Why Cardiac Troponin Test need to be Repeated Several Times in a case of Suspected Acute Coronary Syndrome (ACS)

Importance:
Cardiac Troponin (cTn) I or T need to be repeated at least once after 12 hours of onset of the symptoms, if patient is seen within 12 hours and the initial result is negative to exclude the diagnosis of Myocardial Infarction. Highly sensitive cTn may be repeated 2-3 hourly for two to three times for the same purpose.
Normal Values ¹
Cardiac troponin levels are normally so low they cannot be detected with most blood tests. Troponins are found only in skeletal muscles and heart muscles; smooth muscle cells do not contain troponins.
Test results are usually considered normal if the results are:

• Troponin I : less than 10 µg/L
  
• Troponin T : 0–0.1 µg/L
  

Normal troponin levels after 12 hours of chest pain mean a heart attack is unlikely.
What abnormal results mean:
An increase in the troponin level, even a slight one, usually means there has been some damage to the heart. Significantly high levels of troponin are a sign that a heart attack has occurred.
Most patients who have had a heart attack have increased troponin levels within 6 hours. After 12 hours almost everyone who has had a heart attack will have raised levels.
Troponin levels may remain high for 1 to 2 weeks after a heart attack.
Increased troponin levels may also be due to:

• Abnormally fast heart beat
  
• High blood pressure in lung arteries (pulmonary hypertension)
  
• Blockage of a lung artery by a blood clot, fat, or tumor cells (pulmonary embolus)
• Congestive heart failure
  
• Coronary artery spasm
  
• Inflammation of the heart muscle usually due to a virus (myocarditis)
  
• Strenuous exercise (for example, due to marathons or triathlons)
  
• Trauma that injures the heart such as a car accident
  
• Weakening of the heart muscle (cardiomyopathy)
  

Increased troponin levels may also result from certain medical procedures such as:

• Cardiac angioplasty/stenting
  
• Heart defibrillation or electrical cardioversion (purposeful shocking of the heart by medical personnel)
  
• Open heart surgery
  
• Radiofrequency ablation of the heart
  

The Changing Scenario:
Previously, clinicians often had to wait an average of 6 hours with the lower-sensitivity, lower-precision cTn assays to see a conclusive increase in plasma cTn levels after the first troponin measurement, but today's high-sensitivity cTn tests that are separated by a mere 2 to 3 hours, can be highly informative.
Given the urgent need for early diagnosis of ACS and appropriate emergency intervention, as well as the ease of performing this relatively inexpensive assay, clinicians do not need to wait 6 to 8 hours before ordering a second troponin test to rule in ACS.
It is recommend to collect a second specimen for cTn testing within 2 to 3 hours from the collection of the blood sample at presentation to help confirm the diagnosis of MI.
Why dynamics of Troponin is Important:
The most common cause of cardiac injury is myocardial ischemia, ie, acute myocardial infarction. To be detectable, Troponin T takes 2 to 4 hours after the onset of myocardial necrosis, attends peak after about 12 hours and can remain elevated for up to 14 days.
In patients with MI, there is a lag before troponin elevations can be detected.Thus, the markers should be serially monitored upon suspicion for acute coronary syndrome (ACS). The initial recommendations were to check the markers every 6 hours until the expected peak was reached. However, with the more sensitive assays now available, very low concentrations of elevated cardiac markers can be detected, and evidence has demonstrated that checking troponins 3-4 hours after the initial draw can help in early diagnosis of ACS.

The safest rule of thumb is that a single negative test result for troponin does not exclude AMI in a patient with current or very recent symptoms, nor does it exclude clinically significant coronary artery disease.

Let us go here to recapitulate the physiological Role of Troponin in cardiac muscle contraction to appreciate it

 
Importance of the Dynamics of Troponin:
The dynamics of troponin levels (rise and/or fall over time) help distinguish AMI from non-AMI conditions, thus serial troponin testing is the standard approach recommended for assessing patients with suspected acute coronary syndrome (ACS).
The safest rule of thumb is that a single negative test result for troponin does not exclude AMI in a patient with current or very recent symptoms, nor does it exclude clinically significant coronary artery disease.
About acute myocardial infarction (AMI)

1. AMI is part of a group of conditions collectively known as acute coronary syndrome (ACS), which includes both ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation myocardial infarction (NSTEMI), and unstable angina.
   
2. These conditions are associated with common symptoms but have different underlying pathologies; STEMI is usually associated with a relatively large amount of damage (Transmural) to the myocardium (heart muscle) caused by a major blockage in the coronary artery, and can be detected with ST-elevation on an ECG trace. By comparison, NSTEMI is associated with relatively less damage to myocardium (Sub-endocardial) caused by partial blockage of the coronary artery or blockage of a smaller artery, and does not produce ST-elevation on ECG.
   
3. Acute coronary syndromes arise from an obstruction in the coronary arteries, usually caused by atherosclerosis and build-up of plaque which ruptures. When blood flow to the heart is reduced or blocked for a significant length of time (around 30-60 minutes) damage to cardiomyocytes (heart muscle cells) occurs, a pathological change which distinguishes an AMI from unstable angina.
   
4. Patients with ACS generally present with chest pain, a symptom which is responsible for around 700,000 emergency department attendances per year in England and Wales and 253,765 emergency admissions per year.
   
5. During 2011/12, the Myocardial Ischaemia National Audit Project (MINAP) reported 79,433 admissions with AMI recorded in England and Wales, 32,439 (41%) of which were categorised as STEMI, and 46,994 (59%) were categorised as NSTEMI.
   
6. The incidence of acute myocardial infarction increases with age, with the average age of first STEMI being 65 years, and of first NSTEMI 70 years. The incidence is also greater amongst men, with men being twice as likely to have an AMI as women.
   

^{Why Troponin test is preferred to Creatine Kinase MB}

The skeletal and cardiac muscle troponin T and troponin I are immunologically distinct entities. Separate sets of genes code for these proteins. Thus, the cardiac troponin assays, which rely on antigen antibody interaction, are specific for cardiac troponins and can be used to differentiate between the skeletal and cardiac troponins.
Cardiac troponin levels do not rise in the presence of skeletal damage without cardiac myocyte damage. However, this is not the case for creatine kinase MB, which, being present to some extent in skeletal muscle and several other tissues such as the intestines, tongue, diaphragm, uterus, and prostate, may be elevated upon injury to these tissues, potentially resulting in false-positive results. Because of this, troponin testing is superior to creatine kinase MB testing.
Status of Electrocardiography (ECG) as a single mode of diagnosis of AMI:
Electrocardiography (ECG) was one of the earliest diagnostic modalities introduced to evaluate ischemic injury to the heart. Despite its usefulness, ECG continues to be nonsensitive in diagnosing ischemic cardiac events, as ECG findings are normal in many patients with ischemic injury.
The introduction of various markers of cardiac injury, such as creatinine kinase MB, troponins, and myoglobins, has revolutionized the diagnosis of myocardial injury. The cardiac troponins, by virtue of being the most sensitive and specific, have become the preferred biomarker for evaluation of patients with suspected MI.

Determining infarct size:
Peak troponin values can provide an estimate of the infarct size and the severity of myocardial damage. These values are more sensitive in the setting of transmural infarction (ST-segment–elevation MI [STEMI]) than in subendocardial infarctions (NSTEMI). This correlation holds true for both troponin T and troponin I (peak or values at 72-96 hours). Higher values generally correlate with a larger infarct
Significance of degree of troponin elevation
The degree of troponin elevation correlates well with both the 30-day mortality and long-term mortality. Various clinical trials have evaluated the degree of elevation of both troponin I and troponin T and found that higher elevations at presentation and peak are associated with worse long-term outcomes. The absolute values have been used to guide treatment decisions and to identify patients who are at an increased risk of death.
Prognostic value of the timing of elevation
Patients who present with elevated troponin levels at baseline tend to have worse outcomes than those in whom troponin levels are elevated at 8 hours. Outcomes are best in patients in whom troponin levels never elevate.
In both STEMI and NSTEMI, elevated levels of troponin T and troponin I at presentation are associated with a worse prognosis in terms of both short-term and long-term mortality. 
 
How often to perform troponin testing and the need for serial testing

In patients with MI, there is a lag before troponin elevations can be detected.Thus, the markers should be serially monitored upon suspicion for acute coronary syndrome (ACS). The initial recommendations were to check the markers every 6 hours until the expected peak was reached. However, with the more sensitive assays now available, very low concentrations of elevated cardiac markers can be detected, and evidence has demonstrated that checking troponins 3-4 hours after the initial draw can help in early diagnosis of ACS.





Reference:
http://emedicine.medscape.com/article/2073935-overview#a30
Jaffe AS: 2001-A biomarker odyssey. Clin Chim Acta 1999;284:197-211