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Cardiac biomarkers in ACS Dr Frijo Jose A. The Ideal Cardiac Biomarker Absolute cardiac specificity Specific for irreversible injury Early release High.

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Presentation on theme: "Cardiac biomarkers in ACS Dr Frijo Jose A. The Ideal Cardiac Biomarker Absolute cardiac specificity Specific for irreversible injury Early release High."— Presentation transcript:

1 Cardiac biomarkers in ACS Dr Frijo Jose A

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3 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

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

5 Lactate dehydrogenase (LD) myocytes,sktl musc, 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%

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

7 Aspartate aminotransferase (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

8 NECROSIS BIOMARKERS OF THE PRESENT CK CK-MB Isoenzyme cTnT and cTnI Myoglobin

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10 CK: Total, Isoenzymes 3 major isoenzymes- CK- MM, MB & BB total CK activity →sk musc (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

11 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 Oct 24;313(17):1050-4

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

13 CK-MB ISOFORMS Release →M of tissue CK-MB →posttranslatnl modification (C-terminal lys cleavage by blood enz carboxypeptidase) →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 MB 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%)

14 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%

15 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)

16 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%

17 TnC-cTnT-cTnI and cTnI-TnC complexes

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20 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?

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

22 LACK OF STANDARDIZATION

23 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

24 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

25 ↑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%

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28 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

29 30 day outcome according to cTnI value Kontos et al JACC 2004; 43:958-65

30 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

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32 Gp2b3ai, ntg, nicorandil, atorvastatin

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37 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

38 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%

39 Timing Summary TESTONSETPEAKDURATION CK/CK-MB4-8 hours18-24 hours36-48 hours Troponins3-12 hours18-24 hoursUp to 10 days Myoglobin1-4 hours6-7 hours24 hours LDH6-12 hours24-48 hours6-8 days

40 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

41 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

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

43 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 sk musc 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

44 Carbonic anhydrase (III) (CAIII) cytosolic protein ~exclusively in type I (slow- switch) sk muscle Myoglobin:CAIII - from sk musc in 3:1 ratio not present in myocardium Combining CAIII & myoglobin - proposed to improve specificity of myoglobin as an early marker for MI

45 Ischemia Modified Albumin

46 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

47 thanks..

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