Chemistry, toxicology & urinalysis

• Cardiac troponins are the preferred biomarkers for the evaluation, detection and diagnosis of acute chest pain or myocardial injury
• Myocardial injury is defined as blood levels of cardiac troponin (cTn) that are elevated above the 99th percentile upper reference limit (URL) (Glob Heart 2018;13:305)

• High sensitivity troponin (hs-cTn) by definition is the assay that detects cTn concentrations with a coefficient of variation (CV) < 10% at or below the 99th percentile upper reference limits and measurable in > 50% of normal healthy individuals (J Am Heart Assoc 2014;3:e000403)
• The definition of myocardial injury was defined by the Fourth Universal Definition of Myocardial Infarction (2018) as cTn levels that are elevated above the 99th percentile URL (Glob Heart 2018;13:305)
• No myocardial injury: cTn values ≤ 99th percentile URL or not detectable (Glob Heart 2018;13:305)
• Myocardial injury: cTn values > 99th percentile URL without symptoms or signs of myocardial ischemia
• All nonischemic myocardial injury is classified as acute if there is a rise or fall of cTn values, unless a change of ≤ 20% was observed on serial testing (Circulation 2020;141:161)
• Myocardial infarction: clinical evidence of myocardial ischemia and a rise or fall of cTn values > 99th percentile URL (Glob Heart 2018;13:305)
• A single positive hs-cTn value > 99th percentile upper reference limit is sensitive for but not specific for myocardial infarction, for which diagnosis may require serial testing
• Pattern change in hs-cTn values (delta) is also assay specific
• Interpretation of the delta needs to account for other clinical data such as the history (notably the onset of symptoms), electrocardiography changes and imaging
• In patients with chronically elevated hs-cTn, the absence of significant change defined as < 20% delta is indicative of chronic myocardial injury (Circulation 2022;146:569)
• hs-cTn is recommended as an important biomarker for the evaluation and diagnosis of acute chest pain by the 2021 American Heart Association (AHA) / American College of Cardiology (ACC) / American Society of Echocardiography / American College of Chest Physicians / Society for Academic Emergency Medicine / Society of Cardiovascular Computed Tomography and International Federation of Clinical Chemistry and Laboratory Medicine Task Force on Clinical Applications of Bio-Markers (IFCC TF-CB) (Circulation 2021;144:e368)

• hs-cTn assays should measure cTn above the limit of detection in ≤ 50% of healthy subjects (J Am Heart Assoc 2014;3:e000403)
• Analytical requirement for hs-cTn is the assay that has a CV of ≤ 10% at the 99th percentile (Clin Biochem 2015;48:201, J Am Heart Assoc 2014;3:e000403)
  • High precision of the assay allows the determination of small differences in cTn over time
• 99th percentile may be different for serum, plasma and whole blood (Clin Biochem 2015;48:201)
• 99th percentile must be determined individually for each assay, as assays are not standardized (Clin Biochem 2015;48:201)
• Assay specific 99th percentile URL should be derived from a sample size of at least 400 male and 400 female healthy subjects
• Healthy subjects should be screened with questionnaires to exclude those with cardiovascular comorbidities and those on cardiovascular medications
• NT-proBNP (N terminal pro-B type natriuretic peptide), hemoglobin A1C and estimated glomerular filtration rate (eGFR) are used to exclude subclinical disease, recommended by the most recent (2022) IFCC and American Association of Clinical Chemistry (AACC) guidelines (Clin Chem 2022;68:1022)
• There have been multiple hs-cTn assays approved by the U.S. Food and Drug Administration (FDA) for clinical use in the United States since 2017 (Clin Chem 2021;67:70)
• Women have lower 99th percentiles than men and all the FDA approved hs-cTn assays report gender specific 99th percentile URL
• 2021 AHA / ACC guidelines recognize gender specific hs-cTn URLs but do not encourage their use (Circulation 2021;144:e368)
• Below are the recommendations of hs-cTn assays by the American Association for Clinical Chemistry Academy and International Federation of Clinical Chemistry and Laboratory Medicine Task Force on Clinical Applications of Bio-Markers (IFCC TF-CB) (Clin Chem 2018;64:645)

2018 Fourth Universal Definition of Myocardial Infarction criteria

Myocardial infarction (MI)	Criteria
Type 1	Detection of a rise or fall of cTn values with at least 1 value above the 99th percentile URL and with at least 1 of the following: Symptoms of acute myocardial ischemia New ischemic electrocardiogram (ECG) changes Development of pathological Q waves Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology Identification of a coronary thrombus by angiography, including intracoronary imaging or by autopsy
Type 2	Detection of a rise or fall of cTn values with at least 1 value above the 99th percentile URL and evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute coronary atherothrombosis, requiring at least 1 of the following: Symptoms of acute myocardial ischemia New ischemic electrocardiogram changes Development of pathological Q waves Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology
Type 3	Patients who suffer cardiac death, with symptoms suggestive of myocardial ischemia accompanied by presumed new ischemic electrocardiogram changes or ventricular fibrillation but die before blood samples for biomarkers can be obtained or before increases in cardiac biomarkers can be identified or myocardial infarction is detected by autopsy examination
Type 4a	Coronary intervention related myocardial infarction is arbitrarily defined by an elevation of cTn values > 5 times the 99th percentile URL in patients with normal baseline values; in patients with elevated preprocedure cTn in whom the cTn level is stable (≤ 20% variation) or falling, the postprocedure cTn must rise by > 20%; however, the absolute postprocedural value must still be at least 5 times the 99th percentile URL and in addition, 1 of the following elements is required: New ischemic electrocardiogram changes Development of new pathological Q waves Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology Angiographic findings consistent with a procedural flow limiting complication such as coronary dissection, occlusion of a major epicardial artery or a side branch occlusion / thrombus, disruption of collateral flow or distal embolization
Type 4b	A subcategory of percutaneous coronary intervention (PCI) related myocardial infarction is stent / scaffold thrombosis, as documented by angiography or autopsy using the same criteria for type 1 myocardial infarction
Type 4c	Defined as focal or diffuse restenosis or a complex lesion associated with a rise or fall of cTn values above the 99th percentile URL applying, the same criteria utilized for type 1 myocardial infarction
Type 5	Coronary artery bypass grafting (CABG) related myocardial infarction is arbitrarily defined as an elevation of cTn values > 10 times the 99th percentile URL in patients with normal baseline cTn value; in patients with elevated preprocedure cTn in whom cTn levels are stable (≤ 20% variation) or falling, the postprocedure cTn must rise by > 20%; however, the absolute postprocedural value still must be > 10 times the 99th percentile URL and in addition, 1 of the following elements is required: Development of new pathological Q waves Angiographic documented new graft occlusion or new native coronary artery occlusion Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology

European Society of Cardiology (ESC) guidelines

Years	Recommendations	References
2011	0 and 3 hour high sensitivity cardiac troponin (hs-cTns) tests are recommended	Eur Heart J 2011;32:2999
2015	0 and 3 hour hs-cTns tests are recommended A validated 0/1 h algorithm with hs-cTns tests is recommended for a rapid rule out and rule in diagnosis; if the first 2 hs-cTns measurements are not conclusive and the clinical condition is still suggestive of acute coronary syndrome, then additional hs-cTns testing after 3 to 6 hours is recommended	Eur Heart J 2016;37:267
2020	A validated 0/1 h algorithm with hs-cTns tests is recommended for a rapid rule out and rule in diagnosis If the first 2 hs-cTns measurements are not conclusive and the clinical condition is still suggestive of acute coronary syndrome, then additional hs-cTns testing after 3 to 6 hours is recommended A validated 0/2 h algorithm with hs-cTns tests can be used as an alternative to the 0/1 h algorithm A validated 0/3 h algorithm with hs-cTns tests can be used as an alternative to the 0/1 h algorithm	Eur Heart J 2021;42:1289

For the high sensitivity cardiac troponin (hs-cTn) assay, which of the following criteria are correct?

1. CV of ≤ 10% at the 99th percentile and detected in at least 50% of acute myocardial infarction patients
2. CV of ≤ 10% at the 99th percentile and detected in at least 50% of healthy subjects
3. CV of ≤ 10% at the 99th percentile and detected in at least 99% of healthy subjects
4. CV of ≤ 20% at the 99th percentile and detected in at least 50% of acute myocardial infarction patients

B. CV of ≤ 10% at the 99th percentile and detected in at least 50% of healthy subjects. High sensitivity troponin (hs-cTn) by definition is the assay that detects cTn concentrations with a coefficient of variation (CV) ≤ 10% at or below the 99th percentile upper reference limits and measurable in > 50% of normal healthy individuals (J Am Heart Assoc 2014;3:e000403).

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Reference: Cardiac troponins

Which of the following is the correct recommendation for the 99th percentile of high sensitivity cardiac troponin (hs-cTn)?

1. The 99th percentile may be different for serum, plasma and whole blood
2. The analytical requirement for hs-cTn is the assay has a % CV at the 99th percentile of ≤ 20%
3. The assay specific 99th percentile URL should be derived from a sample size of 120 male and 120 female healthy subjects
4. The hs-cTn assays are standardized and the 99th percentile does not need to be determined individually for each assay

A. The 99th percentile may be different for serum, plasma and whole blood (Clin Biochem 2015;48:201). Analytical requirement for hs-cTn is the assay that has a CV of ≤ 10% at the 99th percentile (Clin Biochem 2015;48:201, J Am Heart Assoc 2014;3:e000403). Assay specific 99th percentile URL should be derived from a sample size of at least 400 male and 400 female healthy subjects. 99th percentile must be determined individually for each assay, as assays are not standardized (Clin Biochem 2015;48:201).

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Reference: Cardiac troponins