1. Ischaemic Heart Disease CASE A

2. CASE A: Mr HA, aged 60 years, was brought in to A&E complaining of chest pain, nausea and a suspected AMI.

3. The Biochemical Markers Creatinine Kinase: Biochemical marker of myocardial damage. CK is a ubiquitous enzyme found in nearly all tissues including striated muscle and the brain and this reduces its specificity as a biochemical marker for myocardial injury. CK values are the first to rise after an AMI, and the first to return to normal if no further coronary damage occurs

4. CK the first to rise!

5. CK-MB CK-MB: An isoenzyme of CK which is more specific to myocardial tissue Remains the most widely used enzyme marker, and is still the preferred marker for the diagnosis of AMI More specific than CK for MI The MB fraction is found predominantly in cardiac muscle. It is important to show both a rise in the serum concentration of CK-MB, and a rise in the ratio of CK-MB to total CK to diagnose MI

6. LDH Lactate Dehydrogenase (LDH): Isozymes composed of combinations of two different subunits "H" and "M". Subunit "H" predominates in heart muscle LDH which is geared for aerobic oxidation of pyruvate. Rises acutely on initiation of an AMI. However, they take 2-3 days to reach maximum and thus do not play a major role in the diagnosis of AMI.

7. CK INDEX CK-Index: The ratio of CK-MB to total CK In AMI the value rises 5-15 folds and takes 24hrs to reach maximum. A low percentage can suggest the CK to be from a purely skeletal source and therefore rule out the possibility of MI.

8. CASE A: Mr HA, aged 60 years, was brought in to A&E complaining of chest pain, nausea and a suspected AMI.

9. CK-MB Index [ CK-MB in ng/mL] / Total CK in U/L 100

10. Clinical Chemistry Hrs after admission CK CK-MB (immunoassay) CK-MB index LDH Normal Range 60-220U/L0-6.0ug/L0-1.9100-210U/L On admission 915.6 6.15 297 2 hrs 382 29 7.6260 10 hrs 668 66.1 9.9 18 hrs 470 43.3 9.2 26 hrs 331 28.1 8.5 34 hrs 219 11.6 5.3 44 hrs 1424.2 2.95

11. Consistent with AMI? The level of CK-MB in Mr HA’s clinical chemistry results follows the classic pattern of rise and fall related to a cardiac event. The usual pattern of CK-MB levels after an AMI:  Increase 3-10hrs after the onset of infarction  Peak at 12-24hrs  Return to baseline after 36-72hrs

12. Clinical Chemistry

14. Consistent with AMI? Mr HA’s clinical chemistry shows the CK-MB levels from the time of admission to A and E Therefore, we can reasonably conclude that the results have shown that an AMI has occurred. Based on this assumption, these results are consistent with an AMI

16. CURRENT CRITERIA CURRENT CRITERIA Mr HA, aged 60 years, was brought in to A&E complaining of chest pain, nausea and a suspected AMI. Outline the current criteria for diagnosing acute myocardial infarction

17. WHO CRITERIA A clinical history of ischaemic-type chest discomfort Changes on serially obtained ECG A rise and fall in serum cardiac markers

18. CASE A Outline the current criteria for diagnosing acute myocardial infarction and the role played by the measurement of serum levels of the enzymes CK-MB1 and 2 in diagnosis of myocardial infarction. Define the difference in measuring CK-MB activity compared to CK-MB mass

19. An Ideal Marker Present early and in high concentration in the myocardium Absent from non-myocardial tissue and serum Rapidly released into the blood at the time of the myocardial injury Creatinine kinase (CK) isoforms, CK-MB1 and CK-MB2 has long been upheld as biochemical standards for diagnosing AMI

20. Cardiac Markers Cardiac troponin I and CK-MB1&2 and their ratio are lab tests that have improved the diagnostic accuracy of MI Other markers compared to CK-MB

21. Identifying Risk Factors In ACS Troponin I&T: are both important establishing risk stratification of patients with acute coronary syndrome Also CK-MB isoforms have a superior role

22. CASE A Outline the current criteria for diagnosing acute myocardial infarction and the role played by the measurement of serum levels of the enzymes CK-MB1 and 2 in diagnosis of myocardial infarction. Define the difference in measuring CK-MB activity compared to CK-MB mass

23. CK-MB mass Vs CK-MB activity CK-MB activity measurements only measure enzyme catalytic activity CK-MB mass measurements only measure the amount of CK-MB released regardless of its activity Compare and contrast both these terms

24. CK-MB mass Vs CK-MB activity CK-MB activity Activity is detected using electrophoresis and immunoinhibition, it has limited reliability due to interferences CK-MB mass Not subject to interferences mentioned in immunoinhibition Measure of CK-MB mass by immunoassay involving monoclonal antibodies is much reliable, sensitive and specific under 1µg/L

25. CK-MB mass Vs CK-MB activity CK-MB activity increases in MI in a greater extent (>6%) than in skeletal muscle trauma (<3%) Specific for late diagnosis but not sensitive enough for early use ie relatively non-specific and requires longer time CK-MB mass is increased in both skeletal muscle trauma and myocardial infarction Specific diagnosis marker at 6 hours of onset

26. Cardiac Troponins Troponins are complex regulatory proteins that are tightly complexed to the contractile apparatus of muscle cells. Different Troponins isoforms appear in different muscle cells. Troponin T (cardiac selective) Troponin I (cardiac selective) Troponin C (non-cardiac selective) Circulating levels are normally low, but they rise rapidly after an AMI

27. Advantages of Cardiac Troponins as Biomarkers of MI Cardiac troponins cTnT and cTnI: High Sensitivity High Specificity Remain elevated in serum for a number of days giving it a long diagnostic window Reference interval effectively zero giving very little background noise

28. Disadvantages of Cardiac Troponins as Biomarkers of MI cTnT and cTnI measured in different laboratories show different results Non diagnostic marker due to cardiac trauma other than an MI. Ischaemic heart disease can exist even in the absence of a raised cardiac troponin level. Cannot be used as an early marker (appear 3-6 hrs after MI) Prolonged troponin levels do allow detection of re-infarction

29. Monitoring Following Thrombolytic Therapy With Streptokinase. Trials clearly show that hospital and 30-40 day mortality are statistically related to the level of reperfusion at 90 minutes following thrombolytic therapy. Kinetics of myocardial protein appearance in circulation, namely CK-MB, myoglobin, cTnI and cTnT, following their release from the injured myocardium, depend on infarct perfusion and can be used to assess coronary reperfusion early after administration of thrombolytic therapy.

30. Reperfusion Monitoring: The Use of Myoglobin Compared to total CK activity, cTnI and cTnT release, myoglobin can be used very early (within 90 minutes of thrombolytic therapy) to detect reperfusion. A myoglobin to total CK activity ratio of >5.0 obtained from a single sample taken at the time of admission predicts spontaneous reperfusion 90 minutes following thrombolytic therapy. A single myoglobin measurement at 90 min after the start of therapy combined with clinical variables improve prediction of reperfusion.

31. Reperfusion Monitoring: The Use of Cardiac Troponins Guidelines to assess reperfusion: 1. An increase of cTnT levels to >0.5 µg/mL at 60 minutes following therapy. 2. A relative increase in cTnT levels at 90 minutes following therapy of >6.8. 3. A 90 minute concentration/baseline concentration following therapy of <6.0