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The Ideal Cardiac Biomarker: ACS Insights

Explore the evolution of cardiac biomarkers in Acute Coronary Syndrome (ACS) and their role in diagnosing myocardial infarction (MI), including necrosis biomarkers of the past and present, CK-MB isoforms, and troponin. Discover the sensitivity, specificity, and controversies surrounding CK, CK-MB, troponin, and their significance in detecting cardiac tissue damage in ACS.

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The Ideal Cardiac Biomarker: ACS Insights

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  1. Cardiac biomarkers in ACS Dr Frijo Jose A

  2. The Ideal Cardiac Biomarker • Absolute cardiac specificity • Specific for irreversible injury • Early release • High tissue sensitivity • Stable release • Predictable clearance • Complete release (infarct sizing) • Measurable by conventional methods

  3. NECROSIS BIOMARKERS OF THE PAST • Lactate dehydrogenase (LD) • Myosin Light Chains • Aspartate aminotransferase (AST)

  4. Lactate dehydrogenase (LD) • myocytes ,sktlmusc, liver, kidney, platlts & RBCs • 5 major LD isoenzymes, LD1–LD5 • LD1 & LD2 – MI (LD1 > LD2) • LD4 & LD5 – hepatic or Skl muscle injury • LD2, LD3 & LD4 – platelets/Lymphatic • (Total activity)LD →24–48 h, peak-3–6 d & N in 8–14 d • LD1 > LD2 pattern →10–12 h, peak-2 to 3d & N in 7–10 d • ↑LD1 & ↑ratio –sens & spec - 75–90%

  5. Myosin Light Chains • cardiac isoform of MLC is also produced by slow-twitch skeletal muscle

  6. Aspartateaminotransferase (AST,SGOT) • skltl muscle, liver, RBCs & myocardium • T½(mitochondrial)- 10 d, (cytoplasmic)- 10 h. • Isoenzymes not fractionated for clinical use • 6–8 h ,peak 18–24 h, N- 4 to 5 d

  7. NECROSIS BIOMARKERS OF THE PRESENT • CK • CK-MB Isoenzyme • cTnT and cTnI • Myoglobin

  8. CK: Total , Isoenzymes • 3 major isoenzymes- CK- MM, MB & BB • total CK activity →skmusc (2500 U/g); hrt (473 U/g); brain (55 U/g). • small intest,tongue,diaphragm,uterus&prostate • ↑tissue-to-plasma ratio –sk muscle & myocard • total CK -not recomm for routine MI

  9. CK-MB Isoenzyme • LVH ± CAD → ↓CK activity, ↑CK-MB content & activity (20%), & ↓creatine content • CAD (− LVH) → N CK activity, ↑ CK-MB content & activity (20%), & ↓total creatine content • N (− LVH,− CAD) → almost no CK-MB content or activity (1.1%) • higher and consistently elevated CK-MB in vulnerable pts with signi CAD confers excellent myocardial tissue specificity N Engl J Med. 1985 Oct 24;313(17):1050-4

  10. sk muscle injury • 7 fold ↑ total CK on a per-gram basis • potential for release of substantial CK-MB upon injury • Body mass of skmusc ~100-fold ↑ than myocard • Hence, CK-MB index = 100% (CK-MB/Total CK) • CK-MB index ↑ 2.5% usually myocardial source Problem (both myo & skmusc injury) • Skmusc CK-MB may confound CK-MB index by masking relatively subtle myocard CK-MB & effectively “swamping” the denominator

  11. CK-MB ISOFORMS • Release →M of tissue CK-MB →posttranslatnl modification (C-terminal lys cleavage by blood enzcarboxypeptidase) →differently charged CK-MB →CK-MB1→can be separated from tissue form,CK-MB2, by electrophoresis • N →CK-MB2/CKMB1≈1.0, totl CK-MB<1.5 IU/L • MB2-1-1.5 Hrs, MB-4-8 Hrs • ABN→ >2.5 IU/L CK-MB, CK-MB2/CK-MB1 ratio ≥1.5 (6-h ∆MI sens 95.7% & speci 93.9%)

  12. Kontos et al Positive test for AMI, • (1) 0- or 3-h CK-MB above diagnostic cutoff • (2) an ↑ in CK-MB by 3 ng/mL within 3 h • (3) a doubling of CK-MB within 3 h Using this definition, a sensitivity of 93% and a specificity of 98%

  13. measurable amount of CK-MB biological “background noise” in blood, probably from sk muscle turnover. • For ∆ use, CK-MB from myo must substantially exceed this noise • CK-MB less ∆ sensitive compared with cTnT or cTnI (physiological background noise is zero)

  14. initial sensitivity of CK-MB for the detection of AMI -23–57% • Additional CK-MB improves sensitivity • repeat testing at 3 h after initial presentation –sensitivity 88% • sensitivity maximized when CK-MB performed over a 9-h evaluation period • CK-MB has excellent specificity-97–99%

  15. TnC-cTnT-cTnI and cTnI-TnC complexes

  16. Controversy: whether or not troponin can be released following reversible ischemia? • CK-MB (84kDa) • LDH(135 kDa) • cTnT (37 kDa) • cTnI (24 kDa) in situ degradation?

  17. Assay Standardization • cTnI assays - lack of industry standardization • cTnT assays - only one manufacturer (Roche) has the intellectual property rights for use of this test

  18. LACK OF STANDARDIZATION

  19. cTnT and cTnI • Not early biomarkers of necrosis • ↑ diagnostic sensitivity and specificity • at pt presentation, 6–9 h later & at 12–24 h if clinical suspicion is ↑ and earlier results are negative • ↑ in conc is prolonged • release varies among individuals and is unpredictable • ↓ useful in reocclusion or for infarct sizing • Tool for risk stratification • detection of MI up to 2 wk; high specificity for cardiac tissue

  20. Troponin is far more sensitive • 13-15fold Trop than CK-MB per gram myocard • Most Trop complexed to contractile apparatus • Amount that in “cytosolic pool,”(release acutely) ≈same conc as that of CK-MB • persist in plasma for a prolonged period

  21. ↑cardiac trop − ↑CK-MB (“microinfarctions”) • powerful predictor of future AC Events, even when ↑CK-MB or ST deviation is absent • benefit more from antithrombotics, GPIIb-IIIa-I, early PCI • Sensitivity(initial measurement)cardiac trop -51 to 66% • 0 h & 4 h-sensitivity ↑from 51% -94% (tropT) and 66% -100%(trop I) • specificity -89–98%

  22. Spontaneous myocardial infarction • Baseline concentration unknown-↑cardiac trop above value defined by 10% CV • baseline value known- value exceeding 10% CV cutoff value • ↑cardiac trop above 10% CV- Increase >25%- recurrent or ongoing injury • TACTICS-TIMI 18-baseline cTnI >99th percentile (0.1 ng/mL) but below ESC/ACC limit (0.4 ng/Ml,10% CV) 3fold ↑ risk of death/MI (p < 0.001) LOW-LEVEL ELEVATION

  23. 30 day outcome according to cTnI value Kontos et al JACC 2004; 43:958-65

  24. Infarction after (PCI). • Baseline concentration unknown-↑cardiac trop above value defined by 10% CV • baseline value known- value exceeding 10% CV cutoff value + a 25% ↑ –periproc MI • ↑cardiac trop above 10% CV- Increase >25%- recurrent or ongoing injury • Prolonged balloon inflations, transient abrupt closure, distal embolization, and side-branch occlusion • Troponin I vs Troponin T

  25. Gp2b3ai, ntg, nicorandil, atorvastatin

  26. In a 2002 study in Circulation, 733 asymptomatic patients with ESRD were evaluated • Using conservative cutoff values, • 82% had elevated cTnT • 6% had elevated cTnI • cTnI -much less likely to be associated with false positives in the CKD population than cTnT →preferred biomarker in this setting

  27. Myoglobin • cytoplasm of cardiac & sk muscle cells • tissue/plasma ratio of myoglobin is very ↑ • Earliest appearing marker routinely available • same for both cardiac & sk muscle • cleared by kidneys (RF-↑) • rule out myocardial necrosis with a negative predictive value approx 96%

  28. Timing Summary

  29. Quantitative vs Qualitative Biomarker Testing • Qualitative testing of trop →appropriate quantitative assays may vary by up to 30-fold • quali testing help avoid discord betw point-of-care testing & quanti testing in main lab • Quant assays necess for monitoring the release & clearance of markers Quali →∆ of MI Quanti →risk stratification,reperfusion monitoring & prognosis assessment

  30. Serial Sampling • When initial results are negative • Serial sampling at presentation, 6–9 h later, and after 12 h is recommended if the earlier results are negative and clinical suspicion remains high

  31. NECROSIS BIOMARKERS STILL IN DEVELOPMENT • Heart-Type Fatty Acid-Binding Protein(FABPs) • Carbonic anhydrase (III) (CAIII)

  32. Heart-Type Fatty Acid-Binding Protein (H-FABP) • abundant in cytoplasm of striated musc • Specifically & reversibly bind long-chain f a • Myo & Sk muscle - same isoform of FABP, (H-FABP) • Content in skmusc is only 10–30% of that found in cardiac musc • very good tissue/plasma ratio • Released soon after onset of MI- early marker • ↑ <3 h after MI & returns ≤12–24 h • ? myoglobin/H-FABP

  33. Carbonic anhydrase (III) (CAIII) • cytosolic protein ~exclusively in type I (slow-switch) sk muscle • Myoglobin:CAIII - from sk musc in 3:1 ratio • notpresent in myocardium • Combining CAIII & myoglobin - proposed to improve specificity of myoglobin as an early marker for MI

  34. Ischemia Modified Albumin

  35. Ischemia Modified Albumin • Albumin’s capacity to bind to cobalt is reduced during myocardial ischemia (N-terminal) • Rises within minutes of ischemia, stays up for 6-12 hrs and normalises within 24 hrs • Elevated after enduring sports,but;aft 24 hrs (?GI Ischemia) • Inhibited by endogenous lactate-limited use in DKA,Sepsis,CKD… • Less specific-cancers,CKD,sepsis,liver disease

  36. thanks..

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