Clinical and Interpretive

         High Sensitivity Troponin Assays

The International Federation of Clinical Chemistry (IFCC) has issued guidance on high-sensitivity troponin assays. In order to be classified as a high sensitivity assay, two performance requirements must be met:•Theassay must have analytical imprecision ≤ 10% CV at the 99thpercentile URL of a healthy population.•The assay must be able to measure cTn above the Limit of Detection (LOD) in ≥ 50% of a healthy population. Compared to contemporary troponin assays, high sensitivity assays demonstrate significantly improved precision at and below the 99th percentile URL, allowing better discrimination of small differences in cTn values between serial measurements. More precise determination of the 99thpercentile URL has also led to an ability to report distinct reference ranges for male and female subjects. SUMMARY AND EXPLANATIONThe troponins (I, C, and T) are members of a complex of proteins that modulate the calcium‐mediated interaction between actin and myosin within muscle cells.1The nomenclature of these distinct proteins of the troponin complex is derived from their respective function in muscle contraction. Troponin T anchors the troponin complex to tropomyosin of the thin filament, whereas troponin I inhibits actomyosin ATPase, and troponin C is a calcium‐binding subunit. Three isoforms of troponin I (TnI) have been identified: one associated with fast-twitch skeletal muscle, one with slow-twitch skeletal muscle, and one with cardiac muscle. The slow and fast-twitch isoforms have a similar molecular weight of approximately 20,000 dalton (Da) each. The cardiac-specific TnI isoform has a molecular weight of approximately 24,000 Da and contains a post-translational tail of 31 amino acids on the N–terminus of the molecule. This sequence and the 42% and 45% dissimilarity with the sequences of the other two isoforms have made possible the generation of highly specific monoclonal antibodies without cross-reactivity with other non–cardiac TnI forms. As a result of its high tissue specificity cTnI is a cardio–specific, highly sensitive marker for myocardial injury. The Access hsTnI assay uses monoclonal antibodies specifically directed against human cTnI.In myocardial infarction, cTnI levels rise in the hours after the onset of cardiac symptoms, reaching a peak at 12–16 hours, and can remain elevated for 4–9 days post-MI. Numerous pathologies can potentially cause troponin elevations without overt ischemic heart disease. These pathologies include but are not limited to, congestive heart failure, acute and chronic trauma, electrical cardioversion, hypertension, hypotension, arrhythmias, pulmonary embolism, severe asthma, sepsis, critical illness, myocarditis, stroke, non–cardiac surgery, extreme exercise, drug toxicity (adriamycin, 5–fluorouracil, herceptin, snake venoms), end-stage renal disease, and rhabdomyolysis with cardiac injury. Importantly, these other etiologies rarely demonstrate the classic rising and falling pattern experienced with a MI, which highlights the importance of serial monitoring when the clinical scenario is unclear. Definition of Myocardial InfarctionIn 2012, a Task Force of the Joint European Society of Cardiology (ESC), American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and World Heart Federation (WHF) published an updated redefinition of MI in which cardiac troponin (cTn) plays a central role. The 2012 Third Universal Definition of Myocardial Infarction document states that inpatients presenting to the Emergency Department with chest pain, or other ischemic symptoms, the criteria for diagnosis of MI are: Detection of a rise and/or fall of cardiac biomarkers values [preferably cardiac troponin] with at least one value above the99thpercentile of the upper reference limit (URL) and with at least one of the following:•Symptoms of ischemia;•New or presumed new ST-segment-T wave (ST-T) changes or new left bundle branch block (LBBB);

•Development of pathological Q waves in the ECG;•Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality;•Identification of an intracoronary thrombus by angiography or autopsy. Additionally, the Third Universal Definition of Myocardial Infarction document recommends an optimal imprecision level (coefficient of variation, or CV) for troponin assays ≤ 10% at the 99thpercentile URL of a healthy population. Cardiac troponin should be measured upon admission, and then serially at regular intervals to demonstrate a rise and/or fall in cTn values. When an increased cTn value does not support the diagnosis of acute myocardial ischemia, a careful search for other possible etiologies of myocardial injury should be undertaken.