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The prognostic use of serum concentrations of cardiac troponin-I, CK-MB and myoglobin in patients with idiopathic dilated cardiomyopathy
Heart & Lung 43 (2014) 219e224
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The prognostic use of serum concentrations of cardiac troponin-I, CK-MB and myoglobin in patients with idiopathic dilated cardiomyopathy Xiaoping Li, MD, PhD a, b, *, Rong Luo, PhD c, Rongjian Jiang, MD a, Hong Kong, MD a, Yijia Tang, MD a, Yan Shu, MD a, Wei Hua, MD, PhD b, ** a
Department of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China c The Center of Heart Development, Key Lab of MOE for Development Biology and Protein Chemistry, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, China b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 October 2013 Received in revised form 28 February 2014 Accepted 1 March 2014
Objective: To examine the association between survival and serum concentrations of cTnI, CK-MB, and myoglobin in patients with idiopathic dilated cardiomyopathy (IDC). Background: It has been suggested that elevated circulating biomarkers of myocardial damage such as cardiac troponin-I (cTnI), creatine kinase MB (CK-MB) and myoglobin are independent risk factors for mortality in patients with heart failure, and recent studies, although limited, showed that there was a potential association between cTnI and the prognosis of patients with dilated cardiomyopathy (DCM). Methods: A cohort study was undertaken in 310 patients with IDC. Standard demographic information, transthoracic echocardiography, and routine blood tests were obtained shortly after hospital admission. Outcome was assessed with all-cause mortality. Results: Among the 310 patients studied, 61 (19.7%) died during a mean follow-up of 2.2 years. There was a significant difference in the all-cause mortality rate between patients with serum cTnI >0.05 ng/mL and with cTnI 0.05 ng/mL (37.5% vs 15%, log-rank c2 ¼ 18.423, P < 0.001). After adjustment for other factors associated with prognosis at baseline, serum cTnI >0.05 ng/mL, QRS duration, NYHA functional class and systolic blood pressure predicted all-cause mortality in patients with IDC. There was no association between circulating CK-MB and myoglobin levels and all-cause mortality in the studied IDC patients. Conclusion: Serum concentrations of cTnI but not CK-MB or myoglobin are an independent predictor of all-cause mortality in patients with IDC. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Cardiac troponin-I CK-MB Myoglobin Idiopathic dilated cardiomyopathy Prognosis
Introduction Abbreviations: DCM, Dilated cardiomyopathy; cTnI, Cardiac troponin-I; CK-MB, Creatine kinase MB; CMR, Cardiovascular magnetic resonance; MIBG, (123) I-metaiodobenzylguanidine; HF, Heart failure; IDC, Idiopathic dilated cardiomyopathy; LV, Left ventricular; LVEDd, Left ventricular end-diastolic diameter; LVEF, Left ventricular ejection fraction; NYHA, New York Heart Association; LA, Left atrial; NT pro-BNP, N-terminal fragment pro-brain natriuretic peptide; CK, Creatine kinase; LDH, Lactate dehydrogenase; RV, Right ventricle. * Corresponding author. Department of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China. Tel.: þ86 28 87393927; fax: þ86 28 87394013. ** Corresponding author. Cardiac Arrhythmia Center, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China. Tel.: þ86 10 88398290; fax: þ86 10 68313019. E-mail addresses: [email protected] (X. Li), [email protected] (W. Hua). 0147-9563/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2014.03.001
Dilated cardiomyopathy (DCM), the most common cardiomyopathy, is a disease of the heart muscle characterized by ventricular dilatation and impaired systolic function.1 Although significant progress has been made in the treatment of DCM, patients continue to have a poor quality of life and an unacceptably high mortality, and prediction of death in patients with DCM is still challenging.2 Recently, serum C-reactive protein, (123) I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, cardiovascular magnetic resonance (CMR), cardiac troponin-I (cTnI), ect3e6 were reported as prognostic factors in DCM patients. Among these predictors, cTnI was easier and more inexpensive to perform in clinic practice.
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Circulating cTnI, creatine kinase MB (CK-MB) and myoglobin are biochemical markers of myocardial injury; the diagnostic and prognostic value of these biomarkers has been firmly established in acute coronary syndrome,7e11 and these markers are currently the subject of extensive research in patients with heart failure (HF). Elevated circulating cTnI and CK-MB levels predicted poor outcomes in HF patients12e19; however, there is relatively little data regarding the prognostic value of circulating cTnI, CK-MB and myoglobin in DCM. Two small studies that attempted to address the role of circulating cTnI as a prognostic factor in patients with DCM had inconsistent results.6,20 Therefore, the present study aimed to further explore the prognostic implications of circulating cTnI, CKMB and myoglobin concentrations in idiopathic dilated cardiomyopathy (IDC). Subjects and methods Patients and follow-up A retrospective, observational cohort study of 336 patients admitted to the hospital with IDC was performed from 2006 to 2011 in Fuwai Hospital. Patients were admitted for clinical decompensation with symptoms and physical signs of HF. IDC was defined as systolic dysfunction [left ventricular (LV) ejection fraction <50%] with LV dilation in the absence of an apparent secondary cause of cardiomyopathy, the LV dilation was defined as left ventricular end-diastolic diameter (LVEDd) >55 mm for males or LVEDd >50 mm for females.21 Of the 336 enrolled patients, 61 patients underwent coronary angiography, 117 underwent cardiovascular magnetic resonance (CMR) examination, 58 underwent cardiac CT scan and 49 undertaken cardiac nuclear examination. Patients with cardiomyopathy secondary to the following conditions were excluded from the study: ischemic heart disease (19 patients), thyroid disease (3 patients), congenital heart disease (2 patients), left ventricular noncompaction (1 patient) and chronic anemia (hemoglobin <60 g/L; 1 patient). Thus, the final analysis included 310 patients. The endpoint of the study was all-cause mortality, which was assessed for all patients by medical record review and follow-up calls. Mortality data were obtained for all study patients from hospitalization to death. The follow-up rate was 93.2%, with a mean follow-up of 2.2 years, and the study protocol was approved by the Ethics Commission of Fuwai Hospital. Laboratory screening Fasting blood samples were obtained 12e36 h after admission. Peripheral venous blood was collected in tubes without additives, and serum was analyzed for cTnI, CK-MB and myoglobin within 4 h. Serum cTnI, CK-MB and myoglobin levels were measured using an electrochemiluminescent immunoassay with Access AccuTnI Reagent, Access AccuCK-MB Reagent, and Access AccuMyoglobin Reagent, respectively (Beckman Coulter, Inc., USA). In all of the assays, both the intra- and inter-assay coefficients of variation were 10.0%. Echocardiography Patients were imaged in the left lateral decubitus position using a commercially available system equipped with a 3.5 MHz transducer. Two-dimensional grayscale, pulsed, continuous, and color Doppler images were acquired at the parasternal and apical views. Left ventricular ejection fraction (LVEF) was calculated as 100 (LV end-diastolic volume e LV end-systolic volume)/LV end-diastolic volume by the biplanar Simpson’s technique.22
Statistical analysis Continuous variables are expressed as the mean SD or medians and interquartile ranges. Comparisons of categorical variables among groups were made using chi-square tests. The independent t-test was used for comparison of means between two groups. Pearson correlation and multivariable linear regression analysis were used to test the associations between baseline variables and cTnI. KaplaneMeier survival curves were compared using the logrank test. Cox proportional hazard models were used to estimate the univariate and multivariable hazards of all-cause mortality associated with each individual parameter. The following covariates (which were found to be statistically significant in univariate Cox analysis) were used in the multivariable models: New York Heart Association (NYHA) functional class, systolic blood pressure (SBP), QRS duration, LV and left atrial (LA) diameters, LVEF, N-terminal fragment pro-brain natriuretic peptide (NT pro-BNP) and cTnI >0.05 ng/mL. Statistical analyses were performed using SPSS statistical software (version 16.0, SPSS Inc., Chicago, IL, USA). P values of <0.05 were considered statistically significant, and all statistical tests were two-sided tests.
Results Characteristics of the study population The cohort consisted of 310 patients with IDC; 74 (23.9%) were women, and 236 were (76.1%) men, with a mean age of 51.8 14.3 years. Of these, 20.6% (n ¼ 64) had increased serum cTnI (>0.05 ng/ mL), and 79.4% (n ¼ 246) had normal circulating cTnI (0.05 ng/ mL). Table 1 summarize the baseline clinical characteristics of the cohort. Compared to patients with normal cTnI levels, patients with increased cTnI had higher circulating levels of fasting blood glucose, creatinine, creatine kinase (CK) and lactate dehydrogenase (LDH), longer PR intervals, larger LVED, LA, and right ventricle (RV) diameters, and less frequent usage of beta-blockers, aspirin/anticoagulation and spironolactone at admission. Compared to the patients with normal CK-MB, patients with increased CK-MB (>1.0 ng/mL) also had higher fasting glucose, CK, LDH, NT proBNP, larger RV diameters, lower triglyceride levels, as well as less usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and aspirin. Compared to the patients with normal myoglobin, patients with increased myoglobin had higher creatinine, blood urea nitrogen and CK levels, as well as smaller RV diameters.
Association of baseline variables with cTnI concentrations In this study, Pearson correlation analysis showed that serum LDH levels (r ¼ 0.200, P < 0.001) and the presence of diabetes mellitus (r ¼ 0.116, P ¼ 0.041) were positively correlated with cTnI concentrations. The multivariable linear regression models used the following covariates: age, gender, history of DM, NYHA functional class, smoking and drinking status, blood pressure, QRS duration, left ventricle diameter, LVEF and serum LDH concentrations; this analysis showed that serum LDH concentration (P ¼ 0.01) and DM (P ¼ 0.028) were independent predictors of serum cTnI concentrations. Although serum CK-MB concentrations were elevated in patients with cTnI >0.05 ng/mL, there was no association between serum CK-MB and cTnI concentrations in our study.
Table 1 Patient characteristics categorized by serum concentrations of cTn-I, CK-MB and myoglobin.a cTnI >0.05 ng/mL cTnI 0.05 ng/mL (n ¼ 64) (n ¼ 246)
51.8 14.3 74 (23.9)
50.6 15.3 13 (20.3)
52.1 14.0 61 (24.8)
0.432 0.453
52.56 13.9 37 (23.0)
51.0 15.3 27 (24.5)
51 (16.5) 148 (47.7) 103 (33.2) 246 (79.4)
11 27 19 55
40 (16.3) 121 (49.2) 84 (34.1) 191 (77.6)
0.859 0.318 0.500 0.144
25 (15.5) 75 (46.6) 56 (34.8) 128 (79.5)
20 51 34 90
114.2 18.0 73.2 12.7 80.6 16.3
111.0 16.2 70.8 11.3 81.8 19.9
115.1 18.4 73.8 13.0 80.3 15.3
0.106 0.092 0.509
5.63 1.77 1.72 1.14 4.52 1.08 93.2 37.1 8.24 3.66 56 (40e86.5) 193 (165e233) 2037.4 1530.0
6.03 2.74 1.50 0.79 4.36 1.06 102.5 58.0 8.91 4.14 65 (39e118) 230 (183e323) 2775.3 1605.2
121.9 32.5 406.7 52.2
124.6 33.0 407.9 58.0
68.2 31.2 23.7 44.0
296 260 282 248 212 289
(95.5) (83.9) (91.0) (80.0) (68.4) (93.2)
9.3 8.4 5.1 7.2
(17.2) (42.2) (29.7) (85.9)
70.7 29.6 24.9 46.2 60 51 54 50 35 55
10.8 7.7 4.1 7.3
(93.8) (79.7) (84.4) (78.1) (54.7) (85.9)
Myoglobin P value 60 ng/mL (CK-MB 1.0 ng/mL (n ¼ 164) vs CK-MB >1.0)
Myoglobin >60 ng/mL (n ¼ 107)
P value (Myoglobin60 vs > 60 ng/mL)
0.382 0.766
50.2 14.6 41 (25)
54.2 14.2 23 (21.5)
0.025 0.507
(18.2) (46.8) (31.2) (81.8)
0.564 0.972 0.506 0.637
31 (18.9) 70 (42.7) 57 (34.8) 128 (78)
15 55 31 90
(14.0) (51.4) (29.0) (84.2)
0.295 0.159 0.320 0.219
114.9 18.8 74.4 13.1 80.4 15.3
112.5 16.8 72.3 12.1 82.7 18.1
0.301 0.190 0.261
1141 17.3 73.7 12.8 81.8 17.2
112.7 17.2 72.7 12.1 81.1 15.9
0.514 0.506 0.739
5.52 1.41 0.044 1.78 1.21 0.095 4.57 1.08 0.177 90.8 29.1 0.026 8.06 3.51 0.101 53.5 (40e77) 0.021* 187 (158.75e221.75) <0.001* 1868.3 1464.6 0.526
5.38 1.33 1.85 1.21 4.57 1.07 92.6 30.0 8.19 3.63 53 (39e75.5) 183 (157e220) 1915.0 1356.1
6.06 2.34 0.003 1.53 1.05 0.026 4.35 0.98 0.099 91.6 28.5 0.787 8.34 362 0.733 62.5 (42e102) 0.001* 211 (179.5e289.75) <0.001* 2436.1 1748.9 0.012
5.64 1.57 1.65 1.08 4.44 1.01 87.2 29.8 7.58 3.04 54 (39e80) 190 (164e229.5) 2062.1 1363.9
5.67 2.17 1.78 1.23 4.50 1.03 98.5 27.3 9.09 3.95 59.5 (41.75e91.5) 205 (169.75e248.25) 2191.0 1763.3
0.882 0.386 0.661 0.002 0.001 0.012* 0.313* 0.536
121.2 32.4 407.0 50.8
0.470 0.908
121.0 32.6 406.3 50.4
124.2 34.6 405.8 58.7
0.434 0.946
119.6 31.4 403.1 55.9
126.6 35.9 410.0 51.4
0.097 0.311
67.6 31.6 23.4 43.4
8.8 8.5 5.3 7.0
0.017 0.104 0.050 0.007
67.1 30.9 23.4 43.7
0.066 0.925 0.028 0.184
68.1 30.8 24.6 44.4
9.7 8.1 4.0 7.4
0.906 0.792 0.028 0.409
236 209 228 198 177 234
(95.9) (85.0) (92.7) (80.5) (72.0) (95.1)
0.453 0.307 0.039 0.674 0.008 0.009
157 144 151 135 119 152
(97.5) (89.4) (93.8) (83.9) (73.9) (94.4)
0.203 0.001 0.022 0.662 0.035 0.575
157 137 149 135 118 154
(95.7) (83.5) (90.9) (82.3) (72.0) (93.9)
104 (97.2) 89 (83.2) 96 (89.7) 89 (83.2) 68 (63.6) 100 (93.5)
0.532 0.938 0.757 0.855 0.145 0.883
CK-MB P value 1.0 ng/mL (cTnI >0.05 ng/mL (n ¼ 161) vs cTnI 0.05 ng/mL)
8.7 8.2 4.6 6.7
CK-MB >1.0 ng/mL (n ¼ 110)
69.3 30.8 24.9 44.9
10.3 8.4 5.9 7.8
104 (94.5) 82 (74.5) 94 (85.5) 90 (81.8) 68 (61.8) 102 (92.7)
9.3 8.1 5.7 7.1
68.2 31.1 23.1 43.6
X. Li et al. / Heart & Lung 43 (2014) 219e224
Age (years) Female, n (%) History Diabetes mellitus, n (%) Smoker, n (%) Drinker, n (%) NYHA class III and IV, n (%) Admission vital signs SBP (mm Hg) DBP (mm Hg) Heart rate, beats/min Laboratory values at admissionc Glucose (mmol/L) Triglycerides (mmol/L) TC (mmol/L) Creatinine (umol/L) BUN (umol/L) CK (IU/L)b LDH (IU/L)b NT Pro-BNP (fmol/mL) Electrocardiogram datac QRS duration (ms) QT (ms) Echocardiography datac LV (mm) LVEF (mm) RV (mm) LA (mm) Medicine at admission Diuretics, n (%) ACEI/ARB, n (%) Beta-blockers, n (%) Digoxin, n (%) Aspirin/anticoagulation n (%) Spironolactone, n (%)
All patients (n ¼ 310)
NYHA, New York Heart Association; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; BUN, blood urea nitrogen; LDH, lactate dehydrogenase; CK-MB, creatine kinase MB; CK, creatine kinase; NT pro-BNP, N-terminal fragment pro-brain natriuretic peptide; LV, left ventricle; LA, left atrium; LVEF, left ventricular ejection fraction; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker. p < 0.05 was considered to be statistically significant and the values were given in bold font. a Data are expressed as the mean SD, median (interquartile range) or percentages. b *indicates that the P value was analyzed and the data were normalized by log-arithmetic transformation. c Eight patients lacked data on electrocardiograms, 4 patients lacked echocardiography data, 10 patients lacked AST/ALT levels, 7 patients lacked fasting blood glucose levels, 3 patients lacked creatinine and BUN levels, 4 patients lacked CK levels, 39 patients lacked CK-MB and myoglobin levels, 3 patients lacked LDH levels, and 58 patients lacked NT pro-BNP levels.
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Relation between cTnI, CK-MB, myoglobin concentrations and allcause mortality Among the 310 patients studied, 61 died during a mean followup of 2.2 years. Fig. 1 displays mortality rates within the subgroups. Of the patients who died, 37 had normal cTnI levels (0.05 ng/mL) and 24 had increased cTnI levels (>0.05 ng/mL). There was a significant difference in all-cause mortality risk between the two groups (log-rank c2 ¼ 18.423, P < 0.001). There was no significant difference in the all-cause mortality between patients with CK-MB 1.0 ng/mL and CK-MB >1.0 ng/mL (16.8% vs 22.7%, log-rank c2 ¼ 2.270, P ¼ 0.132); in addition, there was no significant difference in the all-cause mortality between patients with myoglobin 60 ng/mL and myoglobin >60 ng/mL (20.7% vs 16.8%, log-rank c2 ¼ 0.633, P ¼ 0.426). Cox proportional hazard models Table 2 summarizes the results of the Cox models, in which each of the parameters was entered separately as the mortality explanatory variable. After adjustment for disease duration, LVED and LA diameter, and LVEF and NT pro-BNP, the Cox multivariable analysis showed that serum cTnI >0.05 ng/mL, QRS duration and SBP were the most powerful independent predictors of all-cause mortality in patients with IDC. Neither CK-MB >1.0 ng/mL or myoglobin >60 ng/mL was a significant predictor of all-cause mortality in IDC patients in either univariate or multivariate Cox analysis. Discussion This study demonstrates that an elevated level of serum cTnI is an independent predictor of increased all-cause mortality in patients with IDC and that the clinical baseline variables of serum LDH concentration and underlying DM were independent predictors of cTnI concentrations. CK-MB and myoglobin levels did not predict all-cause mortality in IDC patients. Cardiac troponins (troponin I, T and C) are 3-unit complex intracellular contractile-regulating proteins of the cardiac muscle and are essential for calcium-mediated regulation of cardiac muscle contraction. They are tissue-specific isoforms of troponin I, T and C.23 Cardiac troponins in blood are the preferred markers for diagnosing myocardial damage. As troponins are normally not found in the circulation, these markers have high clinical sensitivity and specificity, even when cardiac lesions are small.24 The use of these markers in acute coronary syndromes has prompted a revision of the criteria for diagnosis of myocardial infarction by the Joint European Society of Cardiology/American College of Cardiology Committee.10,11 The relationship between cTnI and chronic HF has been studied in various clinical settings, and the presence of troponin in decompensated chronic HF has been found to be associated with more profound clinical and hemodynamic deterioration, more extensive left ventricle remodeling, and worse shortand long-term prognosis.14e16,25e28 Recently, two studies addressed the association of circulating cTnI concentration with outcomes in patients with DCM.6,20 Nellessen et al6 found that permanent cTnI release is a common finding in DCM and is a strong prognosticator in patients with DCM (n ¼ 58); however, another study of 40 patients with DCM suggested that cTnI concentrations at baseline were not significantly different between survivors and patients who died.20 Lower levels of serum cTnI in chronic HF or DCM could signify the presence of limited, irreversible myocyte injury and death or could represent leakage of the cytosolic pool of cTnI due to a loss of cell
Fig. 1. KaplaneMeier survival curves for idiopathic dilated cardiomyopathy patients with elevated cardiac troponin-I (>0.05 ng/mL), CK-MB (>1.0 ng/mL) and myoglobin (>60 ng/mL), respectively.
X. Li et al. / Heart & Lung 43 (2014) 219e224
Conclusions
Table 2 Cox regression analysis of all-cause mortality in patients with DCM. Variable
Univariate analysis HR
Age Gender NYHA functional class Disease duration Smoker Drinker Heart rate Systolic blood pressure Diastolic blood pressure QRS duration Left ventricular diameter Left atrial diameter LVEF NT pro-BNPa cTnI >0.05 ng/mL Myoglobin >60 ng/mL CK-MB >1.0 ng/mL
95% CI
Multivariable analysis P value HR
95% CI
P value
1.009 0.991e1.028 1.409 0.819e2.423 2.522 1.681e3.784
0.321 e e e 0.216 e e e <0.001 1.601 0.946e2.707 0.079
1.023 1.001 0.813 0.999 0.963
0.202 0.995 0.244 0.898 <0.001
0.988e1.059 0.755e1.327 0.573e1.152 0.984e1.015 0.946e0.980
0.961 0.939e0.984 1.013 1.006e1.020 1.057 1.030e1.085 1.052 0.950 4.750 2.928 0.793
e e e e 0.973
0.001 e
1.515 0.879e2.611
e e e e 0.952e0.995
e e e e 0.018
e
e
0.001 1.012 1.003e1.022 0.012 <0.001 1.008 0.965e1.052 0.721
1.014e1.091 0.006 1.019 0.922e0.978 0.001 0.980 1.893e11.918 0.001 1.522 1.750e4.899 <0.001 2.725 0.448e1.405 0.428 e 0.135 e
223
0.973e1.020 0.941e1.020 0.556e4.164 1.409e5.271 e
0.422 0.319 0.413 0.003 e
e
e
The variables analyzed in the multivariate Cox model included disease duration, NYHA functional class, systolic blood pressure, QRS duration, left ventricular diameter, left atrial diameter, LVEF, NT Pro-BNP and TnI >0.05 ng/mL. p < 0.05 was considered to be statistically significant and the values were given in bold font. a NT Pro-BNP was normalized by log-arithmetic transformation.
membrane integrity during reversible injury.29 Progressive myocyte loss through necrotic and apoptotic cell death is increasingly recognized as a prominent pathophysiologic mechanism in the evolution of cardiac dysfunction in HF and DCM.15,30e32 In addition, changes in mechanical loading in the ventricles of patients with DCM can upregulate kinases such as c-Jun N-terminal kinase (JNK1/2) and p38 kinase and cause circulating cTnI concentrations to increase.33 Therefore, circulating cTnI appears to be correlated with the pathophysiology and evolution of cardiac dysfunction in chronic HF and DCM. In the present study, circulating cTnI levels were correlated with the presence of DM in IDC patients. Elevated circulating cTnI levels were associated with larger LV, LA and RV diameters, along with a higher mortality rate in IDC patients, indicating the presence of an association between cTnI levels and cardiac remodeling. Although limited studies have shown that circulating CK-MB is a marker of deterioration in chronic HF or DCM,18,19 we did not find any association between all-cause mortality and elevated serum CK-MB or myoglobin levels in the present study. Limitations The present study has several limitations, including the fact that it is a retrospective analysis. As with many studies of chronic disease, the time of disease onset is not precisely known, and variations in the length of the preclinical phase of disease can influence the relationship between serum cTnI concentrations and death. In addition, there were a few patients with ischemic heart disease in the present study, possibly because some patients had undergone coronary artery angiography or cardiac CT scan in the other hospitals before they were admitted to our hospital. Finally, it is well known that renal insufficiency can be a cause for a non-specific elevation in troponins, and there were 27 patients with plasma creatinine 130 mmol/L in the present study, therefore, the influence of the renal insufficiency on the serum concentrations of cTnI did not exclude in the present study.
In this cohort of patients with IDC, serum cTnI concentration (but not CK-MB or myoglobin) was a significant predictor of increased all-cause mortality rates. Patients with increased serum concentrations of cTnI (>0.05 ng/mL) were at particularly high risk of death. Serum cTnI may be a novel and useful tool in identifying patients with IDC who are at increased risk of death and are likely to benefit from aggressive treatment strategies. Acknowledgments This study was supported in part by grants from the National Natural Science Foundation of China (no. 81000104), the China Postdoctoral Science Foundation (no. 2012M510356) and the Postdoctoral Fellows Foundation of the Chinese Academy of Medical Sciences (no. 2011-XH-9). Competing interests: The authors declare that they have no competing interest. References 1. Richardson P, McKenna W, Bristow M, et al. Report WHOISFCTFDCC: report, of the 1995 World Health Organization/International society and Federation of Cardiolgy Task Force on the Definition and Classification of cardiomyopathies. Circulation. 1996;93:841e842. 2. Grogan M, Redfield MM, Bailey KR, et al. Long-term outcome of patients with biopsy-proven myocarditis: comparison with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1995;26:80e84. 3. Ishikawa C, Tsutamoto T, Fujii M, Sakai H, Tanaka T, Horie M. Prediction of mortality by high-sensitivity C-reactive protein and brain natriuretic peptide in patients with dilated cardiomyopathy. Circ J. 2006;70:857e863. 4. Momose M, Okayama D, Nagamatsu H, Kondo C, Hagiwara N, Sakai S. Longterm prognostic stratification by a combination of (123)I-metaiodobenzylguanidine scintigraphy and ejection fraction in dilated cardiomyopathy. Ann Nucl Med. 2011;25:419e424. 5. Gulati A, Ismail TF, Jabbour A, et al. Clinical utility and prognostic value of left atrial volume assessment by cardiovascular magnetic resonance in nonischaemic dilated cardiomyopathy. Eur J Heart Fail. 2013;15:660e670. 6. Nellessen U, Goder S, Schobre R, Abawi M, Hecker H, Tschöke S. Serial analysis of troponin I levels in patients with ischemic and nonischemic dilated cardiomyopathy. Clin Cardiol. 2006;29:219e224. 7. Donnelly R, Millar-Craig MW. Cardiac troponins: IT upgrade for the heart. Lancet. 1998;351:537e539. 8. Coudrey L. The troponins. Arch Intern Med. 1998;158:1173e1180. 9. Christenson RH, Azzazy HM. Biochemical markers of the acute coronary syndromes. Clin Chem. 1998;44:1855e1864. 10. Heidenreich PA, Alloggiamento T, Melsop K, McDonald KM, Go AS, Hlatky MA. The prognostic value of troponin in patients with noneST elevation acute coronary syndromes: a meta-analysis. J Am Coll Cardiol. 2001;38:478e485. 11. The Joint ESC/ACC Committee. Myocardial infarction redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J. 2000;21:1502e1513. 12. Peacock 4th WF, De Marco T, Fonarow GC, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med. 2008;358:2117e2126. 13. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008;358(20): 2148e2159. 14. La Vecchia L, Mezzena G, Zanolla L, et al. Cardiac troponin I as diagnostic and prognostic marker in severe heart failure. J Heart Lung Transplant. 2000;19: 644e652. 15. Logeart D, Beyne P, Cusson C, et al. Evidence of cardiac myolysis in severe nonischemic heart failure and the potential role of increased wall strain. Am Heart J. 2001;141:247e253. 16. Horwich TB, Patel J, MacLellan WR, Fonarow GC. Cardiac troponin I is associated with impaired hemodynamic, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation. 2003;108: 833e838. 17. Setsuta K, Seino Y, Ogawa T, Arao M, Miyatake Y, Takano T. Use of cytosolic and myofibril markers in detection of ongoing myocardial damage in patients with chronic heart failure. Am J Med. 2002;113:717e722. 18. Hossein-Nia M, Baig K, Goldman JH, et al. Creatine kinase isoforms as circulating markers of deterioration in idiopathic dilated cardiomyopathy. Clin Cardiol. 1997;20:55e60. 19. Sugiura T, Takase H, Toriyama T, Goto T, Ueda R, Dohi Y. Circulating levels of myocardial proteins predict future deterioration of congestive heart failure. J Card Fail. 2005;11:504e509.
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20. Miller WL, Hartman KA, Burritt MF, Burnett Jr JC, Jaffe AS. Troponin, B-type natriuretic peptides and outcomes in severe heart failure: differences between ischemic and dilated cardiomyopathies. Clin Cardiol. 2007 May;30: 245e250. 21. Luk A, Ahn E, Soor GS, Butany J. Dilated cardiomyopathy: a review. J Clin Pathol. 2009;62:219e225. 22. Lang RM, Bierig M, Devereux RB, et al, Chamber Quantification Writing Group; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440e1463. 23. Biesiadecki BJ, Cong SM, Nosek TM, Jin JP. Troponin T core structure and the regulatory NH2-terminal variable region. Biochemistry. 2007;46: 1368e1379. 24. Göser S, Andrassy M, Buss SJ, et al. Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the m-yocardium. Circulation. 2006;114:1693e1702.
25. Missov E, Calzolari CH, Pau B. Circulating cardiac troponin I in severe congestive heart failure. Circulation. 1997;96:2953e2958. 26. Setsuta K, Seino Y, Takahashi N, et al. Clinical significance of elevated levels of cardiac troponin T in patients with chronic heart failure. Am J Cardiol. 1999;84: 608e611. 27. Del Carlo CH, O’Connor CM. Cardiac troponins in congestive heart failure. Am Heart J. 1999;138:646e653. 28. La Vecchia L, Mezzena G, Ometto R, et al. Detectable serum troponin I in patients with heart failure of nonmyocardial ischemia origin. Am J Cardiol. 1997;80:87e90. 29. Wu AH, Ford L. Release of cardiac troponin in acute coronary syndromes: ischemia or necrosis? Clin Chim Acta. 1999;284:161e174. 30. Mann DL. Mechanisms and models in heart failure. Circulation. 1999;100:999e 1008. 31. Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, et al. Apoptosis in the failing human heart. N Engl J Med. 1997;336:1131e1141. 32. Anversa P, Kajstura J. Myocyte cell death in the diseased heart. Circ Res. 1998;82:1231e1233. 33. Haq S, Choukroun G, Lim H, et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation. 2001;103:670e677.
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The prognostic use of serum concentrations of cardiac troponin-I, CK-MB and myoglobin in patients with idiopathic dilated cardiomyopathy Xiaoping Li, MD, PhD a, b, *, Rong Luo, PhD c, Rongjian Jiang, MD a, Hong Kong, MD a, Yijia Tang, MD a, Yan Shu, MD a, Wei Hua, MD, PhD b, ** a
Department of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China c The Center of Heart Development, Key Lab of MOE for Development Biology and Protein Chemistry, College of Life Science, Hunan Normal University, Changsha, Hunan 410081, China b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 October 2013 Received in revised form 28 February 2014 Accepted 1 March 2014
Objective: To examine the association between survival and serum concentrations of cTnI, CK-MB, and myoglobin in patients with idiopathic dilated cardiomyopathy (IDC). Background: It has been suggested that elevated circulating biomarkers of myocardial damage such as cardiac troponin-I (cTnI), creatine kinase MB (CK-MB) and myoglobin are independent risk factors for mortality in patients with heart failure, and recent studies, although limited, showed that there was a potential association between cTnI and the prognosis of patients with dilated cardiomyopathy (DCM). Methods: A cohort study was undertaken in 310 patients with IDC. Standard demographic information, transthoracic echocardiography, and routine blood tests were obtained shortly after hospital admission. Outcome was assessed with all-cause mortality. Results: Among the 310 patients studied, 61 (19.7%) died during a mean follow-up of 2.2 years. There was a significant difference in the all-cause mortality rate between patients with serum cTnI >0.05 ng/mL and with cTnI 0.05 ng/mL (37.5% vs 15%, log-rank c2 ¼ 18.423, P < 0.001). After adjustment for other factors associated with prognosis at baseline, serum cTnI >0.05 ng/mL, QRS duration, NYHA functional class and systolic blood pressure predicted all-cause mortality in patients with IDC. There was no association between circulating CK-MB and myoglobin levels and all-cause mortality in the studied IDC patients. Conclusion: Serum concentrations of cTnI but not CK-MB or myoglobin are an independent predictor of all-cause mortality in patients with IDC. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Cardiac troponin-I CK-MB Myoglobin Idiopathic dilated cardiomyopathy Prognosis
Introduction Abbreviations: DCM, Dilated cardiomyopathy; cTnI, Cardiac troponin-I; CK-MB, Creatine kinase MB; CMR, Cardiovascular magnetic resonance; MIBG, (123) I-metaiodobenzylguanidine; HF, Heart failure; IDC, Idiopathic dilated cardiomyopathy; LV, Left ventricular; LVEDd, Left ventricular end-diastolic diameter; LVEF, Left ventricular ejection fraction; NYHA, New York Heart Association; LA, Left atrial; NT pro-BNP, N-terminal fragment pro-brain natriuretic peptide; CK, Creatine kinase; LDH, Lactate dehydrogenase; RV, Right ventricle. * Corresponding author. Department of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China. Tel.: þ86 28 87393927; fax: þ86 28 87394013. ** Corresponding author. Cardiac Arrhythmia Center, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China. Tel.: þ86 10 88398290; fax: þ86 10 68313019. E-mail addresses: [email protected] (X. Li), [email protected] (W. Hua). 0147-9563/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2014.03.001
Dilated cardiomyopathy (DCM), the most common cardiomyopathy, is a disease of the heart muscle characterized by ventricular dilatation and impaired systolic function.1 Although significant progress has been made in the treatment of DCM, patients continue to have a poor quality of life and an unacceptably high mortality, and prediction of death in patients with DCM is still challenging.2 Recently, serum C-reactive protein, (123) I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, cardiovascular magnetic resonance (CMR), cardiac troponin-I (cTnI), ect3e6 were reported as prognostic factors in DCM patients. Among these predictors, cTnI was easier and more inexpensive to perform in clinic practice.
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Circulating cTnI, creatine kinase MB (CK-MB) and myoglobin are biochemical markers of myocardial injury; the diagnostic and prognostic value of these biomarkers has been firmly established in acute coronary syndrome,7e11 and these markers are currently the subject of extensive research in patients with heart failure (HF). Elevated circulating cTnI and CK-MB levels predicted poor outcomes in HF patients12e19; however, there is relatively little data regarding the prognostic value of circulating cTnI, CK-MB and myoglobin in DCM. Two small studies that attempted to address the role of circulating cTnI as a prognostic factor in patients with DCM had inconsistent results.6,20 Therefore, the present study aimed to further explore the prognostic implications of circulating cTnI, CKMB and myoglobin concentrations in idiopathic dilated cardiomyopathy (IDC). Subjects and methods Patients and follow-up A retrospective, observational cohort study of 336 patients admitted to the hospital with IDC was performed from 2006 to 2011 in Fuwai Hospital. Patients were admitted for clinical decompensation with symptoms and physical signs of HF. IDC was defined as systolic dysfunction [left ventricular (LV) ejection fraction <50%] with LV dilation in the absence of an apparent secondary cause of cardiomyopathy, the LV dilation was defined as left ventricular end-diastolic diameter (LVEDd) >55 mm for males or LVEDd >50 mm for females.21 Of the 336 enrolled patients, 61 patients underwent coronary angiography, 117 underwent cardiovascular magnetic resonance (CMR) examination, 58 underwent cardiac CT scan and 49 undertaken cardiac nuclear examination. Patients with cardiomyopathy secondary to the following conditions were excluded from the study: ischemic heart disease (19 patients), thyroid disease (3 patients), congenital heart disease (2 patients), left ventricular noncompaction (1 patient) and chronic anemia (hemoglobin <60 g/L; 1 patient). Thus, the final analysis included 310 patients. The endpoint of the study was all-cause mortality, which was assessed for all patients by medical record review and follow-up calls. Mortality data were obtained for all study patients from hospitalization to death. The follow-up rate was 93.2%, with a mean follow-up of 2.2 years, and the study protocol was approved by the Ethics Commission of Fuwai Hospital. Laboratory screening Fasting blood samples were obtained 12e36 h after admission. Peripheral venous blood was collected in tubes without additives, and serum was analyzed for cTnI, CK-MB and myoglobin within 4 h. Serum cTnI, CK-MB and myoglobin levels were measured using an electrochemiluminescent immunoassay with Access AccuTnI Reagent, Access AccuCK-MB Reagent, and Access AccuMyoglobin Reagent, respectively (Beckman Coulter, Inc., USA). In all of the assays, both the intra- and inter-assay coefficients of variation were 10.0%. Echocardiography Patients were imaged in the left lateral decubitus position using a commercially available system equipped with a 3.5 MHz transducer. Two-dimensional grayscale, pulsed, continuous, and color Doppler images were acquired at the parasternal and apical views. Left ventricular ejection fraction (LVEF) was calculated as 100 (LV end-diastolic volume e LV end-systolic volume)/LV end-diastolic volume by the biplanar Simpson’s technique.22
Statistical analysis Continuous variables are expressed as the mean SD or medians and interquartile ranges. Comparisons of categorical variables among groups were made using chi-square tests. The independent t-test was used for comparison of means between two groups. Pearson correlation and multivariable linear regression analysis were used to test the associations between baseline variables and cTnI. KaplaneMeier survival curves were compared using the logrank test. Cox proportional hazard models were used to estimate the univariate and multivariable hazards of all-cause mortality associated with each individual parameter. The following covariates (which were found to be statistically significant in univariate Cox analysis) were used in the multivariable models: New York Heart Association (NYHA) functional class, systolic blood pressure (SBP), QRS duration, LV and left atrial (LA) diameters, LVEF, N-terminal fragment pro-brain natriuretic peptide (NT pro-BNP) and cTnI >0.05 ng/mL. Statistical analyses were performed using SPSS statistical software (version 16.0, SPSS Inc., Chicago, IL, USA). P values of <0.05 were considered statistically significant, and all statistical tests were two-sided tests.
Results Characteristics of the study population The cohort consisted of 310 patients with IDC; 74 (23.9%) were women, and 236 were (76.1%) men, with a mean age of 51.8 14.3 years. Of these, 20.6% (n ¼ 64) had increased serum cTnI (>0.05 ng/ mL), and 79.4% (n ¼ 246) had normal circulating cTnI (0.05 ng/ mL). Table 1 summarize the baseline clinical characteristics of the cohort. Compared to patients with normal cTnI levels, patients with increased cTnI had higher circulating levels of fasting blood glucose, creatinine, creatine kinase (CK) and lactate dehydrogenase (LDH), longer PR intervals, larger LVED, LA, and right ventricle (RV) diameters, and less frequent usage of beta-blockers, aspirin/anticoagulation and spironolactone at admission. Compared to the patients with normal CK-MB, patients with increased CK-MB (>1.0 ng/mL) also had higher fasting glucose, CK, LDH, NT proBNP, larger RV diameters, lower triglyceride levels, as well as less usage of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and aspirin. Compared to the patients with normal myoglobin, patients with increased myoglobin had higher creatinine, blood urea nitrogen and CK levels, as well as smaller RV diameters.
Association of baseline variables with cTnI concentrations In this study, Pearson correlation analysis showed that serum LDH levels (r ¼ 0.200, P < 0.001) and the presence of diabetes mellitus (r ¼ 0.116, P ¼ 0.041) were positively correlated with cTnI concentrations. The multivariable linear regression models used the following covariates: age, gender, history of DM, NYHA functional class, smoking and drinking status, blood pressure, QRS duration, left ventricle diameter, LVEF and serum LDH concentrations; this analysis showed that serum LDH concentration (P ¼ 0.01) and DM (P ¼ 0.028) were independent predictors of serum cTnI concentrations. Although serum CK-MB concentrations were elevated in patients with cTnI >0.05 ng/mL, there was no association between serum CK-MB and cTnI concentrations in our study.
Table 1 Patient characteristics categorized by serum concentrations of cTn-I, CK-MB and myoglobin.a cTnI >0.05 ng/mL cTnI 0.05 ng/mL (n ¼ 64) (n ¼ 246)
51.8 14.3 74 (23.9)
50.6 15.3 13 (20.3)
52.1 14.0 61 (24.8)
0.432 0.453
52.56 13.9 37 (23.0)
51.0 15.3 27 (24.5)
51 (16.5) 148 (47.7) 103 (33.2) 246 (79.4)
11 27 19 55
40 (16.3) 121 (49.2) 84 (34.1) 191 (77.6)
0.859 0.318 0.500 0.144
25 (15.5) 75 (46.6) 56 (34.8) 128 (79.5)
20 51 34 90
114.2 18.0 73.2 12.7 80.6 16.3
111.0 16.2 70.8 11.3 81.8 19.9
115.1 18.4 73.8 13.0 80.3 15.3
0.106 0.092 0.509
5.63 1.77 1.72 1.14 4.52 1.08 93.2 37.1 8.24 3.66 56 (40e86.5) 193 (165e233) 2037.4 1530.0
6.03 2.74 1.50 0.79 4.36 1.06 102.5 58.0 8.91 4.14 65 (39e118) 230 (183e323) 2775.3 1605.2
121.9 32.5 406.7 52.2
124.6 33.0 407.9 58.0
68.2 31.2 23.7 44.0
296 260 282 248 212 289
(95.5) (83.9) (91.0) (80.0) (68.4) (93.2)
9.3 8.4 5.1 7.2
(17.2) (42.2) (29.7) (85.9)
70.7 29.6 24.9 46.2 60 51 54 50 35 55
10.8 7.7 4.1 7.3
(93.8) (79.7) (84.4) (78.1) (54.7) (85.9)
Myoglobin P value 60 ng/mL (CK-MB 1.0 ng/mL (n ¼ 164) vs CK-MB >1.0)
Myoglobin >60 ng/mL (n ¼ 107)
P value (Myoglobin60 vs > 60 ng/mL)
0.382 0.766
50.2 14.6 41 (25)
54.2 14.2 23 (21.5)
0.025 0.507
(18.2) (46.8) (31.2) (81.8)
0.564 0.972 0.506 0.637
31 (18.9) 70 (42.7) 57 (34.8) 128 (78)
15 55 31 90
(14.0) (51.4) (29.0) (84.2)
0.295 0.159 0.320 0.219
114.9 18.8 74.4 13.1 80.4 15.3
112.5 16.8 72.3 12.1 82.7 18.1
0.301 0.190 0.261
1141 17.3 73.7 12.8 81.8 17.2
112.7 17.2 72.7 12.1 81.1 15.9
0.514 0.506 0.739
5.52 1.41 0.044 1.78 1.21 0.095 4.57 1.08 0.177 90.8 29.1 0.026 8.06 3.51 0.101 53.5 (40e77) 0.021* 187 (158.75e221.75) <0.001* 1868.3 1464.6 0.526
5.38 1.33 1.85 1.21 4.57 1.07 92.6 30.0 8.19 3.63 53 (39e75.5) 183 (157e220) 1915.0 1356.1
6.06 2.34 0.003 1.53 1.05 0.026 4.35 0.98 0.099 91.6 28.5 0.787 8.34 362 0.733 62.5 (42e102) 0.001* 211 (179.5e289.75) <0.001* 2436.1 1748.9 0.012
5.64 1.57 1.65 1.08 4.44 1.01 87.2 29.8 7.58 3.04 54 (39e80) 190 (164e229.5) 2062.1 1363.9
5.67 2.17 1.78 1.23 4.50 1.03 98.5 27.3 9.09 3.95 59.5 (41.75e91.5) 205 (169.75e248.25) 2191.0 1763.3
0.882 0.386 0.661 0.002 0.001 0.012* 0.313* 0.536
121.2 32.4 407.0 50.8
0.470 0.908
121.0 32.6 406.3 50.4
124.2 34.6 405.8 58.7
0.434 0.946
119.6 31.4 403.1 55.9
126.6 35.9 410.0 51.4
0.097 0.311
67.6 31.6 23.4 43.4
8.8 8.5 5.3 7.0
0.017 0.104 0.050 0.007
67.1 30.9 23.4 43.7
0.066 0.925 0.028 0.184
68.1 30.8 24.6 44.4
9.7 8.1 4.0 7.4
0.906 0.792 0.028 0.409
236 209 228 198 177 234
(95.9) (85.0) (92.7) (80.5) (72.0) (95.1)
0.453 0.307 0.039 0.674 0.008 0.009
157 144 151 135 119 152
(97.5) (89.4) (93.8) (83.9) (73.9) (94.4)
0.203 0.001 0.022 0.662 0.035 0.575
157 137 149 135 118 154
(95.7) (83.5) (90.9) (82.3) (72.0) (93.9)
104 (97.2) 89 (83.2) 96 (89.7) 89 (83.2) 68 (63.6) 100 (93.5)
0.532 0.938 0.757 0.855 0.145 0.883
CK-MB P value 1.0 ng/mL (cTnI >0.05 ng/mL (n ¼ 161) vs cTnI 0.05 ng/mL)
8.7 8.2 4.6 6.7
CK-MB >1.0 ng/mL (n ¼ 110)
69.3 30.8 24.9 44.9
10.3 8.4 5.9 7.8
104 (94.5) 82 (74.5) 94 (85.5) 90 (81.8) 68 (61.8) 102 (92.7)
9.3 8.1 5.7 7.1
68.2 31.1 23.1 43.6
X. Li et al. / Heart & Lung 43 (2014) 219e224
Age (years) Female, n (%) History Diabetes mellitus, n (%) Smoker, n (%) Drinker, n (%) NYHA class III and IV, n (%) Admission vital signs SBP (mm Hg) DBP (mm Hg) Heart rate, beats/min Laboratory values at admissionc Glucose (mmol/L) Triglycerides (mmol/L) TC (mmol/L) Creatinine (umol/L) BUN (umol/L) CK (IU/L)b LDH (IU/L)b NT Pro-BNP (fmol/mL) Electrocardiogram datac QRS duration (ms) QT (ms) Echocardiography datac LV (mm) LVEF (mm) RV (mm) LA (mm) Medicine at admission Diuretics, n (%) ACEI/ARB, n (%) Beta-blockers, n (%) Digoxin, n (%) Aspirin/anticoagulation n (%) Spironolactone, n (%)
All patients (n ¼ 310)
NYHA, New York Heart Association; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; BUN, blood urea nitrogen; LDH, lactate dehydrogenase; CK-MB, creatine kinase MB; CK, creatine kinase; NT pro-BNP, N-terminal fragment pro-brain natriuretic peptide; LV, left ventricle; LA, left atrium; LVEF, left ventricular ejection fraction; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker. p < 0.05 was considered to be statistically significant and the values were given in bold font. a Data are expressed as the mean SD, median (interquartile range) or percentages. b *indicates that the P value was analyzed and the data were normalized by log-arithmetic transformation. c Eight patients lacked data on electrocardiograms, 4 patients lacked echocardiography data, 10 patients lacked AST/ALT levels, 7 patients lacked fasting blood glucose levels, 3 patients lacked creatinine and BUN levels, 4 patients lacked CK levels, 39 patients lacked CK-MB and myoglobin levels, 3 patients lacked LDH levels, and 58 patients lacked NT pro-BNP levels.
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Relation between cTnI, CK-MB, myoglobin concentrations and allcause mortality Among the 310 patients studied, 61 died during a mean followup of 2.2 years. Fig. 1 displays mortality rates within the subgroups. Of the patients who died, 37 had normal cTnI levels (0.05 ng/mL) and 24 had increased cTnI levels (>0.05 ng/mL). There was a significant difference in all-cause mortality risk between the two groups (log-rank c2 ¼ 18.423, P < 0.001). There was no significant difference in the all-cause mortality between patients with CK-MB 1.0 ng/mL and CK-MB >1.0 ng/mL (16.8% vs 22.7%, log-rank c2 ¼ 2.270, P ¼ 0.132); in addition, there was no significant difference in the all-cause mortality between patients with myoglobin 60 ng/mL and myoglobin >60 ng/mL (20.7% vs 16.8%, log-rank c2 ¼ 0.633, P ¼ 0.426). Cox proportional hazard models Table 2 summarizes the results of the Cox models, in which each of the parameters was entered separately as the mortality explanatory variable. After adjustment for disease duration, LVED and LA diameter, and LVEF and NT pro-BNP, the Cox multivariable analysis showed that serum cTnI >0.05 ng/mL, QRS duration and SBP were the most powerful independent predictors of all-cause mortality in patients with IDC. Neither CK-MB >1.0 ng/mL or myoglobin >60 ng/mL was a significant predictor of all-cause mortality in IDC patients in either univariate or multivariate Cox analysis. Discussion This study demonstrates that an elevated level of serum cTnI is an independent predictor of increased all-cause mortality in patients with IDC and that the clinical baseline variables of serum LDH concentration and underlying DM were independent predictors of cTnI concentrations. CK-MB and myoglobin levels did not predict all-cause mortality in IDC patients. Cardiac troponins (troponin I, T and C) are 3-unit complex intracellular contractile-regulating proteins of the cardiac muscle and are essential for calcium-mediated regulation of cardiac muscle contraction. They are tissue-specific isoforms of troponin I, T and C.23 Cardiac troponins in blood are the preferred markers for diagnosing myocardial damage. As troponins are normally not found in the circulation, these markers have high clinical sensitivity and specificity, even when cardiac lesions are small.24 The use of these markers in acute coronary syndromes has prompted a revision of the criteria for diagnosis of myocardial infarction by the Joint European Society of Cardiology/American College of Cardiology Committee.10,11 The relationship between cTnI and chronic HF has been studied in various clinical settings, and the presence of troponin in decompensated chronic HF has been found to be associated with more profound clinical and hemodynamic deterioration, more extensive left ventricle remodeling, and worse shortand long-term prognosis.14e16,25e28 Recently, two studies addressed the association of circulating cTnI concentration with outcomes in patients with DCM.6,20 Nellessen et al6 found that permanent cTnI release is a common finding in DCM and is a strong prognosticator in patients with DCM (n ¼ 58); however, another study of 40 patients with DCM suggested that cTnI concentrations at baseline were not significantly different between survivors and patients who died.20 Lower levels of serum cTnI in chronic HF or DCM could signify the presence of limited, irreversible myocyte injury and death or could represent leakage of the cytosolic pool of cTnI due to a loss of cell
Fig. 1. KaplaneMeier survival curves for idiopathic dilated cardiomyopathy patients with elevated cardiac troponin-I (>0.05 ng/mL), CK-MB (>1.0 ng/mL) and myoglobin (>60 ng/mL), respectively.
X. Li et al. / Heart & Lung 43 (2014) 219e224
Conclusions
Table 2 Cox regression analysis of all-cause mortality in patients with DCM. Variable
Univariate analysis HR
Age Gender NYHA functional class Disease duration Smoker Drinker Heart rate Systolic blood pressure Diastolic blood pressure QRS duration Left ventricular diameter Left atrial diameter LVEF NT pro-BNPa cTnI >0.05 ng/mL Myoglobin >60 ng/mL CK-MB >1.0 ng/mL
95% CI
Multivariable analysis P value HR
95% CI
P value
1.009 0.991e1.028 1.409 0.819e2.423 2.522 1.681e3.784
0.321 e e e 0.216 e e e <0.001 1.601 0.946e2.707 0.079
1.023 1.001 0.813 0.999 0.963
0.202 0.995 0.244 0.898 <0.001
0.988e1.059 0.755e1.327 0.573e1.152 0.984e1.015 0.946e0.980
0.961 0.939e0.984 1.013 1.006e1.020 1.057 1.030e1.085 1.052 0.950 4.750 2.928 0.793
e e e e 0.973
0.001 e
1.515 0.879e2.611
e e e e 0.952e0.995
e e e e 0.018
e
e
0.001 1.012 1.003e1.022 0.012 <0.001 1.008 0.965e1.052 0.721
1.014e1.091 0.006 1.019 0.922e0.978 0.001 0.980 1.893e11.918 0.001 1.522 1.750e4.899 <0.001 2.725 0.448e1.405 0.428 e 0.135 e
223
0.973e1.020 0.941e1.020 0.556e4.164 1.409e5.271 e
0.422 0.319 0.413 0.003 e
e
e
The variables analyzed in the multivariate Cox model included disease duration, NYHA functional class, systolic blood pressure, QRS duration, left ventricular diameter, left atrial diameter, LVEF, NT Pro-BNP and TnI >0.05 ng/mL. p < 0.05 was considered to be statistically significant and the values were given in bold font. a NT Pro-BNP was normalized by log-arithmetic transformation.
membrane integrity during reversible injury.29 Progressive myocyte loss through necrotic and apoptotic cell death is increasingly recognized as a prominent pathophysiologic mechanism in the evolution of cardiac dysfunction in HF and DCM.15,30e32 In addition, changes in mechanical loading in the ventricles of patients with DCM can upregulate kinases such as c-Jun N-terminal kinase (JNK1/2) and p38 kinase and cause circulating cTnI concentrations to increase.33 Therefore, circulating cTnI appears to be correlated with the pathophysiology and evolution of cardiac dysfunction in chronic HF and DCM. In the present study, circulating cTnI levels were correlated with the presence of DM in IDC patients. Elevated circulating cTnI levels were associated with larger LV, LA and RV diameters, along with a higher mortality rate in IDC patients, indicating the presence of an association between cTnI levels and cardiac remodeling. Although limited studies have shown that circulating CK-MB is a marker of deterioration in chronic HF or DCM,18,19 we did not find any association between all-cause mortality and elevated serum CK-MB or myoglobin levels in the present study. Limitations The present study has several limitations, including the fact that it is a retrospective analysis. As with many studies of chronic disease, the time of disease onset is not precisely known, and variations in the length of the preclinical phase of disease can influence the relationship between serum cTnI concentrations and death. In addition, there were a few patients with ischemic heart disease in the present study, possibly because some patients had undergone coronary artery angiography or cardiac CT scan in the other hospitals before they were admitted to our hospital. Finally, it is well known that renal insufficiency can be a cause for a non-specific elevation in troponins, and there were 27 patients with plasma creatinine 130 mmol/L in the present study, therefore, the influence of the renal insufficiency on the serum concentrations of cTnI did not exclude in the present study.
In this cohort of patients with IDC, serum cTnI concentration (but not CK-MB or myoglobin) was a significant predictor of increased all-cause mortality rates. Patients with increased serum concentrations of cTnI (>0.05 ng/mL) were at particularly high risk of death. Serum cTnI may be a novel and useful tool in identifying patients with IDC who are at increased risk of death and are likely to benefit from aggressive treatment strategies. Acknowledgments This study was supported in part by grants from the National Natural Science Foundation of China (no. 81000104), the China Postdoctoral Science Foundation (no. 2012M510356) and the Postdoctoral Fellows Foundation of the Chinese Academy of Medical Sciences (no. 2011-XH-9). Competing interests: The authors declare that they have no competing interest. References 1. Richardson P, McKenna W, Bristow M, et al. Report WHOISFCTFDCC: report, of the 1995 World Health Organization/International society and Federation of Cardiolgy Task Force on the Definition and Classification of cardiomyopathies. Circulation. 1996;93:841e842. 2. Grogan M, Redfield MM, Bailey KR, et al. Long-term outcome of patients with biopsy-proven myocarditis: comparison with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1995;26:80e84. 3. Ishikawa C, Tsutamoto T, Fujii M, Sakai H, Tanaka T, Horie M. Prediction of mortality by high-sensitivity C-reactive protein and brain natriuretic peptide in patients with dilated cardiomyopathy. Circ J. 2006;70:857e863. 4. Momose M, Okayama D, Nagamatsu H, Kondo C, Hagiwara N, Sakai S. Longterm prognostic stratification by a combination of (123)I-metaiodobenzylguanidine scintigraphy and ejection fraction in dilated cardiomyopathy. Ann Nucl Med. 2011;25:419e424. 5. Gulati A, Ismail TF, Jabbour A, et al. Clinical utility and prognostic value of left atrial volume assessment by cardiovascular magnetic resonance in nonischaemic dilated cardiomyopathy. Eur J Heart Fail. 2013;15:660e670. 6. Nellessen U, Goder S, Schobre R, Abawi M, Hecker H, Tschöke S. Serial analysis of troponin I levels in patients with ischemic and nonischemic dilated cardiomyopathy. Clin Cardiol. 2006;29:219e224. 7. Donnelly R, Millar-Craig MW. Cardiac troponins: IT upgrade for the heart. Lancet. 1998;351:537e539. 8. Coudrey L. The troponins. Arch Intern Med. 1998;158:1173e1180. 9. Christenson RH, Azzazy HM. Biochemical markers of the acute coronary syndromes. Clin Chem. 1998;44:1855e1864. 10. Heidenreich PA, Alloggiamento T, Melsop K, McDonald KM, Go AS, Hlatky MA. The prognostic value of troponin in patients with noneST elevation acute coronary syndromes: a meta-analysis. J Am Coll Cardiol. 2001;38:478e485. 11. The Joint ESC/ACC Committee. Myocardial infarction redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J. 2000;21:1502e1513. 12. Peacock 4th WF, De Marco T, Fonarow GC, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med. 2008;358:2117e2126. 13. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008;358(20): 2148e2159. 14. La Vecchia L, Mezzena G, Zanolla L, et al. Cardiac troponin I as diagnostic and prognostic marker in severe heart failure. J Heart Lung Transplant. 2000;19: 644e652. 15. Logeart D, Beyne P, Cusson C, et al. Evidence of cardiac myolysis in severe nonischemic heart failure and the potential role of increased wall strain. Am Heart J. 2001;141:247e253. 16. Horwich TB, Patel J, MacLellan WR, Fonarow GC. Cardiac troponin I is associated with impaired hemodynamic, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation. 2003;108: 833e838. 17. Setsuta K, Seino Y, Ogawa T, Arao M, Miyatake Y, Takano T. Use of cytosolic and myofibril markers in detection of ongoing myocardial damage in patients with chronic heart failure. Am J Med. 2002;113:717e722. 18. Hossein-Nia M, Baig K, Goldman JH, et al. Creatine kinase isoforms as circulating markers of deterioration in idiopathic dilated cardiomyopathy. Clin Cardiol. 1997;20:55e60. 19. Sugiura T, Takase H, Toriyama T, Goto T, Ueda R, Dohi Y. Circulating levels of myocardial proteins predict future deterioration of congestive heart failure. J Card Fail. 2005;11:504e509.
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