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Cardiac biomarkers in ACS

Cardiac biomarkers in ACS. Dr Frijo Jose A. The Ideal Cardiac Biomarker. Absolute cardiac specificity Specific for irreversible injury Early release High tissue sensitivity Stable release Predictable clearance Complete release ( infarct sizing)

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Cardiac biomarkers in ACS

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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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