Defining a reference population to determine the 99th percentile of a contemporary sensitive cardiac troponin I assay

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Abstract

Background

Diagnosis of acute myocardial infarction (AMI) according to the universal definition is based on ischemic symptoms, imaging findings and elevated myocardial necrosis markers, preferably cardiac troponin I/T with diagnostic threshold representing the 99th percentile of a reference population. It is not clearly defined if this should be an unselected population-based or a healthy cohort with respect to cardiac diseases. Aim of the current study was to describe the distribution of troponin I using a sensitive assay and to evaluate the impact of cardiac diseases and cardiovascular risk factors in apparently healthy individuals.

Methods

Troponin I was determined using a contemporary sensitive assay (TnI Ultra, Siemens) with 10% coefficient of variation (0.03 ng/mL) below the published 99th percentile (0.04 ng/mL) in 5000 participants (49.2% female) of the Gutenberg Health Study, a community-based, prospective, observational single-center cohort study. The calculated 99th percentile cut-offs were tested in 1818 patients with suspected AMI.

Results

Troponin I concentration representing the 99th percentile of the overall study population was 0.04 ng/mL. Excluding individuals with prevalent cardiovascular disease lowers the 99th percentile to 0.034 ng/mL. Exclusion of individuals with traditional risk factors or elevated natriuretic peptide leads to further reduction with 0.029/0.028 ng/mL. These lower cut-offs detect more patients at risk in individuals with suspected AMI. Correlations of troponin I with age, gender and traditional risk factors were observed.

Conclusions

Troponin I concentrations in apparently healthy individuals are dependent on prevalent cardiovascular diseases, traditional risk factors, gender and age. Application of corresponding cut-offs in diagnosis of AMI alters the group of patients potentially at risk.

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

. Baseline characteristics of 5,000 individuals of the Gutenberg Health Study (GHS) according to troponin I level.

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)

  • P.M. McKie 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)
  • K. Thygesen et al.

    Universal definition of myocardial infarction

    Circulation

    (Nov. 27 2007)
  • F.S. Apple 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)
  • A.R. Macrae 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)
  • F.S. Apple 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)
  • T. Keller et al.

    Sensitive troponin I assay in early diagnosis of acute myocardial infarction

    N Engl J Med

    (Aug. 27 2009)
  • T. Reichlin et al.

    Early diagnosis of myocardial infarction with sensitive cardiac troponin assays

    N Engl J Med

    (Aug. 27 2009)
  • C. Prontera et al.

    Evaluation of analytical performance of the Siemens ADVIA TnI ultra immunoassay

    Clin Chem

    (Sep 2007)
  • F.S. Apple et al.

    Serum and plasma cardiac troponin I 99th percentile reference values for 3 2nd-generation assays

    Clin Chem

    (Aug. 2007)
  • T.W. Wallace et al.

    Prevalence and determinants of troponin T elevation in the general population

    Circulation

    (Apr. 25 2006)
  • J.R. Tate et al.

    The determination of the 99th centile level for troponin assays in an Australian reference population

    Ann Clin Biochem

    (May 2008)
  • P.O. Collinson et al.

    Influence of population selection on the 99th percentile reference value for cardiac troponin assays

    Clin Chem

    (2012)
  • T. Zeller et al.

    Genetics and beyond—the transcriptome of human monocytes and disease susceptibility

    PLoS One

    (2010)
  • P.S. Wild et al.

    Distribution and categorization of left ventricular measurements in the general population: results from the population-based gutenberg heart study

    Circ Cardiovasc Imaging

    (Sep. 14 2010)
  • A.S. Levey et al.

    A simplified equation to predict glomerular filtration rate from serum creatinine

    J Am Soc Nephrol

    (2000)
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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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