Cardiac biomarkers in ACS

1
Cardiac biomarkers in ACS

• Dr Frijo Jose A

2
(No Transcript)
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, LD1LD5
• LD1 LD2 MI (LD1 gt LD2)
• LD4 LD5 hepatic or Skl muscle injury
• LD2, LD3 LD4 platelets/Lymphatic
• (Total activity)LD ?2448 h, peak-36 d N in
  814 d
• LD1 gt LD2 pattern ?1012 h, peak-2 to 3d N in
  710 d
• ?LD1 ?ratio sens spec - 7590

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
• 68 h ,peak 1824 h, N- 4 to 5 d

8
NECROSIS BIOMARKERS OF THE PRESENT

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

9
(No Transcript)
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. 1985 Oct 24313(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/CKMB11.0, totl CK-MBlt1.5 IU/L
• MB2-1-1.5 Hrs, MB-4-8 Hrs
• ABN? gt2.5 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 -2357
• 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-9799

17
TnC-cTnT-cTnI and cTnI-TnC complexes
18
(No Transcript)
19
(No Transcript)
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, 69 h later at 1224 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 -8998

26
(No Transcript)
27
(No Transcript)
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 gt25-
  recurrent or ongoing injury
• TACTICS-TIMI 18-baseline cTnI gt99th percentile
  (0.1 ng/mL) but below ESC/ACC limit (0.4
  ng/Ml,10 CV) 3fold ? risk of death/MI (p lt
  0.001) LOW-LEVEL ELEVATION

29
30 day outcome according to cTnI value
Kontos et al JACC 2004 43958-65
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 gt25-
  recurrent or ongoing injury
• Prolonged balloon inflations, transient abrupt
  closure, distal embolization, and side-branch
  occlusion
• Troponin I vs Troponin T

31
(No Transcript)
32
Gp2b3ai, ntg, nicorandil, atorvastatin
33
(No Transcript)
34
(No Transcript)
35
(No Transcript)
36
(No Transcript)
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
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
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, 69 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 1030 of that found
  in cardiac musc
• very good tissue/plasma ratio
• Released soon after onset of MI- early marker
• ? lt3 h after MI returns 1224 h
• ? myoglobin/H-FABP

44
Carbonic anhydrase (III) (CAIII)

• cytosolic protein exclusively in type I
  (slow-switch) sk muscle
• MyoglobinCAIII - from sk musc in 31 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
Ischemia Modified Albumin

• Albumins 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,butaft 24 hrs
  (?GI Ischemia)
• Inhibited by endogenous lactate-limited use in
  DKA,Sepsis,CKD
• Less specific-cancers,CKD,sepsis,liver disease

47

• thanks..

48
(No Transcript)