Cardiac Troponin Universal Definitions
Universal Definition of MI and the Evolution of Troponin Assays
Troponin use has rapidly evolved ever since the release of the first commercially available assay in 1997. Testing for the protein was originally performed only for the diagnosis of acute myocardial infarction (AMI), but now, with the advances in technology, the assay has assumed broader application in areas such as risk stratification and prognosis of patients with acute coronary syndromes. Over the years there have also been a number of changes that have helped the medical community better understand myocardial infarction (MI). Specifically, advances in precise imaging techniques have allowed clinicians to detect very small zones of myocardial necrosis. These small zones of necrosis are indicative of myocardial damage and can release small amounts of troponin into circulation. With the availability of more specific information, there have been modifications to the definition of a “positive troponin” and even myocardial infarction.
World Health Organization’s (WHO) Original Definition of MI
The term myocardial infarction is generally used when myocardial necrosis due to myocardial ischemia is evidenced in a clinical setting. Published in 1971, WHO criteria for the identification of MI recommended that the condition can be diagnosed if any two of the following three features are present:
- Symptoms of myocardial ischemia (continuous chest pain for 20 minutes)
- ECG changes with ST segment elevation or Q wave development
- Elevation of sensitive and specific cardiac enzymes in circulation1
New Universal Definition of MI
With advances in imaging techniques and the availability of more sensitive and specific cardiac biomarkers such as troponin, the joint committee of the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) convened a consensus conference in 1999 to re-examine the definition of MI. The joint committee recommended the following new universal definition of MI in 2000:
- The term myocardial infarction should be used when there is evidence of myocardial necrosis in a clinical setting consistent with of myocardial ischemia.
Under these conditions, any of the following meets the diagnosis for
- Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with
at least one value above the 99th percentile of the upper reference limit
(URL) together with evidence of myocardial ischemia with one of the following:
- Symptoms of ischemia
- ECG changes indicative of new ischemia
- Development of pathological Q waves
- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality2
Under the new definition of MI, the joint committee stipulated that troponin was the biomarker of choice for diagnosing MI and that troponin assays used in diagnosis meet the following performance criteria:
Troponin assays should have acceptable precision at the 99th percentile (≤10% of coefficient of variation).
Troponin Assays Following the Redefinition of MI
At the time of the ESC/ACC publication redefining MI, none of the troponin assays in the market met the specified guideline for precision at the 99th percentile. Most troponin assays had a 20-35% CV at the critical decision point.
These new guidelines show less focus on separate decision limits for AMI, but more focus on early detection of myocardial injury along with symptoms of ischemia. This change in practice within the clinical community resulted in a similar shift in laboratory guidelines as represented by the National Academy of Clinical Biochemistry (NACB).
Troponin for Risk Stratification
The concept of risk stratification was introduced in the early 1990s, and was based on serial testing over the first 24 hours after the onset of chest pain or admission to the hospital. It helped in estimating an individual’s probability of suffering a major cardiac event in the ensuing 30-60 days, and was applicable only for patients diagnosed with unstable angina, non-ST segment elevation MI (NSTEMI) or chest pain.
National Academy of Clinical Biochemistry (NACB) Guidelines
The NACB released their “Standards of Laboratory Practice: Recommendations for the Use of Cardiac Markers” consensus statement in the late 1990s, which suggested the following:
- using a specific cardiac marker such as cardiac troponin-I for detecting any myocardial injury and incorporation of a low abnormal decision limit for the optimum use of such markers in ACS patients
- a lower decision limit or cutpoint for cardiac assays, guided by the 97.5th percentile among healthy individuals3
The ‘Thrombolysis in Myocardial Infarction’ (TIMI) study expanded on the NACB guideline for using the 97.5th percentile of normal population as a decision limit in ACS patients. The outcome of unstable angina and non-ST elevation MI (NSTEMI) patients, as defined by electrocardiographic profiles, were assessed in the study to form guidelines.4
Employing the ACS:180 cTn-I assay (Siemens Healthcare Diagnostics), the study observed a 3- to 4-fold enhanced risk of a coronary event in patients with cTn-I levels ≥0.1 ng/mL, compared to individuals with lower values. This led to use of cTn-I at cutpoints nearly 10-fold lower than what was previously recommended (initially called the ‘Risk Stratification of Acute Coronary Syndromes’)
NACB Guidelines Today5
In conjunction with the new universal definition of MI, the NACB recommends the following for the analytical aspects of ACS biomarkers:
- One decision-limit, the 99th percentile, is recommended as the optimum cutoff for cTn-I, cTn-T, and CK-MB mass. ACS patients with cTn-I and cTn-T results above the decision-limit should be labeled as having myocardial injury and a high-risk profile.
Assays for cardiac biomarkers should strive for a total imprecision (%CV) of ≤10% at the 99th percentile reference limit.
1. Nomenclature and criteria for diagnosis of ischemic heart disease. Report of the Joint International Society and Federation of Cardiology/World Health Organization task force on standardization of clinical nomenclature. Circulation. 1979;59:607-9. http://www.ncbi.nlm.nih.gov/pubmed/761341?ordinalpos=&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.SmartSearch &log$=citationsensor
2. Alpert JS, et al. J Am Coll Cardiol. 2000;36:959-69. http://www.ncbi.nlm.nih.gov/pubmed/10987628
3. Wu AH, et al. Clin Chem. 1999;45:1104-21. http://www.ncbi.nlm.nih.gov/pubmed/10388496
4. Morrow DA, et al. Clin Chem. 2000;46:453-60. http://www.ncbi.nlm.nih.gov/pubmed/10759468
5. Apple FS, et al. Clin Chem 2007 ;53:547–51. http://www.ncbi.nlm.nih.gov/pubmed/17384000?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Default ReportPanel.Pubmed_RVDocSum