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8/11/2019 Biochemical Markers in Cardiac Diseases
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Biochemical Markers in Cardiac
Disease
Dr/Ehsan Mohamed Rizk
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ACUTE CORONARY SYNDROME
ACS)
Ischemic heart diseases (acute coronary syndrome) includes:
1-Angina
2-Unstable angina
3-Myocardial infarction: most serious form of ischemia thatleads to injury or even death of myocardium.
The most common cause of myocardial ischemia is atherosclerosis. Risk factors for Coronary Artery Disease:
1-Age
2-Gender
3-Family history
4-Hyperlipidemia5-Smoking
6-Hypertension
7-Diabetes
8-Obesity
9-High plasma homocysteine levels
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CRITERIA FOR DIAGNOSIS OF ACS
Triad of criteria:
Clinical picture
Severe & prolonged chest painAtypical pain (epigastric)
Silent ischemia.
ECG changes consistent with acute MIElevated serum cardiac MARKERS
Diagnosis requires at least two of them.
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CARDIAC MARKERS MUST BE:
Located in the myocardium.
Released in cardiac injury.
Myocardial infarction
Non-Q-wave infarction
Unstable angina pectoris
Other conditions affecting cardiac muscle
(trauma, cardiac surgery, myocarditis etc.)
Can be measured in blood samples.
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THE IDEAL CARDIAC MARKER
HIGH SENSITIVITY
High concentration in myocardium
Released after myocardial injury:
Rapid release for earlydiagnosis
Long half-life in blood for late
diagnosis
HIGH SPECIFICITY
Absent in non-myocardial tissue
Not detectable in blood of non-
diseased subjects
CLINICAL CHARACTERISTICS
fk
Ability to influence therapy
Ability to improve patient outcome
ANALYTICAL
CHARACTERISTICS
Measurable by cost-effective
method
Simple to perform
Rapid turnaround time
Sufficient precision & accuracy
The ideal cardiac
marker does
NOT yet exist
Scand J Clin Lab Inves 1999;59 (Suppl 230):113-123
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CARDIAC MUSCLE CELL
Size and subcellular distribution of myocardial proteins determines time
course of biomarker appearance in the general circulation
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CLASSIFICATION OF LABORATORY
TESTS IN CARDIAC DISEASE
Markers of cardiac tissue damage
Markers of myocardial function
Cardiovascular risk factor markers
Genetic analysis for candidate genes or riskfactors
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PATHOPHYSIOLOGY OF ACS
Proinflammatory Cytokines
IL-6
Plaque Destabilization
MPO
Plaque Rupture
sCD40L Acute Phase Reactants
hs-CRP
Ischemia
IMA
Necrosis
cTnT
cTnI Myocardial Dysfunction
BNP
NT-proBNP
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BIOCHEMICAL MARKERS IN
MYOCARDIAL ISCHAEMIA / NECROSIS
RECENT
CK-MB (mass)
c.Troponins (I or T)
Myoglobin
Traditional
AST activity
LDH activity
LDH isoenzymes CK-Total
CK-MB activity
CK-IsoenzymesFUTURE:
Ischaemia Modified Albumin Glycogen Phosphorylase BB
Fatty Acid binding Protein
Highly sensitive CRP.
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LACTATE DEHYDROGENASE
LDH)
LDH is a hydrogen transfer enzyme that catalysis theoxidation of L-Lactate to Pyruvate.
It is composed of 4 subunits of 2 types
M type encoded by a gene on ch 11H type encoded by a gene on ch 12.
There are 5 isoenzymes:
LD-1 (4 H subunits)
LD-2 (3 H and 1 M sumunits)LD-3 (2 H and 2 M sumunits)
LD-4 (1 H and 3 M sumunits)
LD-5 (4 M subunits)
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LDH
Both total and LDH isoenzymes are elevatedin myocardial injury.
Level of LD-1 are elevated 10 12 after
acute myocardial infarction, peak in 2 daysand return to normal in 7 -10 days
Usually the amount of LD-2 in the blood ishigher than amount of LD-1. Patient with AMIhave more LD-1 than LD-2 (ratio > 1) this is
called "Flipped Ratio".An elevated level of LD=1 with flipped ratio
has a sensitivity and specificity ofapproximately 75% - 90% for detection of
AMI.
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CREATINE KINASE
CK is a dimeric enzyme that regulates high energy phosphate
production and utilization in contractile tissues.
It is composed of two subunits:
M subunit encoded by a gene on chromosome 14.
B subunit encoded by a gene on chromosome 19. There are different isoenzymes:
CK1 (CK-BB): the predominant isoenzyme found in brain.
CK2 (CK-MB): represent 20 30 % of total CK in diseased cardiac
tissue
CK3 (CK-MM): 98% in skeletal muscles and 1% in cardiac muscles.
CK-mitochondrial (CK-Mt): located in mitochondria and encoded by a
different gene on chromosome 15.
Macro-CK: CK complexed with Igs.
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CREATINE KINASE
NORMAL VALUES:
Vary according to
age sex
race
physical condition
muscle mass
PATHOLOGICAL INCREASES:
Myocardial infarction or injury
Skeletal muscle injury or disease
Hypothyroidism
IM injections
Generalised convulsions Cerebral injury
Malignant hyperpyrexia
Prolonged hypothermia
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CREATINE KINASE: CK-MB
In normal population CK-MB < 6% Total CKSensitive marker with rapid rise & fall:
Serum CK-MB levels rise within 2~8 hours after AMI.
CK-MB values return to normal 2~3 days after the
event.
More specific than total CK but has limitations:
False elevations in:
-perioperative patients without cardiac injury
-Skeletal muscle injury
-Marathon runners-Chronic renal failure
-Hypothyroidism
MB Index = (CKMB /total CK) x 100
Combined use with MB Index helps to rule-out patients with
skeletal muscle injury
CK MB RELATIVE INDEX AND CK
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CK-MB RELATIVE INDEX AND CK-MB mass:
CK-MB MASS:
Measure the concentration of CK-MB
protein is now available using sandwichtechnique with a detection limit < 1g/dl.
More sensitive than measurement ofactivity.
MB Index = (CKMB /total CK) x 10
Combined use with MB Index helps to rule-
out patients with skeletal muscle injury
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CK-isoforms:
Both M and B subunits have N-terminal lysine residues butonly M subunit is hydrolyzed by carboxypeptidase-N enzymefound in blood.
CK-MM is present in three isoforms:
CK-MM3: tissue form.CK-MM2: (one lysine residue is removed).
CK-MM1: (both lysine residue are removed)
CK-MB has two isoforms:
CK-MB2: tissue form.CK-MB1: circulating form.
The ratio of tissue isoforms and plasma modified isoformsare used as markers of recent myocardial damage (elevatedCK-MM3/CK-MM2 and CK-MB2/CK-MB1/CK-MB1 indicatesa rise in tissue isoforms caused by recent release).
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MYOGLOBIN Mb)
Low MW protein
Skeletal & cardiac muscle Mb identical
Serum levels increase within 2h of muscle damage
Peak at 6 9h
Normal by 24 36h
Excellent NEGATIVE predictorof myocardial injury
2 samples 2 4 hours apart with no rise in levels virtually
excludes AMI
Rapid, quantitative serum immunoassays
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THE TROPONIN REGULATORY
COMPLEX
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1. Cardiac Troponin I (cTnl) is acardiac muscle protein with amolecular weight of 24 kilo-Daltons.
2. The human cTnl has a additional
amino acid residues on its N-terminal that are not exist on theskeletal form.
3. The half life of cTnI is estimated tobe 2~4 hours.
4. Serum increase is found between
2-8 hours and returns to normal7~10 days after AMI.
5. Cardiac TnI levels provide usefulprognostic information.
6. Reference range: cTnI
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TROPONIN SUMMARY
Regulatory complex of striated muscle
contraction
Early release ex cytosolic pool
Prolonged release due degradation of
myofilaments
Distinct skeletal & myocardial muscle forms High specificity for myocardial injury
Sensitive to minor myocardial damage
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ISCHAEMIA-MODIFIED ALBUMIN(IMA)
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 baselinewithin 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
Spectrophotometric assay for IMA adapted for automated clinical
chemistry analysers
FDA approved as a rule-out marker in low risk ACS patients (2003)
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Glycogen phosphorylase BB GPBB):
Glycogen phosphorylase (GP) is a glycolytic enzyme whichplays an essential role in the regulation of carbohydratemetabolism.
It functions to provide energy supply for muscle contraction
Three GP isoenzymes are found in human tissues:
o GP-LL in liver
o GP-MM in muscle
o GP-BB in brain.
GP-BB is the predominant isoenzyme in myocardium. With theonset of tissue hypoxia when glycogen is broke down, GP-BB is
converted from structurally bound to cytoplasmic form. In AMI GP-BB: Increases 1 4 after onset of chest pain
Peaks before CK-MB and cTnT
Return to reference interval 1 2 days afterAMI.
However it is not cardiac specific.
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BIOCHEMICAL MARKERS IN ACS:
RELEASE, PEAK AND DURATION OF ELEVATION
Marker start Peak Duration ofelevation
LD-1 2447 h 4872 h 710 days
Total CK 38 h 1230 h 34 days
CK-MB 46 h 24 h 4872 h
CK-MB
isoforms
23 h 18 h < 24 h
cTnI 6 h 24 h 710 dayscTnT 6 h 1248 h 710 days
Myoglobin 2 h 67 h 24 h
IMA Few minutes 24 h 6 h
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BIOCHEMICAL MARKERS IN ACS:
RELEASE, PEAK AND DURATION OF ELEVATION
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BIOCHEMICAL MARKERS IN ACSUNSTABLE ANGINA PECTORIS (UA)
Characterised by chest pain at rest
? Caused by disruption of liquid-filled atheroscleroticplaque with platelet aggregation & thrombus formation
Variable degree of ischaemia resulting in reversible orirreversible injury
Non-occlusive plaques may produce sufficient ischaemiafor release of low molecular weight markers
cTnI & cTnT are often elevated in patients with unstableangina pectoris without additional clinical signs (ECG) orclassical laboratory signs of acute MI (elevated CK-MB)
These patients have a very high risk of cardiac events
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CARDIAC TROPONINS INUNSTABLE ANGINA PECTORIS (UA)
Does an elevated Troponin level in the absence of
other signs reflect irreversible myocardial damage?
Epidemiological studies
Animal experiments
Clinical trials
Sensitive imaging techniques
Say
YES!
MImust be REDEFINED!
QUESTION:
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ACS REDEFINED
If Troponins are not available, best alternative is CK-
MBmass
Degree of elevation of the marker is related to clinical risk
CK(total), AST & LDH (Cardiac Enzymes) should NOT be
used!
Combine early (myoglobin) & late (Troponins) markers
Serial testing: admission, 6 9 h, 12 24 h
An elevated Troponin level in the absence of clinical
evidence of ischaemia should prompt searching for other
causes of cardiac damage
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BIOCHEMICAL MARKERS IN AMIASSESSMENT OF REPERFUSION
Washout phenomenon
enzymes & proteins have
direct vascular access when
occluded coronary circulation
becomes patent
Peak concentrations earlier &
at higher levels if reperfusion
successful
Due to short plasma half life (t = 10 min) Myoglobin is considered the
best re-perfusion marker
Time
MarkerLevel
Successful
reperfusion
Unsuccessful
reperfusion
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BIOCHEMICAL MARKERS IN ACSCURRENT RECOMMENDATIONS
AMI Routine diagnosis Troponins (CK-MBmass)
Retrospective diagnosis Troponins
Skeletal muscle pathology Troponins
Reinfarction Mb, CK-MBmass
Reperfusion Mb, Tn, CK-Mbmass
Infarct size Troponins
Risk stratification in UA Troponins
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BIOCHEMICAL MARKERS OFMYOCARDIAL FUNCTION
CARDIAC NATRIURETIC PEPTIDES:
(ANP, BNP & pro-peptide forms)
Family of peptides secreted by cardiac atria (+ ventricles)with potent diuretic, natriuretic & vascular smooth musclerelaxing activity
Levels of these neuro-hormonal factors can be measuredin blood
Clinical usefulness (especially BNP/N-terminal pro-BNP) Detection of LV dysfunction
Screening for heart disease
Differential diagnosis of dyspnea
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CARDIOVASCULAR RISK FACTORS
ESTABLISHED RISK FACTORS EVIDENCERaised serum low density lipoprotein cholesterol ++
Decreased serum high density lipoprotein cholesterol ++
Smoking ++
High Blood pressure ++
Increased plasma glucose concentrations +
Physical inactivity +
Obesity +
Advanced age +
EMERGING RISK FACTORS
Inf lammatory Markers
Sensitive C-reactive protein +
Interleukins +
Serum amyloid A +
Pregnancy-associated plasma protein A ?
Chronic infection (Chlamydia pneumoniae, ?
Helicobacter pylori, etc)Procoagu lant Markers
PlasmaHomocysteine +
Tissue plasminogen activator +
Plasminogen activator inhibitor +
Lipoprotein A +
Process Markers
Fibrinogen +
D-dimer ?
Coronary artery calcification ?
Boersma et al, Lancet, 2003:361,p849
++ Clear evidence, and modification
of the risk factor decreases the risk of
cardiovascular disease
+ Clear evidence, but less clear
whether modification of the risk factor
decreases the risk of cardiovascular
disease
? Risk factor under scrutiny
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GENETIC ANALYSIS OF CANDIDATE GENESOR RISK FACTORS FOR CARDIOVASCULARDISEASE
Recent explosion of genetic analysis & micro-array
technology
Common cardiovascular diseases are polygenic. Multiple
susceptibility loci interact with lifestyle & environment
Single gene defects may account for some of the
cardiomyopathies, inherited cardiac arrhythmias
Possible genetic cardiovascular risk factors underassessment
Technology is still complex & expensive but is developing
very rapidly
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