Transcript Biochemical Markers in Acute coronary syndrome

Head of Cardiology Department , 6th October University
Head of Egypt Hearts Society
Pathophysiology of ACS and
biochemichal markers release
Biochemical profile in ACS patients: vascular
inflammation to plaque rupture to ischemia to cell
death to myocardial dysfunction
Apple, F. S. et al. Clin Chem 2005;51:810-824
Copyright ©2005 American Association for Clinical Chemistry
5/42
Interdependence of Cardiac Biomarkers
Pathophysiology
Coronary artery disease
Coronary inflammation
Biochemical Markers
Risk factors (eg, cholesterol)
CRP, Lp-PLA2*, homocysteine, MPO
Plaque instability/disruption MPO, Lp(a), Lp-PLA2
Myocardial ischemia/necrosis
Cardiac troponins, CK-MB,
myoglobin
Ventricular overload
BNP, Nt-proBNP
Adapted from Panteghini. Eur Heart J. 2004;25:1187-1196.
* Lipoprotein associated phospholipase A 2
TIME LINE OF MARKERS OF
MYOCARDIAC DAMAGE & FUNCTION
Myoglobin assay
CK – MB
CK-MB
mass assay
Electrophoresis
for CK and LD
AST in
AMI
RIA for BNP
and proANP
CK in
AMI
RIA for
ANP
RIA for
proBNP
cTnl assay
cTnT assay
POCT for myoglobin CKMB, cTnI
Immuno assay for
proBNP
IMA
Genetic
Markers
1950
1960
1970
1980
1990
Time [years]
Timeline history of assay methods for markers of cardiac tissue damage and myocardial function.
AST: aspartate aminotransferase
ANP: atrial natriuretic peptide
CK: creatine kinase
BNP: brain natriuretic peptide
LD: lactate dehyydrogenase
cTn: cardiac-specific troponin
POCT: point-of-care testing
IMA: ischaemia-modified albumin
2000
2005
CLINICAL CHARACTERISTICS AND UTILIZATION
OF BIOCHEMICAL MARKERS IN ACS
USE OF BIOCHEMICAL MARKERS IN THE
INITIAL EVALUATION OF ACS
MANAGEMENT OF NSTEACS
MANAGEMENT OF STEMI
USE OF BIOCHEMICAL MARKERS IN
THE INITIAL EVALUATION OF ACS
A. Diagnosis of myocardial infarction
1. Biochemical markers of myocardial necrosis
2. Optimal timing of sample acquisition
3. Criteria for diagnosis of MI
4. Additional considerations in the use of bio-markers for diagnosis of MI
B. Early Risk Stratification
1. Biochemical markers of cardiac injury
2. Natriuretic peptides
3. Biochemical markers of inflammation
4. Biochemical markers of ischemia
5. Multimarker approach
6. Other novel markers
QUESTIONS ANSWERED BY CARDIAC
MARKERS
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Rule in/out an acute MI
Confirm an old MI (several days)
Monitor the success of thrombolytic therapy
Risk stratification of patients with unstable angina pectoris
N.B. Risk stratification in apparently healthy persons is not
done with cardiac markers, but by measurement and
assessment of cardiac risk factors
R. Hinzmann, 2002
BIOCHEMICAL MARKERS IN
MYOCARDIAL ISCHAEMIA / NECROSIS
OUT:
IN:
CK-MB (mass)
c.Troponins (I or T)
Myoglobin
FUTURE:
 Ischaemia Modified Albumin
 Glycogen Phosphorylase BB
 Fatty Acid binding Protein
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AST activity
LDH activity
LDH isoenzymes
CK-MB activity
CK-Isoenzymes
?CK-Total
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“CARDIAC ENZYMES”
are
Obsolete!
KINETICS OF CARDIAC MARKERS
AFTER AMI
MARKER
DETECTION
PEAK
DISAPPEARANCE
Myoglobin
CK-MB mass
Total CK
cTnT
cTnI
IMA (ischaemia)
1–4h
3 – 12 h
4–8h
4 – 12 h
4 – 12 h
few minutes
6–7h
12 – 18 h
12 – 30 h
12 – 48 h
12 – 24 h
2–4h
24 h
2 – 3 days
3 – 4 days
5 – 15 days
5 – 7 days
6 hours
These values represent averages.
Marker of Ischemia
ISCHAEMIA-MODIFIED ALBUMIN
(IMA)
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Serum albumin is altered by free radicals released from
ischaemic tissue
Angioplasty studies show that albumin is modified within
minutes of the onset of ischaemia.
IMA levels rise rapidly, remain elevated for 2-4 h + return to
baseline within 6h
Clinically may detect reversible myocardial ischaemic damage
Not specific (elevated in stroke, some neoplasms, hepatic
cirrhosis, end-stage renal disease)
Thus potential value is as a negative predictor
FDA approved as a rule-out marker in low risk ACS patients
(2003).
Established biomakrkers:
• Creatinin Kinase-MB (mass)
• Myoglobin.
• Troponin.
CREATINE KINASE
NORMAL VALUES:
Vary according to –
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age
sex
race
physical condition
muscle mass
PATHOLOGICAL INCREASES:
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Myocardial infarction or injury
Skeletal muscle injury or disease
Hypothyroidism
IM injections
Generalised convulsions
Cerebral injury
Malignant hyperpyrexia
Prolonged hypothermia
CREATINE KINASE: CK-MB
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CK-MB is the most cardiac-specific CK
isoenzyme
Sensitive marker with rapid rise & fall
“Gold standard” biochemical marker for ~ 2
decades
Only CK-MBmass should be measured
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Myoglobin
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Currently earliest marker
Like total CK it is by no means
cardio-specific
Troponins
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R. Hinzmann, 2002
Kinetics comparable with total CK
and CK-MB
Cardio-specific
Sensitivity
Specificity
MYOGLOBIN (Mb)
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Peak at 6 – 9h
Normal by 24 – 36h
Excellent NEGATIVE predictor of
myocardial injury
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2 samples 2 – 4 hours apart with no rise in levels
virtually excludes AMI
CARDIAC TROPONINS
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Striated and cardiac muscle filaments consist
of:
 Actin
 Myosin
 Troponin regulatory complex
Troponin consists of 3 sub-units TnC, TnT
& TnI
TROPONIN SUMMARY
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High specificity for myocardial injury
Sensitive to minor myocardial damage
THE DUAL APPROACH LEAVES AN OPEN
QUESTION
Troponin concentration
normal
acute MI
97.5 th
percentile
Acute MI cut-off
value
Troponin IN UA
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Several studies have investigated the role of TnT/I
in risk stratification of unstable angina (UA)
Of importance is that UA patients with elevated Tn
showed same incidence of cardiac death or AMI at 6
months as did patients with pre-existing AMI (15%)
Risk of AMI in UA patients with normal Tn was 4
%.
Irreversible minor myocardial injury detected by
TnT/I may stratify UA patients as high risk for
progression to AMI
INCIDENCE OF DEATH OR MI IN ACS
PATIENTS
Baseline levels of troponin have been shown to predict the risk of adverse cardiac events
in patients with non-ST elevation ACS
From: NEJM 1997;337:1648 (Study 1);JACC 1998;32:8 (Study 2); Circulation 1997;95:2053 (Study 3); Am J Cardiol 2002;89:1035 (Study 4).
CLINICAL OUTCOME AT DIFFERENT
FOLLOW-UP PERIODS
The prognostic information of an elevated cTnI upon presentation is maintained over time.
From: JACC 2000;36:1812 and Am J Cardiol 2002;89:1035
CARDIAC TROPONINS IN UNSTABLE
ANGINA PECTORIS (UA)
QUESTION:
 Does an elevated Troponin level in the absence of other signs reflect
irreversible myocardial damage?
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Epidemiological studies
Animal experiments
Clinical trials
Sensitive imaging techniques
Say
YES!
MI must be REDEFINED!
New criteria for acute, evolving or
recent MI
Either one of the following criteria satisfies the diagnosis for an
acute, evolving or recent MI :
1. Typical rise and gradual fall (troponin) or more rapid rise
and fall (CK-MB) of biochemical markers of myocardial
necrosis with at least one of the following:
a) ischemic symptoms;
b) development of pathologic Q waves on the ECG;
c) ECG changes indicative of ischemia (ST segment
elevation or depression); or
d) coronary artery intervention (e.g. coronary angioplasty).
2. Pathologic findings of an acute MI
Etiologies for Cardiac Troponin Increases
TROPONIN
AMI
NSTEMI
Pericarditis
Pulmonary Embolism
Sepsis Shock
Acute LVF
Trauma
Hypertension/Hypotension
Drug Toxicity
False +ve
(eg heterophilic antibodies)
Iatrogenic
•Cardiac Surgery
•PCI
•Cardioversion
•Cardiotoxin Drugs
•EP Ablation
TROPONIN AND MI DIAGNOSIS
Ischemic Discomfort
No ST Elevation
ST Elevation
STEMI
NSTEMI
Myocardial Infarction
Unstable
angina
Non QWave MI
Q-Wave
MI
Acute Coronary Syndromes
Cardiac Markers Clinical Utility
NSTEMI
STEMI
•Diagnosis
•Prognosis
• Prognosis
• Reperfusion
"It is estimated that about 30% of patients who present with chest pain without STsegment elevation and would otherwise be diagnosed as having unstable angina
because of a lack of CK-MB elevation actually have NSTEMI when assessed with
cardiac-specific troponin assays"
From:JACC and Circulation 2002
PREDICTION OF RISK/PROGNOSIS
Non ST Elevation Ischemic Discomfort
Troponin
(admission and 6-12 hrs)
Troponin
Negative
Low risk
Other disease?
Troponin
Positive
NSTEMI High Risk
Troponin can be used to efficiently categorise patients into high and low
risk groups for appropriate management pathways.
Adapted from: ACC/AHA Guideline Update for the Management of patients with UA and NSTEMI. 2002
BIOCHEMICAL MARKERS IN ACS
CLINICAL DECISION POINTS
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Unstable Angina
AMI
Infarct size
Prognosis
Thrombolysis and Reperfusion
 Peri-operative infarcts
 Coronary surgery complications
 Transplant rejection
BIOCHEMICAL MARKERS IN AMI
ASSESSMENT OF REPERFUSION
•
Marker Level
Successful
reperfusion
Unsuccessful
reperfusion
•
“Washout” phenomenon –
enzymes & proteins have direct
vascular access when occluded
coronary circulation becomes
patent
Peak concentrations earlier & at
higher levels if reperfusion
successful
Time
Due to short plasma half life (t½ = 10 min) Myoglobin is considered the best reperfusion marker
BIOCHEMICAL MARKERS IN ACS
CURRENT RECOMMENDATIONS
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AMI – Routine diagnosis Troponins (CK-MBmass)
Retrospective diagnosis Troponins
Skeletal muscle pathologyTroponins
Reinfarction
Mb, CK-MBmass
Reperfusion
Mb, Tn, CK-Mbmass
Infarct size
Troponins
Risk stratification in UA Troponins
Problems with the current
biochemical markers
The perfect marker
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Marker for myocardial necrosis, and also for cardiac ischemia
Linear relationship between blood levels and extent of
myocardial injury (and prognosis)
100% sensitive
100% specific
Immediate increase (+ constant blood level for hours to days)
Test kits : reliable, rapid, universally available and inexpensive
What about troponin T and I ?
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Very high sensitivity for myocardial necrosis
Related to prognosis
BUT
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Not 100% specific for atherosclerotic coronary artery
disease
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myocarditis, cardiomyopathy, myocardial contusion, ...
renal failure, auto-immune diseases, ...)
Up to 6 hours before raised blood levels
no early MI diagnosis possible
Raised blood levels for many days
troublesome diagnosis of re-infarction
Role for myoglobin ?
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Initial elevation : 1 to 4h after onset
better early marker than troponins
BUT : early myoglobin is less sensitive and
less specific (due to skeletal muscle
trauma) than late troponin
decisions mainly based on clinical
skills, ECG and late troponin (except
rarely for reperfusion therapy)
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Duration of elevation : 24 – 48h
useful for re-infarction diagnosis
Role for CK-MB ?
•
Initial elevation comparable with troponins
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Less sensitive than troponins
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High specificity (comparable with troponins)
•
Rapid rise and fall (instead of gradual fall for
troponins) allowing more accurate estimation
of MI extent
OTHER MARKERS CURRENTLY UNDER
INVESTIGATION
Free fatty acids
 Fibrin peptide A
 Fatty acid binding protein
 Glycogen phosphorylase BB
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Markers of myocardial function
BIOCHEMICAL MARKERS OF
MYOCARDIAL FUNCTION
CARDIAC NATRIURETIC PEPTIDES:
(ANP, BNP & pro-peptide forms)
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Family of peptides secreted by cardiac atria (+ ventricles) with potent
diuretic, natriuretic & vascular smooth muscle relaxing activity
Levels of these neuro-hormonal factors can be measured in blood
Clinical usefulness (especially BNP/N-terminal pro-BNP)
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Detection of LV dysfunction
Screening for heart disease
Differential diagnosis of dyspnea
Stratification of CCF patients
New generation markers currently under development
SOME COMMON DISEASES IN WHICH PLASMA CARDIAC
NATRIURETIC PEPTIDES HAVE BEEN FOUND TO BE
ALTERED, COMPARED TO HEALTHY SUBJECTS
DISEASES
ANP/BNP LEVELS
a)
Cardiac diseases
Heart
failure
AMI (first 2 – 3
days)
Essential hypertension with
CMP
Greatly increased
Greatly increased
Increased
b)
Pulmonary diseases
Acute
dyspnea
Obstructive
pulmonary disease
Increased
Increased
c)
Endocrine & metabolic diseases
Hyperthyroidism
Hypothyroidism
Cushing’s syndrome
Primary
aldosteronism
Addison’s disease
Diabetes mellitus
d)
Liver cirrhosis with ascites
e)
Renal failure (acute or chronic)
Increased
Decreased
Increased
Increased
Normal or increased
Normal or increased
Increased
Greatly increased
AMI = acute myocardial infarction; CMP = cardiomyopathy with left ventricular hypertrophy
Clarico; Clin Chem Lab Med, 2003; 41 (17) p876
CARDIOVASCULAR RISK FACTORS
EMERGING RISK FACTORS
Inflammatory Markers
Sensitive C-reactive protein
Interleukins
Serum amyloid A
Pregnancy-associated plasma protein A
Chronic infection (Chlamydia pneumoniae,
Helicobacter pylori, etc)
Procoagulant Markers
+
+
+
?
?
Plasma Homocysteine
+
Tissue plasminogen activator
Plasminogen activator inhibitor
Lipoprotein A
Process Markers
Fibrinogen
+
+
+
D-dimer
Coronary artery calcification
?
?
+
+ Clear evidence, but less clear
whether modification of the risk
factor decreases the risk of
cardiovascular disease
?
Boersma et al, Lancet, 2003:361,p849
Risk factor under scrutiny
GUIDELINES:
USE OF CARDIAC MARKERS IN PATIENTS WITH
CHEST PAIN
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Serial sampling is critical for accurate diagnosis
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Do NOT discharge patients on the basis of negative results on
a single (admission) specimen
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If onset of chest pain >9-12 h before admission only
Troponin is necessary
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CK-MBmass is most useful in assessing a recent vs an older MI
or to confirm reinfarction (occurs in 17% of AMI’s). Repeat
CK-MBmass if chest pain recurs in AMI patients
GUIDELINES:
USE OF CARDIAC MARKERS IN PATIENTS WITH
CHEST PAIN
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Mb, CK-MBmass, Troponin
 AMI
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Mb ONLY
POSITIVE
 Possible early infarction or skeletal muscle injury
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Repeat markers
(NB importance of Mb is as a Negative Predictor)
Mb + CK-MB
 Probable early infarction
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POSITIVE
Repeat markers
A rising CK-MB.
POSITIVE
GUIDELINES:
USE OF CARDIAC MARKERS IN PATIENTS WITH
CHEST PAIN
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TnI < 0.06 ng/mL OR TnT < 0.03 ng/mL
on two specimens > 6 hours apart
 Unstable Angina
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Troponin I > 0.06 OR TnT > 0.1 ng/mL
(TnT levels > 0.03 and < 0.1 ng/mL are equivocal and
should be repeated)
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? High risk ACS(AMI) or non-ischaemic myocardial damage
depending on clinical cardiac ischaemia
These patients require follow-up!!
Troponin I > 0.4 ng/mL
 “traditional” AMI
GUIDELINES:
USE OF CARDIAC MARKERS IN PATIENTS WITH
CHEST PAIN
FOR ASSESSMENT OF:
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Reperfusion
Intra- or post-operative AMI
MI after percutaneous
coronary artery intervention
Reinfarction
Mb, CK-MBmass
Troponin
Troponin ( in 30 - 40 % patients)
CK-MB ( in 5 - 30 % patients)
(compare with baseline or use
5-15 fold higher cut-off level)
serial CK-MBmass determinations
Prognostic Markers and Markers of
Risk Stratification
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C-reactive protein
Myeloperoxidase
Homocysteine
Glomerular filtration rate
C-Reactive Protein
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Multiple roles in cardiovascular disease have
been examined
Screening for cardiovascular risk in otherwise
“healthy” men and women
 Predictive value of CRP levels for disease severity in
pre-existing CAD
 Prognostic value in ACS
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Myeloperoxidase
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Released by activated leukocytes at elevated
levels in vulnerable plaques
Predicts cardiac risk independently of other
markers of inflammation
May be useful in triage of ACS (levels elevate in
the 1st two hours)
Also identifies patients at increased risk of CV
event in the 6 months following a negative
troponin
NEJM 349: 1595-1604
Homocysteine
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Intermediary amino acid formed by the
conversion of methionine to cysteine
Moderate hyperhomocysteinemia occurs in 57% of the population
Recognized as an independent risk factor for the
development of atherosclerotic vascular disease
and venous thrombosis
Can result from genetic defects, drugs, vitamin
deficiencies, or smoking
Homocysteine
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Elevated levels appear to be an independent risk
factor, though less important than the classic CV
risk factors
Screening recommended in patients with
premature CV disease (or unexplained DVT)
and absence of other risk factors
Treatment includes supplementation with folate,
B6 and B12
Glomerular Filtration Rate
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Reduced GFR has been associated with:
Increased inflammatory factors
 Abnormal lipoprotein levels
 Elevated plasma homocysteine
 Anemia
 Arterial stiffness
 Endothelial dysfunction
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So much information!
What does it all mean?!?
The Future of Cardiac Biomarkers
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Many experts are advocating the move
towards a multimarker strategy for the
purposes of diagnosis, prognosis, and
treatment design
As the pathophysiology of ACS is
heterogeneous, so must be the diagnostic
strategies
Multiple Markers
Are Needed for Diagnosis and Prognosis of ACS
 No
single ideal marker exists for ACS
 Complicated diseases are not likely to be
associated with single markers
 Multiple markers define disease
categories
 Multi-marker panels can aid in
differential diagnosis
7/7/2015
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markers of inflammation
Leukocyte chemoattractants
(MCP-1, IL-8, PDGF, MC-SF)
Adhesion molecules
E-selectin, ICAM-1, VCAM-1
Procoagulant activity
(tissue factor)
Cytokines
(TNFa, FAS,CD40L)
Permeability
Apoptosis
NO
ET-1
• Markers of protection?
IL-10
T
Leukocyte chemoattractants
(MCP-1, IL-8, PDGF, MC-SF)
markers of inflammation
IL-10
Procoagulant activity
(tissue factor)
Adhesion molecules
E-selectin, ICAM-1, VCAM-1
Permeability
IL-10
Cytokines
(TNFa, FAS,CD40L etc.)
T
IL-10
Apoptosis
NO
ET-1
T
IL-10
hepatocyte
growth factor
SUMMARY
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“Cardiac Enzymes” are obsolete
Medical & laboratory progress has required a redefinition of
Myocardial Infarction
Cardiac Troponins & Myoglobin now play a pivotal role in the
diagnosis of AMI
Cardiac Troponins play an important role in the risk
stratification of ACS patients
Elevated Troponin levels in patients without ECG changes &
with normal CK-MB levels may identify patients at increased
risk of cardiac events
SUMMARY
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Elevated Troponins in the absence of clinical
signs of ischaemic heart disease require
consideration of other causes of cardiac injury
Additional roles for cardiac markers in:
Reperfusion monitoring
 Infarct size/prognosis
 Intra/post-operative
MI
surgery).

(non-cardiac/cardiac