Cardiac biomarkers

CARDIAC BIOMARKERS

M.PRASAD NAIDUMSC MEDICAL BIOCHEMISTRY, PH.D,.

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.

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 ).

CARDIAC BIOMARKERSDEFINED 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.

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.

MYOCARDIAL NECROSIS MARKERS(CLINICAL SIGNS & SYMPTOMS, ECG)

1.MYOGLOBIN

2.CK-MB

3.CK-NAC

4.CARDIAC TROPONIN T

5.CARDIAC TROPONIN I

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

SENSITIVITY;90%, SPECIFICITY;86%

NEGATIVE PREDICTIVE VALUE;96%

CK-MB (2-500 NG / ML)POINT OF CARE TEST AVAILABLEMOL.WT;85,000CARDIAC SPECIFICADVANTAGE:ABILITY TO DETECT REINFARCTION, LARGE CLINICAL EXPERIENCE,PREVIOUS"GOLD STANDARD"FOR

MYOCARDIAL NECROSIS.

DISADVANTAGE;LOWERED SPECIFICITY IN SKELETAL MUSCLE INJURY.DURATION OF ELEVATION 24-36 HOURS

DIAGNOSTIC PERFORMANCE;TWO SERIAL VALUES ABOVE 99TH PERCENTILE OF CONTROL REFERANCE POPULATION IN THE SETTING OF ISCHEMIA IS

BENCHMARK FOR MYOCARDIAL NECROSIS.

CK-NAC( < 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.

CARDIAC TROPONIN TPOINT OF CARE TEST AVAILABLEMOL.WT;37,000

CARDIAC SPECIFIC

ADVANTAGE;TOOL FOR RISK STRATIFICATION,DETECTION OF MI UPTO 2 WEEKS,HIGHLY SPECIFIC FOR CARDIAC TISSUE"GOLD STANDERD"

DISADVANTAGE;NOT AN EARLY MARKER OF MYOCARDIAL NECROSIS, LIMITED ABILITY TO DETECT RE- INFARCTION.

DURATION OF ELEVATION;10-14 DAYSASSAY RANGE : O.I – 2 NG / ML

CARDIAC TROPONIN – IPOINT OF CARE TEST AVAILABLEMOL.WT;23,500CARDIAC SPECIFIC

ADVANTAGE;TOOL 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

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)

B-TYPE NATRIURETIC PEPTIDE

32 AA POLYPEPTIDEFUNCTIONS AS A CARDIAC HORMONE SECRETED FROM THE CARDIAC VENTRICLES AS AN

"EMERGENCY" MEASURE AGAINST VENTRICULAR OVERLOAD & PRESSURE VOLUME EXPANSION.

BNP : 100 – 300 PG / MLNT-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).

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 ) .

C-REACTIVE PROTEINHS-CRP : ASSAY RANGE -30-50,000 NG / MLCRP 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.

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.

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.

1.SOLUBLE CD 40 LIGAND

2.PLACENTAL GROWTH FACTOR

3.PREGNANCY ASSOCIATED PLASMA PROTEIN A

PLAQUE RUPTURE

CD 40 LIGAND RAPIDLY UPREGULATED IN FRESH THROMBUS

>95% 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

PLGF STIMULATES ANGIOGENESIS ACTIVATES VASCULAR ENDOTHELIAL GROWTH FACTOR ( VEGF)

ANGIOGENESIS IMPROVES CIRCULATION

VEGF PLAYS ESSENTIAL RO;E IN BOTH PHYSIOLOGIC & PATHOLOGIC ANGIOGENESIS

PLGF RESTRICTED TO PATHOLOGIC CONDITIONS

-KEY ROLE IN ATHEROMA EXPANSION

-UPREGULATED IN ASCHEMIC MYOCARDIUM

PLACENTAL GROWTH FACTOR

PLGF-POWERFUL INDEPENDENT PREDICTOR OF ADVERSE CARDIAC EVENTS IN BOTH HIGH RISK ACS & IN UNDIFFERENTIATED ED POPULATION

DOWNSIDE: >5% OF PATIENTS WITH NEGATIVE PLGF EXPERIENCE A CARDIAC EVENT WITHIN 30 DAYS

CTNT MORE POWERFUL INDEPENDENT PREDICTOR

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 BURDEN

7

PAPP-A

1.FREE FATTY ACIDS UNBOUND TO ALBUMIN (FFAU)

2.WHOLE BLOOD CHOLINE & PLASMA CHOLINE

3.ISCHEMIA-MODIFIED ALBUMIN (IMA)

PRE-NECROSIS ISCHEMIA

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:SENSITIVITY 40.5%SPECIFICITY 78.7%

FOR UNSTABLE ANGIINA:SENSITYVITY 86.4%SPECIFICITY 86.2%

WBCHO & PLCHO

ALBUMIN’S 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 PRODUCTIONLIMITS USEFULNESS IN DKA,SEPSIS,RENAL FAILURE,OTHER CAUSES OF INCREASED LACTIC ACID.

ISCHEMIA- MODIFIED ALBUMIN

IN STUDY WITH 63% PREVALENCE ACSSENSITIVITY:80% PPV:72%SPECIFICITY:45% NPV:59%

“IMA, ECG, CTNT COMBINED IDENTIFIED 95% OF … ISCHEMIC HEART DISEASE”TRIPLE TEST.

D-dimeris 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

BIOMARKERS NOT NEEDED

BIOMARKER’S MENU: MYOCYTE INJURY, INFLAMMATION, NEUROHUMERAL,PLAQUE MARKERS

CPK-MB, CK-NAC, MYOGLOBIN

CTN-T, CTN-I, BNP, NT-PRO-BNP

ISCHEMIA MOD ALBUMIN

HS-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)

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

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

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

THANK YOU