Defining a reference population to determine the 99th percentile of a contemporary sensitive cardiac troponin I assay☆
Introduction
Early and accurate identification of acute myocardial infarction (AMI) in patients presenting with chest pain is a major goal in emergency care. The current consensus document of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) defines acute myocardial infarction on the basis of ischemic symptoms as well as imaging findings in addition to determination of cardiac troponin I or T as marker for myocardial necrosis [1]. The use of the 99th percentile of a reference population as cut-off in diagnosis of an acute myocardial infarction is recommended by this universal definition of myocardial infarction [1]. At least one elevated troponin I or T measurement within 24 hours after onset of chest pain has to be observed with a kinetic indicative of an acute cause for troponin I or T release. As diagnostic criteria, a 30% [2] rise or fall in troponin I or T concentration within 6 hours [3] is suggested to unravel the acute coronary cause of myocardial necrosis.
Introduction of robust sensitive troponin I and T assays with a coefficient of variation of 10% or less at the concentration representing the 99th percentile of a reference population used as diagnostic cut-off has proven to deliver impressive sensitivity in early identification of AMI [4], [5], [6].
This contemporary assay generation with enhanced analytical sensitivity compared to conventional assays further allows more accurate troponin I determination in apparently healthy individuals. It could be shown that gender as well as age influence troponin I concentrations [7] in the general population.
To establish a diagnostic cut-off for evaluation of chest pain patients the distribution of troponin I or T including determination of the 99th percentile has been performed in different healthy populations [8]. It could be shown that asymptomatic individuals with elevated troponin T levels above the 99th percentile more often have an underlying cardiac disease compared to those with lower troponin concentrations [9]. Furthermore, individuals defined as cardio-healthy showed lower troponin concentrations compared to the published reference values of the respective assays [10], [11].
The impact of prevalent cardiovascular disease and cardiovascular risk factors as well as gender on the calculation of the 99th percentile of a contemporary sensitive troponin I assay has not been evaluated in large representative population based studies. The aim of the present study is to establish possible cut-offs for a commercially available contemporary sensitive troponin I assay among women and men of a population based cohort considering prevalent cardiac diseases and traditional cardiovascular risk factors. Furthermore, aim of the analysis is to evaluate the impact of these different potential cut-off values in a real-world setting of chest pain patients.
Section snippets
Study population
The Gutenberg Health Study (GHS) is designed as a community-based, prospective, observational single-center cohort study in the Rhein-Main-Region in western Mid-Germany. The primary aim of the study is to improve individual cardiovascular risk stratification [12], [13].
Participants were randomly selected from the register of the local registry offices in the city of Mainz and the district of Mainz-Bingen. Individuals between 35 and 74 years of age were eligible to participate; exclusion criteria
Results
Cardiac troponin I was detectable with values above 0.006 ng/mL in 1701 (34.7%) of the analyzed population based cohort. The characteristics of the overall study population as well as the two defined subgroups according to presence of cardiovascular risk factors or cardiac diseases are provided in Table 1. As expected, individuals with known cardiovascular disease (n = 342) were older, more often male with a higher percentage of cardiovascular risk factors. Individuals in the group with
Discussion
As newer more sensitive troponin I or T assays are commercially available, reliable routine measurement in very low concentrations of troponin I or T near a 99th percentile is possible. Diagnosis of acute myocardial infarction relies on the excess of troponin I or T above a predefined diagnostic cut-off. The universal definition of myocardial infarction recommends the 99th percentile of a general population as such a threshold [1]. Individuals enrolled in population based cohorts constitute a
Conflict of interest statement
TK, DP and SB received speaker honoraria from Siemens diagnostics.
The following is the supplementary data related to this article
Acknowledgments
We thank the study staff of the Gutenberg Health Study and the chest pain cohort as well as the technicians of the biomarker laboratory. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
References (30)
- et al.
The prognostic value of N-terminal pro-B-type natriuretic peptide for death and cardiovascular events in healthy normal and stage A/B heart failure subjects
J Am Coll Cardiol
(May 11 2010) - et al.
Universal definition of myocardial infarction
Circulation
(Nov. 27 2007) - et al.
Role of monitoring changes in sensitive cardiac troponin I assay results for early diagnosis of myocardial infarction and prediction of risk of adverse events
Clin Chem
(May 1 2009) - et al.
Assessing the requirement for the 6-hour interval between specimens in the American Heart Association Classification of Myocardial Infarction in Epidemiology and Clinical Research Studies
Clin Chem
(May 1 2006) - et al.
Use of the Centaur TnI-Ultra assay for detection of myocardial infarction and adverse events in patients presenting with symptoms suggestive of acute coronary syndrome
Clin Chem
(Apr. 1 2008) - et al.
Sensitive troponin I assay in early diagnosis of acute myocardial infarction
N Engl J Med
(Aug. 27 2009) - et al.
Early diagnosis of myocardial infarction with sensitive cardiac troponin assays
N Engl J Med
(Aug. 27 2009) - et al.
Evaluation of analytical performance of the Siemens ADVIA TnI ultra immunoassay
Clin Chem
(Sep 2007) - et al.
Serum and plasma cardiac troponin I 99th percentile reference values for 3 2nd-generation assays
Clin Chem
(Aug. 2007) - et al.
Prevalence and determinants of troponin T elevation in the general population
Circulation
(Apr. 25 2006)
The determination of the 99th centile level for troponin assays in an Australian reference population
Ann Clin Biochem
Influence of population selection on the 99th percentile reference value for cardiac troponin assays
Clin Chem
Genetics and beyond—the transcriptome of human monocytes and disease susceptibility
PLoS One
Distribution and categorization of left ventricular measurements in the general population: results from the population-based gutenberg heart study
Circ Cardiovasc Imaging
A simplified equation to predict glomerular filtration rate from serum creatinine
J Am Soc Nephrol
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Funding: The Gutenberg Health Study is funded through the government of Rheinland-Pfalz (“Stiftung Rheinland-Pfalz für Innovation”), the research program “Wissen schafft Zukunft” and “Schwerpunkt Vaskuläre Prävention” of the Johannes Gutenberg-University Mainz and its contract with Boehringer Ingelheim and Philips Medical Systems including an unrestricted grant.
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Both authors contributed equally to the present manuscript.