High-sensitive cardiac troponin I (hs-cTnI) values in patients with stable cardiovascular disease: An initial foray

Clinica Chimica Acta 411 (2010) 812–817

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Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m

High-sensitive cardiac troponin I (hs-cTnI) values in patients with stable cardiovascular disease: An initial foray Olaf Schulz a, Markus Reinicke a, Gunnar H. Berghoefer a, Ricarda Bensch a, Jochen Kraemer a, Ingolf Schimke b, Allan S. Jaffe c,⁎ a b c

Interventionelle Kardiologie Spandau, Berlin, Germany Klinik für Kardiologie, Universitätsmedizin Berlin-Charite, Berlin, Germany Mayo Clinic and Medical School, 200 First Street SW, Rochester MN 55905, United States

a r t i c l e

i n f o

Article history: Received 17 December 2009 Received in revised form 18 February 2010 Accepted 19 February 2010 Available online 24 February 2010 Keywords: High sensitivity troponin Chronic cardiac disease

a b s t r a c t Background: How to use the information from novel high sensitivity troponin assays in stable cardiac patients is unclear. Preliminary data from randomized controlled trial analyses suggest it helps with risk stratification. We investigated the determinants, diagnostic impact and prognostic value of a novel highsensitive cardiac troponin I (hs-cTnI) assay in patients with stable cardiac disease. Methods: hs-cTnI was measured with a pre-commercial assay in 222 outpatients after clinical testing before cardiac catheterization. Mean follow-up was 1103 ± 299 days. Results: hs-cTnI was detectable in all patients (median (interquartile range) 6.20 (4.85;8.25) ng/l). Creatinine (p b 0.001), systolic wall stress (p = 0.004), the presence of myocardial impairment (p = 0.049) and coronary artery stenosis ≥70% (p = 0.050) were predictors of hs-cTnI concentration. hs-cTnI values could not distinguish elevations due to myocardial abnormalities from those related to coronary artery abnormalities. Patients with elevations above the 99th percentile had a higher rate of hospitalizations but otherwise prognosis was not predicted robustly by hs-cTnI values. Conclusion: Stable cardiovascular patients have detectable hs-cTnI concentrations irrespective of their underlying disease. In this heterogeneous group of patients with diverse etiologies for cardiac disease, values were not helpful in distinguishing the etiology of the elevations or in predicting prognosis. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Cardiac troponin (cTn) is the marker of choice for evaluation of patients with acute coronary syndromes. Elevations are a prerequisite for the diagnosis of acute myocardial infarction (AMI) [1,2]. Due to high myocardial specificity and sensitivity, cTns detect myocardial injury from a variety of different causes; e.g. myocardial inflammation [3], pulmonary embolism [4] and heart failure [5,6]. Elevations presage an adverse prognosis. Low level chronic elevations with contemporary assays identify patients at short and long term risk [7–12]. Increased assay sensitivity might identify still more [13]. Several novel high-sensitive troponin assays, including the one used in this study allow for the earlier detection of patients with AMI and identify more patients at risk [7] and can define values in most normal healthy individuals [14]. It is possible that these assays will improve our ability to diagnose patients with stable cardiovascular disease [15] and perhaps to anticipate their

⁎ Corresponding author. Fax: + 1 507 266 0228. E-mail address: [email protected] (A.S. Jaffe). 0009-8981/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2010.02.066

prognosis. Recent publications with a high sensitivity cTnT assay support this contention in patients with stable heart disease [16] and heart failure patients [10]. However, only a small percentage of patients had values above the 99th% value and the groups studied were homogeneous. To determine if we could confirm these observations in a non selected cohort, we studied outpatients with clinically stable cardiac disease, referred for cardiac catheterization using a novel high sensitivity troponin assay. Our initial goal was to assess the ability of assay values to detect patients with coronary artery disease. 2. Materials and methods 2.1. Study population Stable outpatients (n = 222) scheduled for heart catheterization were prospectively enrolled between October 11th, 2004 and April 19th, 2007. The study was approved by the local ethics committee, and written informed consent was obtained from all patients. The investigation conformed to the principles of the Declaration of Helsinki.

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2.2. Exclusion criteria

2.6. Follow-up evaluation

Exclusions included a recent acute coronary syndrome; acute pulmonary embolism, decompensated heart failure; clinical peri/ myocarditis, a systemic inflammatory or malignant disease, or marked renal or hepatic impairment. Patients who could not perform an exercise test and those who refused informed consent also were excluded.

Follow-up-information was complete for all patients. Eight outcome measures were assessed: all-cause death, cardiac death, nonfatal AMI, hospitalization, emergency service calls, cardiac surgery as well as percutaneous coronary interventions not related to the baseline coronary status, recatheterization. Combined parameters evaluated were: all-cause death or nonfatal AMI, cardiac death or nonfatal AMI, all-cause death or hospitalization, all-cause death or nonfatal AMI or hospitalization, procedures [cardiac surgery or percutaneous coronary intervention (PCI)], revascularization (bypass surgery or PCI), all-cause death or nonfatal AMI or revascularization, cardiac death or nonfatal AMI or revascularization.

2.3. Diagnostic procedures A symptom-limited semi-supine exercise test (Equipment Ergoline®), a resting echocardiographic evaluation (equipment System FiVe®, GE), and a left heart catheterization (equipment Integris Allura 9F®, Philips) were performed per guidelines [17–21]. A second stress test with imaging was performed when clinically indicated. Two– three days before angiography, blood was obtained for laboratory measurements. 2.4. Reference variables and patient classification The following baseline and clinical parameters were collected: age, gender, body mass index, creatinine, urea, alanine aminotransferase, total cholesterol, high and low density cholesterol, triglycerides, achieved workload (Watt), the presence or absence of significant stress-test-ST-depression (defined as ≥10 mm), the presence or absence of significant ischemic stress test (either ST-depression or positive imaging), echocardiographic left atrial and end-systolic and end-diastolic left ventricular dimensions indexed per m2, left ventricular mass/m2 [22], left ventricular ejection fraction (EF), systolic [23] and diastolic wall stress [24], end-diastolic pressure, and EF, determined by left heart catheterization (n = 162). Coronary stenoses were coded by severity in steps of 5%; lesions ≥50% were further classified by lesion-type [25]. Coronary lesions were categorized by: severity b50 vs 50–69 vs 70–98 vs 99/100 (for subtotal and total occlusion), %-with 1–2–3-vessel disease (stenosis ≥70%) and lesion complexity. A complex lesion was defined as a B2 type lesion associated with a stenosis of ≥50% or a C lesion. When our primary hypothesis related to detection of coronary artery disease was proven null, we defined additional patient groups to explore differences in hs-cTnI values that might be related to the nature of the underlying cardiovascular disease. These groups included patients with: A) a stenosis ≥70% (i.e. flow-limiting [21] for a diagnosis of coronary artery disease (CAD)). B) the presence of B-type coronary lesions ≥50% whether with or without a total (C-type) lesion. C) myocardial impairment defined as an EF b50% or end-diastolic pressure ≥20 mm Hg or regional wall-motion abnormalities. D) global myocardial impairment (EF b 50% or end-diastolic pressure ≥20 mm Hg) alone. E) severe disease [groups A–D or having modest or greater valvular heart disease] in comparison to patients called milder pathologies (without the above characteristics).

2.7. Statistical analyses SPSS software (ver. 13.0, SPSS Inc, Chicago, IL) was used. Reference parameters are given as mean ± SD. hs-cTnI values are presented as median and interquartile ranges. After demonstration of a non normal distribution of hs-cTnI-values by the Kolmogorov–Smirnov test, data were log10 transformed for statistical analysis. Group differences were analyzed by t-test for continuous variables and by χ2/Fisher exact test for categorical variables. Associations of hs-cTnI with baseline, clinical and follow-up data were analyzed by: First, univariate analyses were performed for continuous and categorical variables by independent t-tests. Ordinal parameters were analyzed by ANOVA and with the Scheffe as a post hoc test to analyze differences between single steps. For continuous variables, results were given as the increase of hs-cTnI (ng/l) per increase of the continuous independent variable from interquartile quartile range I to III. Second, receiver operator characteristic curves (ROC) were constructed to estimate the accuracy of hs-cTnI to detect characteristics in patient groups and to predict follow-up outcome measures. Multiple backward regression analyses were performed with hs-cTnI as the dependent variable. A possible role of hs-cTnI for a diagnostic workup of patients with chronic heart diseases was assessed by logistic regression analysis for patient groups A–D with the presence or absence of respective disease conditions serving as dependent variables. In regression models, hscTnI values were compared with 17 (for groups A and B) or 20 (for groups C and D) of these disease states. Furthermore, two cut off values were assessed for their ability to predict clinical as well as prognostic findings. The putative 99th percentile (9.20 ng/l) was used as well as a value calculated as the median of the best cut off values derived from the ROC-analyses with significant AUCs (values with the highest sum of sensitivity and specificity). Kaplan–Meier survival curves were constructed for all prognostic parameters and tested globally with log-rank tests. In case of significance, pair wise comparisons of the four groups were performed. Two-sided p-values of less than 5% were regarded as significant. 3. Results

2.5. Blood sampling and assays 3.1. Patient characteristics Lithium heparin samples for hs-cTnI were analyzed by technicians blinded to the clinical data. A pre-commercial assay (Beckman– Coulter) was used to measure hs-cTnI. Performance characteristics of this assay have been published [7]. The limit of detection, the 10% coefficient of variation and the 99th percentile of a normal population for lithium heparin samples are 2.06, 8.66 and 9.2 ng/l, i.e. pg/ml, respectively. Others have reported similar but slightly different values with this assay [26].

The characteristics of the patient groups and those with milder disease group are in Table 1. Even the 16 not included in groups A–E and without left atrial enlargement or left ventricular hypertrophy had substantial disease e.g. arterial hypertension (n = 11), diabetes mellitus (n = 6), a positive stress test (n = 10), mild-moderately elevated filling pressure (n = 7), or moderate valvular heart disease (n = 2). Thus, comparisons with a normal control group could not be

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Table 1 Baseline characteristics of study population. Variables

Milder disease More severe disease n = 73 n = 149

Age, yr Men (%) Body mass index Diabetes, n (%) Hypertension, n (%) Laboratory Serum creatinine (µmol/l) Serum urea (mmol/l) Serum alanine aminotransferase (µkat/l) Total cholesterol (mmol/l) HDL (mmol/l) LDL (mmol/l) Medication ACEI/ARB, n (%) Betablockers, n (%) Statin, n (%) Echocardiography LV EDD/m2, (mm/m2) LV ESD/m2, (mm/m2) LV EF, (%) LV M/m2 (g/m2) LA/m2 (mm/m2) Bicycle stress test Peak workload (Ws)

61.5 ± 10.5 47.9 27.4 ± 4.0 16 (21.9) 52 (71.2)

66.8 ± 8.4‡ 67.1† 27.9 ± 4.3 41 (27.5) 124 (83.2)

76.0 ± 18.6 5.68 ± 15.8 0.44 ± 0.22 5.30 ± 1.14 1.42 ± 0.04 3.21 ± 0.88

83.1 ± 2.1† 6.53 ± 2.26† 0.46 ± 0.29 5.22 ± 2.51 1.34 ± 0.35 2.92 ± 0.97*

36 (49.3) 44 (60.3) 32 (49.8)

100 (67.1) 101 (67.8) 89 (59.7)

25.9 ± 3.1 17.0 ± 3.0 66.8 ± 3.8 132 ± 34 19.8 ± 2.6

26.3 ± 3.3 17.9 ± 3.5 61.1 ± 9.4‡ 145 ± 37† 20.5 ± 3.8

104.0 ± 39.3

102.9 ± 36.3

*p b 0.05, †p b 0.01, ‡p b 0.001 in comparison between groups. ACEI = angiotensinconverting enzyme inhibitor; ARB = angiotensin receptor blocker; CAD = coronary artery disease; EDD = end-diastolic diameter; EF = ejection fraction; ESD = endsystolic diameter; LA = left atrial diameter; LV = left ventricular; M = mass.

accomplished. CAD was found in 103 patients (A), 74 had a B-type lesion (B), 98 had myocardial impairment (C), and 68 had global myocardial impairment (D). One hundred and forty-nine patients had more severe disease (E); compared to 73 patients who did not meet these criteria. Patients with severe disease (group E) were older, and had more comorbidities. 3.2. hs-cTnI values All 222 patients had detectable hs-cTnI values (N2.06 ng/l); the median was 6.20 (4.85; 8.25) ng/l. None of the values was above the 99th% value. Patients in groups A)–E) had higher hs-cTnI values than patients without these characteristics, however, there was substantial overlap: group A) 6.45 (5.40–8.65) vs 5.75 (4.50–7.60) ng/l in patients without CAD, p = 0.009, group B) 6.725 (5.29–8.93) vs 6.05 (4.66– 7.60) ng/l in patients without B-type lesion, p = 0.0426, group C) 6.425 (5.24–8.96) vs 5.775 (4.54–7.38) ng/l in patients without myocardial impairment, p = 0.0021, group D) 7.25 (5.44–9.30) vs 5.975 (4.69–7.41) ng/l in patients without global myocardial impairment, p = 0.0026, group E) 6.60 (5.23–8.70) vs 5.40 (4.40–6.75) ng/l in patients with milder disease, p b 0.0001. 3.3. Associations with hs-cTnI values hs-cTnI was independently associated with: invasively as well as echocardiographically determined EF (increase of hs-cTnI 1.99 and a 1.49 ng/l per change of the independent parameter from IQR I–III), end-systolic diameter/m2 (increase 1.34 ng/l), systolic wall stress (increase 1.34 ng/l), creatinine (increase 1.28; each p b 0.001), number of diseased coronary arteries (p = 0.002), presence of myocardial impairment (16.19 ± 44.02 vs 6.77 ± 4.34 ng/l; p = 0.002), presence of global myocardial impairment (20.12 ± 52.42 vs 6.87 ± 4.25 ng/l; p = 0.003), age (increase 0.99 ng/l, p = 0.008), presence of coronary artery disease (15.29 ± 42.78 vs 7.16 ± 6.41 ng/l; p = 0.009), gender (13.62 ± 37.79 for males vs 6.75 ± 3.81 ng/l for females; p = 0.010), urea (increase 0.89 ng/l; p = 0.012), presence of regional wall-motion abnormalities (18.87 ± 51.61 vs 7.82 ± 13.13 ng/l;

p = 0.019), presence of a B-type lesion (13.91 ± 33.34 vs 9.44 ± 27.73 ng/l; p = 0.043), diastolic wall stress (increase 1.03 ng/l; p = 0.045), severity of the culprit coronary stenosis (p = 0.048). Multiple backward regression analysis revealed that serum creatinine (p b 0.001), systolic left ventricular wall stress (p = 0.004) and myocardial impairment (p = 0.049) had an independent influence on hs-cTnI concentrations. The presence of CAD manifested borderline significance (p = 0.05). 3.4. Role of hs-cTnI values in predicting the type of chronic heart disease To evaluate relationships of hs-cTnI to CAD, logistic regression models were constructed using CAD and B-type lesions as dependent variables. CAD was predicted by gender (p = 0.002), ischemia during stress testing (p = 0.002) and age (p = 0.012). A B-type lesion was predicted by typical angina (p = 0.003), regional wall-motion abnormalities at rest (p = 0.005) and Bun (p = 0.011). hs-cTnI did not manifest independent predictive effects. In logistic regression models myocardial impairment was predicted by B-type coronary lesions (p = 0.001), end-systolic diameter/ m2 (p = 0.001), left ventricular mass/m2 (p = 0.001), end-diastolic diameter/m2 (p = 0.004) and total or near total coronary occlusion (p = 0.009) but not hs-cTnI. Global myocardial impairment was predicted by hs-cTnI (p = 0.004), total or near total coronary occlusion (p = 0.009), left ventricular mass/m2 (p = 0.01) and creatinine (p = 0.045). ROC values needed to detect the group C and D characteristics had AUCs of 0.616 (95% CI 0.542– 0.690); p = 0.0029 and 0.645 (95% CI 0.567– 0.723), p = 0.0006. Three of the 23 ROC curves revealed areas N0.7. They were chronic renal failure (0.749, 95%CI 0.619–0.878, p = 0.0054), global left ventricular dysfunction (0.732, 95%CI 0.642–0.822, p = 0.0005) and atrial fibrillation (0.710, 95%CI 0.575; 0.844, p = 0.0086). From the significant AUCs, the best cut off hs-cTnI value of 6.75 (5.14/7.68) ng/l was determined by the highest sum of sensitivity and specificity. This cut off was compared with the 99th percentile for detection of patients risk (Table 2). Only the cut point of 6.75 ng/l significantly identified patients with B-type coronary lesions. It also manifested stronger separation of patients with global myocardial impairment. 3.5. Prognostic role of hs-cTnI After a follow-up of 1103 ± 299 days, there were 12 deaths (6 cardiac), 7 nonfatal AMI, 36 hospitalizations, 22 emergency calls, 9 cardiac surgical procedures, 43 percutaneous interventions, and 61 repeated heart catheterizations. There were no differences in hs-cTnI in patients with compared to those without events or combinations of events. ROCs were not predictive. Using the 99th percentile, there was a higher rate of hospitalizations alone (p = 0.002) or in combination with all-cause death (p = 0.005) and with all-cause death and nonfatal AMI (p = 0.006; Table 2). The same parameters were found to show significant differences between the groups defined by the quartiles of the hs-cTnI (p = 0.029, 0.012, and 0.015, respectively; see Fig. 1a–c). No clear trend was observed. Significant differences were found for these parameters mostly between patients in groups hscTnI-quartiles 3 and 4 (p = 0.0061, 0.0029 and 0.0028). For all-cause death or hospitalization as well as all-cause death or AMI or hospitalization also groups 1 and 4 differed significantly (p = 0.0261 and 0.0427). 3.6. Patients with severe compared to milder disease and hs-cTnI Patients with more severe disease (group E) had poorer outcomes. This group contained 11 of 12 patients who died (p = 0.1096), all 6 patients with cardiovascular death (p = 0.1812), all patients with nonfatal AMI (p = 0.0990), 32/36 hospitalizations (p = 0.0018), 40/43

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Table 2 Differences of clinical and prognostic variables in relation to different cut offs of hs-cTnI. Rationale of the cut off parameter

n Clinical variables Age Creatinine (µmol/l) Bun (mmol/l) LV end-systolic diameter/m2 (mm/m2) LV-wall stress systolic (kdyn cm2) LV-ejection fraction (%) B-type lesion (n) Myocardial impairment (n) Global myocardial impairment (n) Atrial fibrillation (n) Global wall-motion abnormalities (n) Prognostic variables Hospitalization ACD or hospitalization ACD or nonfatal AMI or hospitalization

Median of best cut offs from 40 ROC

99th percentile of healthy population

b6.75 ng/l

6.75 ng/l or N

135

87

63.9 (9.6) 76.0 (15.9) 5.83 (1.80)

66.9 (9.1) 88.4 (25.6) 6.87 (2.33)

0.021 b0.001 0.001

211 (61.1) 64.5 (6.5) 98/37

233 (67.5) 60.7 (10.4) 37/87

0.019 0.003 0.028

104/31 131/4 130/5

50/37 77/10 69/16

p value

0.003 0.020 b0.001

b9.20 ng/l

9.20 ng/l or N

185

37

77.8 (19.4) 6.05 (1.96) 17.3 (3.3) 214 (62.2) 63.9 (7.6)

93.7 (26.5) 7.23 (2.53) 18.9 (3.6) 248 (69.0) 58.6 (11.0)

0.002 0.020 0.021 0.011 0.008

110/75 134/51

14/23 20/17

0.019 0.032

126/23 156/29 155/30

24/13 23/14 23/14

0.002 0.005 0.006

p value

Continuous variables are given as mean (SD), categorical variables as relation of n without vs with presence of the variable. ACD = all-cause death; AMI = acute myocardial infarction; LV = left ventricular; ROC = receiver operator characteristics.

percutaneous interventions (p b 0.001), and 55/61 recatheterizations (p b 0.001). There were significant differences in: all-cause mortality and nonfatal AMI (p = 0.0082), cardiovascular death and nonfatal AMI (p = 0.0099), all-cause-mortality and hospitalization (p = 0.0009), all-cause-death or nonfatal AMI or hospitalization (p = 0.0005), percutaneous interventions or cardiac surgery (p b 0.0001), all-cause death or nonfatal AMI or revascularizations (p b 0.0001), cardiovascular death or nonfatal AMI or revascularizations (p b 0.0001). hs-cTnI was higher in group E patients than others (6.60 (5.23; 8.70) vs 5.4 (4.40; 6.75) ng/l; p b 0.001). Sixty-eight of the 73 patients not in group E had hs-cTnI values below the 99th percentile whereas 32 of the 37 patients with values above the 99th percentile belonged in group E and had more adverse outcomes (p = 0.0067). By ROC-analysis hscTnI predicted more severe disease (AUC 0.6617, 95%CI 0.5876– 0.7359; p b 0.001) with a best cut off value of 7.68 ng/l. In the logistic regression model with characteristics of group E as the dependent variable, gender (p = 0.001), dyspnea at exercise test (p = 0.004), age (p = 0.013) and LDL (p = 0.028), but not hs-cTnI were independent predictors. In group E, ROC analysis did not show a predictive role for hs-cTnI.

4. Discussion These data start to explore the potential of high sensitivity cTn assays in the assessment of patients with stable cardiac disease in a real world environment. Judging from the data from PEACE-trial [27] and in heart failure patients [10], one might have expected that values would be easily distinguishable from each other and lead to important clinical distinctions. However, we found relatively poor diagnostic and prognostic performance for these values. We could not substantiate the concept that more sensitive assays would allow for the more facile detection of patients with stable CAD [8,11,12,15]. It may be that hscTnI will be capable of distinguishing normal subjects from abnormal subjects and thus could detect patients with CAD from those who are normal. However, our data suggest that all chronic cardiac diseases will be associated with detectable levels of hs-cTnI and that facile discrimination between those with CAD and those with other cardiac abnormalities may not be possible. Even the prognostic data we observed were less robust than expected. Based on the data from the PEACE trial [27], one might have expected more of a separation predicated on risk. However, that study used a different hs-cTn assay

Fig. 1. Survival curves for a) hospitalization (p = 0.029), b) all-cause death or hospitalization (p = 0.012), and c) all-cause death or nonfatal AMI or hospitalization (p = 0.015) per quartiles of hs-cTnI values (per b4.85 vs 4.85–b6.20 vs 6.20–b8.25 vs ≥8.25 ng/l).

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and the study cohort was comprised of a fairly homogeneous group of patients with stable CAD. In that situation the higher the values, the worse the prognosis. In our group of the sorts of patients seen in routine practice, those without CAD often had other cardiac comorbidities so perhaps the reality is that distinctions within homogeneous group may be facilitated but those that take a more heterogeneous cohort such as that seen in the private practice setting, may be less well triaged. 4.1. hs-cTnI and myocardial impairment hs-cTnI showed a strong but complex association with abnormal myocardial function. ROC analysis showed reasonable discrimination for both regional and global dysfunctions (AUC 0.645, 95%CI 0.567– 0.723, p = 0.0006 and 0.685, 95%CI 0.546–0.773, p = 0.0002 respectively). Multiple regression analysis, however, showed an independent relation only for the larger patient group C. These data are in agreement with data in older adults [9] and patients with heart failure [10]. They are also similar to those of Eggers et al. [28] who reported that elevations of cTnI post ACS were predicted by left ventricular dysfunction, CRP and NTproBNP. We found a strong independent association of hs-cTnI with systolic wall stress. Univariate analysis showed associations with both systolic and diastolic wall stress. These findings are consistent with experimental data [29] and confirm that wall stress is a stimulus for cTn release. They also support reports of concordant increases of cTn and natriuretic peptides [9,30] and suggest that hs-cTnI assays may be very helpful in detecting subclinical left ventricular dysfunction. Although we found associations with hospitalizations alone and in combination with all-cause mortality and AMI, this group was too small in and of itself to show robust prognostic associations. Perhaps had the group been larger, it might have provided more potent within group prognostic significance. 4.2. hs-cTnI and coronary artery disease The associations with CAD were weaker. An association of borderline significance was found for a coronary stenosis ≥70%. We [8] and others [31] have published data arguing against liberation of cTn by exercise-induced ischemia. Even when ischemia is reported to elaborate cTn, the amounts are modest [32]. It may be that severe CAD causes increases in hs-cTnI only intermittently when it becomes unstable [33] or when there is supply–demand imbalance. Chronic CAD absent an acute decompensation that causes injury may not be associated with increases in hs-cTn above the level reached in most chronic heart diseases with myocardial impairment. Our data support that interpretation made in the recent Event publication [11]. 4.3. Extra cardiac factors influencing hs-cTnI Renal function demonstrated the strongest independent factor on hs-cTnI and the greatest AUC. Renal function was either normal or only slightly abnormal in our patients. Age and gender also influenced hs-cTnI values. Perhaps different cut off values may be necessary for different groups when stable cardiac diseases are evaluated. 4.4. Role of hs-cTnI in the management of stable heart patients hs-cTnI was the strongest independent indicator of global myocardial impairment, supporting its role in heart failure [5,6,10]. However, our study did not contain many heart failure patients. Instead it was oriented towards those with coronary and hypertensive heart disease prior to the onset of heart failure. In this cohort, we were not able to use hs-cTnI values to predict prognosis. The only outcome variable that was predicted by hs-cTnI was the rate of hospitalizations alone and in combination with all-cause death and nonfatal AMI. This is in conflict with other studies [9,34] on larger patient cohorts that

were more heterogeneous than our group. These studies included normal subjects and hs-cTnI or T elevations were associated with most clinical heart disease but lacked specificity. Perhaps this is not unexpected as cTn is tissue but not disease-specific. Thus, interpretation of hs-cTnI values appears to be possible only in concert with the other clinical data. These data start to investigate the use of hs-cTnI assays in the evaluation of patients with chronic heart disease. For acute disease, high-sensitive assays provide more sensitive and more rapid detection using rising and falling patterns [7]. Given the range of values we observed, it may be that using an individual's baseline value and assessing for dynamic change rather than relying on an arbitrary cut off value might provide better sensitivity and specificity. For chronic diseases, this approach may be worthwhile for screening and in distinguishing normals from those with cardiovascular disease. However, our data suggest that hs-cTn assays will not be capable of distinguishing patients with abnormalities in ventricular performance from those with abnormalities in coronary vasculature. 5. Limitations This was a real world heterogeneous group of patients with a broad variety of chronic underlying cardiac pathologies. After excluding patients with known disease (groups A–E) and those with atrial enlargement and left ventricular hypertrophy, only 16 patients remained all of whom had significant cardiac comorbidities. Thus, this cohort had a higher frequency of abnormalities than most studies that includes all patients undergoing coronary angiography [35] and no patient subset that could be used as a normal control group. To compare our values with those from healthy persons, see histogram of heparin results in Fig. 1 in [7]. hs-cTnI might identify patients at greater and lesser risk within more homogeneous cohorts of patients or in groups where there are substantial numbers of normal individuals as well. In this exploratory hypothesis-generating study, we did not adjust for the increasing type-I error alpha. The findings are therefore to be tested and validated by an external and independent cohort. 6. Conclusion hs-cTnI was measurable in all patients with stable heart disease and an indication for heart catheterization. hs-cTnI varied in relation to left ventricular wall stress and dysfunction and coronary artery disease. Age, gender, and renal function influenced hs-cTnI. Our data start the important process of evaluation how best to use hs-cTnI values. The prognostic information, perhaps because of the absence of a control group were disappointing. Even if other studies suggest a role for the use of high sensitivity assays in patients with chronic cardiac disease to predict prognosis, ours would suggest that values will not be able to establish with specificity, the etiology of the chronic pathology. Acknowledgement Reagents for measuring high-sensitive cardiac troponin I and funds for technical support were provided by Beckman-Coulter. References [1] 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;21:1502–13. [2] Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction: Kristian Thygesen, Joseph S. Alpert and Harvey D. White on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Eur Heart J 2007;28:2525–38.

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