1. MYOCARDIAL
INJURY MARKERS
D. Robert Dufour, M.D.
Washington VA Medical Center
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2. IDEAL MARKER
FOUND ONLY IN TISSUE OF
INTEREST
HIGH GRADIENT ALLOWS EARLY
DETECTION
DETECTION OF MARKER ALLOWS
INTERVENTION THAT PREVENTS OR
MINIMIZES EFFECTS OF DISEASE
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3. MYOCARDIAL INJURY
IRREVERSIBLE INJURY TYPICALLY
REQUIRES 30 MINUTES OF ISCHEMIA
CHRONIC O DEFICIENCY MAKES
2
CELLS MORE RESISTANT
AFTER 30-60 MIN, CELL DEATH
STARTS; 80% OF CELLS AT RISK DIE
WITHIN 3 HOURS, ALMOST 100% BY 6
HOURS OF ISCHEMIA
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4. SPECTRUM OF ISCHEMIA
ACUTE CORONARY SYNDROMES:
Q-WAVE MI
NON-Q MI
UNSTABLE ANGINA
CLOT
Crescendo No Symptoms
Angina
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ANGINA 4
6. IDEAL CARDIAC MARKER
DETECTS ONLY CARDIAC DAMAGE
DETECTABLE WHILE DAMAGE
REVERSIBLE OR PREVENTABLE
CORRELATES WITH AMOUNT OF
INJURY
PREDICTS PROGNOSIS
CHEAP, RAPIDLY MEASURED
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7. MYOCARDIAL CONTENTS
WITH CELL DEATH, HOLES
DEVELOP IN CELL MEMBRANE
CONTENTS LEAK DEPENDENT ON
SIZE, SOLUBILITY
SMALL, CYTOPLASMIC MARKERS
LEAK SLOWLY
LARGER, COMPLEXED MARKERS
RELEASED SLOWLY
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8. RELEASE MECHANISM
STANDARD TEACHING - MARKERS
ONLY RELEASED WITH
IRREVERSIBLE INJURY
BECAUSE MARKERS ARE
PROTEINS, WILL NOT LEAK WITH
ISCHEMIA
MARKER RELEASE = CELL DEATH
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9. RELEASE MECHANISM
FENG et al., A J Clin Pathol 1998;110:70
INDUCED CORONARY STENOSIS IN
12 PIGS, COMPARED TO 5 CONTROLS
MEASURED TnI, MYO, CK MB
STUDIED MYOCARDIUM BY BIOPSY
AND AUTOPSY WITH GROSS, MICRO,
HISTOCHEMISTRY, EM
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10. RELEASE MECHANISM
WITH STENOSIS, 8 PIGS HAD
NECROSIS, 4 NO NECROSIS (ONLY EM
LESIONS)
ALL MARKERS WENT UP AFTER
INDUCTION OF ISCHEMIA IN BOTH
GROUPS; ONLY TnI SIGNIFICANTLY
HIGHER THAN CONTROL IN
NECROSIS AND ISCHEMIA (HIGHER
IN FORMER)
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13. MYOCARDIAL CONTENTS
CONCENTRATION GRADIENT ALSO
IMPORTANT
HIGH GRADIENT BETWEEN SERUM
AND CELLS ALLOWS EARLY
DETECTION
LOW GRADIENT MAKES TEST
INSENSITIVE TO MYOCARDIAL
INJURY
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15. CREATINE KINASE
FOUND MAINLY IN STRIATED
MUSCLE, BRAIN (DOES NOT CROSS
BLOOD-BRAIN BARRIER)
MUCH MORE PER gm OF TISSUE IN
SKELETAL COMPARED TO CARDIAC
MUSCLE
RELATIVELY HIGH GRADIENT
(2000x PLASMA IN CARDIAC)
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16. CK MB
TRACE FORM IN ALL MUSCLE; 1-2%
IN SKELETAL, 15-20% IN CARDIAC
HIGHER IN SKELETAL IN
NEONATES, CHRONIC MUSCLE
INJURY, RESPIRATORY MUSCLES
DIFFERENT ASSAYS; RESULTS NOT
INTERCHANGEABLE
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17. CK MB ISOFORMS
AFTER RELASE, CK MB CLEAVED
BY REMOVING SINGLE AMINO ACID,
CHANGING CHARGE
HALF-LIFE OF TISSUE ISOFORM
ONLY 3 HOURS
DIFFERENTIATES ACUTE FROM
CHRONIC OR REMOTE MUSCLE
INJURY; NOT CARDIAC SPECIFIC
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21. MYOGLOBIN
FOUND IN SKELETAL, CARDIAC
MUSCLE
SMALL SIZE ALLOWS EARLY
DETECTION, RAPID CLEARANCE
NOT SPECIFIC FOR CARDIAC
MUSCLE
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22. TROPONIN
FOUND ONLY IN MUSCLE
PREDOMINANTLY BOUND TO
MYOFIBERS; SMALL FRACTION FREE
FOR TnI AND TnT, DIFFERENCES
BETWEEN CARDIAC AND SKELETAL
MUSCLE FORMS
RELEASE FROM FIBRILS CAUSES
HIGH LEVELS FOR MANY DAYS
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24. TROPONIN T (TnT)
CARDIAC-LIKE FORM FOUND IN
FETAL SKELETAL MUSCLE
ABOUT 6% CYTOSOLIC,
DETECTABLE EARLIER THAN TnI
SECOND GENERATION ASSAY
DETECTS LESS DAMAGE THAN TnI
ONE ASSAY MANUFACTURER
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25. TROPONIN I (TnI)
FOUND ONLY IN CARDIAC MUSCLE
ONLY ABOUT 2% CYTOSOLIC,
LATER DETECTION THAN TnT
NO STANDARDIZATION;
DIFFERENT ASSAYS PRODUCE
DIFFERENT RESULTS, DETECTION
LIMITS
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26. Tn IN RENAL FAILURE
ELEVATED TnT SEEN COMMONLY
IN RENAL FAILURE (UP TO 50%)
HIGH TnI SEEN OCCASIONALLY
PATIENTS WITH Tn HAVE HIGH
LIKELIHOOD OF CARDIAC DEATH IN
YEAR AFTER DETECTION
? HIGHER LIKELIHOOD FOR TnI
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27. PROBLEMS WITH TnI
DIFFERENT FORMS OF TROPONIN I
FOUND IN SERUM (FREE, BOUND,
AND FORMS OF BOUND)
DIFFERENT MANUFACTURER’S
ASSAYS VARIABLY MEASURE THESE
NO STANDARDIZATION, MAKING
COMPARISON BETWEEN LABS
DIFFICULT
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28. PROBLEMS WITH TnI
IN ASSAYS, FIBRIN MAY TRAP
LABELED ANTIBODY
PATIENTS WITH UA/MI OFTEN ON
HEPARIN, PREVENTING FULL USE OF
FIBRINOGEN
RESIDUAL FIBRINOGEN MAY FORM
FIBRIN IN INSTRUMENT, CAUSING
FALSE POSITIVE RESULTS
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29. PROBLEMS WITH TnI
RHEUMATOID FACTOR,
AUTOANTIBODIES MAY CAUSE
FALSE POSITIVE WITH SOME ASSAYS
CANNOT CONFIRM TROPONIN
RESULTS WITH ANY OTHER ASSAY
SINCE IT IS MORE “SENSITIVE”
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31. ISSUES
POSITIVE MARKERS WITHOUT
CLINICAL PICTURE OF “MI”
WHICH MARKER(s) TO OFFER?
DO IDEAL MARKERS DIFFER IN
VARYING CIRCUMSTANCES?
IS ONE MARKER ENOUGH?
WHAT TURNAROUND TIME?
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32. MYOCARDIAL MARKERS
MARKER 1st SEEN REL. ↑DURATION SENS. SENS.
(median) (x Nl) (hrs) MI U.A.
MYOGLOBIN 2-3 hr 12 18-24 85-90 ?
TROPONIN I 4-6 50 > 144 100 30
TROPONIN T 3-4 50 > 240 100 40
MB MASS 4-6 12 24-36 100 25
CK TOTAL 6-8 8 36-48 80-85 ?
CK ISOFORM 2-3 N/A 6-12 100 10?
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33. RELATIVE CONCENTRATION
Myoglobin
Troponin
CK, AST
LDH
Normal
0 6 12 18 24 2 3 4 5 6 7 8 9 10
Hours Days
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34. ACUTE CORONARY
SYNDROMES
TERM DESCRIBING SPECTRUM OF
ISCHEMIC CHANGES
INCLUDES UNSTABLE ANGINA,
“NON-Q WAVE” MI, “Q-WAVE MI”
REFLECTS GROWING AWARENESS
OF SIMILARITIES IN PATHOGENESIS,
PROGNOSIS
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35. SENSITIVITY
MYOCARDIAL MARKERS CAN
DETECT SMALLER AMOUNTS OF
DAMAGE THAN CLINICAL CRITERIA
NEED TO REVISE CRITERIA TO
REFLECT ABILITY OF MARKERS TO
DETECT SIGNIFICANT DAMAGE
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36. CATEGORY NUMBER % MI
ANY CHEST PAIN 1420 20
PAIN > 30 min, EKG CHANGE 312 49
PAIN > 30 min OR EKG CHANGE 551 16
PAIN < 30 min NO EKG CHANGE 557 6
Wasimuddin et al. Crit Care Med, 1994
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38. CLINICAL SIGNIFICANCE
NUMEROUS STUDIES SHOW
PATIENTS WITH “UNSTABLE
ANGINA” AND POSITIVE MARKERS
HAVE HIGH INCIDENCE OF CARDIAC
EVENTS IN FOLLOW-UP
PATTERN SIMILAR TO MI
NEGATIVE MARKERS INDICATE
LOW RISK PATIENTS
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40. CLINICAL SIGNIFICANCE
RELATIVE RISK WITH POSITIVE
MARKERS AVERAGES 6:1 COMPARED
TO NEGATIVE
HIGHER FOR TnT THAN TnI
DIRECT RELATION BETWEEN
LEVEL OF Tn, RISK (UP TO ABOUT 2
ng/mL)
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41. CLINICAL SIGNIFICANCE
ONLY ABOUT 20% OF THOSE WITH
POSITIVE MARKERS HAVE
SUBSEQUENT CARDIAC EVENT
LOW LEVEL POSITIVE MAY BE
FALSE DUE TO FACTORS
MENTIONED EARLIER
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42. WHICH MARKERS?
NATIONAL ACADEMY OF
BIOCHEMISTRY DRAFT GUIDELINES
(www.nacb.org)
JOINT GROUP OF LABORATORIANS,
CARDIOLOGISTS, EMERGENCY MED
PHYSICIANS
PUBLISHED JULY 1999 (CLIN CHEM
1999;45:1104-1121)
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43. WHICH MARKERS?
NO SINGLE MARKER MEETS ALL
NEEDS
RECOMMEND EARLY MARKER (+
BY 6 hrs) AND MORE DEFINITIVE
MARKER (HIGH SPECIFICITY)
SUGGEST EARLY MARKES AS R/O
IF NEGATIVE; LATE MARKERS TO
CONFIRM (R/IN)
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44. WHICH MARKERS?
RECOMMEND MYOGLOBIN AS
BEST EARLY MARKER; ISOFORMS
ALSO POSSIBLE CHOICE
SUGGEST CARDIAC TnI OR TnT FOR
DEFINITIVE MARKER
MARKERS NOT NEEDED FOR
DIAGNOSIS WITH DIAGNOSTIC ECG
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45. IDEAL MARKERS?
TnI AND TnT ARE CURRENTLY
CONSIDERED DEFINITIVE AND
EQUIVALENT
RAPID CHANGE MARKER (SUCH AS
MYOGLOBIN) NEEDED TO DETECT
REINFARCTION
NO ROLE SEEN FOR CK MB AS
COSTS OF Tn COME DOWN
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46. SAMPLING FREQUENCY
GUIDELINES SUGGEST 0, 3, 6, 9, 12 hr
AFTER PRESENTATION FOR BOTH
EARLY AND LATE MAARKER
IF POSITIVE, MAY DISCONTINUE
AFTER 9 hr SPECIMEN
NOT CLEAR IF LATE MARKER
SHOULD BE MEASURED AT 3 hr OR
NOT
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47. SAMPLING FREQUENCY
IF PATIENT NOT HELD IN CHEST
PAIN CLINIC, LESS FREQUENT
SAMPLING RECOMMENDED
MAY VARY APPROACH FOR LATE
ONSET AFTER SYMPTOMS
ALWAYS RECOMMEND AT LEAST
TWO DETERMINATIONS
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48. Tn SIGNIFICANCE
SEVERAL STUDIES SUGGEST
POSITIVE Tn AT PRESENTATION
ASSOCIATED WITH POORER
PROGNOSIS
NOT CLEAR IF RELATED TO OTHER
VARIABLES (LARGER INFARCT,
DELAYED PRESENTATION)
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49. ONE MARKER?
GUIDELINES SUGGEST NEED FOR
TWO MARKERS IN ALL CASES,
ALTHOUGH RATIONALE NOT GIVEN
FOR LATE PRESENTATION
NEW EARLY MARKERS (SUCH AS
GLYCOGEN PHOSPHORYLASE B,
FATTY ACID BINDING PROTEIN)
MAY EMERGE
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50. REPERFUSION?
GUIDELINES SUGGEST USE OF
MARKERS AT BASELINE, 90 MINUTES
TO DETECT REPERFUSION, BUT DO
NOT OFFER SPECIFIC CUT POINTS TO
DETERMINE REPERFUSION
INCREASE ALSO DEPENDS ON
INFARCT SIZE, TIME SINCE ONSET
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51. CARDIAC PROTEIN CHANGES
WITH THROMBOLYSIS
Successful thrombolysis
CONCENTRAITON
Normal MI,
RELATIVE
unsuccessful
thrombolysis
TIME AFTER INFARCTION
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