Myocardial Injury Markers

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MYOCARDIAL INJURY MARKERS
D. Robert Dufour, M.D. Washington VA Medical
Center
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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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MYOCARDIAL INJURY

• IRREVERSIBLE INJURY TYPICALLY REQUIRES 30
  MINUTES OF ISCHEMIA
• CHRONIC O2 DEFICIENCY MAKES 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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• SPECTRUM OF ISCHEMIA

ACUTE CORONARY SYNDROMES Q-WAVE MI NON-Q
MI UNSTABLE ANGINA
CLOT
No Symptoms
Crescendo Angina
ANGINA
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• SURVIVAL OF MYOCARDIUM

100
Fraction of ischemic cells already dead
50
0
0 1 2 3 4 5 6
Hours of Ischemia
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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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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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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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RELEASE MECHANISM

• FENG et al., A J Clin Pathol 199811070
• 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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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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• MYOCARDIAL PROTEINS

Myoglobin
Actin, Myosin
CK, AST
Troponin
LDH
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RELATIVE SIZE OFMYOCARDIAL PROTEINS
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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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CARDIAC ENZYMES

• CREATINE KINASE (CK)
• CK MB
• CK ISOFORMS
• LACTATE DEHYDROGENASE (LDH)
• LDH ISOENZYMES
• ASPARTATE AMINOTRANSFERASE

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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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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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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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MYOGLOBIN

• FOUND IN SKELETAL, CARDIAC MUSCLE
• SMALL SIZE ALLOWS EARLY DETECTION, RAPID
  CLEARANCE
• NOT SPECIFIC FOR CARDIAC MUSCLE

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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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• MYOFIBER STRUCTURE

TnI
TnC
TnT
Tropomyosin
Actin
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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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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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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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PROBLEMS WITH TnI

• DIFFERENT FORMS OF TROPONIN I FOUND IN SERUM
  (FREE, BOUND, AND FORMS OF BOUND)
• DIFFERENT MANUFACTURERS ASSAYS VARIABLY MEASURE
  THESE
• NO STANDARDIZATION, MAKING COMPARISON BETWEEN
  LABS DIFFICULT

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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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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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MYOCARDIAL INJURYDETECTION
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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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MYOCARDIAL MARKERS
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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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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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CATEGORY
NUMBER
MI
ANY CHEST PAIN
1420
20
PAIN gt 30 min, EKG CHANGE
312
49
PAIN gt 30 min OR EKG CHANGE
551
16
PAIN lt 30 min NO EKG CHANGE
557
6
Wasimuddin et al. Crit Care Med, 1994
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(No Transcript)
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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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UNSTABLE ANGINA, - MARKERS
100
UNSTABLE ANGINA, MARKERS
80
SURVIVAL
60
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MYOCARDIAL INFARCTION
20
0
0 3 6 9 12 15 18 21 24 27 30 33
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TIME AFTER EVENT (mos)
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CLINICAL SIGNIFICANCE

• RELATIVE RISK WITH POSITIVE MARKERS AVERAGES 61
  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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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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WHICH MARKERS?

• NATIONAL ACADEMY OF BIOCHEMISTRY DRAFT
  GUIDELINES (www.nacb.org)
• JOINT GROUP OF LABORATORIANS, CARDIOLOGISTS,
  EMERGENCY MED PHYSICIANS
• PUBLISHED JULY 1999 (CLIN CHEM 1999451104-1121)

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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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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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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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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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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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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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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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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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• CARDIAC PROTEIN CHANGES WITH THROMBOLYSIS

Successful thrombolysis
Normal MI, unsuccessful thrombolysis
RELATIVE CONCENTRAITON
TIME AFTER INFARCTION