Prognostic Value of Serum Tenascin-C Levels on Long-Term Outcome After Acute Myocardial Infarction

Journal of Cardiac Failure Vol. 18 No. 6 2012

Prognostic Value of Serum Tenascin-C Levels on Long-Term Outcome After Acute Myocardial Infarction AKIRA SATO, MD,1 MICHIAKI HIROE, MD,2 DAIKI AKIYAMA, MD,3 HIROYUKI HIKITA, MD, PhD,3 TOSHIHIRO NOZATO, MD, PhD,3 TOMOYA HOSHI, MD,1 TAIZO KIMURA, MD, PhD,1 ZHENG WANG, MD,1 SATOSHI SAKAI, MD, PhD,1 KYOKO IMANAKA-YOSHIDA, MD, PhD,4 TOSHIMICHI YOSHIDA, MD, PhD,4 AND KAZUTAKA AONUMA, MD, PhD1 Tsukuba, Tokyo, Yokosuka, and Tsu City, Japan

ABSTRACT Background: Tenascin-C (TN-C), an extracellular matrix glycoprotein, is not normally expressed in the adult heart but transiently reappears under various pathologic conditions to play important roles in tissue remodeling. It is unclear whether serum TN-C levels add prognostic information independent from traditional prognostic markers. Methods and Results: We assessed 239 patients with first ST-segment elevation myocardial infarction who underwent successful percutaneous coronary intervention. We measured serum TN-C and plasma B-type natriuretic peptide (BNP) levels on day 5 after admission and compared long-term clinical outcome. During the follow-up period (24.3 6 13 months), 54 patients experienced primary composite cardiac events (cardiac death or hospitalization for worsening heart failure). Multivariable Cox proportional hazards analysis indicated that serum TN-C (hazard ratio 2.92, 95% confidence interval [CI] 1.55e5.67; P ! .001) and plasma BNP levels (hazard ratio 1.84, 95% CI 1.17e2.97; P 5 .008) were significant independent predictors for cardiac events after adjustment for multiple confounders. The combination of TN-C and BNP resulted in an increase of the c-statistic from 0.821 to 0.877 (P ! .001) and an integrated discrimination improvement gain of 14.0% (P ! .001). Conclusions: Serum TN-C level on day 5 after admission is potentially useful for early risk stratification after AMI beyond established prognostic markers. (J Cardiac Fail 2012;18:480e486) Key Words: Tenascin-C, B-type natriuretic peptide, myocardial infarction, matricellular protein, prognosis.

ability of cardiac biomarkers, including B-type natriuretic peptide (BNP),3,4 cardiac troponins T and I,5,6 C-reactive protein,7 and matrix metalloproteinase (MMP) 9,8 to predict infarct size, LV function, and prognosis after AMI.9 Recent data has shown that LV remodeling is also accompanied by changes in structure and composition of myocardial extracellular matrix (ECM).10 Tenascin-C (TN-C) is an ECM glycoprotein sparsely detected in the healthy adult heart but that is expressed under various pathologic conditions, such as AMI,11,12 myocardial hibernation,13 myocarditis,14,15 and dilated cardiomyopathy,16,17 and is closely associated with inflammation and tissue injury. TN-C synthesized in injured sites could enter the bloodstream and cause elevation of serum TN-C levels in AMI patients. In our previous study of AMI patients, we noted significantly elevated TN-C levels within 24 hours after onset. Levels peaked at day 5 after admission and then gradually decreased, reflecting local expression in the myocardium. Furthermore, we showed that serum peak TN-C levels at day 5 after admission might be a useful

Primary percutaneous coronary intervention (PCI) has improved the prognosis of patients with acute myocardial infarction (AMI)1; however, left ventricular (LV) remodeling occurs in an appreciable proportion of patients with AMI, and LV remodeling after AMI is a major predictor of adverse prognosis.2 Earlier studies have examined the

From the 1Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; 2Department of Cardiology, International Medical Center of Japan, Tokyo, Japan; 3Cardiovascular Center, Yokosuka Kyosai Hospital, Yokosuka, Japan and 4Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu City, Japan. Manuscript received December 4, 2011; revised manuscript received February 23, 2012; revised manuscript accepted February 27, 2012. Reprint requests: Akira Sato, MD, Cardiovascular Division, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan. Tel: þ81-29-853-3143; Fax: þ81-29-853-3143. E-mail: [email protected] See page 486 for disclosure information. 1071-9164/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2012.02.009

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Tenascin-C: Novel Indicator of Prognosis

biomarker for LV remodeling after AMI.12 However, it is unclear whether serum TN-C levels add prognostic information independent from that of traditional prognostic markers and whether there is incremental value in combining serum TN-C levels with plasma BNP levels to predict prognosis after AMI. BNP and TN-C reflect different disease pathways, because BNP is the true ‘‘ventricular’’ hormone and is released from cardiomyocytes in response to increased ventricular wall stress. We hypothesized that serum TN-C levels can add important clinical information on long-term prognosis following AMI beyond that of traditional prognostic markers. In the present study, we evaluated the predictive value of serum TN-C level as a prognostic biomarker in patients with AMI. Methods



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Table 1. Clinical Characteristics of the Patients Characteristic Age (y) Male Hypertension Dyslipidemia Diabetes Current smoker BMI (kg/m2) Reperfusion time (h) Infarct location (anterior/inferior/lateral) Drugs on discharge ACE-I/ARB b-Blockers Statin Diuretics

n 5 239 67 6 11 184 (77%) 135 (57%) 147 (62%) 89 (38%) 139 (59%) 24.7 (22.0e26.3) 7.0 6 5.9 120/84/35 194 102 216 69

(82%) (42%) (90%) (29%)

BMI, body mass index; ACE-I/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker.

Study Population We initially studied a prospective series of 250 patients with first AMI who underwent primary PCI at Yokosuka Kyosai Hospital from January 2005 to February 2008. Inclusion criteria for the study patients were: 1) chest pain O30 minutes in duration and presenting to hospital within 12 hours after onset of symptoms; 2) ST-segment elevation O0.1 mV in 2 contiguous electrocardiographic leads; 3) total occlusion of the infarct-related artery; 4) elevated creatine kinaseeMB (CK-MB) isoenzymes within 12 hours of chest pain; and 5) successful primary coronary angioplasty (defined as Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 and residual stenosis diameter !30%).18 Given the role of TN-C in cancer19,20 and chronic inflammatory disease,21 exclusion criteria were defined as a history of cancer or concomitant cancer and chronic inflammatory disease, such as rheumatoid arthritis, osteoarthritis, and inflammatory bowel disease. Left main trunk occlusion caused cardiogenic shock and death in 3 patients, 5 patients refused to give consent, and 3 patients were lost to follow-up. The remaining 239 patients were the subjects of this study. Clinical characteristics of the AMI patients on hospital admission are described in Table 1. Time to reperfusion was defined as the period from time of onset of symptoms to time of reperfusion. Written informed consent was obtained from each of the patients, and the study protocol was approved by the Institutional Review Board of Yokosuka Kyosai Hospital. Biochemical Analyses Blood samples for plasma BNP, serum TN-C, and creatinine were obtained from all patients on day 5 after admission. Samples were centrifuged at 15,000g for 15 minutes, and resulting supernatants were stored at 80 C until analysis. Serum TN-C levels were determined using an enzyme-linked immunosorbent assay kit with 2 monoclonal antibodies, 4F10TT and 19C4MS (sensitivity 0.01 ng/mL; intra- and interassay precisions !6.6% and !7%, respectively, according to the manufacturer’s instructions; IBL, Gunma, Japan), as previously described.21 Serum CK-MB levels were analyzed by enzymatic means, and plasma BNP concentrations were measured with a commercial kit containing a specific immunoradiometric assay (Shionogi, Osaka, Japan). The estimated glomerular filtration rate (eGFR) values were determined by the following equation: eGFR 5 194  serum creatinine1.094  age0.287  0.739 if female.22

Echocardiographic Assessment Echocardiography was performed immediately before patient discharge by a single operator with a Sonos 6000 cardiac ultrasound system. LV end-diastolic volume (LVEDV), LV endsystolic volume (LVESV), and LV ejection fraction (LVEF) were measured by the modified Simpson method from 2- and 4-chamber views. End Points and Definitions The primary end point was a composite of cardiac deaths or hospitalizations for worsening heart failure (major adverse cardiac events [MACE]). Cardiac death was defined as patient death from heart failure or sudden cardiac death, and heart failure was defined as an unplanned hospital admission, the primary reason for which was clinical heart failure requiring high-dose diuretics, intravenous nitrates, or inotropic support. After hospital discharge, all patients on medications were monitored every month at our outpatient clinic during the follow-up period (24.3 6 13 months). Statistical Analyses All data are expressed as mean 6 SD or median and interquartile range. Comparisons of categoric variables between groups were performed with the chi-square test. Comparisons of continuous variables were analyzed by 1-way analysis of variance or Kruskal-Wallis test. A Cox proportional hazards analysis was performed to identify independent predictors of MACE and cardiac death by using variables including age, TIMI risk score, eGFR, log peak CK-MB, log TN-C, log BNP, and LVEF. Because serum peak CK-MB, TN-C, and plasma BNP level were not normally distributed, we selected log peak CK-MB, log TN-C, and log BNP for analysis. The hazard ratio (HR) for continuous variables is per unit increase. Receiver-operating characteristic (ROC) analysis was used to determine optimal cutoff values of clinical variables for prediction of MACE and cardiac death. The ROC curve represents relationships between sensitivity and specificity by plotting true-positive rates against false-positive rates as the cutoff level of the model varies. The area under the ROC curve (AUC) provides a measure of overall accuracy that is independent from decision criteria. The best cutoff value was defined as the point with the highest sum of sensitivity and specificity. Event-free survival curves for MACE and cardiac death were constructed by the

482 Journal of Cardiac Failure Vol. 18 No. 6 June 2012 Kaplan-Meier method, and statistical differences between curves were assessed by log-rank test. The incremental prognostic value regarding MACE and cardiac death in a model including serum TN-C levels in addition to established prognostic factors was tested by calculating the respective C-statistics. Then integrated discrimination improvement (IDI), a novel method for evaluating improvement in risk discrimination proposed by Pencina et al.,23 was assessed. P values of !.05 were considered to be significant.

Results Patient Characteristics

The 239 patients included in the study comprised 184 men and 55 women with an overall mean age of 67 6 11 years. Baseline clinical characteristics of the patients are summarized in Table 1. Comparison of Clinical Characteristics and LV Parameters Between MACE and Non-MACE Groups

Of the 239 patients, 54 patients (22.6%) suffered MACE during the follow-up period. MACE included 23 (9.2%) cardiac deaths and 31 (13%) episodes of heart failure. Clinical characteristics of the study patients suffering MACE and those without are shown in Table 2. There were no significant differences in sex, reperfusion time, systolic blood pressure, and use of cardiovascular medications between the 2 groups. Age, infarct location, TIMI risk score, peak CK-MB, and TN-C and BNP levels on day 5 after onset of AMI were significantly higher in the MACE group than in the group without MACE, whereas eGFR and LVEF were significantly lower in the MACE group than in the group without MACE. Serum TN-C levels correlated inversely with eGFR (r 5 0.23; P 5 .004; Fig. 2). There was a significant positive correlation between serum TN-C

levels and plasma BNP levels on day 5 (r 5 0.52; P ! .001); however, there was no significant correlation between serum TN-C levels and peak CK-MB levels (r 5 0.03; P 5 .644; Fig. 3). ROC Analysis of Clinical Variables for Predicting MACE and Cardiac Death

We performed ROC analysis of clinical variables, including serum TN-C levels and plasma BNP levels on day 5, _after onset of AMI for predicting MACE and cardiac death. For prediction of MACE, the AUC for peak serum TN-C level was 0.822, and the best cutoff value for a serum TN-C value to predict cardiac death was 104 ng/mL, with a sensitivity of 85% and a specificity of 70%. The AUC for the plasma BNP level on day 5 for prediction of MACE was also high (0.819). The best cutoff value for BNP level on day 5 was 263 pg/mL, with a sensitivity of 73% and a specificity of 82%. For prediction of cardiac death, the AUC for peak serum TN-C level was 0.791, and the best cutoff value for a serum TN-C value to predict cardiac death was 122 ng/mL, with a sensitivity of 82% and a specificity of 70%. The AUC for plasma BNP level on day 5 for prediction of cardiac death was also high (0.761). The best cutoff value for BNP level on day 5 was 371 pg/mL, with a sensitivity of 73% and a specificity of 74%. Survival Curves by Kaplan-Meier Analysis

Patients for whom BNP level was $263 pg/mL or for whom TN-C level was $104 ng/mL had markedly increased risk of MACE (log rank P ! .001; Fig. 1A). Patients for whom BNP level was $371 pg/mL or for whom TN-C level

Table 2. Clinical Characteristics of the Patients in Relation to Major Adverse Cardiac Events (MACE) Characteristic Age (y) Male Hypertension Dyslipidemia Diabetes Current smoker Anterior MI Reperfusion time (h) SBP (mm Hg) TIMI risk score Peak CK-MB (IU/L) TN-C on day 5 (ng/mL) BNP on day 5 (pg/mL) eGFR on day 5 (mL min1 1.73 m2) Post-TIMI flow 3 LVEF (%) Drugs on discharge ACE-I/ARB b-Blockers Statin Diuretics

MACE (þ) (n 5 54)

MACE () (n 5 185)

P Value

71 6 11 40 (76%) 35 (61%) 34 (61%) 24 (45%) 34 (67%) 35 (64%) 7.1 6 6.2 115 6 12 6.6 6 2.8 300 (177e421) 147 (91e177) 354 (158e700) 52.3 6 24.4 43 (80%) 41 6 7

65 6 12 144 (78%) 100 (54%) 113 (61%) 65 (35%) 105 (58%) 83 (46%) 6.5 6 4.9 120 6 12 3.4 6 2.1 216 (100349) 61 (44e91) 100 (59e185) 71.5 6 20.8 164 (89%) 52 6 12

!.001 .563 .251 .867 .416 .624 .023 .573 .411 !.001 .005 !.001 !.001 !.001 .292 .008

41 21 45 23

(76%) (40%) (83%) (43%)

153 81 171 46

(83%) (43%) (92%) (25%)

.317 .726 .210 .144

MI, myocardial infarction; SBP, systolic blood pressure; TIMI, Thrombolysis in Myocardial Infarction; CK-MB, creatine kinaseeMB; TN-C, tenascin-C; BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; ACE-I/ARB, angiotensin-converting enzyme inhibitors/angiotensin receptor blocker.

Tenascin-C: Novel Indicator of Prognosis

was $122 ng/mL had markedly increased risk of cardiac death (log rank P ! .001; Fig. 1B). Univariate and Multivariate Predictors of MACE and Cardiac Death

The results of univariate and multivariate analyses of clinical variables related to MACE and cardiac death are presented in Tables 3 and 4. According to the Cox proportional hazard analysis, log serum TN-C level on day 5 (HR 2.92, 95% confidence interval [CI] 1.55e5.67 [P ! 0.001]; and HR 3.79, 95% CI 1.25e13.0 [P 5 0.017]), log plasma BNP level on day 5 (HR 1.84, 95% CI 1.17e2.97 [P 5 0.008]; and HR 2.46, 95% CI 1.04e6.44 [P 5 0.040]), and eGFR (HR 0.98, 95% CI 0.96e0.99 [P 5 0.047]; and HR 0.96, 95% CI 0.93e0.99 [P 5 0.025]) were independently associated with MACE and cardiac death, respectively, during the follow-up period. Incremental Prognostic Value of Serum TN-C Levels

The C-statistics for TIMI risk score regarding MACE and cardiac death were 0.821 and 0.754, respectively. Addition of serum TN-C and plasma BNP levels individually to the TIMI risk score resulted in a significant increase in the C-statistics and IDI values (Table 5), indicating that each biomarker offered value in predicting MACE and cardiac death beyond that of traditional prognostic factors. Furthermore, addition of the combination of serum TN-C and



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plasma BNP levels to the TIMI risk score for the prediction of MACE increased the C-statistic from 0.821 to 0.877, and the IDI was estimated to be 14.0% (P ! .001). For the prediction of cardiac death, the C-statistic increased from 0.754 to 0.827, and the IDI was estimated to be 10.0% (P ! .001). Discussion The major important findings in this are as follows. First, serum TN-C level measured in patients on day 5 after admission for AMI has a prognostic value similar to that of plasma BNP level, the predictive biomarker of prognosis after AMI. Second, the incorporation of a combination of serum TN-C and plasma BNP levels with the established prognostic markers improved risk stratification for MACE and cardiac death, as evidenced by a substantial increase in the C-statistics and IDI values. Therefore, these findings may provide promising information about early risk stratification of AMI by adding multiple biomarkers that reflect different disease pathways. Characteristics of ventricular remodeling at the cellular level include myocyte hypertrophy and loss, ECM deposition, interstitial fibrosis, and the up-regulation of proinflammatory cytokines. The composition of the cardiac ECM includes structural proteins, such as fibrillar collagen and matricellular proteins, which serve as biologic mediators

Fig. 1. (A) Kaplan-Meier analysis of major adverse cardiac event (MACE)efree survival. The highest MACE rates occurred in acute myocardial infarction (AMI) patients with levels of B-type natriuretic peptide (BNP) $262 pg/mL and tenascin-C (TN-C) $104 ng/mL as measured on day 5 after admission. (B) Kaplan-Meier analysis of cardiac deathefree survival. The highest cardiac death rates occurred in AMI patients with levels of BNP $371 pg/mL and TN-C $122 ng/mL as measured on day 5 after admission.

484 Journal of Cardiac Failure Vol. 18 No. 6 June 2012

Fig. 2. Relation between serum tenascin-C (TN-C) levels and estimated glomerular filtration rate (eGFR). y 5 0.79x þ 148; r 5 0.23; P 5 .004.

of cell function by interacting directly with cells or by modulating the activity of growth factors, cytokines, proteases, and the other ECM proteins.10 Matricellular proteins modulate the fibrotic process in ventricular remodeling, which leads to cardiac dysfunction. TN-C is a typical matricellular protein not normally expressed in adult heart but which transiently appears during pathologic conditions and plays important roles in tissue remodeling.11,14 Our recent study showed that ventricular remodeling in TN-C knockout (KO) mice was significantly reduced, and cardiac function was improved compared with wild-type (WT) mice at day 28 after permanent ligation of a coronary artery.24 Interstitial fibrosis of residual myocardium at day 28 in TN-C KO mice was markedly reduced compared with the WT mice in peri-infarct areas where TN-C normally is deposited during the acute stage. It appears that TN-C plays critical roles in the modulation of responses to myocardial injury and exerts harmful effects on the infarcted heart in later stages. These results correspond to our previous clinical finding that patients with high serum TN-C levels at day 5 after AMI onset have a greater incidence of LV ventricular remodeling.12 Therefore, this finding may suggest that TN-C may

aggravate the progression of ventricular remodeling. Ventricular remodeling is accompanied by changes in ECM during early stages of tissue repair, and several molecules related to matrix turnover, such as MMPs and their tissue inhibitors, have been central to the development of LV remodeling and prognosis after AMI.25 TN-C weakens the adhesion of cardiomyocytes to connective tissues and upregulates MMP expression and activity.11 Therefore, TNC may be a novel candidate for a biomarker of ECM remodeling. In the present study, we performed TN-C sampling at 5 days after AMI onset and found that serum TN-C level has a prognostic value similar to that of plasma BNP. In our previous study of AMI patients, we noted significantly elevated TN-C levels within 24 hours after onset. Levels peaked at day 5 and then gradually decreased, reflecting local expression in the myocardium.12 This time course of serum TN-C levels was previously shown to correspond to local expression of TN-C in infarcted myocardium of rats11 and humans,26 as detected by immunohistochemistry. BNP is secreted from cardiomyocytes in response to increasing cardiac wall stress, whereas TN-C is synthesized in interstitial fibroblasts that have been provoked by various cytokines, growth factors, hypoxia, acidosis, and mechanical stress, all of which could be closely related to myocardial injury and inflammation during the healing process.11,14 TN-C has many biologic effects, including regulation of cell activity during early stages of tissue repair. Previously, it was shown that TN-C activates MMPs, including MMP-9, via transforming growth factor b.27 However, TN-C also has the potential to promote myocardial repair and prevent ventricular dilation by recruitment of myofibroblasts and enhancement of collagen fiber contraction.28 Thus, the effects of TN-C on ventricular remodeling are not simple but rather bidirectional. In the present study, TN-C has prognostic power similar to that of BNP; consideration of both TN-C and BNP levels together provides additive prognostic information after AMI beyond that of traditional prognostic markers by reflecting the condition of both cardiomyocytes and interstitial cells.

Fig. 3. (A) Relationship between serum tenascin-C (TN-C) levels and plasma B-type natriuretic peptide (BNP) levels on day 5 ( y 5 2.38x þ 15.3; r 5 0.52; P ! .001). (B) Relationship between serum TN-C levels and peak creatine kinaseeMB (CK-MB) levels ( y 5 0.09x þ 267; r 5 0.03; P 5 .644).

Tenascin-C: Novel Indicator of Prognosis Table 3. Univariate Analyses of Predictors of Major Adverse Cardiac Events (MACE) and Cardiac Deaths Cardiac Deaths (n 5 23)

MACE (n 5 54) Factor Age TIMI risk score eGFR LVEF Log CK-MB Log TN-C Log BNP

HR (95% CI)

P Value

HR (95% CI)

P Value

1.04 (1.02e1.07) 1.36 (1.25e1.47)

!.001 !.001

1.06 (1.02e1.11) 1.32 (1.17e1.49)

.001 !.001

0.96 0.92 1.77 6.01 3.25

!.001 .006 .001 !.001 !.001

0.95 0.94 1.91 7.62 3.89

!.001 .008 .028 !.001 !.001

(0.95e0.98) (0.85e0.97) (1.23e2.64) (3.82e9.53) (2.36e4.51)

(0.93e0.97) (0.84e0.97) (1.06e3.83) (3.91e15.21) (2.23e7.02)

HR, hazard ratio; CI, confidence interval; TIMI, Thrombolysis in Myocardial Infarction; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; CK-MB, creatine kinase-MB; TN-C, tenascin-C; BNP, B-type natriuretic peptide.

Table 4. Multivariate Analyses of Predictors of Major Adverse Cardiac Events (MACE) and Cardiac Deaths Cardiac Deaths (n 5 23)

MACE (n 5 54) Factor

HR (95% CI)

TIMI risk score eGFR LVEF Log CK-MB Log TN-C Log BNP

1.07 (0.94e1.21) 0.98 0.95 1.96 2.92 1.84

(0.96e0.99) (0.84e1.04) (1.23e3.26) (1.55e5.67) (1.17e2.97)

P Value .282 .047 .257 .003 !.001 .008

HR (95% CI)

P Value

1.11 (0.87e1.46)

.375

0.96 0.92 1.70 3.79 2.46

.025 .190 .178 .017 .040

(0.93e0.99) (0.71e1.07) (0.79e4.10) (1.25e13.0) (1.04e6.44)

HR, hazard ratio; CI, confidence interval; TIMI, Thrombolysis in Myocardial Infarction; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; CK-MB, creatine kinase-MB; TN-C, tenascin-C; BNP, B-type natriuretic peptide.

Renal function is a well known predictor after AMI and hospitalization for heart failure.29,30 In the present study, eGFR was also a significant predictor of MACE and cardiac death. Furthermore, there was a significant inverse correlation between eGFR and serum TN-C levels, suggesting that serum TN-C may accumulate when renal function declines.31 Although TN-C and BNP represent two different pathophysiologic processes, infarcts will likely cause substantial elevations in both biomarkers correlatively. BNP



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synthesis is increased with cardiac injury, whereas TN-C molecules resulting from ECM metabolism are synthesized by ‘‘interstitial’’ cells residing in injured sites. However, peaks of TN-C levels did not significantly correlate with peaks of CK-MB levels, indicating that elevation of TN-C levels might not directly reflect cardiomyocyte death but rather reflect tissue remodeling activity instead of damage to cardiomyocytes. Clinical Implications

Our previous study suggested that serum TN-C might be a useful biomarker reflecting active structural remodeling in the myocardium at 6 months after AMI, with high TN-C levels at acute stages possibly predicting progression of LV remodeling.12 In the present study, we confirmed in a larger sample size that higher serum concentration of TN-C was powerfully associated with greater risk of adverse prognosis during the mean follow-up of 24 months, and we expanded our data for a new biomarker from the ECM. Furthermore, consideration of both TN-C and BNP levels provides additive prognostic information as very early predictive biomarkers for clinical events after AMI with a novel method for evaluating improvement in risk discrimination. If this observation is confirmed by further studies, then a combination of TN-C and BNP levels may be used to risk-stratify post-AMI patients, potentially identifying more patients who would benefit from enhanced, tailored therapy, such as increased doses of angiotensin-converting enzyme inhibitors, b-blockers, and/or an aldosterone antagonist. Study Limitations

The present study has some limitations. First, the sample size was relative small. The prognosis of our patients undergoing primary PCI was good, with 23 cardiac deaths during the follow-up period. Therefore, the ability to predict cardiac death could be limited. Second, we chose CK-MB as an alternative to cardiac troponin, which has been established for diagnosis and which also provides robust prognostic information.32 Third, we did not measure other markers of ECM, such as MMPs, tissue inhibitors of MMPs, type I collagen carboxyterminal telopeptide, and procollagen type I carboxy-terminal propeptide. A multicenter trial will be necessary to confirm the clinical value

Table 5. Incremental Value of Biomarkers Regarding Major Adverse Cardiac Events (MACE) and Cardiac Deaths MACE (n 5 54) Variables TIMI TIMI TIMI TIMI

risk risk risk risk

score score þ BNP score þ TNC score þ BNP þ TNC

Cardiac Deaths (n 5 23)

C-Statistic

IDI (%)

C-Statistic

IDI (%)

0.821 0.845y 0.875z 0.877z

Referent 5.3y 10.4z 14.0z

0.754 0.774* 0.816z 0.827z

Referent 4.0* 9.9z 10.0z

IDI, integrated discrimination improvement; TIMI, Thrombolysis in Myocardial Infarction; BNP, B-type natriuretic peptide; TN-C, tenascin-C. *P ! .05. y P ! .01. z P ! .001 (for difference from TIMI risk score).

486 Journal of Cardiac Failure Vol. 18 No. 6 June 2012 of serum TN-C level as a predictive biomarker for future clinical events after AMI.

13.

Conclusion 14.

Inclusion of serum TN-C level measured on day 5 after admission for AMI is potentially useful in addition to established prognostic markers for early risk stratification of patients after AMI. Identification of this and other biomarkers will lead to more aggressive follow-up and medical intervention as potential strategies to prevent MACE and cardiac deaths. Disclosures

15.

16.

17.

None.

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