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)• Measurable by conventional methods

NECROSIS BIOMARKERS OF THE PAST

• Lactate dehydrogenase (LD)• Myosin Light Chains• Aspartate aminotransferase (AST)

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%

Myosin Light Chains

• cardiac isoform of MLC is also produced by slow-twitch skeletal muscle

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

NECROSIS BIOMARKERS OF THE PRESENT

• CK• CK-MB Isoenzyme• cTnT and cTnI• Myoglobin

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

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

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

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• 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%)

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 hUsing this definition, a sensitivity of 93% and a

specificity of 98%

• 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)

• 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%

TnC-cTnT-cTnI and cTnI-TnC complexes

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?

Assay Standardization

• cTnI assays - lack of industry standardization • cTnT assays - only one manufacturer (Roche)

has the intellectual property rights for use of this test

LACK OF STANDARDIZATION

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

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

• ↑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%

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

30 day outcome according to cTnI value

0

10

20

30

4050

60

70

8090

Death/|MI + Revasc Death/MI/Dis with pos Stress

None <LLD (3229) Low LLD-10% CV (270)

Intermediate 10% CV-MI cut-off (198) High > MI cut-off (426)

Kontos et al JACC 2004; 43:958-65

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

Gp2b3ai, ntg, nicorandil, atorvastatin

• 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

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%

Timing Summary

TEST ONSET PEAK DURATION

CK/CK-MB 4-8 hours 18-24 hours 36-48 hours

Troponins 3-12 hours 18-24 hours Up to 10 days

Myoglobin 1-4 hours 6-7 hours 24 hours

LDH 6-12 hours 24-48 hours 6-8 days

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 MIQuanti →risk stratification,reperfusion monitoring

& prognosis assessment

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

NECROSIS BIOMARKERS STILL IN DEVELOPMENT

• Heart-Type Fatty Acid-Binding Protein(FABPs)• Carbonic anhydrase (III) (CAIII)

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

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

Ischemia Modified Albumin

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

thanks..