Cardiac BioMarkers

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CARDIAC BIOMARKERS M.Prasad
NaiduMSc Medical Biochemistry, Ph.D,.
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CORONARY VASCULAR DISEASE (CVD) IS THE WORLDS
LEADING CAUSE OF MORTALITY, ACCOUNTING FOR
NEARLY HALF OF ALL DEATHS IN THEWESTERN
WORLD. BIOCHEMICAL MARKERS OF CARDIAC INJURY
PLAY AN ESSENTIAL ROLE IN THE DIAGNOSIS,
PROGNOSIS, MONITORING, RISK STRATIFICATION OF
SUSPECTED HEART ATTACK PATIENTS, HAVE BECOME
A CENTRAL PART OF THERAPEUTIC INTERVENTIONAL
GUIDELINES FOR CLINICIANS. MORE RECENTLY
POINT-OF-CARE TESTING (POCT) FOR CARDIAC MARKERS
HAS BEEN DRIVEN BY THE TIME-CRITICAL CLINICAL
NEED FOR IMMEDIATE CARDIAC MARKER TASTING, TO
PROVIDE TIMELY PATIENT RISK STRATIFICATION,
EXPEDITE APPROPRIATE TREATMENT, IMPROVE
OUTCOMES.
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ACUTE CORONARY SYNDROMES(ACS) THE VAST ARRAY OF
CLINICAL SYMPTOMS EVIDENT AFTER CORONARY PLAQUE
DISRUPTION ARE OFTEN CUMULATIVELY REFERRED TO AS
ACS. INITIALLY, RUPTURE OF UNSTABLE CORONARY
PLAQUES RESULTS IN INTRA CORONARY THROMBOSIS,
WHERE THE THROMBUS (BLOOD CLOT) LEADS TO A
REDUCTION IN BLOOD FLOW (CARDIAC ISCHEMIA),
THEREBY RESTRICTING THE SUPPLY OF OXYGEN TO THE
MYOCARDIUM. THE CONTINUUM OF THIS MYOCARDIAL
ISCHEMIA IS ACS WHICH RANGES FROM UNSTABLE
ANGINA (ASSOCIATED WITH REVERSIBLE MYOCARDIAL
INJURY ) TO MYOCARDIAL ISCHEMIA WITH LARGE
AREAS OF IRREVERSIBLE DAMAGE (CARDIAC NECROSIS
).
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CARDIAC BIOMARKERS DEFINED AS BIOLOGICAL
ANALYTES THAT ARE DETECTABLE IN THE BLOOD STREAM
AT ELEVATED LEVELS DURING THE CONTINUM OF CVD OR
IN THE IMMEDIATE AFTERMATH OF MYOCARDIAL
DAMAGE. IDEAL CARDIAC BIOMARKERS SHOULD BE
HIGHLY SPECIFIC FOR CARDIAC TISSUE ABSENT FROM
NON MYOCARDIAL TISSUE NEED TO BE AESILY
ACCESSIBLE TO ACHIEVE HIGH DIAGNOSTIC
SENSITIVITY. HENCE, SMALLER SOLUBLE MOLECULES
WITH FASTER RELEASE KINETICS RAPID CLEARANCE
FROM INJURED TISSUE ARE REGARDED AS THE MOST
SUITABLE BIOMARKERS FOR EARLY DIAGNOSIS.
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HOWEVER, IN THE CASE OF LATE DIAGNOSIS, A
HIGHLY STABLE BIOMARKER WITH A LONG PLASMA HALF
LIFE IS eSSENTIAL. CONSEQUENTLY , PEAK LEVELS
SHOULD BE REACHED RELATIVELY QUICKELY PERSIST
IN CIRCULATION FOR A FEW HOURS, AS IN THE CASE
WITH THE CARDIC TROPONIN I T. A RAPID
CLEARENCE OF THE BIOMARKER FROM PLASMA IS A
CRUCIAL FEATURE OF BIOMARKERS OF RECURRENT
INJURY. IT SHOULD ALSO HAVE The ABILITY TO
DIFFERENTIATE BETWEEN REVERSIBLE (ISCHEMIA)
IRREVERSIBLE (NECROSIS) DAMAGE. CRUCIALLY,
IT MUST HAVE THE ABILITY TO INFLUENCE THERAPY.
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MYOCARDIAL NECROSIS MARKERS (clinical signs
symptoms, ecg) 1.MYOGLOBIN 2.CK-MB 3.CK-NAC
4.CARDIAC TROPONIN T 5.CARDIAC TROPONIN I
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MYOGLOBIN ( 30-700 ng / ml ) POINT OF CARE TEST
AVAILABLE MOLECULAR WEIGHT 18,000 ADVANTAGE
HIGH SENSITIVITY , NPV USEFUL FOR EARLY
DETECTION OF MI REPERFUSION. DISADVANTAGE
LOW SPECIFICITY IN PRESENCE OF SKELETAL MUSCLE
INJURY WITH RENAL INSUFFICIANCY. RAPID
CLEARANCE AFTER NECROSIS. DURATION OF
ELEVATION 12-24 hours sensitivity90,
specificity86 negative predictive
value96
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ck-mb (2-500 ng / ml) point of care test
available mol.wt85,000 cardiac
specific advantage ability to detect
reinfarction, large clinical experience,previous"
gold standard"for myocardial necrosis. Disadvan
tagelowered specificity in skeletal muscle
injury. Duration of elevation 24-36
hours diagnostic performancetwo serial values
above 99th percentile of control referance
population in the setting of ischemia
is benchmark for myocardial necrosis.
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ck-nac( lt 200 iu / ml ) cardiac
specific measures ck-m isoform, specificity
more than ck-mb. Gold standerd test for
myocardial necrosis point of care test not
available.
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cardiac troponin t point of care test
available mol.wt37,000 cardiac
specific advantagetool for risk
stratification, detection of mi upto 2
weeks, highly specific for cardiac tissue "gold
standerd" disadvantagenot an early marker of
myocardial necrosis, limited ability to detect
re- Infarction. Duration of elevation10-14
days assay range o.i 2 ng / ml
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cardiac troponin I point of care test
available mol.wt23,500 cardiac
specific advantagetool for risk
stratification, detection of mi upto 7
days, highly specific for cardiac
tissue. Disadvantage not an early marker of
myocardial necrosis, no analytical referance
standerd, limited ability to detect
re-infarction. Duration of elevation 4 7
days. Assay range o.o2 50 ng / ml
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markers of heart failure (echocardiogram-gold
standerd) 1.atrial natriuretic
peptide(anp) 2.b-type (brain) natriuretic
peptide (bnp) 3.n-terminal pro-b-type
natriuretic peptide (nt-pro-bnp)
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b-type natriuretic peptide 32 aa
polypeptide functions as a cardiac hormone
secreted from the cardiac ventricles as an
"emergency" measure against ventricular
overload pressure volume expansion. bnp
100 300 pg / ml nt-pro-bnp 900 2000 pg /
ml most heart failure specialists agree with
the use of plasma bnp or nt-pro-bnp testing to
confirm the diagnosis of hf in patients
presenting with signs symptoms that are
either ambiguous or confounding with certain
disease states (copd).
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biomarkers of inflammation 1.c-reactive
protein 2.myeloperoxidase upto half of the
events associated with cvd occur in asymptomatic
individuals. Inflammatory process play a
prominent role in development of both the
intermediate mature ateromatous plaque also
contribute to the destabilization of vulnerable
plaque resulting in acute coronary syndrome (
acs ) .
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c-reactive protein hs-crp assay range
-30-50,000 ng / ml CRP IS AN ACUTE PHASE
REACTANT, PRODUCED IN THE LIVER IN RESPONSE TO
INTERLEUKIN-6 (IL-6). IT IS HIGHLY STABLE
PENTAMERIC PROTEIN ITS SERUM CONCENTRATION CAN
INCREASE 10,000 FOLD DURING ACCUTE PHASE
RESPONSE. A STUDY OBSERVED THE LOSS OF THE
PENTAMERIC SYMMETRY OF CRP RESULTING IN A
MODIFIED OR MONOMERIC (m-crp) form,which may be
the major isoform promoting the proinflammatory
response in coronary arteries. INVESTIGATIVE
DATA SUGGESTS THAT CRP MAY EVEN PLAY AN ACTIVE
ROLE IN ATHEROGENESIS.
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in january 2003 both the centres for disease
control prevention (cdc) the american heart
association (aha) recommended crp as the
inflammatory biomarker of choice for assessment
of cardiovascular risk. The high sensitivity
crp assay (hs-crp) was originally developed to
aid evaluation of conditions associated with
inflammation in otheerwise healthy
individuals. Several large scale
epidemiological studies examining apparantly
healthy populations have found crp eo be a
strong independent predictor of future
cardiovascular events, including mi, ischemic
stroke, peripheral vascular disease sudden
cardiac death.
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furthermore, hs-crp has been found to have
prognostic value among patients without myocyte
necrosis, notably even among patients with
normal levels of ctn-t . As of yet, there is
insufficient evidence to substantiate the
ability of hs-crp to identify acs patients who
will benefit from a perticular treatment. This
is further compounded by estimates that more
than 30 of patients with severe unstable angina
do not present with elevated hs-crp levels.
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1.SOLUBLE CD 40 LIGAND 2.PLACENTAL GROWTH
FACTOR 3.PREGNANCY ASSOCIATED PLASMA PROTEIN A

• PLAQUE RUPTURE

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CD 40 LIGAND RAPIDLY UPREGULATED IN FRESH
THROMBUS gt95 OF CIRCULATING CD40L DERIVED
FROM PLATELETS ASSOCIATED WITH INCREASED RISK
OF CARDIOVASCULAR EVENTS IN APPARENTLY HEALTHY
WOMEN CHRONIC ELEVATIONS POSSIBLE DUE TO
SHEDDING INTO PLASMA FROM UNSTABLE
ATHEROSCLEROTIC PLAQUE REDUCED LEVELS FROM
STATINS,GLITAZONES,CLOPIDOGREL

• SOLUBLE CD 40 LIGAND

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PLGF STIMULATES ANGIOGENESIS ACTIVATES VASCULAR
ENDOTHELIAL GROWTH FACTOR ( VEGF) ANGIOGENESIS
IMPROVES CIRCULATION VEGF PLAYS ESSENTIAL ROE
IN BOTH PHYSIOLOGIC PATHOLOGIC
ANGIOGENESIS PLGF RESTRICTED TO PATHOLOGIC
CONDITIONS -KEY ROLE IN ATHEROMA
EXPANSION -UPREGULATED IN ASCHEMIC
MYOCARDIUM

• PLACENTAL GROWTH FACTOR

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PLGF-POWERFUL INDEPENDENT PREDICTOR OF
ADVERSE CARDIAC EVENTS IN BOTH HIGH RISK ACS
IN UNDIFFERENTIATED ED POPULATION DOWNSIDE
gt5 OF PATIENTS WITH NEGATIVE PLGF EXPERIENCE A
CARDIAC EVENT WITHIN 30 DAYS CTnT MORE POWERFUL
INDEPENDENT PREDICTOR
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PREGNANCY ASSOCIATED PLASMA PROTEIN A ZINC
BINDING MATRIX METALLOPROTEINASE
(MMP) ABUNDANTLY EXPRESSED IN ERODED RUPTURED
PLAQUES, LOWER IN STABLE PLAQUES INCREASED
CIRCULATING LEVELS IN HYPERCHOLESTEROLEMIA
CORONARY ATHEROSCLEROSIS,EVEN IN ASYMPTOMATIC
PATIENTS MAY SERVE AS MARKER FOR TOTAL LIPID
BURDEN7

• PAPP-A

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1.FREE FATTY ACIDS unbound to albumin
(ffaU) 2.WHOLE BLOOD CHOLINE PLASMA
CHOLINE 3.ISCHEMIA-MODIFIED ALBUMIN (ima)

• PRE-NECROSIS ISCHEMIA

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BOTH INCREASE RAPIDLY AFTER STIMULATION OF
PHOSPHOLIPASE D IN PLAQUE DESTABILIZATION /
TISSUE ISCHEMIA PLD KEY IN DESTABILIZING
PLAQUE CHOLINE RELEASED INTO PLASMA THEN TAKEN
UP BY RBCs ACUTE MYOCARDIAL INFARCTION SENSI
TIVITY 40.5 SPECIFICITY 78.7 FOR UNSTABLE
ANGIINA SENSITYVITY 86.4 SPECIFICITY 86.2

• WBCHO PLCHO

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ALBUMINS CAPACITY TO BIND WITH COBALT IS
REDUCED DURING ISCHEMIA IMA RISES WITHIN
MINUTES OF ISCHEMIA, STAYS UP FOR 6 TO 12 HOURS,
NORMAL WITIN 24 HOURS. BUT ALSO FOUND IN
PATIENTS WIT SOME CANCERS LIVER
DISEASE END-STAGE RENAL DISEASE BRAIN
ISCHEMIA LEVELS INHIBITED BY ENDOGENOUS LACTATE
PRODUCTION?LIMITS USEFULNESS IN
DKA,SEPSIS,RENAL FAILURE,OTHER CAUSES OF
INCREASED LACTIC ACID.

• ISCHEMIA- MODIFIED ALBUMIN

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IN STUDY WITH 63 PREVALENCE
ACS SENSITIVITY80 PPV72 SPECIFICITY45 NP
V59 IMA, ECG, cTnT COMBINED IDENTIFIED 95
OF ISCHEMIC HEART DISEASE?TRIPLE TEST.
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D-dimer is a fibrin degradation product (or
FDP), a small protein fragment present in the
blood after a blood clot is degraded by
fibrinolysis. It is so named because it contains
two crosslinked D fragments of the fibrinogen
protein. D-dimer concentration may be
determined by a blood test to help diagnose
thrombosis. Since its introduction in the
1990s, it has become an important test performed
in patients suspected of thrombotic disorders.
While a negative result practically rules out
thrombosis, a positive result can indicate
thrombosis but does not rule out other potential
causes. Its main use, therefore, is to exclude
thromboembolic disease where the probability is
low. In addition, it is used in the diagnosis of
the blood disorder disseminated intravascular
coagulation
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BIOMARKERS NOT NEEDED
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BIOMARKERs MENU Myocyte injury, Inflammation,
Neurohumeral,Plaque markers CPK-MB, CK-NAC,
Myoglobin cTn-T, cTn-I, bnp,
NT-pro-BNPIschemia Mod Albuminhs-CRPD-DIMER

• HomocysteineOX LDL,Lp(a),
• Soluble CD40 Ligand
• Myeloperoxidase(s) MPO
• Matrix Metalloproteinase
• Heart - Fatty Acid Binding
• Protien (H-FABP)
• Pregnancy Assoc Plasma
• Protein A (PAPP-A)

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DEFINITION POINT OF CARE TESTING (POCT) IS
LABORATORY TESTING CONDUCTED CLOSE TO THE SITE
OF PATIENT CARE. POINT OF CARE TESTING IS ALSO
COMMONLY DESCRIBED AS BED-SIDE,NEAR
PATIENT,SATELLITE,REMOTE DECENTRALIZED
TESTING.

• POINT-OF-CARE TESTING

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ADVANTAGES 1.PORTABLE / TURNAROUND TIME /
LENGTH OF STAY 2.RAPID RESULT / PATIENT
SATISFACTION 3.SMALL SAMPLE VOLUME / PAIN
SUFFERING 4.UNPROCESSED SAMPLES 5.EASE OF USE
/ NUMBER OF TESTS 6.RETURN TO WORK
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DISADVANTAGES 1.QUALITY OF RESULT /
LABORATORIES NOT FOLLOWING MANUFACTURER'S
INSTRUCTIONS 2.CLINICALLY FOCUSSED
OPERATORS 3.INAPPROPRIATE OVER-UTILIZATION 4
.REGULATORY COMPLIANCE / POOR STORAGE OF
REAGENTS / POOR RECORD KEEPING /
COST 6.FAILURE TO IDENTIFY INCORRECT
RESULTS 7.UNTRAINED STAFF / LACK OF QUALITY
CONTROLS 8.TESTING OUTSIDE OF THE LABORATORY
CERTIFICATE LEVEL
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