit with two monoclonal antibodies, 4F10TT and 19C4MS (IBL, Gunma, Japan), as previously described (16).

Biochemical analyses.   Serum CK-MB levels were analyzed by enzymatic means and plasma BNP concentrations were measured using a specific immunoradiometric commercial assay kit (Shionogi, Japan).

Radionuclide imaging.   Electrocardiogram-gated myocardial single-photon emission computerized tomography (SPECT) with 99mTc-tetrofosmin was performed on admission and 6 months later. Imaging was performed at rest in the supine position 1 h after intravenous injection of 740 MBq 99mTc-tetrofosmin as the radiotracer at both time points using a double-detector SPECT system (Picker Prism 2000 XP, Shimadzu Corp., Kyoto, Japan) equipped with a low-energy high-resolution collimator. Seventy-two projection data were obtained with a 64 x 64 matrix over 360°. Data were acquired for 40 s for each projection. The total acquisition time was approximately 24 min. Images were gated at 16 frames per cardiac cycle with an R-wave trigger and standard parameters similar to the left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), which are commercially available with Germano software (17). The SPECT images of the LV were divided into 17 segments according to the American Heart Association/American College of Cardiology recommendations (18). Short-axis slices were separated into eight segments at the basal and midventricular levels, and the apical portion of one segment was evaluated using vertical long-axis slices. Each segment was visually scored according to four grades (0 = normal uptake; 1 = mildly decreased uptake; 2 = moderately decreased uptake; 3 = severely decreased uptake), and total defect scores (TDS) were calculated by summation.

Definition of LV remodeling and monitoring of clinical events.   The LV remodeling was defined as an increase in end-diastolic volume at six months after infarction of ≥20% in comparison with that based on measurements in individual patients, according to Bolognese et al. (19). Major adverse cardiac events (MACE), defined as cardiac death, nonfatal AMI, and hospitalization for CHF, were the primary outcomes for the present analysis. After hospital discharge, all patients on medication were monitored at our outpatient clinic for up to 5.5 years.

Immunohistochemistry of TN-C.   Immunostainings of heart tissues obtained from three AMI, three OMI, and three noncardiac disease autopsy cases were performed as previously described (20) using two anti–TN-C mouse monoclonal antibodies. In brief, after treatment with pepsin for 10 min or heating in an autoclave for antigen retrieval, sections were incubated with antibody clone 4F10TT (1 µg/ml) or 6C6MS (10 µg/ml), and then processed using an LSAB kit (Dako Japan, Kyoto, Japan). The 6C6MS antibody recognizes the same FNIII repeat of TN-C as 19C4MS antibody but gives more intense immunostaining than 19C4MS in paraffin-embedded tissues.

Statistical analysis.   The multivariate analysis included all risk factors with probability values of <0.05 in a backward stepwise regression model. Receiver-operating characteristic (ROC) analysis was used to determine optimal cut-off values of clinical variables for predictions of LV remodeling and MACE. The ROC curve represents relationships between sensitivity and specificity by plotting true-positive rates against false-positive rates as the cut-off level of the model varies. The area under the ROC curve (AUC) provides a measure of overall accuracy that is independent of decision criterion. The best cut-off value was defined as the point with the highest sum of sensitivity and specificity. Evaluation of statistical differences between groups was determined using Kruskal-Wallis analysis, the Mann-Whitney U test and one-way analysis of variance. Correlations were estimated using the Spearman rank correlation test. Event-free survival curves for MACE were constructed using the Kaplan-Meier method, and statistical differences between curves were assessed using the log rank test. Values of p < 0.05 were considered significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Expression of TN-C in human myocardium following myocardial infarction.   Positive immunostainings with the two monoclonal antibodies, 6C6MS and 4F10TT, were observed in infarct lesions of myocardia in AMI patients. In contrast, scar tissue in OMI patients and normal myocardia were negative with both antibodies (Fig. 1).


Figure 1
View larger version (100K):
[in this window]
[in a new window]
  		Figure 1 Representative microscopic images of tenascin-C expression in autopsied human myocardia from a normal case (A, D, G), an acute myocardial infarction (AMI) patient 36 h after myocardial infarction (B, E, H), and an old myocardial infarction (OMI) patient (C, F, I). (A, B, C) H & E staining; (D, E, F) immunolabeling with antibody clones 4F10TT and (G, H, I) 6C6MS. Positive immunostainings with the two monoclonal antibodies were observed in the infarcted myocardial lesion of the AMI patients. Bar = 100 µm.

 
Sequential changes in serum TN-C concentrations following AMI.   The peak TN-C levels in AMI patients (85.9 ± 41.7 ng/ml) were significantly higher than in OMI (27.4 ± 11.7 ng/ml) (p < 0.01) and control patients (30.9 ± 8.8 ng/ml) (p < 0.01) (Fig. 2). The TN-C levels were not statistically distinguishable between control and OMI patients. Whereas CK-MB levels peaked within 12 h and rapidly decreased within 5 days following infarction, serum TN-C levels were elevated on admission (63.3 ± 30.1 ng/ml), peaked at day 5 (83.2 ± 43.0 ng/ml), and then gradually decreased, although they remained elevated at day 28 (51.8 ± 17.8 ng/ml) (Fig. 3).


Figure 2
View larger version (22K):
[in this window]
[in a new window]
  		Figure 2 Comparisons of serum tenascin-C (TN-C) levels between acute myocardial infarction (AMI), old myocardial infarction (OMI), and control cases. n.s. = not significant.

 

Figure 3
View larger version (18K):
[in this window]
[in a new window]
  		Figure 3 Serial changes in serum tenascin-C (TN-C) and creatine kinase (CK)-MB levels in patients with acute myocardial infarction (AMI). Values represent the mean and standard error. Serum TN-C levels were elevated on admission, peaked at day 5, and then gradually decreased (A). In contrast, CK-MB levels peaked within 12 h and then rapidly decreased (B).

 
Comparison of clinical characteristics and LV parameters between remodeling and nonremodeling groups.   Out of 105 patients, 25 (23.8%) showed LV remodeling at 6 months. During the follow-up period (mean 43.9 ± 19.6 months), 15 MACE (14.3%) including 8 deaths and 7 hospitalizations for worsening heart failure were observed. Incidence of MACE in the LV remodeling group was higher (12 of 25) than in the nonremodeling group (3 of 80) (p < 0.01).

Clinical characteristics and LV parameters of the study patients are shown in Table 2. There were no significant differences in age, perfusion time, infarct location, systolic blood pressure, and use of cardiovascular medications between the two groups. Peak TN-C levels were significantly higher in the remodeling group than in the nonremodeling group (112 ± 37 vs. 66 ± 29; p < 0.0001). Peak CK-MB, LVESV and total defect scores on admission, and BNP levels on days 5 and 28 after onset of AMI were also significantly higher in the remodeling group than in the nonremodeling group, whereas LVEF on admission was significantly lower in the remodeling group. No siginificant relationship was found between peak TN-C and peak CK-MB or total defect score.

ROC analysis of clinical variables for predicting LV remodeling and MACE.   We performed ROC analysis of the following clinical variables: peak serum TN-C levels and plasma BNP levels on days 5 and 28 after AMI and peak CK-MB, LVEDV, LVESV, and LVEF on admission for prediction of LV remodeling and MACE (Table 3). For prediction of LV remodeling, the AUC of the peak serum TN-C level was 0.849, and highest among the analyzed variables. The best cut-off value of serum TN-C for prediction of LV remodeling was 84.8 ng/ml, with a sensitivity of 84% and specificity of 77%.


View this table:
[in this window]
[in a new window]
  		Table 3. Prognostic Value of Each Clinical Variable in Predicting LV Remodeling and Cardiac Events According to Receiver-Operating Characteristic Analysis
 
For prediction of MACE, the AUC of the peak serum TN-C level was 0.788, which was also higher than any other variables. The best cut-off value for prediction of MACE was 92.8 ng/ml, with a sensitivity of 73% and specificity of 80%. The AUC of plasma BNP on day 28 was also high for prediction of MACE (0.783). The best cut-off value of BNP level was 163 pg/ml with a sensitivity of 80% and specificity of 59%.

Univariate and multivariate predictors of MACE.   Table 4 shows the results of univariate and multivariate Cox proportional hazards model analyses between 10 variables related to MACE. In the univariate analysis, the peak TN-C level, plasma BNP level on days 5 and 28, LVESV, LVEF, and total defect scores on admission were predictive factors. According to multivariate analysis, peak TN-C level was the most important independent predictor of MACE during a follow-up period of up to 5.5 years after infarction. Plasma BNP level on day 28 was also a significant predictor of MACE.


View this table:
[in this window]
[in a new window]
  		Table 4. Univariate and Multivariate Analyses of the Value of Each Variable in Predicting Cardiac Events
 
Kaplan-Meier analysis.   During the follow-up period (mean 43.9 ± 19.6 months), there were five deaths and five hospitalizations for worsening heart failure in patients with TN-C ≥92.8 ng/ml, and three deaths and two hospitalizations for worsening heart failure in patients with TN-C <92.8 ng/ml. Kaplan-Meier MACE demonstrated the higher risks of death and hospitalization of patients with TN-C ≥92.8 ng/ml than of those with TN-C <92.8 ng/ml (p < 0.0001).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Major novel findings in the present study were as follows: 1) Serum TN-C levels were significantly elevated during acute stages after AMI; 2) TN-C levels were significantly higher in the LV remodeling group than in the nonremodeling group; and 3) AMI patients with high TN-C levels were at much higher risk of MACE for up to 5.5 years. Thus, serum TN-C levels in acute stages following AMI might be a predictive biomarker of LV remodeling during the recovery phase and prognosis.

Elevated serum TN-C levels in AMI patients.   Using rat and mouse myocardial infarction models, we previously reported that TN-C was synthesized during acute stages by interstitial fibroblasts in the border zone myocardium surrounding infarcted lesions (8) and could play several important roles in myocardial repair (8,14,21). In the present paper, we demonstrated that serum TN-C levels in AMI patients were significantly higher than those in OMI patients and controls. Immunostaining of autopsied specimens confirmed expression of TN-C in human myocardium in acute stages following infarction, whereas no expression was detected in normal myocardium or in scar tissues of OMI patients. Therefore, TN-C synthesized in infarcted myocardium could enter the bloodstream and cause elevation of serum TN-C levels in AMI patients. In various tissue injuries, TN-C molecules are synthesized by interstitial cells residing in injured sites. While molecules are deposited in extracellular spaces and regulate cell behavior in the local environment, soluble forms might also be released into body fluids. For example, TN-C levels in synovial fluid from patients with osteoarthritis (16) and aseptic loosening after arthroplasty (22) and in serum of patients with hepatic fibrosis (23) are reported to increase in correlation with disease activity.

In our AMI patients, significantly elevated TN-C levels were noted within 24 h after onset. Levels peaked at day 5 and then gradually decreased. This time course of serum TN-C levels was previously shown to correspond to local expression of TN-C in infarcted myocardia of humans (9) and rats (8), as detected by immunohistochemistry. It is noteworthy that the peak of serum TN-C occurred later than that for CK-MB, and persisted much longer. Furthermore, peaks of TN-C did not significantly correlate with total defect scores on myocardial SPECT with 99mTc-tetrofosmin or with peaks of CK-MB. These results indicate that elevation of TN-C levels might not directly reflect cardiomyocyte death. Synthesis of TN-C by cardiac fibroblasts is stimulated by various cytokines, growth factors, hypoxia, acidosis, mechanical stress, and angiotensin II (21), which could be closely related to myocardial injury and inflammation during the wound healing process. Although the infarct size could be one of major determinants of TN-C expression levels, which might reflect interstitial response secondary to myocardial injury, some other factors of individual patients might also influence TN-C expression.

TN-C as a marker for LV remodeling and long-term clinical outcomes.   Most importantly, patients with LV remodeling showed higher peak TN-C levels than patients without LV remodeling, and patients with higher peak TN-C levels had a greater incidence of MACE and worse long-term prognosis. A previous report revealed that patients with significant LV remodeling six months after infarction had worse long-term clinical outcomes (2). Because TN-C levels peaked within one week after infarction, our results suggest that TN-C could be an early predictive marker for future ventricular remodeling.

One of the major determinants of ventricular remodeling following AMI could be infarct size (2,24). Therefore, myocyte injury markers such as cardiac troponin I and T, CK, and CK isoforms appear to be useful in predicting late ventricular dilation (2). It was also suggested that the systemic inflammatory marker C-reactive protein (25,26) and neurohormones secreted by cardiomyocytes, including atrial natriuretic peptide (27) and BNP (28), are further biomarkers of ventricular remodeling. A recent report suggested that plasma BNP levels at three to four weeks after AMI could be independent predictors of cardiac death (29). In the present study, our analysis of the prognostic value of various clinical variables also supported the possibility that large infarction and high plasma BNP levels might predict MACE.

Left ventricular remodeling involves multi-step reactions which orchestrate structural alteration and rearrangement of cells and connective tissues. During these processes, disproportionate activation of matrix metalloproteinases (MMPs) has recently received increasing attention in progression of unfavorable tissue remodeling (30–33). Several reports have suggested that deletions of MMP2 and MMP9 attenuate ventricular remodeling (34–36) and that MMPs could act as biomarkers of ventricular remodeling (37–39).

Tenascin-C has many biologic effects, including regulation of cell activity during early stages of tissue repair (4,8,11,14,40). It up-regulates MMP expression in a number of cell types (41,42) and inhibits strong linkages between cardiomyocytes and connective tissues (8,21). Therefore, excessive amounts of TN-C might cause disproportionate MMP activation, which would lead to progressive degradation of connective tissues and slippage of myocytes within the LV wall, finally resulting in LV wall thinning and dilation. On the other hand, TN-C also has the potential to promote myocardial repair and prevent ventricular dilation by recruitment of myofibroblasts and enhancement of collagen fiber contraction (14,43). Thus, the effects of TN-C on ventricular remodeling are not simple but rather are bidirectional. In the present study, we found that high levels of serum TN-C could be related to a greater incidence of ventricular remodeling and poor prognosis, suggesting that excessive and sustained increments of TN-C could cause inappropriate reconstruction of infarcted ventricular walls.

Clinical implications and limitations.   This preliminary study suggests that serum TN-C might be a novel marker reflecting active structural remodeling in the myocardium following infarction, with high TN-C levels at acute stages possibly predicting progression of LV remodeling.

However, despite the findings, the current study has some limitations. First, the sample size was relative small. Second, prognosis of our AMI patients receiving primary coronary angioplasty was good, and there were only eight deaths and seven hospitalizations due to heart failure out of 105 patients during the follow-up period of 3 to 5.5 years. Further large-scale prospective investigations and careful comparisons with other clinical parameters are therefore required to confirm the predictive ability of TN-C in LV remodeling and MACE.


   Footnotes
 
Supported by a grant-in-aid for scientific research (no. 15590735) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, to Dr. Imanaka-Yoshida, and a grant for intractable disease from the Ministry of Health, Labor and Welfare, Japan, to Dr. Hiroe. Mr. Kawase and Dr. Kinoshita are employees of IBL Co., which is the commercial source of the tenascin-C antibody and tenascin-C assay ELISA kit.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications Circulation 1990;81:1161-1172.[Abstract/Free Full Text]
  2. Bolognese L, Neskovic AN, Parodi G, et al. Left ventricular remodeling after primary coronary angioplastypatterns of left ventricular dilation and long-term prognostic implications. Circulation 2002;106:2351-2357.[Abstract/Free Full Text]
  3. Chiquet-Ehrismann R, Tucker RP. Connective tissuessignaling by tenascins. Int J Biochem Cell Biol 2004;36:1085-1089.[CrossRef][Medline]
  4. Chiquet-Ehrismann R, Chiquet M. Tenascinsregulation and putative functions during pathological stress. J Pathol 2003;200:488-499.[CrossRef][ISI][Medline]
  5. Jones FS, Jones PL. The tenascin family of ECM glycoproteinsstructure, function, and regulation during embryonic development and tissue remodeling. Dev Dyn 2000;218:235-259.[CrossRef][ISI][Medline]
  6. Jones PL, Jones FS. Tenascin-C in development and diseasegene regulation and cell function. Matrix Biol 2000;19:581-596.[CrossRef][ISI][Medline]
  7. Imanaka-Yoshida K, Matsumoto K, Hara M, Sakakura T, Yoshida T. The dynamic expression of tenascin-C and tenascin-X during early heart development Differentiation 2003;71:291-298.[CrossRef][ISI][Medline]
  8. Imanaka-Yoshida K, Hiroe M, Nishikawa T, et al. Tenascin-C modulates adhesion of cardiomyocytes to extracellular matrix during tissue remodeling after myocardial infarction Lab Invest 2001;81:1015-1024.[ISI][Medline]
  9. Willems IE, Arends JW, Daemen MJ. Tenascin and fibronectin expression in healing human myocardial scars J Pathol 1996;179:321-325.[CrossRef][ISI][Medline]
  10. Frangogiannis NG, Shimoni S, Chang S, et al. Active interstitial remodelingan important process in the hibernating human myocardium. J Am Coll Cardiol 2002;39:1468-1474.[Abstract/Free Full Text]
  11. Imanaka-Yoshida K, Hiroe M, Yasutomi Y, et al. Tenascin-C is a useful marker for disease activity in myocarditis J Pathol 2002;197:388-394.[CrossRef][ISI][Medline]
  12. Sato M, Toyozaki T, Odaka K, et al. Detection of experimental autoimmune myocarditis in rats by 111In monoclonal antibody specific for tenascin-C Circulation 2002;106:1397-1402.[Abstract/Free Full Text]
  13. Morimoto S, Imanaka-Yoshida K, Hiramitsu S, et al. The diagnostic utility of tenascin-C for evaluation of activity of human acute myocarditis J Pathol 2005;205:460-467.[CrossRef][Medline]
  14. Tamaoki M, Imanaka-Yoshida K, Yokoyama K, et al. Tenascin-C regulates recruitment of myofibroblasts during tissue repair after myocardial injury Am J Pathol 2005;167:71-80.[Abstract/Free Full Text]
  15. TIMI Study Group The Thrombolysis In Myocardial Infarction (TIMI) trial. Phase I findings N Engl J Med 1985;312:932-936.[Medline]
  16. Hasegawa M, Hirata H, Sudo A, et al. Tenascin-C concentration in synovial fluid correlates with radiographic progression of knee osteoarthritis J Rheumatol 2004;31:2021-2026.[Medline]
  17. Germano G, Kiat H, Kavanagh PB, et al. Automatic quantification of ejection fraction from gated myocardial perfusion SPECT J Nucl Med 1995;36:2138-2147.[Abstract/Free Full Text]
  18. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the hearta statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539-542.[Free Full Text]
  19. Bolognese L, Cerisano G, Buonamici P, et al. Influence of infarct-zone viability on left ventricular remodeling after acute myocardial infarction Circulation 1997;96:3353-3359.[Abstract/Free Full Text]
  20. Tsunoda T, Inadal H, Kalembeyil I, et al. Involvement of large tenascin-C splice variants in breast cancer progression Am J Pathol 2003;162:1857-1867.[Abstract/Free Full Text]
  21. Imanaka-Yoshida K, Hiroe M, Yoshida T. Interaction between cell and extracellular matrix in heart diseasemultiple roles of tenascin-C in tissue remodeling. Histol Histopathol 2004;19:517-525.[Medline]
  22. Hasegawa M, Sudo A, Nagakura T, et al. Tenascin-C levels in pseudosynovial fluid of loose hip prostheses Scand J Rheumatol 2005;34:464-468.[Medline]
  23. Yamauchi M, Mizuhara Y, Maezawa Y, Toda G. Serum tenascin levels in chronic liver disease Liver 1994;14:148-153.[ISI][Medline]
  24. Kern MJ. Patterns of left ventricular dilation with an opened artery after acute myocardial infarctionmissing links to long-term prognosis. Circulation 2002;106:2294-2295.[Free Full Text]
  25. Anzai T, Yoshikawa T, Shiraki H, et al. C-reactive protein as a predictor of infarct expansion and cardiac rupture after a first Q-wave acute myocardial infarction Circulation 1997;96:778-784.[Abstract/Free Full Text]
  26. Takahashi T, Anzai T, Yoshikawa T, et al. Serum C-reactive protein elevation in left ventricular remodeling after acute myocardial infarction—role of neurohormones and cytokines Int J Cardiol 2003;88:257-265.[CrossRef][ISI][Medline]
  27. Groenning BA, Nilsson JC, Hildebrandt PR, et al. Neurohumoral prediction of left-ventricular morphologic response to beta-blockade with metoprolol in chronic left-ventricular systolic heart failure Eur J Heart Fail 2002;4:635-646.[Medline]
  28. Nagaya N, Nishikimi T, Goto Y, et al. Plasma brain natriuretic peptide is a biochemical marker for the prediction of progressive ventricular remodeling after acute myocardial infarction Am Heart J 1998;135:21-28.[CrossRef][ISI][Medline]
  29. Suzuki S, Yoshimura M, Nakayama M, et al. Plasma level of B-type natriuretic peptide as a prognostic marker after acute myocardial infarctiona long-term follow-up analysis. Circulation 2004;110:1387-1391.[Abstract/Free Full Text]
  30. Mann DL, Spinale FG. Activation of matrix metalloproteinases in the failing human heartbreaking the tie that binds. Circulation 1998;98:1699-1702.[Free Full Text]
  31. Mann DL. Inflammatory mediators and the failing heartpast, present, and the foreseeable future. Circ Res 2002;91:988-998.[Abstract/Free Full Text]
  32. Spinale FG. Matrix metalloproteinasesregulation and dysregulation in the failing heart. Circ Res 2002;90:520-530.[Abstract/Free Full Text]
  33. Heeneman S, Cleutjens JP, Faber BC, et al. The dynamic extracellular matrixintervention strategies during heart failure and atherosclerosis. J Pathol 2003;200:516-525.[CrossRef][ISI][Medline]
  34. Hayashidani S, Tsutsui H, Ikeuchi M, et al. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction Am J Physiol 2003;285:H1229-H1235.
  35. Ducharme A, Frantz S, Aikawa M, et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction J Clin Invest 2000;106:55-62.[ISI][Medline]
  36. Cleutjens JPM, Blankesteijn WM, Daemen MJAP, Smits JFM. The infarcted myocardiumsimply dead tissue, or a lively target for therapeutic interventions. Cardiovasc Res 1999;44:232-241.[Free Full Text]
  37. Miyamoto S, Nagaya N, Ikemoto M, et al. Elevation of matrix metalloproteinase-2 level in pericardial fluid is closely associated with left ventricular remodeling Am J Cardiol 2002;89:102-105.[CrossRef][ISI][Medline]
  38. Kameda K, Matsunaga T, Abe N, et al. Correlation of oxidative stress with activity of matrix metalloproteinase in patients with coronary artery diseasepossible role for left ventricular remodeling. Eur Heart J 2003;24:2180-2185.[Abstract/Free Full Text]
  39. Sundstrom J, Evans JC, Benjamin EJ, et al. Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measuresthe Framingham Heart Study. Circulation 2004;109:2850-2856.[Abstract/Free Full Text]
  40. Imanaka-Yoshida K, Matsuura R, Isaka N, Nakano T, Sakakura T, Yoshida T. Serial extracellular matrix changes in neointimal lesions of human coronary artery after percutaneous transluminal coronary angioplastyclinical significance of early tenascin-C expression. Virchows Arch 2001;439:185-190.[CrossRef][ISI][Medline]
  41. Kalembeyi I, Inada H, Nishiura R, Imanaka-Yoshida K, Sakakura T, Yoshida T. Tenascin-C upregulates matrix metalloproteinase-9 in breast cancer cellsdirect and synergistic effects with transforming growth factor. Int J Cancer 2003;105:53-60.[CrossRef][ISI][Medline]
  42. Nishiura R, Noda N, Minoura H, et al. Expression of matrix metalloproteinase-3 in mouse endometrial stromal cells during early pregnancyregulation by interleukin-1alpha and tenascin-C. Gynecol Endocrinol 2005;21:111-118.[Medline]
  43. Toma N, Imanaka-Yoshida K, Takeuchi T, et al. Tenascin-C coated on platinum coils for acceleration of organization of cavities and reduction of lumen size in a rat aneurysm model J Neurosurg 2005;103:681-686.[Medline]



This article has been cited by other articles:


Home page
 Circ. Res.Home page
M. S. Penn and A. A. Mangi
Genetic Enhancement of Stem Cell Engraftment, Survival, and Efficacy
Circ. Res., June 20, 2008; 102(12): 1471 - 1482.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
K. E. Kip, K. Hollabaugh, O. C. Marroquin, and D. O. Williams
The Problem With Composite End Points in Cardiovascular Studies The Story of Major Adverse Cardiac Events and Percutaneous Coronary Intervention.
J. Am. Coll. Cardiol., February 19, 2008; 51(7): 701 - 707.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
A. Sato, M. Hiroe, T. Nozato, H. Hikita, Y. Ito, H. Ohigashi, M. Tamura, A. Takahashi, M. Isobe, and K. Aonuma
Early validation study of 64-slice multidetector computed tomography for the assessment of myocardial viability and the prediction of left ventricular remodelling after acute myocardial infarction
Eur. Heart J., February 2, 2008; 29(4): 490 - 498.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
j.jacc.2006.03.033v1
47/11/2319    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sato, A.
Right arrow Articles by Hiroe, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sato, A.
Right arrow Articles by Hiroe, M.

HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK