Challenging Issues in Cardiac Biomarker interpretation. F. Nikaeen. MD interventional Cardiologist

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1 Challenging Issues in Cardiac Biomarker interpretation F. Nikaeen. MD interventional Cardiologist

2 Biomarkers

3 Types of Troponin Troponin C Binds calcium Troponin I Binds actin Troponin T Binds tropomyosin

4 Introduction Myocardial necrosis is accompanied by the release of structural proteins and other intracellular macromolecules into the cardiac interstitium, such as ctn, creatine kinase, and myoglobin. The preferred biomarker for myocardial necrosis is ctn, which has nearly absolute myocardial tissue specificity as well as high clinical sensitivity, thereby reflecting even microscopic zones of myocardial necrosis

5 Introduction The troponin complex regulates the contraction of striated muscles and consists of three subunits (troponin C, troponin T, and troponin I) Troponin C is a 18 ku protein binds to calcium. It is not cardiac specific, and thus is not used for the diagnosis of cardiac injury. Troponin T is a 37 ku protein that binds to tropomyosin, thereby attaching the troponin complex to the thin filament. Troponin I is a 24 ku protein that binds to actin and decreases troponin C affinity for calcium, thus inhibiting actin myosin interactions.

6 Introduction The majority of cardiac troponin (ctn) is bound to myofilaments, and the remainder is free in the cytosol which accounts for 3% 8% of the total amount. After disruption of the sarcolemmal membrane of the cardiomyocyte, troponin from the cytoplasmic pool is initially released, followed by a more protracted release from quantities bound to deteriorating myofilaments In peripheral blood, ctnt begins to rise within two to four hours after the onset of myocardial injury and remains increased for days.

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8 Causes of release of Troponins from Cardiomyocytes, include: Myocardial Injury Normal turn over of myocardial cells, Apoptosis Increased cellular wall permeability

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10 Myocardial injury Troponin releases Transient release Persistent release Cytosolic pool Sarcomere of the myocyte Reversible ischemia Irreversible ischemic necrosis

11 1-Elevations of cardiac troponin values because of myocardial injury

12 1-Elevations of cardiac troponin values because of myocardial injury

13 1-Elevations of cardiac troponin values because of myocardial injury

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15 Causes of False Positive Troponin Results Antibodies( Heterophile, Human anti-animal, Autoantibodies Rheumatoid factor Microparticles in specimen Fibrin clots in serum as a result of incompletely clotted specimen:in patients with coagulopathy Hemolysis Interferencec : Blood Sampling from catheters ( most common cause of hemolysis) Interference from other endogenous components in the blood such as bilirubin and hemoglobin High concentration ofalkaline phosphatase Immunocomplex formation Analyzer malfunction

16 High sensitivity troponin Test High-sensitivity troponin tests measure the troponin in the blood as thestandard test but at much lower levels. They are more sensitive than standard ones,and become positive sooner and may help detect acute coronary syndrome earlier Sensitive (i.e. allow for detection of cardiac troponin in 20 50% of healthy individuals) assays High-sensitivity (detection in 50 90% of healthy individuals) assays The hs-troponin test may also be positive in people with stable angina and even in normal people. In these cases, a positive test indicates an increased risk of future heart events such as heart attacks.

17 Troponin assay Limitations It does not indicate the mechanism responsible for the necrosis It is not an early biomarker of cardiac necrosis The troponins persist in blood for a long period of time after an initial injury, may be of no value in detecting reinfarction.

18 Definition of MI Detection of rise and/or fall of cardiac biomarkers (preferably troponin) above the 99th percentile of the upper reference limit + with evidence of ischaemia with at least one of the following: Ischaemic symptoms ECG changes of new ischaemia, development of pathologic Q-waves in the ECG or Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

19 Peri-procedural myocardial infarction Post PCI MI: three-fold increase from the normal baseline value. Post CABG: a five-fold increase from the baseline during 1 st 72 hours, along with associated findings, such as new Q waves. After non-cardiac surgery: The same cut-off levels used to diagnose an acute MI should be used to detect perioperative injury.

20 Serial testing, as well as clinical context and co-existing diseases, are likely to become increasingly important for the interpretation of hs-ctnt assay results. The universal definition of MI recommends performing serial measurements of troponins and emphasizes the importance of rising and/or falling levels to distinguish acute MI from other sources of troponin elevation.

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22 Changing Pattern Conventional ctn: more than 20% relative change High Sensitive ctn: more than 50% relative change High Sensitive ctn allowing better triage and division Making

23 Strategies for rule out MI Conventional ctn: 6hr interval or more than 6hr of symptoms 2-3hr interval or more than 6hr of symptoms (if low risk) High sensitive ctn: 1-3hr interval

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