Transcript cardiac biomarkers

Cardiac biomarkers in ACS
Dr Frijo Jose A
The Ideal Cardiac Biomarker
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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)
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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)
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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
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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 CKMB →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 h
Using 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-IIIaI, 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
None <LLD (3229)
Low LLD-10% CV (270)
Intermediate 10% CV-MI cut-off (198)
High > MI cut-off (426)
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Death/|MI
+ Revasc
Death/MI/Dis
with pos Stress
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
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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-ofcare 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
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, (HFABP)
• 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 (slowswitch) 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..