Published online before print April 17, 2006, doi: 10.1161/CIRCULATIONAHA.105.609974
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2006;113:1958-1965.)
© 2006 American Heart Association, Inc.
Epidemiology |
Prevalence and Determinants of Troponin T Elevation in the General Population
From the Donald W. Reynolds Cardiovascular Clinical Research Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (T.W.W., S.M.A., M.H.D., S.R.D., A.K., D.K.M., F.W., J.A.d.L.); and Donald W. Reynolds Cardiovascular Clinical Research Center, Brigham and Women’s Hospital, Boston, Mass (M.S.S., D.A.M.).
Correspondence to James A. de Lemos, MD, Division of Cardiology, University of Texas Southwestern Medical Center, 5909 Harry Hines Blvd, Room HA9.133, Dallas, TX 75390-9047. E-mail James.delemos{at}utsouthwestern.edu
Received November 7, 2005; de novo received December 21, 2005; revision received February 21, 2006; accepted February 23, 2006.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— The prevalence and determinants of cardiac troponin T (cTnT) elevation in the general population are unknown, and the significance of minimally increased cTnT remains controversial. Our objective was to determine the prevalence and determinants of cTnT elevation in a large, representative sample of the general population.
Methods and Results— cTnT was measured from stored plasma samples in 3557 subjects of the Dallas Heart Study, a population-based sample. cTnT elevation (
0.01 µg/L) was correlated with clinical variables and cardiac MRI findings. The sample weight-adjusted prevalence of cTnT elevation in the general population was 0.7%. In univariable analyses, cTnT elevation was associated with older age, black race, male sex, coronary artery calcium by electron beam CT, a composite marker of congestive heart failure (CHF), left ventricular hypertrophy (LVH), diabetes mellitus (DM), and chronic kidney disease (CKD) (P<0.001 for each). Subjects with minimally increased (0.01 to 0.029 µg/L) and increased (0.03 µg/L) cTnT had a similar prevalence of these characteristics. In multivariable logistic regression analysis, LVH, CHF, DM, and CKD were independently associated with cTnT elevation.
Conclusions— In the general population, cTnT elevation is rare in subjects without CHF, LVH, CKD, or DM, suggesting that the upper limit of normal for the immunoassay should be <0.01 µg/L. Even minimally increased cTnT may represent subclinical cardiac injury and have important clinical implications, a hypothesis that should be tested in longitudinal outcome studies.
Key Words: diabetes mellitus • hypertrophy • kidney • population • troponin
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Cardiac troponins are well established as specific biomarkers for myocyte injury in the setting of acute coronary syndromes (ACS).1 Troponin measurement aids in the diagnosis of acute myocardial infarction (MI), facilitates risk stratification, and helps to direct treatment modalities.1–3 Although troponin elevation in disorders such as congestive heart failure (CHF) and chronic kidney disease (CKD) portends worsened prognoses,4–6 physicians struggle to interpret troponin values in non-ACS settings, especially when concentrations approach the lower limit of detection for the assay. Troponin levels are increasingly being measured in subjects without typical ischemic chest pain, and the resultant uncertainty as to the interpretation of values in these settings may promote clinical confusion.
Clinical Perspective p 1965
Compounding these clinical issues is controversy with regard to the appropriate lower limits to define troponin elevation and the importance of imprecision with current troponin assays around these lower limits of detection. Expert committees have recommended that troponin elevation be defined, with the use of a normal reference population, as the lowest detectable troponin concentration above the 99th percentile that has <10% coefficient of variation (CV).1 For cardiac troponin T (cTnT), this level is 0.03 µg/L, whereas the lower detection limit is <0.01 µg/L. The choice of the threshold has important clinical implications because recent studies suggest that in patients with ACS, cTnT levels between 0.01 and 0.03 µg/L have important prognostic and therapeutic implications.2 In addition, minimally increased cardiac troponin I levels in patients without definite ACS are also associated with poor prognosis.7
To date, few data are available with regard to the prevalence of cTnT elevation within the general population. To better understand the prevalence, etiology, and clinical implications of cTnT elevation that occurs in the general population (including subjects with and without cardiovascular disease), we measured cTnT levels within the Dallas Heart Study, a population-based, representative sample of the Dallas community.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Population
The Dallas Heart Study is a population-based, multiethnic, probability sample of residents of Dallas County, designed to study subclinical cardiovascular disease. Self-reported blacks were oversampled to ensure that 50% of the final sample included this ethnic group. Details of the study design and cohort have been described previously.8 The study was approved by the University of Texas Southwestern Medical Center institutional review board, and all subjects provided written informed consent. The initial in-home visit included 6101 participants and consisted of demographic and medical history data collection, as well as objective measurements (weight, heart rate, and blood pressure). Participants in the 30- to 65-year-old age group were invited for a second visit for collection of fasting blood and urine samples. Participants completing the second visit returned for a final visit, at which time ECG, cardiac and aortic MRI, electron beam CT, and dual-energy x-ray absorptiometry scanning studies were performed. A total of 3557 and 2971 subjects completed the second and third visits, respectively. No significant differences in demographics, medical history, blood pressure, or body mass index (BMI) occurred between the subjects in the second and third visits.8 Sampling weights, reflecting the different probabilities of selection for participants and sample attrition between visits, were constructed to generate unbiased estimates of population frequencies.8
Biomarker Assays
Fasting blood samples were collected in tubes containing EDTA and maintained at 4°C for 
4 hours before being centrifuged at 1430g for 15 minutes. Plasma aliquots were frozen at –80°C until assays were performed. cTnT (Elecsys Troponin T, Roche Diagnostics, Inc, Indianapolis, Ind) was measured with a third-generation immunoassay. The 99th percentile value from the reference population of 1951 subjects used by the manufacturer of the assay was <0.01 µg/L, and the lowest level at which the CV was <10% was 0.03 µg/L.9,10 B-type natriuretic peptide (BNP) and N-terminal-proBNP (NT-proBNP) measurements were performed with commercially available assays from Biosite, Inc (San Diego, Calif) and Roche Diagnostics, Inc, respectively.11 High-sensitivity C-reactive protein measurements were performed on thawed samples with the use of the Roche/Hitachi 912 System, Tina-quant assay (Roche Diagnostics, Inc), a latex-enhanced immunoturbidimetric method with a measurement range of 0.1 to 20 µg/L.12
Cardiac Imaging
Electron beam CT scans were performed with an Imatron C-150XP electron beam CT scanner (Imatron Inc, San Bruno, Calif) as described.13 Coronary artery calcium (CAC) scores were classified with the use of a previously described classification scheme14: no calcium (CAC score 0 to 10), mild (>10 to 100), moderate (>100 to 400), and severe (>400).
Cardiac MRI was performed with the use of a Phillips Medical Systems 1.5-T Intera magnet (Bothell, Wash) as described.15 Low left ventricular ejection fraction (LVEF) was defined as <0.40.16 Sex-specific left ventricular hypertrophy (LVH) was defined as ratios of LV mass to body surface area >89 g/m2 in women and >112 g/m2 in men.15
Definition of Variables
Subjects completed an extensive self-reporting survey in which past medical history of MI, CHF, valvular heart disease, coronary artery bypass grafting, smoking, arrhythmias, recent hospitalization (<1 year before visit 1), alcohol and cocaine use, and medication use were obtained. Stable angina pectoris was defined as self-reported chest pain with exertion plus at least 1 affirmative answer to an additional criterion from the Rose Angina Questionaire17: location, effect of level of exertion on chest pain, improvement of pain with rest, or duration of chest pain.
Diabetes mellitus (DM) was defined by a fasting serum glucose 126 mg/dL (7 mmol/L), nonfasting serum glucose >200 mg/dL (>11.1 mmol/L), or use of an antihyperglycemic medication. Five sequential blood pressure measurements were obtained at visit 1, and hypertension was defined as mean systolic blood pressure 140 mm Hg, mean diastolic blood pressure 90 mm Hg, or use of antihypertensive medication. Hypercholesterolemia was defined as a calculated fasting low-density lipoprotein cholesterol 160 mg/dL (4.1 mmol/L), direct low-density lipoprotein 160 mg/dL (4.1 mmol/L) on a nonfasting sample, total cholesterol 240 mg/dL (6.2 mmol/L), or use of statin medication. Hypertriglyceridemia was defined as a fasting triglyceride concentration 200 mg/dL (2.3 mmol/L); low high-density lipoprotein was defined as 40 mg/dL (1.0 mmol/L) in men and 50 mg/dL (1.3 mmol/L) in women.
Estimated glomerular filtration rate (eGFR) was determined by the Modification of Diet and Renal Disease calculation [eGFR=186xserum creatinine (mg/dL)–1.154xage (years)–0.203x0.742 (if female)x1.21 (if black)] and classified with the use of standards set forth by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative.18 The Modification of Diet and Renal Disease calculation may overestimate kidney disease when applied to the general population; for this reason, we defined chronic kidney disease as eGFR <60 mL/min.19
Statistical Analysis
All statistical analysis was performed with the use of SAS (version 9.1; Cary, NC) statistical software. Because of the skewed distribution, cTnT levels were analyzed as categorical variables as undetectable (<0.01 µg/L), minimally increased (0.01 to 0.029 µg/L), and increased (0.03 µg/L). To estimate the population prevalence of detectable cTnT, we used the SAS procedure SURVEYMEANS to account for the stratified sampling design and unequal sample weights due to intentional oversampling of blacks. Statistical comparisons of variables between cTnT categories were made with the use of the 
2 or Fisher exact test for categorical variables and the Kruskal-Wallis or Wilcoxon 2-sample test for continuous variables. The Cochran-Armitage trend test was used to evaluate the association between cTnT prevalence and CKD, BMI, and CAC classifications. Stepwise multivariable logistic regression was performed to identify variables independently associated with cTnT elevation requiring a probability value of 0.1 to be entered and 0.05 to remain in the model. Because of the small number of subjects with cTnT elevation, our ability to perform multivariable adjustment was limited; therefore, we created composite factors to characterize CHF and coronary artery disease (CAD).The CHF factor was defined as either a prior history of CHF, LVEF <0.40 by MRI, or BNP >100 pg/mL. The CAD factor was defined as either a history of stable angina, history of MI, or CAC score >100. Finally, in exploratory analyses, the quantitative association between the cumulative independent determinants and the probability of cTnT elevation was evaluated with the use of the Cochran-Armitage trend test to determine statistical significance.
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Prevalence of Troponin Elevation and Associations With Clinical Variables
Of the 3557 subjects who provided blood samples for cTnT testing, 41 subjects (1.15%) had detectable values of cTnT. After we accounted for sampling weights, the estimated population prevalence of cTnT elevation was 0.70% (95% CI, 0.34% to 1.07%). The range of detectable cTnT within our sample was 0.01 to 0.37 µg/L with a median value of 0.024 µg/L. Four subjects (0.1% of sample) had cTnT concentrations >0.1 µg/L. The subject with a cTnT of 0.37 µg/L had end-stage renal disease for 6 years requiring peritoneal dialysis with several recent hospitalizations for dehydration, nausea, and vomiting. He had a CAC score of 2326 but did not have evidence of a recent ACS event or stable angina, and he had normal LV mass and LVEF.
In univariable analyses, cTnT elevation (0.01 µg/L) was significantly associated with older age, black race, male gender, and a history of MI, coronary artery bypass grafting, CHF, valvular disease, arrhythmias, stable angina, DM, hypertension, and CKD. Additional factors demonstrating significant associations were low HDL cholesterol; high triglycerides; higher BMI; recent hospitalization; therapy with aspirin, statins, ACE inhibitors, or ß-blockers; LVH; LVEF <40%; increasing CAC score; and increased levels of BNP and NT-proBNP (Table 1).
|
When subjects with undetectable (<0.01 µg/L), minimally increased (0.01 to 0.029 µg/L), and increased (0.03 µg/L) cTnT values were compared, a threshold effect was evident (Table 1). There were marked differences in the presence of high-risk clinical characteristics when the undetectable group was compared with the minimally increased group; in contrast, the minimally increased and increased cTnT groups had a similar prevalence of these high-risk cardiovascular features (Table 1).
Quantitative Associations Between Clinical Variables and cTnT Elevation
The prevalence of cTnT elevation increased in a graded manner with increasing LV mass (Figure 1). Similarly, the prevalence of cTnT elevation increased with an increasing number of components of the CHF factor (history of CHF, EF <0.40, or BNP >100 pg/mL) (Figure 2). Decreasing eGFR was also associated with increased prevalence of cTnT elevation in a steep, dose-dependent fashion (Figure 3).
|
|
|
Multivariable Association of Clinical Variables and Troponin Elevation
In multivariable logistic regression analysis, the CHF factor (odds ratio [OR], 5.3; 95% CI, 1.9 to 14.8), DM (OR, 4.6; 95% CI, 1.8 to 11.6), LVH (OR, 5.4; 95% CI, 2 to 14.6), and CKD (OR, 20.4; 95% CI, 7.5 to 55.3) were independently associated with cTnT elevation (Table 2). Age, race, and the CAD factor were not significantly associated with cTnT elevation and were removed from the final multivariable model. When subjects were categorized on the basis of increasing numbers of independent determinants, a steep, additive association was observed between the number of independent risk determinants and cTnT elevation (Figure 4). At least 1 of these determinants was present in 37 of 41 subjects (90%) with cTnT elevation. When the study population was restricted to a very-low-risk cohort (n=1060) without DM, hypertension, CKD, LVH, CHF, low LVEF, history of MI, or BMI >30, no subjects had detectable cTnT.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Among Dallas County adults aged 30 to 65 years, the population prevalence of cTnT elevation was very low (0.7%). When cTnT was detected, it was associated with underlying cardiovascular disease or high-risk phenotypes associated with cardiovascular disease. Few data are available evaluating the prevalence of cTnT elevation in a large and representative sample of the general population. Previous studies have reported the prevalence of troponin elevation among dialysis patients, patients visiting emergency departments with angina, patients presenting to outpatient clinics, and healthy volunteers.20–23 In addition, although LVH, CKD, and CHF have previously been demonstrated to be associated with elevated troponin levels in small patient populations or subgroups of patients,5,6,10,24–27 we describe the largest cohort of nonhospitalized subjects to date in which independent associations between these conditions and cTnT elevation have been demonstrated. A prior study by Apple et al23 reported higher troponin I values in blacks versus whites and in men versus women with some troponin assays. We also found a higher prevalence of cTnT elevation among blacks and men, but these differences did not remain statistically significant after multivariable adjustment.
Implications for the Lower Detection Limit for Troponin T
The European Society of Cardiology and American College of Cardiology recommended that the lower detection limit for cardiac troponin be the 99th percentile of the assay in a standard reference population provided that the CV at that level was <10%.1 If an assay did not meet that criterion, the recommendation was to set the lower detection limit for troponin T or I at the lowest level at which the CV was <10%. The cTnT immunoassay used in the present study had a 99th percentile value of <0.01 µg/L but a value of 0.03 µg/L at which the CV was <10%. The strong associations between troponin levels of 0.01 to 0.029 µg/L and cardiovascular abnormalities seen in our population-based sample argue that the detection limit for cTnT should be lowered to <0.01 µg/L, so that all detectable cTnT values are characterized as abnormal if the goal of testing is optimal sensitivity.
In the present study we observed no apparent clinical differences between those subjects with minimally increased and increased cTnT values. The present findings suggest that the mandate for assay development should focus on greater sensitivity to detect lower levels of cTnT, and such efforts will require increased assay precision. Our findings do not support the default assumption that troponin concentrations below the 10% CV level are unreliable. Indeed, our data demonstrate that levels in this range carry important clinical implications. Previous clinical trials also demonstrated that patients with minimally increased cTnT levels below the 10% CV level (regardless of etiology or the magnitude of elevation) have worse prognoses.2,3,6,7,28–30 Furthermore, a recent simulation study using assay imprecision values representative of current cTnI assays demonstrated a very low false-positive rate for diagnosing MI when the 99th percentile was used instead of the 10% CV level, thus supporting use of the 99th percentile to define troponin elevation.31
Mechanisms of Troponin Elevation in the Population
Multiple mechanisms may account for cardiac injury and concomitant troponin elevations in our population-based sample.32 Microvascular coronary disease, which occurs in CHF, DM, and CKD, may contribute to troponin elevation in these disease processes. LV strain, decreased subendocardial perfusion, endothelial dysfunction, and apoptosis are potential etiologies of troponin elevation in CHF subjects.33–35 Troponin elevation seen with LVH may be the result of a supply/demand mismatch whereby hypertrophied myocytes physically impair adequate endocardial tissue perfusion.36 Both microvascular disease and lipotoxic mechanisms may lead to myocardial damage in diabetic patients.37,38 One study demonstrated that at autopsy, diabetic patients with normal coronary arteries on angiogram had multiple microvascular infarctions.39,40 Microvascular disease has been demonstrated to be present in CKD patients, and uremia may lead to silent ischemia similar to that seen in diabetic subjects.4,5 Furthermore, in patients with CKD, troponin elevation and LVH appear to be synergistic in regard to prognosis.41 Similarly, the mechanisms that cause cTnT elevation in patients with CHF and those with LVH may also be applicable in those with CKD.
Clinical Implications
In univariable analyses, cTnT elevation was associated with a large number of cardiac risk factors and evidence of cardiac structural and functional abnormalities. In multivariable analyses, cTnT elevation was strongly and independently associated with 4 independent risk determinants: CHF, LVH, DM, and CKD. Importantly, in the absence of these 4 risk determinants, cTnT elevation was extremely rare (0.18%). Indeed, in a cohort free of DM, hypertension, CKD, LVH, CHF, history of MI, low EF, or BMI >30 (n=1060), we did not observe any subjects with detectable cTnT. Thus, in this population-based cohort, cTnT elevation represented either prevalent cardiovascular disease or a high risk for cardiovascular disease. These findings suggest that primary and secondary prevention efforts should be intensified in subjects with otherwise unexplained troponin elevation and that additional cardiovascular evaluation may be warranted. Given the associations seen between troponin elevation and LV structural and functional abnormalities, DM, and renal failure, echocardiography, measurement of fasting glucose, and assessment of renal function would be reasonable. These data do not imply, however, that such an evaluation must occur urgently or require hospitalization. cTnT should only be interpreted together with available data from the patient’s history, physical examination, laboratory findings, and ECG.
These findings may also have implications for the diagnostic specificity of cTnT to detect MI in the setting of DM, LVH, CHF, and moderate CKD. The probability of cTnT elevation increases dramatically with a greater number of these risk determinants present. Clinicians should be aware that patients with multiple risk determinants may have detectable cardiac injury outside the setting of ACS. Such patients likely require evaluation and intervention, but not acutely.
Finally, our findings suggest that cTnT may merit consideration for further study as a screening test for cardiovascular abnormalities in high-risk population subsets. Although sensitivity of the test to detect cardiovascular disease will be low in apparently healthy subjects, given the low prevalence of troponin elevation observed (<0.2%), specificity appears to be quite high. Sensitivity may be improved in high-risk subjects such as those with DM (4.7% prevalence of elevated cTnT) and hypertension (2.8% prevalence of elevated cTnT). If future studies demonstrate increased risk for cardiac events in high-risk subjects with troponin elevation, and appropriate therapies for these subjects are identified, we speculate that troponin may prove to be a useful component of multiple-biomarker panels for screening of at-risk subjects in the general population. These multiple-biomarker panels may include other highly specific but relatively insensitive markers of cardiovascular risk that in the aggregate provide sufficient sensitivity for screening. Development of more sensitive troponin assays may improve the performance of troponin as a screening test.
Limitations
Several limitations of this study should be noted. First, and most notably, the number of subjects with troponin elevation was small, limiting the depth of multivariable analyses that could be performed and reducing statistical power to detect differences between subjects with minimally elevated and elevated cTnT levels. As a result, our conclusion that subjects with minimally elevated and elevated cTnT levels had similar clinical characteristics should be viewed with caution until these findings are replicated in larger data sets. Second, the study is a cross-sectional analysis of a large and ethnically diverse cohort and thus may not be applicable to other populations. Third, our study design cannot fully account for the potential influence of false-positive cTnT values due to analytic random noise or due to heterophile interference with the assay.42,43 However, recent studies suggest that the probability of analytic false-positives is extremely low31 and that heterophile antibodies have a minimal influence on the assay used in the present study.9 Moreover, the finding that almost all subjects with elevated troponin, whether minimally increased or increased, had an abnormal cardiac phenotype identified argues that the influence of false-positives in our study is minimal. Finally, cardiovascular outcome data from this cohort are not yet available, and the prognostic implications of troponin elevation in the general population require further study.
Conclusion
The estimated population prevalence of cTnT elevation among Dallas County residents was 0.7%. cTnT was undetectable among healthy subjects, and almost every subject with cTnT elevation had underlying cardiovascular disease or a high-risk phenotype for cardiovascular disease. Furthermore, the prevalence of high-risk cardiovascular features (including LVH, DM, CKD, and CHF) was increased similarly in subjects with cTnT levels in the minimally increased and increased range. These data suggest that cTnT elevation is indicative of cardiovascular disease or at least a high-risk cardiovascular profile. The clinical and therapeutic implications of these findings require prospective study with outcome data.
|
Acknowledgments |
|---|
This study was supported by grants from the Donald W. Reynolds Foundation, Roche Diagnostics, and Biosite Inc. This study was also supported in part by US Public Health Service General Clinical Research Centers grant M01-RR00633 from National Institutes of Health/National Center for Research Resources–Clinical Research. Reagents for NT-proBNP, cTnT, and C-reactive protein were provided by Roche Diagnostics. Assays for BNP were provided by Biosite. We thank Dr Allan Jaffe for his critical review and insightful comments on this manuscript.
Disclosures
Dr McGuire reports having received research grant support from Biosite via University of Texas Southwestern Medical Center ($10 000) and having served as a consultant and/or on the advisory board for Biosite (<$10 000). Dr Sabatine reports having received research grant support from Roche Diagnostics <$10 000) and Biosite (<$10 000). Dr Morrow reports having received research grant support from Bayer Diagnostics ($10 000), Beckman-Coulter ($10 000), Biosite ($10 000), Dade-Behring ($10 000), and Roche Diagnostics ($10 000) via Brigham and Women’s Hospital; having received honoraria from Bayer Diagnostics (<$10 000), Dade-Behring (<$10 000), and Beckman-Coulter (<10 000); and having served as a consultant and/or on the advisory board for OrthoClinical Diagnostics (<$10 000). Dr de Lemos reports having received research grant support from Roche (<$10 000) and Biosite ($10 000) via University of Texas Southwestern Medical Center; having received other research support from Roche ($10 000) and Biosite ($10 000) via University of Texas Southwestern Medical Center; having served on the Speakers Bureau for Biosite (<$10 000); and having served as a consultant and/or on the advisory board for Biosite (<$10 000). The remaining authors report no conflicts of interest.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000; 36: 959–969.
2. Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH, Hille DA, DeLucca PT, DiBattiste PM, Demopoulos LA, Weintraub WS, Braunwald E. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA. 2001; 286: 2405–2412.
3. Heidenreich PA, Alloggiamento T, Melsop K, McDonald KM, Go AS, Hlatky MA. The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a meta-analysis. J Am Coll Cardiol. 2001; 38: 478–485.
4. Freda BJ, Tang WH, Van Lente F, Peacock WF, Francis GS. Cardiac troponins in renal insufficiency: review and clinical implications. J Am Coll Cardiol. 2002; 40: 2065–2071.
5. Dierkes J, Domrose U, Westphal S, Ambrosch A, Bosselmann HP, Neumann KH, Luley C. Cardiac troponin T predicts mortality in patients with end-stage renal disease. Circulation. 2000; 102: 1964–1969.
6. Sato Y, Yamada T, Taniguchi R, Nagai K, Makiyama T, Okada H, Kataoka K, Ito H, Matsumori A, Sasayama S, Takatsu Y. Persistently increased serum concentrations of cardiac troponin t in patients with idiopathic dilated cardiomyopathy are predictive of adverse outcomes. Circulation. 2001; 103: 369–374.
7. Pham MX, Whooley MA, Evans GT Jr, Liu C, Emadi H, Tong W, Murphy MC, Fleischmann KE. Prognostic value of low-level cardiac troponin-I elevations in patients without definite acute coronary syndromes. Am Heart J. 2004; 148: 776–782.[CrossRef][Medline] [Order article via Infotrieve]
8. Victor RG, Haley RW, Willett DL, Peshock RM, Vaeth PC, Leonard D, Basit M, Cooper RS, Iannacchione VG, Visscher WA, Staab JM, Hobbs HH. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am J Cardiol. 2004; 93: 1473–1480.[CrossRef][Medline] [Order article via Infotrieve]
9. Elecsys [package insert]. Indianapolis, Ind: Roche Diagnostics; 2004. 1010/2010/modular analytics E170; vol V 13 EN:2004–2008.
10. Hamm CW, Giannitsis E, Katus HA. Cardiac troponin elevations in patients without acute coronary syndrome. Circulation. 2002; 106: 2871–2872.
11. Das SR, Drazner MH, Dries DL, Vega GL, Stanek HG, Abdullah SM, Canham RM, Chung AK, Leonard D, Wians FH, de Lemos JA. Impact of body mass and body composition on circulating levels of natriuretic peptides: results from the Dallas Heart Study. Circulation. 2005; 112: 2163–2168.
12. Khera A, McGuire DK, Murphy SA, Stanek HG, Das SR, Vongpatanasin W, Wians FH Jr, Grundy SM, de Lemos JA. Race and gender differences in C-reactive protein levels. J Am Coll Cardiol. 2005; 46: 464–469.
13. Jain T, Peshock R, McGuire DK, Willett D, Yu Z, Vega GL, Guerra R, Hobbs HH, Grundy SM. African Americans and Caucasians have a similar prevalence of coronary calcium in the Dallas Heart Study. J Am Coll Cardiol. 2004; 44: 1011–1017.
14. Rumberger JA, Brundage BH, Rader DJ, Kondos G. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc. 1999; 74: 243–252.[Abstract]
15. Drazner MH, Dries DL, Peshock RM, Cooper RS, Klassen C, Kazi F, Willett D, Victor RG. Left ventricular hypertrophy is more prevalent in blacks than whites in the general population: the Dallas Heart Study. Hypertension. 2005; 46: 124–129.
16. Lorenz CH, Walker ES, Morgan VL, Klein SS, Graham TP Jr. Normal human right and left ventricular mass, systolic function, and gender differences by cine magnetic resonance imaging. J Cardiovasc Magn Reson. 1999; 1: 7–21.[Medline] [Order article via Infotrieve]
17. Rose G, McCartney P, Reid DD. Self-administration of a questionnaire on chest pain and intermittent claudication. Br J Prev Soc Med. 1977; 31: 42–48.[Medline] [Order article via Infotrieve]
18. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease. Am J Kidney Dis. 2002; 39: S76–S110.[CrossRef]
19. Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med. 2004; 141: 929–937.
20. Ng SM, Krishnaswamy P, Morrisey R, Clopton P, Fitzgerald R, Maisel AS. Mitigation of the clinical significance of spurious elevations of cardiac troponin I in settings of coronary ischemia using serial testing of multiple cardiac markers. Am J Cardiol. 2001; 87: 994–999; A994.[CrossRef]
21. Fleming SM, O’Byrne L, Finn J, Grimes H, Daly KM. False-positive cardiac troponin I in a routine clinical population. Am J Cardiol. 2002; 89: 1212–1215.[CrossRef][Medline] [Order article via Infotrieve]
22. Roppolo LP, Fitzgerald R, Dillow J, Ziegler T, Rice M, Maisel A. A comparison of troponin T and troponin I as predictors of cardiac events in patients undergoing chronic dialysis at a Veteran’s Hospital: a pilot study. J Am Coll Cardiol. 1999; 34: 448–454.
23. Apple FS, Quist HE, Doyle PJ, Otto AP, Murakami MM. Plasma 99th percentile reference limits for cardiac troponin and creatine kinase MB mass for use with European Society of Cardiology/American College of Cardiology consensus recommendations. Clin Chem. 2003; 49: 1331–1336.
24. Hamwi SM, Sharma AK, Weissman NJ, Goldstein SA, Apple S, Canos DA, Pinnow EE, Lindsay J. Troponin-I elevation in patients with increased left ventricular mass. Am J Cardiol. 2003; 92: 88–90.[CrossRef][Medline] [Order article via Infotrieve]
25. Abaci A, Ekici E, Oguzhan A, Tokgoz B, Utas C. Cardiac troponins T and I in patients with end-stage renal disease: the relation with left ventricular mass and their prognostic value. Clin Cardiol. 2004; 27: 704–709.[CrossRef][Medline] [Order article via Infotrieve]
26. Ishii J, Nomura M, Nakamura Y, Naruse H, Mori Y, Ishikawa T, Ando T, Kurokawa H, Kondo T, Nagamura Y, Ezaki K, Hishida H. Risk stratification using a combination of cardiac troponin T and brain natriuretic peptide in patients hospitalized for worsening chronic heart failure. Am J Cardiol. 2002; 89: 691–695.[CrossRef][Medline] [Order article via Infotrieve]
27. Hocher B, Ziebig R, Altermann C, Krause R, Asmus G, Richter CM, Slowinski T, Sinha P, Neumayer HH. Different impact of biomarkers as mortality predictors among diabetic and nondiabetic patients undergoing hemodialysis. J Am Soc Nephrol. 2003; 14: 2329–2337.
28. Lindahl B, Diderholm E, Lagerqvist B, Venge P, Wallentin L. Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC II substudy. J Am Coll Cardiol. 2001; 38: 979–986.
29. Aviles RJ, Askari AT, Lindahl B, Wallentin L, Jia G, Ohman EM, Mahaffey KW, Newby LK, Califf RM, Simoons ML, Topol EJ, Berger P, Lauer MS. Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction. N Engl J Med. 2002; 346: 2047–2052.
30. Setsuta K, Seino Y, Ogawa T, Arao M, Miyatake Y, Takano T. Use of cytosolic and myofibril markers in the detection of ongoing myocardial damage in patients with chronic heart failure. Am J Med. 2002; 113: 717–722.[CrossRef][Medline] [Order article via Infotrieve]
31. Apple FS, Parvin CA, Buechler KF, Christenson RH, Wu AH, Jaffe AS. Validation of the 99th percentile cutoff independent of assay imprecision (CV) for cardiac troponin monitoring for ruling out myocardial infarction. Clin Chem. 2005; 51: 2198–2200.
32. Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med. 2005; 142: 786–791.
33. Horwich TB, Patel J, MacLellan WR, Fonarow GC. Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation. 2003; 108: 833–838.
34. Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest. 1995; 96: 2247–2259.[Medline] [Order article via Infotrieve]
35. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA. Apoptosis in myocytes in end-stage heart failure. N Engl J Med. 1996; 335: 1182–1189.
36. Schwartzkopff B, Mundhenke M, Strauer BE. Remodelling of intramyocardial arterioles and extracellular matrix in patients with arterial hypertension and impaired coronary reserve. Eur Heart J. 1995; 16 (suppl I): 82–86.[Abstract]
37. Nielsen LB, Bartels ED, Bollano E. Overexpression of apolipoprotein B in the heart impedes cardiac triglyceride accumulation and development of cardiac dysfunction in diabetic mice. J Biol Chem. 2002; 277: 27014–27020.
38. Unger RH. Lipotoxic diseases. Annu Rev Med. 2002; 53: 319–336.[CrossRef][Medline] [Order article via Infotrieve]
39. Aronow WS, Ahn C, Mercando AD, Epstein S. Prevalence of coronary artery disease, complex ventricular arrhythmias, and silent myocardial ischemia and incidence of new coronary events in older persons with chronic renal insufficiency and with normal renal function. Am J Cardiol. 2000; 86: 1142–1143, A1149.[CrossRef][Medline] [Order article via Infotrieve]
40. Ooi DS, Isotalo PA, Veinot JP. Correlation of antemortem serum creatine kinase, creatine kinase-MB, troponin I, and troponin T with cardiac pathology. Clin Chem. 2000; 46: 338–344.
41. Mallamaci F, Zoccali C, Parlongo S, Tripepi G, Benedetto FA, Cutrupi S, Bonanno G, Fatuzzo P, Rapisarda F, Seminara G, Stancanelli B, Bellanuova I, Cataliotti A, Malatino LS. Diagnostic value of troponin T for alterations in left ventricular mass and function in dialysis patients. Kidney Int. 2002; 62: 1884–1890.[CrossRef][Medline] [Order article via Infotrieve]
42. Marks V. False-positive immunoassay results: a multicenter survey of erroneous immunoassay results from assays of 74 analytes in 10 donors from 66 laboratories in seven countries. Clin Chem. 2002; 48: 2008–2016.
43. White GH, Tideman PA. Heterophilic antibody interference with CARDIAC T quantitative rapid assay. Clin Chem. 2002; 48: 201–203.
|
Footnotes |
|---|
Guest Editor for this article was Harvey D. White, DSc.
Presented in abstract form at the 2005 Scientific Sessions of the American Heart Association, Dallas, Tex, November 13–16, 2005.
This article has been cited by other articles:
 |
|
 |
|
  A. A. Mohammed, A. K. Agnihotri, R. R.J. van Kimmenade, A. Martinez-Rumayor, S. M. Green, R. Quiroz, and J. L. Januzzi Jr Prospective, Comprehensive Assessment of Cardiac Troponin T Testing After Coronary Artery Bypass Graft Surgery Circulation, September 8, 2009; 120(10): 843 - 850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Jacobs, J. J. van de Kerkhof, A. M. Mingels, V. L. Passos, V. W. Kleijnen, A. H. Mazairac, F. M. van der Sande, W. K. Wodzig, C. J. Konings, K. M. Leunissen, et al. Inflammation, overhydration and cardiac biomarkers in haemodialysis patients: a longitudinal study Nephrol. Dial. Transplant., August 19, 2009; (2009) gfp417v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Bankier, J. Barajas, A. Martinez-Rumayor, and J. L. Januzzi Association Between Anxiety and C-Reactive Protein Levels in Stable Coronary Heart Disease Patients Psychosomatics, July 1, 2009; 50(4): 347 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J M Wilson Diagnosis and treatment of acquired coronary artery disease in adults Postgrad. Med. J., July 1, 2009; 85(1005): 364 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, P. Clopton, E. S. Brilakis, S. M. Marcovina, A. Khera, E. R. Miller, J. A. de Lemos, and J. L. Witztum Relationship of Oxidized Phospholipids on Apolipoprotein B-100 Particles to Race/Ethnicity, Apolipoprotein(a) Isoform Size, and Cardiovascular Risk Factors: Results From the Dallas Heart Study Circulation, April 7, 2009; 119(13): 1711 - 1719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sundstrom, E. Ingelsson, L. Berglund, B. Zethelius, L. Lind, P. Venge, and J. Arnlov Cardiac troponin-I and risk of heart failure: a community-based cohort study Eur. Heart J., April 1, 2009; 30(7): 773 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R.J. van Kimmenade and J. L. Januzzi Jr Whose heart will get broken? Troponin testing and future heart failure Eur. Heart J., April 1, 2009; 30(7): 755 - 756. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Emdin, S. Vittorini, C. Passino, and A. Clerico Old and new biomarkers of heart failure Eur J Heart Fail, April 1, 2009; 11(4): 331 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Kavsak, A. R. MacRae, M.-J. Yerna, and A. S. Jaffe Analytic and Clinical Utility of a Next-Generation, Highly Sensitive Cardiac Troponin I Assay for Early Detection of Myocardial Injury Clin. Chem., March 1, 2009; 55(3): 573 - 577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Sabatine, D. A. Morrow, J. A. de Lemos, P. Jarolim, and E. Braunwald Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35 Eur. Heart J., January 2, 2009; 30(2): 162 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. L. Pierpont and E. O. McFalls Interpreting troponin elevations: do we need multiple diagnoses? Eur. Heart J., January 2, 2009; 30(2): 135 - 138. [Full Text] [PDF]
|
|
|
|
|
|
D. A. Morrow and E. M. Antman Evaluation of High-Sensitivity Assays for Cardiac Troponin Clin. Chem., January 1, 2009; 55(1): 5 - 8. [Full Text] [PDF]
|
|
|
|
|
|
K. M. Eggers, A. S. Jaffe, L. Lind, P. Venge, and B. Lindahl Value of Cardiac Troponin I Cutoff Concentrations below the 99th Percentile for Clinical Decision-Making Clin. Chem., January 1, 2009; 55(1): 85 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mingels, L. Jacobs, E. Michielsen, J. Swaanenburg, W. Wodzig, and M. van Dieijen-Visser Reference Population and Marathon Runner Sera Assessed by Highly Sensitive Cardiac Troponin T and Commercial Cardiac Troponin T and I Assays Clin. Chem., January 1, 2009; 55(1): 101 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bankier, J. Barajas, A. Martinez-Rumayor, and J. L. Januzzi Association between C-reactive protein and generalized anxiety disorder in stable coronary heart disease patients Eur. Heart J., September 2, 2008; 29(18): 2212 - 2217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Eggers, L. Lind, H. Ahlstrom, T. Bjerner, C. Ebeling Barbier, A. Larsson, P. Venge, and B. Lindahl Prevalence and pathophysiological mechanisms of elevated cardiac troponin I levels in a population-based sample of elderly subjects Eur. Heart J., September 2, 2008; 29(18): 2252 - 2258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Y.-M. Wang and K.-N. Lai Use of Cardiac Biomarkers in End-Stage Renal Disease J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1643 - 1652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. B. Daniels, G. A. Laughlin, P. Clopton, A. S. Maisel, and E. Barrett-Connor Minimally Elevated Cardiac Troponin T and Elevated N-Terminal Pro-B-Type Natriuretic Peptide Predict Mortality in Older Adults: Results From the Rancho Bernardo Study J. Am. Coll. Cardiol., August 5, 2008; 52(6): 450 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. D White Evolution of the definition of myocardial infarction: what are the implications of a new universal definition? Heart, June 1, 2008; 94(6): 679 - 684. [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. de Lemos and D. M. Lloyd-Jones Multiple Biomarker Panels for Cardiovascular Risk Assessment N. Engl. J. Med., May 15, 2008; 358(20): 2172 - 2174. [Full Text] [PDF]
|
|
|
|
 |
|
 J. R Tate, W. Ferguson, R. Bais, K. Kostner, T. Marwick, and A. Carter The determination of the 99th centile level for troponin assays in an Australian reference population Ann Clin Biochem, May 1, 2008; 45(3): 275 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Eggers, B. Lagerqvist, P. Venge, L. Wallentin, and B. Lindahl Persistent Cardiac Troponin I Elevation in Stabilized Patients After an Episode of Acute Coronary Syndrome Predicts Long-Term Mortality Circulation, October 23, 2007; 116(17): 1907 - 1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Latini, S. Masson, I. S. Anand, E. Missov, M. Carlson, T. Vago, L. Angelici, S. Barlera, G. Parrinello, A. P. Maggioni, et al. Prognostic Value of Very Low Plasma Concentrations of Troponin T in Patients With Stable Chronic Heart Failure Circulation, September 11, 2007; 116(11): 1242 - 1249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yee-Moon Wang, C. Wai-Kei Lam, M. Wang, I. Hiu-Shuen Chan, W. B. Goggins, C.-M. Yu, S.-F. Lui, and J. E Sanderson Prognostic Value of Cardiac Troponin T Is Independent of Inflammation, Residual Renal Function, and Cardiac Hypertrophy and Dysfunction in Peritoneal Dialysis Patients Clin. Chem., May 1, 2007; 53(5): 882 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Sakhuja, S. Green, E. M. Oestreicher, P. M. Sluss, E. Lee-Lewandrowski, K. B. Lewandrowski, and J. L. Januzzi Jr. Amino-Terminal Pro-Brain Natriuretic Peptide, Brain Natriuretic Peptide, and Troponin T for Prediction of Mortality in Acute Heart Failure Clin. Chem., March 1, 2007; 53(3): 412 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Jaffe Chasing Troponin: How Low Can You Go if You Can See the Rise? J. Am. Coll. Cardiol., November 7, 2006; 48(9): 1763 - 1764. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||