CARDIAC BIOMARKERS:

CARDIAC MARKERS

Markers used for

For diagnosing ACS (acute coronary syndrome): MI

Other cardiac disorders: Heart failure
 What is Myocardial Infarction?
 Myocardial ischemia results from the reduction of coronary
blood flow to an extent that leads to insufficiency of oxygen
supply to myocardial tissue

 When this ischemia is prolonged & irreversible, myocardial cell

death & necrosis occurs ---this is defined as:
myocardial infarction
Biochemical Changes in Acute Myocardial Infarction
(mechanism of release of myocardial markers)
ischemia to myocardial muscles (with low O2 supply)

anaerobic glycolysis

increased accumulation of Lactate

decrease in pH

activate lysosomal enzymes

disintegration of myocardial proteins

cell death & necrosis

clinical manifestations release of intracellular ECG

(chest pain) contents to blood changes
BIOCHEMICAL
MARKERS
Diagnosis of Myocardial Infarction

SHOULD depend on THREE items

(as recommended by WHO)

1- Clinical Manifestations
2- ECG
3- Biochemical Markers
 Markers of Cardiac Necrosis

 Cardiac biomarkers are an integral part of the

most recent joint ACC/ESC: American College of
Cardiology and European Society of
Cardiology (ACC/ESC) consensus statement on
the definition of acute or recent MI
 THE IDEAL CARDIAC MARKER

HIGH SENSITIVITY HIGH SPECIFICITY

High concentration in myocardium Absent in non-myocardial tissue
Released after myocardial injury:
Not detectable in blood of non-
Rapid release for early diseased subjects

The ideal cardiac

diagnosis

Long half-life in blood for late

diagnosis

ANALYTICAL
marker does
CLINICAL CHARACTERISTICS
NOT yet exist!
CHARACTERISTICS fk
Measurable by cost-effective Ability to influence therapy
method
Ability to improve patient outcome
Simple to perform
Rapid turnaround time
Sufficient precision & accuracy

Scand J Clin Lab Inves 1999;59 (Suppl 230):113-123

 BIOCHEMICAL MARKERS IN
MYOCARDIAL ISCHAEMIA / NECROSIS

RECENT Traditional
 CK-MB (mass)  AST activity
 c.Troponins (I or T)  LDH activity
 Myoglobin  LDH isoenzymes
 CK-Total
FUTURE:  CK-MB activity
 Ischaemia Modified Albumin  CK-Isoenzymes
 Glycogen Phosphorylase BB
 Fatty Acid binding Protein
 Highly sensitive CRP.
 Markers for Myocardial Infarction

1- Enzymes
 AST (no more in use)

 LDH

 Total CK

 CK-MB activity and CK-MB mass

2- Cardiac proteins:
 Myoglobin

 Troponins
LDH Isoenzymes
 LDH Isoenzymes
Isoenzyme Subunit Electrophoretic Activity at 600 Origin %
mobility for 30 mins distribution

LDH 1 H4 Fastest Not Heart 30

destroyed muscle
LDH 2 H3M1 Faster Not RBC 35
destroyed
LDH 3 H2M2 Fast Partially Brain 20

LDH 4 H1M3 Slow Destroyed Lungs, 10

Spleen
LDH 5 M4 Slowest Destroyed Liver, 5
Skeletal
Muscle
Reference range for LDH- 100-200U/L

Flipped pattern in MI:

LDH1>LDH2

Precautions
 Strenuous exercise

 Haemolysis
Markers of Cardiac Necrosis
 Differential Diagnosis
Haemolytic anaemias
Hepatocellular damage
Muscular dystrophy
Carcinomas
Leukemias
 CK (creatine kinase)

 Creatine kinase (CK) is an enzyme expressed by various tissue

types. It catalyses the conversion of creatine and consumes
adenosine triphosphate (ATP) to create phosphocreatine and
adenosine diphosphate (ADP)
Reference range for CK is 15 – 100 U/L

Advantages
 CK is increased in MI by 3-6hrs.

 Not increased in hemolysis or congestive heart

failure.
Disadvantages

 CK is very much elevated in muscular dystrophies.

 Also in crush injury, fracture and acute

cerebrovascular accidents.
 CK Isoenzyme

 CK enzyme consists of two subunits, which can be

either B (brain type) or M (muscle type).

 There are, therefore, three different isoenzymes: CK-

MM, CK-BB and CK-MB.
Isoenzyme Electrophoretic Origin % distribution
mobility

CK MM -3 Least Sk Muscle 80-90%

CKMB -2 Intermediate Heart 5

CKBB - 1 Maximum Brain 1

 CK-MB
 High specificity for cardiac tissue
 The preferred marker for cardiac injury for many
years
 Begins to rise 4-6 hours after infarction but can take
up to 12 hours to become elevated in all patients
with infarction
 Elevations return to baseline within 36-48 hours, in
contrast to troponins
 CK-MB is the marker of choice for diagnosis of
reinfarction after CABG because of rapid washout
CK and CK-MB
 CK-MB: Shortcomings
False elevations seen in

 CPR and defibrillation

 Cardiac and non-cardiac procedures

 Blunt chest trauma

 Cocaine abuse
 Reference values

CK-MB : Reference values

 For electrophoresis and immunoinhibition are usually set

around 5% of total CK
Reference range for CK is 15 – 100 U/L
CKMB: 10 U/L.

 For immunoassays, decision limits are expressed in mass

quantities and are approximately
CKMB: 5 to 10ng/mL.
 Cardiac Proteins: Myoglobin
 Heme protein rapidly released from damaged muscle
 Appears in blood EARLIER than other markers (within 1-4
hours)
 Has high sensitivity
 Returns to normal in 24 hours
Hence, not for delayed admission cases
Not specific for cardiac tissue (also in sk.ms. & renal tissue)
 Excellent NEGATIVE predictor of myocardial injury
 2 samples 2 – 4 hours apart with no rise in levels virtually
excludes AMI
Markers of Cardiac Necrosis
 Cardiac Troponins
Protein complex located on the thin filament of striated muscles
consists of 3 subunits: cTn T, cTnI & cTn C :with different structures & functions

Cardiac troponins (cTn) are different from skeletal muscle troponins; Specific
cTnI & cTnT are used are biomarkers for MI diagnosis

cTnI
 100 % cardiac specific
 Appears in blood within 6 hours after onset of infarction
 peak: around 24 hours
 Disappears from blood after about one week (stays longer)
 Useful for diagnosis of delayed admission cases
 Prognostic marker (relation between level in blood & extent
of cardiac damage)
Troponins
 4-6 hours to rise post-infarct, similar to CKMB
 6-9 hours to detect pathologic elevations in all
patients with infarct
 Elevated levels can persist in blood for weeks; the
cardiac specificity of troponins thus make them the
ideal marker for retrospective diagnosis of
infarction
CARDIAC MUSCLE CELL

Size and subcellular distribution of myocardial proteins determines time

course of biomarker appearance in the general circulation
TROPONIN
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
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 baseline within
6h
 Clinically may detect reversible myocardial ischaemic damage
 Not specific (elevated in stroke, some neoplasms, hepatic cirrhosis, end-stage
renal disease)
 Glycogen phosphorylase BB
(GPBB):

 Glycogen phosphorylase (GP) is a glycolytic enzyme which plays an

essential role in the regulation of carbohydrate metabolism.
 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 the onset 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 after
AMI.
 However it is not cardiac specific.
 BIOCHEMICAL MARKERS IN
MYOCARDIAL ISCHAEMIA / NECROSIS

RECENT Traditional
 CK-MB (mass)  AST activity
 c.Troponins (I or T)  LDH activity
 Myoglobin  LDH isoenzymes
 CK-Total
FUTURE:  CK-MB activity
 Ischaemia Modified Albumin  CK-Isoenzymes
 Glycogen Phosphorylase BB
 Fatty Acid binding Protein
 High sensitive CRP.
BIOCHEMICAL MARKERS OF
MYOCARDIAL FUNCTION

CARDIAC NATRIURETIC PEPTIDES:

(ANP, BNP & pro-peptide forms)

 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)
 Detection of LV dysfunction
 Screening for heart disease
 Differential diagnosis of dyspnea
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