enzimas cardíacas

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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

No Symptoms

CLO

T

ACUTE CORONARY SYNDROMES: Q-WAVE MI NON-Q MI UNSTABLE ANGINA

CrescendoAngina ANGINA

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SURVIVAL OF MYOCARDIUM

100

50

0

Fra

ctio

n of

isch

emic

cells

alre

ady

dead

0 1 2 3 4 5 6Hours 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 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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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

Troponin

LDH

CK, AST

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RELATIVE SIZE OFMYOCARDIAL PROTEINS

MARKER SIZE (kd) % CYTOPL.

Myoglobin 18 100

Troponin I 24 2

Troponin T 33 6

CK/CK MB 86 100

AST 111 60

LDH 135 100

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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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Causes of Elevated Creatine Kinase

• Inflammatory myopathy• Infectious diseases• Dystrophinopathies• Rhabdomyolysis• Malignant hyperthermia

• Drugs• Motor neuron disease• Endocrine myopathies• Periodic paralysis

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Causes of Elevated Creatine Kinase

• Inflammatory myopathy– Dermatornyositis and

polymyositis– Myositis with associated

connective tissue disease: lupus, rheumatoid arthritis, Sjogren's syndrome, scleroderma

– Sarcoidosis– Behget's disease– Polymyositis associated with

graft-versus-host disease

• Dystrophinopathies– Duchenne's muscular dystrophy– Becker's muscular dystrophy– Facioscapulohumeral muscular

dystrophy– Limb-girdle muscular dystrophy– Myotonic dystrophy

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Causes of Elevated Creatine Kinase

• Drugs– Colchicine – Antimalarials – Penicillamine – Zidovudine – Lipid-lowering agents: statins,

fibrates, niacin – Alcohol– Cocaine – Nondepolarizing muscle

relaxants with high-dose corticosteroids

• Motor neuron disease– Amyotrophic lateral sclerosis– Spinal muscular atrophy

• Endocrine myopathies– Hypothyroidism – Acromegaly

• Periodic paralysis– Familial periodic paralysis– Thyrotoxic periodic paralysis

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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

ActinTropomyosin

TnC TnT

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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 MANUFACTURER’S 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 INJURY

DETECTION

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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

MARKER 1st SEEN(median)

REL. (x Nl)

DURATION(hrs)

SENS.MI

SENS.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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0 6 12 18 24 2 3 4 5 6 7 8 9 10

RE

LA

TIV

E C

ON

CE

NT

RA

TIO

N

DaysHours

TIME AFTER INFARCT

Normal

TroponinMyoglobin

CK, ASTLDH

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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 > 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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10

Siz

e o

f M

yoca

rdia

lIn

farc

tio

n (

gra

ms)

0.01

100

0.001

1

0.1

ECHO CK,AST

CK-MB

TROPONINEKG

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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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% S

UR

VIV

AL

TIME AFTER EVENT (mos)

20

40

80

100

60

0

UNSTABLE ANGINA, - MARKERS

UNSTABLE ANGINA, + MARKERS

MYOCARDIAL INFARCTION

0 3 6 9 12 15 18 21 24 27 30 33 36

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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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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 PHYSICIANSPUBLISHED JULY 1999 (CLIN CHEM 1999;45:1104-1121)

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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

RE

LAT

IVE

C

ON

CE

NT

RA

ITO

N

TIME AFTER INFARCTION

Successful thrombolysis

Normal MI, unsuccessfulthrombolysis