Cardiac Biomarkers

CARDIAC BIOMARKERS
Dr. Prabhash Bhavsar

An indicator used for objective
measurement and evaluation of

Response to
therapeutic
intervention

Normal biological
process
Pathogenic process


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Standardized

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High Sensitivity and Specificity

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Accurate

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Reproducible

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Easy to interpret

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Acceptable to patient

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Consistent and Cost effective

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Has an impact on clinical/risk management

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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.


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CRP is Pentameric structure consisting of five
identical subunits of 23-kDa.
Its plasma levels can increase rapidly to 10,000x
levels.
It is the most extensively studied marker of
inflammation.
Despite
some
controversy
regarding its clinical use, it appears to be the
most promising to date.
Although considered to be a general nonspecific
marker of inflammation, elevated baseline levels
of hsCRP are correlated with higher risk of future
CV morbidity and mortality among those with or
without clinical evidence of CVD.

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Once ligand-bound, CRP can:

Activate the classical compliment pathway
Stimulate phagocytosis
Bind to immunoglobulin receptors
Endothelial dysfunction via ↑ NO synthesis
↑LDL deposition in plaque by CRP-stimulated macrophages


Clinical Uses
◦ Screening for cardiovascular risk in otherwise “healthy”
individuals
◦ Predictive value of CRP levels for disease severity in preexisting Coronary artery disease

Elevated levels are predictive of
• Long-term risk of first MI
• Ischemic stroke


Limitations of CRP


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Low specificity
No evidence that lowering CRP levels decreases CV risk
Industry and FDA staff guidelines 2005 had given clinical cut off
value as less than 1 mg/l as safe levels with hs-CRP tests

CRP

Less than 1.0 mg/L
1.0-2.9 mg/L
Greater than 3.0 mg/L

Risk for CVD

Low
Intermediate
High


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Soluble fragment CD 40 ligand.



It is a signalling protein that reflects both inflammatory and
platelate interaction.



↑ levels of sCD40L is associated with ↑ risk of cardiac events

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However rise is also associated with many other inflammatory
conditions like RA, SCD, SLE etc.

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Furthermore, preanalytical procedure such as anticoagulant
quantity,

temperature,

time

and

centrifugation

speed

significantly affect the final result, which proves to be potential
barrier to practical application of test.

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Intermediary amino acid formed by the conversion of methionine to
cysteine

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Moderate hyperhomocysteinemia occurs in 5-7% of the population

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Recognized as an independent risk factor for the development of
atherosclerotic vascular disease and venous thrombosis

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Can result from genetic defects, drugs, vitamin deficiencies


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Homocysteine is implicated directly in vascular injury including:
◦ Intimal thickening
◦ Disruption of elastic lamina
◦ Smooth muscle hypertrophy

◦ Platelet aggregation

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Proposed mechanisms by which it induces vascular injury are
leukocyte recruitment, foam cell formation, and inhibition of NO
synthesis.

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Normal levels : < 6micro mol/l


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Elevated levels of homocystein appear to be an

independent risk factor, though less important than
the classic CV risk factors.

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Treatment includes supplementation with folate,
B6 and B12.


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Its high relative stability in plasma, have led to its potential
use in the clinical setting.

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Elevated level of PAPP-A are found in patients presenting with
unstable plaques, aggravated unstable angina and acute MI.

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It is also a reliable predictor of mortality in patients with

chronic stable CAD.
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FREE PAPP-A >1.74 mIU/L is considered abnormal

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Currently there is no standardised assay in widespread

clinical use.


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Lp-PLA₂ is also known as platelate activating
factor acetyl hydrolase.
This phospholipase enzyme is encoded by
PLA2G7 gene.
It is a 45 kDa protein of 441 amino acids.
Lp-PLA₂

PAF

LYSO-PAF + acetate


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In the blood it mainly travels with LDL. Less than 20% is
associated with HDL.
It is produced by inflammatory cells and hydrolyzes oxidised
phospholipids in LDL
Two main sources of Lp-PLA₂ are :
1. which is brought from circulation into the intima bound to LDL
2. which is synthesised de novo by plaque inflammatory cells.

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Lp-PLA₂ is involved in the development of atherosclerosis and It
is positively correlated with increased risk of developing coronary
artery disease.
Its level in blood is measured by PLAC test, an assay which uses
sandwich ELISA.
Average value
for females is 174 ng/mL
for males is 251 ng/ml

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Ischemia modified albumin is a marker formed
after damage in the N terminal region of the
albumin in ischemic conditions.
This structural change leads to loss of its ability
to bind with transitional metals (cu/co).
Endothelial or extracellular hypoxia, acidosis and
free oxygen radicals causes increase in IMA.
IMA rises within minutes from onset of ischemia
and remains elevated for several hours after
cessation of ischemia.

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Clinical uses of IMA :
it is used as diagnostic criteria for myocardial
necrosis that develops after CABG operation.
It is a non specific marker, since it is also
reported to be elevated in pulmonary
infarction, critical limb ischemia and
cerebrovascular disorders.
Basically, it is used to rule out ischemia rather
than diagnosing the occurrence of ischemia.
Which is helpful in differentiating pain of
Angina from Myocardial ischemia.

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Heart type fatty acid binding protein is a very
stable low molecular weight (14-15kDa) in the
cytoplasm of myocardial cells.
FABPs are involved in active fatty acid
metabolism where it transports fatty acid from
cell membrane to mitochondria for oxidation.
Small size of H-FABP facilitates rapid diffusion
through interstitial space, appearing as early as
1-3 hrs after onset and peaking within 6hrs. It
return to normal levels with in 12-24hrs.
Normal levels : 1.6 – 19 ng/ml

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H-FABP is 20 times more specific to cardiac
muscle than myoglobin
H-FABP is recommended to be measured with
troponin to identify MI and ACS in patient
presenting with chest pain.
In addition to its diagnostic potential H-FABP
also has prognostic value. The risk associated
with ↑ H-FABP is dependent upon its
concentration. Patients who were cTnI- but
H-FABP+ have more risk of morbidity and
mortality after 1 year follow up than those
with cTnI+HFABP-.

Cardiac
Troponin




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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.


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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

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Usually, Troponin is not detectable in healthy
individual.


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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

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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.



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

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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.


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
dysfunction

SIRS

trauma

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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 CKMB & cTn estimation. So, it is of limited
significance as a biomarker.


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


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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

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Can be used to indicate early re-infarction if
level normalizes and then increases again.


Relative Index =

CK-MB
Total CK

χ 100

*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


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

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It is released from all damaged tissues

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

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Released from damaged tissue within 1 hour

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Normal value:

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Timing:
◦ Earliest Rise:
◦ Peak
◦ Return to normal:

17.4-105.7 ng/ml

1-4 hrs
6-9 hrs
12 hrs

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CONDITIONS FOR MYOGLOBIN INCREASE :

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Acute myocardial infarction

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Skeletal muscle damage, muscular dystrophy,
inflammatory myopathies

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Renal failure, severe uremia

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Shock and trauma


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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


Χ upper limit of reference interval

7
6
5

myoglobin

4

CK-MB

3

cTnT

2

cTnI

1

0
0

4

8

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

The natriuretic peptides (NP) are a group of structurally similar but
genetically distinct peptide hormone.

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It includes :

ANP : -atrial natriuretic peptide (28 a.a.)
N-terminal proANP (98 a.a.)
BNP : brain natriuretic peptide (32 a.a.)
N-terminal proBNP (76 a.a.)
CNP : C-type natriuretic peptide (22 and 53 a.a.)
DNP : D- type natriuretic peptide
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The NPs play important role in regulation of salt and water
balance (CV homeostasis)


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ANP is released primarily in response to atrial wall
stretching and intravascular volume expansion.

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BNP is mainly secreted by the ventricles

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CNP is found predominantly in the brain and also
synthesized by vascular endothelial cells


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Circulating levels of BNP are raised in patients
with cardiovascular or renal disease

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BNP is More important than ANP in heart failure

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Greatest proportion of circulating BNP is thought
to come from the ventricles (left)


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Synthesis in myocyte :


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BNP and the terminal fragment of its prohormone
(NT-proBNP) are released on ventricular stretch or
stress to the myocyte in the absence of the necrosis.

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Therefore, BNP is increased in diseases characterised
by an expanded fluid volume (e.g. CHF,renal
failure,hepatic cirrhosis etc.)

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BNP has circulating T₁/₂ of 20 minutes, so it is
indicative of snapshot of myocardial function, while
NT-proBNP has T₁/₂ of 90 minutes giving a longer
view of myocyte .

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BNP <20pmol/L unlikely to have CHF
>20pmol/L high probability of CHF

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miRNAs are appx. 20-25 nucleotide long non coding
RNAs, that negatively regulate or inhibit gene
expression by binding to sites in the untranslated
regions of targeted messenger RNAs.


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miRNA are found to be involved in almost
every biological process, from cellular
differentiation and proliferation to cell death
and apoptosis
Many different types of miRNA can be
detected in circulating blood and these
miRNA are present in remarkably stable form
that even withstand repetitive
freezing/thawing cycle and are protected
against Rnases.
Thousands of miRNAs have been described in
human to date which ehibits tissue specific
pattern of expression.

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miRNAs that regulates cardiovascular system can
be divided into 4 groups :

1. miRNA regulating endothelium function and
angiogenesis : miR126, miR17-92
cluster, miR130a, miR221, miR21
2. cardiac myocyte specific mRNA : miR208a
3. cardiac myocyte and skeletal muscle miRNA :
miR1, miR133a, miR499
4. smooth muscle miRNAs :miR143, miR145
miRNAs hold promise as very specific and
accurate marker of cardiac dysfunction.


Cardiac Biomarkers

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Notes de l'éditeur