An indicator used for objective

measurement and evaluation of

Response to
Normal biological therapeutic
process intervention
Pathogenic process

Dr. Prabhash Bhavsar

 1954 SGOT (AST)

1955 LDH

1960 CPK

1972 CPK isoforms by electrophoresis

1975 CK-MB by immunoinhibition

1975 Myoglobin

1985 CK-MB mass immunoassay

1989 Troponin T

1992 Troponin I
 a H2 transfer enzyme catalyzes reduction of
L-lactate to pyruvate using a carrier NAD in
an alkaline pH

is a tetramer of 4 peptide chains of 2 types

forming five isoenzymes
1. LD1 (H4)
2. LD2 (H3M)
3. LD3 (H2M2)
4. LD4 (HM3)
5. LD5 (M4)
 Rises at about 10 hours

Peaks at 24-48 hours

Remains elevated for up to 8 days

Pancreas, kidney, stomach tissue, red cells cardiac tissue

contains LD-1 (nonspecific)

Normal LD1/LD2 is between 0.47 0.74

In myocardial injury LD1/LD2 will be > 1

 Isoform LD1 LD2 LD3 LD4 LD5

% of total LD 15 25 % 30 -40 % 20 25 % 7 15 % 7 15 %
activity
Tissue Myocytes, Kidney Hepatocytes & Skeletal
Predominanc cells & RBCs muscles
e
Lungs, LNs, PLTs,
Spleen, Endocrine
glands & non-gravid
uterus
Tissue LD activity is ~ 500 times its activity in serum

LD1/LD2 ratio normally between 0.47 0.74

In Myocardial Injury LD1/LD2 ratio is flipped being > 1

Cardiac Markers
(Mahmoud Abdelwahab)
 Your Subtopics Go Here
NEJM 2002;Vol.346,No.26:2079-82
 Troponin T and I are not detected in healthy
individuals

Significant increase in Troponins reflects

myocardial necrosis

ACC/ESC has defined increase in Troponins as a

measurement above 99th percentile value of
reference group

To reduce false-positive outcomes, CV of 10% at

decision limit is recommended
 Diagnosing AMI/ACS
Detecting myocardial damage whether
due to AMI or other cardiac process
Risk-stratifying patients
Commenting on Prognosis
In ACS, pre and post PCI/reperfusion therapy
CHF
Renal Disease
Stressing interns, confusing residents
and worrying cardiology fellows
CK (CPK)
CK-MB
Troponin-I/T
LD (LDH)
Myoglobin
ALT/AST
Others
 LD (LDH)
Used in the past along with aminotransferases to diagnose AMI. LD is non-
specific for cardiac tissue, which contains LD-1. However, pancreas,
kidney, stomach tissue and red cells also contain LD-1. In the setting of
AMI, LD rises at about 10 hours, peaks at 24-48 hours, and remains
elevated for up to 8 days.
Myoglobin
Ubiquitous small-size heme protein released from all damaged tissues.
Increases often occur more rapidly than TI and CK. Not utilized often for
AMI/cardiac damage assessment because of its very rapid metabolism
(short plasma half-life) causing short burst increases that are difficult to
assess clinically, as well as its lack of specificity for cardiac tissue.
ALT/AST
Used as surrogate markers of cellular damage in the past. Very non-
specific so not used for assessment of myocardial damage any longer
H-FABP
Heart-type fatty acid binding protein
Kinetically similar to myoglobin but more specific to cardiac tissue which
contains a greater percentage of this protein than skeletal muscle
May also have role in prediction- prognosis in patients with NSTEMI
Current studies ongoing to further evaluate its utility
 Standardized
High Sensitivity and Specificity
Accurate
Reproducible
Easy to interpret
Acceptable to patient
Consistent and Cost effective
Has an impact on clinical/risk management
Dr. Prabhash Bhavsar
 Cardiac biomarkers were first developed for
assisting the cardiac events, especially acute
myocardial infarction.

Better understanding of cardiac disease process

and advancement in detection technology has
pushed the application of cardiac biomarkers
beyond the diagnosis boundaries.

Cardiac biomarkers are now used for staging of

cardiac disease, timing of cardiac events and
prognostification.

Dr. Prabhash Bhavsar

Dr. Prabhash Bhavsar
 Cardiac
Troponin

Dr. Prabhash Bhavsar

 Troponin is a complex of three regulatory
proteins (Troponin C, Troponin I and Troponin T)
that is associated with muscle contraction in
skeletal and cardiac muscle.
Cardiac troponin is slightly different from
skeletal troponin structurally hence serve as a
potent and specific marker for cardiac disease.

Dr. Prabhash Bhavsar

Dr. Prabhash Bhavsar
 Individual subunits serve different functions:
Troponin C binds to calcium ions to produce a
conformational change in TnI
Troponin T binds to tropomyosin, interlocking
them to form a troponin-tropomyosin complex
Troponin I binds to actin in thin myofilaments to
hold the troponin-tropomyosin complex in place

Normal value : cTnT : .01ng/ml

cTnI : .04ng/ml

Usually, Troponin is not detectable in healthy

individual.

Dr. Prabhash Bhavsar

 It is extremely useful in patients who do not seek
attention in the 2 to 3 days window when CK-MB is
elevated.
Rise : with in few hours after onset of chest pain
Peak : 2 days
returns normal : 7-10 days

cTnT may show a biphasic release in some patients

with a first peak occurring during first 24 hr of
onset of symptom and second peak on appx. 4th day
after admission.

TnT has cardiac as well as skeletal muscle source.

Dr. Prabhash Bhavsar

 It is cardiac specific because it has additional
amino acid residue on its N-terminal that are non
existent in skeletal muscle.
Rise : b/w 4-6 hr after onset of pain
Peaks : 12-18 hrs
Returns normal : 6 days

Its measurement is advantageous over CK-MB as

it is not found in detectable amount in serum of
patients with multiple injuries, renal disease and
in those with acute and chronic skeletal muscle
disorders.

Dr. Prabhash Bhavsar

arrhythmia congestive heart failure

coronary artery disease coronary vasospasm

Critically ill hypertension

myocarditis pericarditis

Pulmonary embolism severe pulmonary hypertension

Renal failure septic shock

sepsis related myocardial SIRS

dysfunction
trauma
Dr. Prabhash Bhavsar
 Cardiac myosin light chain :

initially they were thought to be unique

myocardial protein but now it is known that it
does not offer any added advantage over CK-
MB & cTn estimation. So, it is of limited
significance as a biomarker.

Dr. Prabhash Bhavsar

 Creatine kinase (CK) is a cytosolic enzyme involved
with the transfer of energy in muscle metabolism.
It catalyses the conversion of creatine to phospho-
creatine degrading ATP to ADP.

CK is a dimer composed of two subunits B (brain

type) and M (muscle type), resulting in three
isoenzyme:
CK-BB (CK1) : is of brain origin, found in blood only
when BBB is damaged.
CK-MB (CK2) : it is relatively specific for myocardial
origin
CK-MM (CK3) : it is found primarily in skeletal muscle

Dr. Prabhash Bhavsar

 CK-MB :

it is a valuable tool for the diagnosis of MI

because of its relative high specificity for
myocardial damage.

Rise : 4-6 hrs after onset of symptoms

Peak : 12 hrs
Return to normal : 24-36 hrs

Can be used to indicate early re-infarction if

level normalizes and then increases again.

Dr. Prabhash Bhavsar

 CK-MB now measured via a highly sensitive monoclonal antibody
assay

Immunological Sandwich technique using two Abs for different

epitopes of CK MB molecule

The first Ab is rendered immobile on a matrix (e.g. CrO2

particles)

The second Ab conjugate to an enzyme (- galacto- sidase)

Separated bound sandwiches are reacted with their substrate

(e.g. Chlorophenol - Red Galactopyranoside)

Liberated end product chlorophenol is measured

spectrophotometrically and is proportionate to CK-MB amount
(not the activity)
 False positive (for MI) CK-MB elevation can be seen in:
Significant skeletal muscle injury
The MB fraction is determined to be expressed during the
process of muscle regeneration
Cardiac injury for reason other than MI
Defibrillation
Blunt chest trauma
Cocaine abuse

The search for cardiac specificity continues

 Small-size heme protein found in all tissues mainly assists in
oxygen transport

It is released from all damaged tissues

Increases often occur more rapidly than TI and CK

Released from damaged tissue within 1 hour

Normal value: 17.4-105.7 ng/ml

Timing:
Earliest Rise: 1-3 hrs
Peak 6-9 hrs
Return to normal: 12 hrs
 Acute myocardial infarction

Skeletal muscle damage, muscular dystrophy,

inflammatory myopathies

Renal failure, severe uremia

Shock and trauma

 Rapid monitor of success of thrombolytic therapy

Negative predictor of MI

DRAWBACKS

Due to poor specificity, myoglobin levels do not

always predict myocardial injury

Not utilized often for AMI/cardiac damage

assessment because of its very rapid metabolism
 Troponin is a complex of three regulatory proteins that is
integral to non-smooth muscle contraction in skeletal as well as
cardiac muscle

Troponin is attached to the tropomyosin sitting in the groove

between actin filaments in muscle tissue

Troponin has three subunits, TnC, TnT, and TnI

Troponin-C has calcium binding ability and has no diagnostic
value
Troponin-T binds the troponin tropomyosin complex,
Troponin-I is an inhibitory protein
1. Cardiac Troponin I (cTnl) is a cardiac muscle protein with a
molecular weight of 24 kilo-Daltons.

2. The cTnl has a additional amino acid residues on its N-

terminal that are not exist on the skeletal form.

3. The half life = 2~4 hours.

4. Serum increase = 2-8 hours

1. Cardiac Troponin T (cTnT) is present in fetal skeletal
muscle.

2. In healthy adult skeletal muscle cTnT is absent.

3. The gene of cTnT may be re-expressed in skeletal muscle

disease. (Clin Chem. 1999;45:2129-2135)

4. Biological half life and early serum increases of cTnT are

similar to that of cTnI.
 Less than 5% in cytosol

Troponin levels begin to rise 2-3 hours after onset of

myocardial injury

Elevations in Troponin-I and Troponin-T can persist for up

to 10 days after MI

Remember, CK-MB returns to baseline by 48 hours

Thus far, studies have failed to find a source of Troponin-

I outside the heart, but have found some Troponin-T in
skeletal muscle
 Less than 5% in cytosol

Troponin levels begin to rise 2-3 hours after onset of

myocardial injury

Elevations in Troponin-I and Troponin-T can persist for up

to 10 days after MI

Remember, CK-MB returns to baseline by 48 hours

Thus far, studies have failed to find a source of Troponin-

I outside the heart, but have found some Troponin-T in
skeletal muscle
 Less than 5% in cytosol

Troponin levels begin to rise 2-3 hours after onset of

myocardial injury

Elevations in Troponin-I and Troponin-T can persist for up

to 10 days after MI

Remember, CK-MB returns to baseline by 48 hours

Thus far, studies have failed to find a source of Troponin-

I outside the heart, but have found some Troponin-T in
skeletal muscle
 CK-MB
Relative Index = 100
Total CK

*The relative index allows the distinction

between increased total CK due to myocardial
damage and that due to skeletal or neural
damage.

*A relative index exceeding 3 is indicative of

AMI

Dr. Prabhash Bhavsar

 Small-size heme protein found in all tissues mainly
assists in oxygen transport

It is released from all damaged tissues

Its level rises more rapidly than cTn and CK-MB.

Released from damaged tissue within 1 hour

Normal value: 17.4-105.7 ng/ml

Timing:
Earliest Rise: 1-4 hrs
Peak 6-9 hrs
Return to normal: 12 hrs

Dr. Prabhash Bhavsar

 CONDITIONS FOR MYOGLOBIN INCREASE :

Acute myocardial infarction

Skeletal muscle damage, muscular dystrophy,

inflammatory myopathies

Renal failure, severe uremia

Shock and trauma

Dr. Prabhash Bhavsar

 Clinical usefulness of myoglobin :
*if myoglobin concentration remains within the
reference range 8 hours after the onset of
chest pain, AMI can be ruled out essentially.
*because of its rapid clearance by the kidney, a
persistently normal Mb concentration will rule
out reinfarction in patient with recurrent chest
pain after AMI
*Rapid monitor of success of thrombolytic
therapy

DRAWBACKS
Due to poor specificity, myoglobin levels do
not always predict myocardial injury

Dr. Prabhash Bhavsar

 7
upper limit of reference interval

5
myoglobin
4
CK-MB
3
cTnT
2 cTnI

0
0 4 8 12 16 20 24 28 32 36 40 44 48
Time after onset of AMI (hours)

Dr. Prabhash Bhavsar

Dr. Prabhash Bhavsar
HEART FAILURE
Heart failure a major and growing health problem
appears to result not only from cardiac overload or
injury but also from complex interplay among genetic,
inflammatory and biological changes acting on cardiac
myocytes, the cardiac interstitium or both.

ACUTE MYOCARDIAL INFARCTION

A sudden occlusion of a coronary artey by
thrombus or by embolisation causes an acute
myocardial infarction.
 Cardiac biomarkers are protein molecules released
into the blood stream from damaged heart muscle

Since ECG inconclusive .biomarkers !!!!!?????

myocardial injury

These biomarkers have a characteristic rise and fall

pattern