Head of Cardiology Department, 6 th October University Head of Egypt Hearts Society.

Head of Cardiology Department , 6th October UniversityHead of Egypt Hearts Society

Pathophysiology of ACS and biochemichal markers release

5/42Copyright ©2005 American Association for Clinical Chemistry

Apple, F. S. et al. Clin Chem 2005;51:810-824

Biochemical profile in ACS patients: vascular inflammation to plaque rupture to ischemia to cell

death to myocardial dysfunction

Interdependence of Cardiac Interdependence of Cardiac BiomarkersBiomarkers

Coronary artery disease Risk factors (eg, cholesterol)

Coronary inflammation CRP, Lp-PLA2*, homocysteine, MPO

Plaque instability/disruption MPO, Lp(a), Lp-PLA2

Myocardial ischemia/necrosis Cardiac troponins, CK-MB, myoglobin

Ventricular overload BNP, Nt-proBNP

Pathophysiology Biochemical Markers

Adapted from Panteghini. Eur Heart J. 2004;25:1187-1196.

* Lipoprotein associated phospholipase A 2

TIME LINE OF MARKERS OF TIME LINE OF MARKERS OF MYOCARDIAC DAMAGE & FUNCTIONMYOCARDIAC DAMAGE & FUNCTION

1950 1960 1970 1980 1990 2000 2005

AST in AMI CK in

AMI

Electrophoresis for CK and LD

CK – MB

Myoglobin assay

RIA for ANP

CK-MB mass assay

cTnT assay

RIA for BNP and proANP

cTnl assay

RIA for proBNP

POCT for myoglobin CK-MB, cTnI

Immuno assay for proBNP

IMA

Genetic Markers

Timeline history of assay methods for markers of cardiac tissue damage and myocardial function.

AST: aspartate aminotransferase ANP: atrial natriuretic peptide

CK: creatine kinase BNP: brain natriuretic peptide

LD: lactate dehyydrogenase POCT: point-of-care testing

cTn: cardiac-specific troponin IMA: ischaemia-modified albumin

Time [years]

CLINICAL CHARACTERISTICS AND CLINICAL CHARACTERISTICS AND UTILIZATIONUTILIZATION OF BIOCHEMICAL OF BIOCHEMICAL

MARKERS IN MARKERS IN ACSACS

USE OF BIOCHEMICAL MARKERS IN THEUSE OF BIOCHEMICAL MARKERS IN THE

INITIAL EVALUATION OF ACSINITIAL EVALUATION OF ACS

MANAGEMENT OF NSTEACSMANAGEMENT OF NSTEACS

MANAGEMENT OF STEMIMANAGEMENT OF STEMI

USE OF BIOCHEMICAL USE OF BIOCHEMICAL MARKERS IN THE MARKERS IN THE INITIAL INITIAL

EVALUATION OF ACSEVALUATION OF ACSA. A. DiagnosisDiagnosis of myocardial infarction of myocardial infarction

11 . .Biochemical markers of myocardial necrosisBiochemical markers of myocardial necrosis22 . .Optimal timing of sample acquisitionOptimal timing of sample acquisition

33 . .Criteria for diagnosis of MICriteria for diagnosis of MI44 . .Additional considerations in the use of bio-markers for Additional considerations in the use of bio-markers for

diagnosis of MIdiagnosis of MI

B. Early Risk B. Early Risk StratificationStratification11 . .Biochemical markers of cardiac injuryBiochemical markers of cardiac injury

22 . .Natriuretic peptidesNatriuretic peptides33 . .Biochemical markers of inflammationBiochemical markers of inflammation

44 . .Biochemical markers of ischemiaBiochemical markers of ischemia55 . .Multimarker approachMultimarker approach

66 . .Other novel markersOther novel markers

QUESTIONS ANSWERED BY CARDIAC QUESTIONS ANSWERED BY CARDIAC MARKERSMARKERS

Rule in/out an acute MIRule in/out an acute MI Confirm an old MI (several days)Confirm an old MI (several days) Monitor the success of thrombolytic therapyMonitor the success of thrombolytic therapy Risk stratification of patients with unstable Risk stratification of patients with unstable

angina pectorisangina pectoris

N.B. Risk stratification in apparently healthy N.B. Risk stratification in apparently healthy persons is persons is notnot done with cardiac markers, but done with cardiac markers, but by measurement and assessment of cardiac by measurement and assessment of cardiac risk factorsrisk factors

R. Hinzmann, 2002

BIOCHEMICAL MARKERS IN BIOCHEMICAL MARKERS IN MYOCARDIAL ISCHAEMIA / NECROSISMYOCARDIAL ISCHAEMIA / NECROSIS

ININ::CK-MB (mass)CK-MB (mass)c.Troponins (I or T)c.Troponins (I or T)MyoglobinMyoglobin

OUTOUT::AST activityAST activityLDH activityLDH activityLDH isoenzymesLDH isoenzymesCK-MB activityCK-MB activityCK-IsoenzymesCK-Isoenzymes??CK-TotalCK-TotalFUTURE:FUTURE:

Ischaemia Modified AlbuminIschaemia Modified Albumin Glycogen Phosphorylase BBGlycogen Phosphorylase BB Fatty Acid binding ProteinFatty Acid binding Protein

““CARDIAC ENZYMES”CARDIAC ENZYMES”

are are

Obsolete!Obsolete!

““CARDIAC ENZYMES”CARDIAC ENZYMES”

are are

Obsolete!Obsolete!

KINETICS OF CARDIAC MARKERS KINETICS OF CARDIAC MARKERS AFTER AMIAFTER AMI

MARKERMARKER DETECTION PEAK DETECTION PEAK DISAPPEARANCEDISAPPEARANCE

MyoglobinMyoglobin 1 – 4 h1 – 4 h 6 – 7 h 6 – 7 h 24 h24 hCK-MB massCK-MB mass 3 – 12 h3 – 12 h 12 – 18 h12 – 18 h 2 – 3 days2 – 3 daysTotal CKTotal CK 4 – 8 h4 – 8 h 12 – 30 h12 – 30 h 3 – 4 days3 – 4 dayscTnTcTnT 4 – 12 h4 – 12 h 12 – 48 h12 – 48 h 5 – 15 days5 – 15 dayscTnIcTnI 4 – 12 h4 – 12 h 12 – 24 h12 – 24 h 5 – 7 days5 – 7 days

These values represent averages.These values represent averages.

IMA IMA (ischaemia)(ischaemia) few minutesfew minutes 2 – 4 h2 – 4 h 6 hours6 hours

Marker of Ischemia

ISCHAEMIA-MODIFIED ISCHAEMIA-MODIFIED ALBUMIN (IMA)ALBUMIN (IMA)

Serum albumin is altered by free radicals released Serum albumin is altered by free radicals released from ischaemic tissuefrom ischaemic tissue

Angioplasty studies show that albumin is modified Angioplasty studies show that albumin is modified within minutes of the onset of ischaemia. within minutes of the onset of ischaemia.

IMA levels rise rapidly, remain elevated for 2-4 h + IMA levels rise rapidly, remain elevated for 2-4 h + return to baseline within 6hreturn to baseline within 6h

Clinically may detect Clinically may detect reversiblereversible myocardial ischaemic myocardial ischaemic damagedamage

Not specific (elevated in stroke, some neoplasms, Not specific (elevated in stroke, some neoplasms, hepatic cirrhosis, end-stage renal disease) hepatic cirrhosis, end-stage renal disease)

Thus potential value is as a Thus potential value is as a negative predictornegative predictor FDA approved as a rule-out marker in low risk ACS FDA approved as a rule-out marker in low risk ACS

patients patients (2003)(2003)..

Established biomakrkers:

• Creatinin Kinase-MB (mass)

• Myoglobin.

• Troponin.

CREATINE KINASECREATINE KINASE

NORMAL NORMAL VALUES:VALUES:

Vary according to –Vary according to – ageage sexsex racerace physical conditionphysical condition muscle massmuscle mass

PATHOLOGICAL PATHOLOGICAL INCREASES:INCREASES:

Myocardial infarction or injuryMyocardial infarction or injury Skeletal muscle injury or diseaseSkeletal muscle injury or disease HypothyroidismHypothyroidism IM injectionsIM injections Generalised convulsionsGeneralised convulsions Cerebral injuryCerebral injury Malignant hyperpyrexiaMalignant hyperpyrexia Prolonged hypothermiaProlonged hypothermia

CREATINE KINASE: CK-MBCREATINE KINASE: CK-MB

CK-MB is the most cardiac-specific CK-MB is the most cardiac-specific CK isoenzymeCK isoenzyme

Sensitive marker with rapid rise & Sensitive marker with rapid rise & fallfall

““Gold standardGold standard”” biochemical biochemical marker for ~ 2 decadesmarker for ~ 2 decades

Only CK-MBOnly CK-MBmassmass should be should be measuredmeasured

MyoglobinMyoglobin Currently earliest markerCurrently earliest marker Like total CK it is by no Like total CK it is by no

means cardio-specificmeans cardio-specific

TroponinsTroponins Kinetics comparable with Kinetics comparable with

total CK and CK-MBtotal CK and CK-MB Cardio-specificCardio-specific

SensitivitSensitivityy

SpecificitSpecificityy

R. Hinzmann, 2002

MYOGLOBIN (Mb)MYOGLOBIN (Mb)

Peak at 6 Peak at 6 –– 9h 9h Normal by 24 Normal by 24 –– 36h 36h Excellent Excellent NEGATIVE predictorNEGATIVE predictor of of

myocardial injurymyocardial injury 2 samples 2 2 samples 2 –– 4 hours apart with no 4 hours apart with no

rise in levels virtually excludes AMIrise in levels virtually excludes AMI

CARDIAC TROPONINSCARDIAC TROPONINS

Striated and cardiac muscle Striated and cardiac muscle filaments consist of:filaments consist of: ActinActin MyosinMyosin Troponin regulatory complexTroponin regulatory complex

Troponin consists of 3 sub-units Troponin consists of 3 sub-units TnC, TnT & TnITnC, TnT & TnI

TROPONIN SUMMARYTROPONIN SUMMARY

High specificity for myocardial injuryHigh specificity for myocardial injury Sensitive to minor myocardial damageSensitive to minor myocardial damage

THE DUAL APPROACH LEAVES AN THE DUAL APPROACH LEAVES AN OPEN QUESTIONOPEN QUESTION

Troponin concentration

normal acute MI

97.5 th percentile

Acute MI cut-off value

Troponin IN UATroponin IN UA

Several studies have investigated the role of Several studies have investigated the role of TnT/I in risk stratification of unstable angina TnT/I in risk stratification of unstable angina (UA)(UA)

Of importance is that UA patients with Of importance is that UA patients with elevated Tn showed same incidence of elevated Tn showed same incidence of cardiac death or AMI at 6 months as did cardiac death or AMI at 6 months as did patients with pre-existing AMI (15%)patients with pre-existing AMI (15%)

Risk of AMI in UA patients with normal Tn Risk of AMI in UA patients with normal Tn was 4 %. was 4 %.

Irreversible minor myocardial injury Irreversible minor myocardial injury detected by TnT/I may stratify UA patients as detected by TnT/I may stratify UA patients as high risk for progression to AMIhigh risk for progression to AMI

INCIDENCE OF DEATH OR MI IN INCIDENCE OF DEATH OR MI IN ACS PATIENTSACS PATIENTS

Baseline levels of troponin have been shown to predict the risk of adverse cardiac events in patients with non-ST elevation ACS

From: NEJM 1997;337:1648 (Study 1);JACC 1998;32:8 (Study 2); Circulation 1997;95:2053 (Study 3); Am J Cardiol 2002;89:1035 (Study 4).

CLINICAL OUTCOME AT DIFFERENT CLINICAL OUTCOME AT DIFFERENT FOLLOW-UP PERIODSFOLLOW-UP PERIODS

The prognostic information of an elevated cTnI upon presentation is maintained over time.

From: JACC 2000;36:1812 and Am J Cardiol 2002;89:1035

CARDIAC TROPONINS IN UNSTABLE CARDIAC TROPONINS IN UNSTABLE ANGINA PECTORIS (UA)ANGINA PECTORIS (UA)

Does an elevated Troponin level in the absence of other signs reflect irreversible myocardial damage?

– Epidemiological studies– Animal experiments– Clinical trials– Sensitive imaging techniques

Say Say YES!YES!

MIMI must be must be REDEFINED!REDEFINED!

QUESTION:QUESTION:QUESTION:QUESTION:

New criteria for acute, New criteria for acute, evolving or recent MIevolving or recent MI

Either one of the following criteria satisfies the Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI :diagnosis for an acute, evolving or recent MI :1. Typical rise and gradual fall (troponin) or more 1. Typical rise and gradual fall (troponin) or more rapid riserapid rise and fall (CK-MB) of biochemical markers and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the of myocardial necrosis with at least one of the following:following:

a) ischemic symptoms;a) ischemic symptoms;b) development of pathologic Q waves on the b) development of pathologic Q waves on the

ECG;ECG;c) ECG changes indicative of ischemia (ST c) ECG changes indicative of ischemia (ST

segment elevation or depression); orsegment elevation or depression); ord)d)coronary artery intervention (e.g. coronary coronary artery intervention (e.g. coronary

angioplasty).angioplasty).

2.2.Pathologic findings of an acute MI Pathologic findings of an acute MI

Etiologies for Cardiac Troponin IncreasesEtiologies for Cardiac Troponin Increases

TROPONINTROPONIN

False +veFalse +ve(eg heterophilic antibodies)

AMI AMI NSTEMINSTEMI

PericarditisPericarditisPulmonary EmbolismPulmonary EmbolismSepsis ShockSepsis ShockAcute LVFAcute LVFTraumaTraumaHypertension/HypotensionHypertension/HypotensionDrug ToxicityDrug Toxicity

IatrogenicIatrogenic•Cardiac SurgeryCardiac Surgery•PCIPCI•CardioversionCardioversion•Cardiotoxin DrugsCardiotoxin Drugs•EP AblationEP Ablation

TROPONIN AND MI DIAGNOSISTROPONIN AND MI DIAGNOSIS

Ischemic Ischemic DiscomfortDiscomfort

No ST ElevationNo ST Elevation ST Elevation ST Elevation

UnstableUnstableanginaangina

Myocardial InfarctionMyocardial Infarction

Acute Coronary SyndromesAcute Coronary Syndromes

Cardiac Markers Clinical UtilityCardiac Markers Clinical Utility

Non Q-Non Q-Wave MIWave MI

Q-Wave Q-WaveMIMI

NSTEMI

•Diagnosis

• Prognosis

STEMI

•Prognosis

• Reperfusion

NSTEMI STEMI

"It is estimated that about 30% of patients who present with chest pain without ST-segment elevation and would otherwise be diagnosed as having unstable angina because of a lack of CK-MB elevation actually have NSTEMI when assessed with cardiac-specific troponin assays"From:JACC and Circulation 2002

PREDICTION OF PREDICTION OF RISK/PROGNOSISRISK/PROGNOSIS

Non ST Elevation Ischemic Discomfort

Troponin(admission and 6-12 hrs)

TroponinNegative

TroponinPositive

NSTEMI -High Risk

Low riskOther disease?

Troponin can be used to efficiently categorise patients into high and low risk groups for appropriate management pathways.

Adapted from: ACC/AHA Guideline Update for the Management of patients with UA and NSTEMI. 2002

BIOCHEMICAL MARKERS IN ACS BIOCHEMICAL MARKERS IN ACS CLINICAL DECISION POINTSCLINICAL DECISION POINTS

Unstable AnginaUnstable Angina AMIAMI Infarct sizeInfarct size PrognosisPrognosis Thrombolysis and ReperfusionThrombolysis and Reperfusion Peri-operative infarcts Coronary surgery complications Transplant rejection

BIOCHEMICAL MARKERS IN AMI ASSESSMENT OF REPERFUSION

• “Washout” phenomenon – enzymes & proteins have direct vascular access when occluded coronary circulation becomes patent

• Peak concentrations earlier & at higher levels if reperfusion successful

Due to short plasma half life (t½ = 10 min) Myoglobin is considered the best re-perfusion marker

TimeTime

Mar

ker

Lev

elM

arke

r L

evel

Successful Successful reperfusionreperfusion

Unsuccessful Unsuccessful reperfusionreperfusion

BIOCHEMICAL MARKERS IN ACS BIOCHEMICAL MARKERS IN ACS CURRENT RECOMMENDATIONSCURRENT RECOMMENDATIONS

AMI AMI –– Routine diagnosis Routine diagnosis Troponins (CK-Troponins (CK-MBMBmassmass))

Retrospective diagnosisRetrospective diagnosis TroponinsTroponins Skeletal muscle pathologySkeletal muscle pathology TroponinsTroponins ReinfarctionReinfarction Mb, CK-MBMb, CK-MBmassmass

ReperfusionReperfusion Mb, Tn, CK-MbMb, Tn, CK-Mbmassmass

Infarct sizeInfarct size TroponinsTroponins Risk stratification in UARisk stratification in UA TroponinsTroponins

Problems with the current biochemical markers

The perfect markerThe perfect marker

► Marker for myocardial necrosis, and also for Marker for myocardial necrosis, and also for cardiac ischemiacardiac ischemia

► Linear relationship between blood levels and Linear relationship between blood levels and extent of myocardial injury (and prognosis)extent of myocardial injury (and prognosis)

► 100% sensitive100% sensitive► 100% specific100% specific► Immediate increase (+ constant blood level for Immediate increase (+ constant blood level for

hours to days)hours to days)► Test kits : reliable, rapid, universally available Test kits : reliable, rapid, universally available

and inexpensiveand inexpensive

What about troponin T What about troponin T and and II? ?

► Very high sensitivity for myocardial Very high sensitivity for myocardial necrosisnecrosis

► Related to prognosisRelated to prognosis

► Not 100% specific for atherosclerotic Not 100% specific for atherosclerotic coronary artery diseasecoronary artery disease myocarditis, cardiomyopathy, myocardial myocarditis, cardiomyopathy, myocardial

contusion, ...contusion, ... renal failure, auto-immune diseases, ...)renal failure, auto-immune diseases, ...)

► Up to 6 hours before raised blood levelsUp to 6 hours before raised blood levelsno early MI diagnosis possibleno early MI diagnosis possible

► Raised blood levels for many daysRaised blood levels for many daystroublesome diagnosis of re-infarctiontroublesome diagnosis of re-infarction

BUT

Role for myoglobinRole for myoglobin? ?

► Initial elevation : 1 to 4h after onsetInitial elevation : 1 to 4h after onsetbetter early marker than troponinsbetter early marker than troponins

BUT : BUT : early myoglobin is less sensitive and early myoglobin is less sensitive and less specific (due to skeletal muscleless specific (due to skeletal muscletrauma) than late troponintrauma) than late troponindecisions mainly based on clinical decisions mainly based on clinical skills, ECG and late troponin (exceptskills, ECG and late troponin (exceptrarely for reperfusion therapy)rarely for reperfusion therapy)

► Duration of elevation : 24 – 48hDuration of elevation : 24 – 48huseful for re-infarction diagnosisuseful for re-infarction diagnosis

Role for CK-MBRole for CK-MB? ?

• Initial elevation comparable with Initial elevation comparable with troponinstroponins

• Less sensitive than troponinsLess sensitive than troponins

• High specificity (comparable with High specificity (comparable with troponins)troponins)

• Rapid rise and fall (instead of gradual Rapid rise and fall (instead of gradual fall for troponins) allowing more fall for troponins) allowing more accurate estimation of MI extentaccurate estimation of MI extent

Free fatty acidsFree fatty acids Fibrin peptide AFibrin peptide A Fatty acid binding Fatty acid binding

proteinprotein Glycogen phosphorylase Glycogen phosphorylase

BBBB

OTHER MARKERS CURRENTLY UNDER OTHER MARKERS CURRENTLY UNDER INVESTIGATIONINVESTIGATION

Markers of myocardial Markers of myocardial functionfunction

BIOCHEMICAL MARKERS OF BIOCHEMICAL MARKERS OF MYOCARDIAL FUNCTIONMYOCARDIAL FUNCTION

CARDIAC NATRIURETIC PEPTIDES:CARDIAC NATRIURETIC PEPTIDES:(ANP, BNP & pro-peptide forms)(ANP, BNP & pro-peptide forms)

Family of peptides secreted by cardiac atria (+ Family of peptides secreted by cardiac atria (+ ventricles) with potent diuretic, natriuretic & vascular ventricles) with potent diuretic, natriuretic & vascular smooth muscle relaxing activitysmooth muscle relaxing activity

Levels of these neuro-hormonal factors can be measured Levels of these neuro-hormonal factors can be measured in bloodin blood

Clinical usefulness (especially BNP/N-terminal pro-BNP)Clinical usefulness (especially BNP/N-terminal pro-BNP) Detection of LV dysfunctionDetection of LV dysfunction Screening for heart diseaseScreening for heart disease Differential diagnosis of dyspneaDifferential diagnosis of dyspnea Stratification of CCF patientsStratification of CCF patients

New generation markers currently under developmentNew generation markers currently under development

SOME COMMON DISEASES IN WHICH PLASMA SOME COMMON DISEASES IN WHICH PLASMA CARDIAC NATRIURETIC PEPTIDES HAVE BEEN CARDIAC NATRIURETIC PEPTIDES HAVE BEEN FOUND TO BE ALTERED, COMPARED TO HEALTHY FOUND TO BE ALTERED, COMPARED TO HEALTHY

SUBJECTSSUBJECTS

DISEASESDISEASES ANP/BNP LEVELSANP/BNP LEVELS

a) Cardiac diseases Heart failure AMI (first 2 – 3 days) Essential hypertension with CMP

b) Pulmonary diseases Acute dyspnea Obstructive pulmonary disease

c) Endocrine & metabolic diseases Hyperthyroidism Hypothyroidism Cushing’s syndrome Primary aldosteronism Addison’s disease Diabetes mellitus

d) Liver cirrhosis with ascites

e) Renal failure (acute or chronic)

Greatly increased Greatly increased Increased

Increased Increased

Increased Decreased Increased Increased Normal or increased Normal or increased

Increased

Greatly increased

AMI = acute myocardial infarction; CMP = cardiomyopathy with left ventricular hypertrophy

Clarico; Clin Chem Lab Med, 2003; 41 (17) p876

CARDIOVASCULAR RISK FACTORSCARDIOVASCULAR RISK FACTORS

EMERGING RISK FACTORSEMERGING RISK FACTORS Inflammatory Inflammatory MarkersMarkers

Sensitive C-reactive protein + Interleukins+ Serum

amyloid A + Pregnancy-associated plasma protein A ? Chronic infection (Chlamydia pneumoniae, ? Helicobacter pylori, etc)

Procoagulant MarkersProcoagulant Markers

Plasma Homocysteine +

Tissue plasminogen activator + Plasminogen activator inhibitor + Lipoprotein A

+ Process Process MarkersMarkers Fibrinogen

+

D-dimer ? Coronary artery calcification ?

Boersma et al, Lancet, 2003:361,p849

+ Clear evidence, but less clear + Clear evidence, but less clear whether modification of the risk whether modification of the risk factor decreases the risk of factor decreases the risk of cardiovascular diseasecardiovascular disease

? Risk factor under scrutiny? Risk factor under scrutiny

GUIDELINES: GUIDELINES: USE OF CARDIAC MARKERS IN PATIENTS USE OF CARDIAC MARKERS IN PATIENTS

WITH CHEST PAINWITH CHEST PAIN

Serial sampling is critical for accurate Serial sampling is critical for accurate diagnosisdiagnosis

Do NOT discharge patients on the basis of Do NOT discharge patients on the basis of negative results on a single (admission) negative results on a single (admission) specimenspecimen

If onset of chest pain >9-12 h before admission If onset of chest pain >9-12 h before admission only Troponin is necessaryonly Troponin is necessary

CK-MBCK-MBmassmass is most useful in assessing a recent is most useful in assessing a recent vs an older MI or to confirm reinfarction vs an older MI or to confirm reinfarction (occurs in 17% of AMI(occurs in 17% of AMI’’s). Repeat CK-MBs). Repeat CK-MBmassmass if if chest pain recurs in AMI patientschest pain recurs in AMI patients

GUIDELINES: GUIDELINES: USE OF CARDIAC MARKERS IN PATIENTS USE OF CARDIAC MARKERS IN PATIENTS

WITH CHEST PAINWITH CHEST PAIN

Mb, CK-MBMb, CK-MBmassmass, Troponin , Troponin POSITIVEPOSITIVE AMIAMI

MbMb ONLY ONLY POSITIVEPOSITIVE Possible early infarction or skeletal muscle Possible early infarction or skeletal muscle

injuryinjury Repeat markers Repeat markers (NB importance of Mb is as a (NB importance of Mb is as a Negative PredictorNegative Predictor))

Mb + CK-MB Mb + CK-MB POSITIVEPOSITIVE Probable early infarctionProbable early infarction Repeat markersRepeat markers A rising CK-MB.A rising CK-MB.

GUIDELINES: GUIDELINES: USE OF CARDIAC MARKERS IN PATIENTS USE OF CARDIAC MARKERS IN PATIENTS

WITH CHEST PAINWITH CHEST PAIN

TnI TnI << 0.06 ng/mL OR TnT 0.06 ng/mL OR TnT << 0.03 ng/mL 0.03 ng/mLon two specimens > 6 hours apart on two specimens > 6 hours apart Unstable AnginaUnstable Angina

Troponin I > 0.06 OR TnT > 0.1 ng/mLTroponin I > 0.06 OR TnT > 0.1 ng/mL(TnT levels > 0.03 and (TnT levels > 0.03 and << 0.1 ng/mL are equivocal and 0.1 ng/mL are equivocal andshould be repeated)should be repeated) ? High risk ACS(AMI) or non-ischaemic ? High risk ACS(AMI) or non-ischaemic

myocardial damagemyocardial damage depending on clinical cardiac depending on clinical cardiac ischaemiaischaemia

These patients require follow-up!!These patients require follow-up!!

Troponin I > 0.4 ng/mLTroponin I > 0.4 ng/mL ““traditionaltraditional”” AMI AMI

GUIDELINES: GUIDELINES: USE OF CARDIAC MARKERS IN PATIENTS USE OF CARDIAC MARKERS IN PATIENTS

WITH CHEST PAINWITH CHEST PAIN

FOR ASSESSMENT OF: FOR ASSESSMENT OF:

ReperfusionReperfusion Mb, CK-MBMb, CK-MBmassmass

Intra- or post-operative AMIIntra- or post-operative AMI TroponinTroponin MI after percutaneousMI after percutaneous Troponin ( in 30 - 40 % Troponin ( in 30 - 40 %

patients)patients)

coronary artery interventioncoronary artery intervention CK-MB ( in 5 - 30 % CK-MB ( in 5 - 30 % patients)patients)

(compare with baseline or (compare with baseline or use use 5-15 fold higher cut-5-15 fold higher cut-off level)off level)

ReinfarctionReinfarction serial CK-MBserial CK-MBmassmass determinationsdeterminations

Prognostic Markers and Prognostic Markers and Markers of Risk Markers of Risk

StratificationStratification

C-reactive proteinC-reactive protein MyeloperoxidaseMyeloperoxidase HomocysteineHomocysteine Glomerular filtration rateGlomerular filtration rate

C-Reactive ProteinC-Reactive Protein

Multiple roles in cardiovascular Multiple roles in cardiovascular disease have been examineddisease have been examined Screening for cardiovascular risk in Screening for cardiovascular risk in

otherwise otherwise ““healthyhealthy”” men and women men and women Predictive value of CRP levels for Predictive value of CRP levels for

disease severity in pre-existing CADdisease severity in pre-existing CAD Prognostic value in ACSPrognostic value in ACS

MyeloperoxidaseMyeloperoxidase

Released by activated leukocytes at Released by activated leukocytes at elevated levels in vulnerable plaqueselevated levels in vulnerable plaques

Predicts cardiac risk independently Predicts cardiac risk independently of other markers of inflammationof other markers of inflammation

May be useful in triage of ACS May be useful in triage of ACS (levels elevate in the 1(levels elevate in the 1stst two hours) two hours)

Also identifies patients at increased Also identifies patients at increased risk of CV event in the 6 months risk of CV event in the 6 months following a negative troponinfollowing a negative troponin

NEJM 349: 1595-1604NEJM 349: 1595-1604

HomocysteineHomocysteine

Intermediary amino acid formed by the Intermediary amino acid formed by the conversion of methionine to cysteineconversion of methionine to cysteine

Moderate hyperhomocysteinemia Moderate hyperhomocysteinemia occurs in 5-7% of the populationoccurs in 5-7% of the population

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

Can result from genetic defects, drugs, Can result from genetic defects, drugs, vitamin deficiencies, or smoking vitamin deficiencies, or smoking

HomocysteineHomocysteine

Elevated levels appear to be an Elevated levels appear to be an independent risk factor, though less independent risk factor, though less important than the classic CV risk important than the classic CV risk factorsfactors

Screening recommended in patients with Screening recommended in patients with premature CV disease (or unexplained premature CV disease (or unexplained DVT) and absence of other risk factorsDVT) and absence of other risk factors

Treatment includes supplementation Treatment includes supplementation with folate, B6 and B12with folate, B6 and B12

Glomerular Filtration Glomerular Filtration RateRate

Reduced GFR has been associated Reduced GFR has been associated with:with: Increased inflammatory factorsIncreased inflammatory factors Abnormal lipoprotein levelsAbnormal lipoprotein levels Elevated plasma homocysteineElevated plasma homocysteine AnemiaAnemia Arterial stiffnessArterial stiffness Endothelial dysfunctionEndothelial dysfunction

So much So much informationinformation!!What does it all meanWhat does it all mean?!??!?

The Future of Cardiac The Future of Cardiac BiomarkersBiomarkers

Many experts are advocating the Many experts are advocating the move towards a move towards a multimarker multimarker strategystrategy for the purposes of for the purposes of diagnosis, prognosis, and diagnosis, prognosis, and treatment designtreatment design

As the pathophysiology of ACS is As the pathophysiology of ACS is heterogeneous, so must be the heterogeneous, so must be the diagnostic strategiesdiagnostic strategies

Multiple MarkersMultiple Markers Are Needed for Diagnosis and Prognosis of ACSAre Needed for Diagnosis and Prognosis of ACS

No single ideal marker exists for ACSNo single ideal marker exists for ACS Complicated diseases are not likely Complicated diseases are not likely

to be associated with single markersto be associated with single markers Multiple markers define disease Multiple markers define disease

categoriescategories Multi-marker panels can aid in Multi-marker panels can aid in

differential diagnosisdifferential diagnosis

04/19/23 58

Adhesion moleculesE-selectin, ICAM-1, VCAM-1

Permeability

Apoptosis

Leukocyte chemoattractants(MCP-1, IL-8, PDGF, MC-SF)

Procoagulant activity(tissue factor)

Cytokines(TNF, FAS,CD40L)

NOET-1

markers of inflammationmarkers of inflammation

• Markers of protection?Markers of protection?

Adhesion moleculesE-selectin, ICAM-1, VCAM-1

Permeability

Apoptosis

Leukocyte chemoattractants(MCP-1, IL-8, PDGF, MC-SF)

Procoagulant activity(tissue factor)

Cytokines(TNF, FAS,CD40L etc.)

NOET-1

markers of inflammationmarkers of inflammation

TT

TT

TTIL-10IL-10

TTIL-10IL-10

IL-10IL-10

IL-10IL-10

TTIL-10IL-10

TThepatocytehepatocytegrowth factorgrowth factor

SUMMARYSUMMARY

““Cardiac EnzymesCardiac Enzymes”” are obsolete are obsolete Medical & laboratory progress has required a Medical & laboratory progress has required a

redefinition of Myocardial Infarctionredefinition of Myocardial Infarction Cardiac Troponins & Myoglobin now play a Cardiac Troponins & Myoglobin now play a

pivotal role in the diagnosis of AMIpivotal role in the diagnosis of AMI Cardiac Troponins play an important role in Cardiac Troponins play an important role in

the risk stratification of ACS patientsthe risk stratification of ACS patients Elevated Troponin levels in patients without Elevated Troponin levels in patients without

ECG changes & with normal CK-MB levels ECG changes & with normal CK-MB levels may identify patients at increased risk of may identify patients at increased risk of cardiac eventscardiac events

SUMMARYSUMMARY

Elevated Troponins in the absence of Elevated Troponins in the absence of clinical signs of ischaemic heart disease clinical signs of ischaemic heart disease require consideration of other causes of require consideration of other causes of cardiac injurycardiac injury

Additional roles for cardiac markers in:Additional roles for cardiac markers in: Reperfusion monitoringReperfusion monitoring Infarct size/prognosisInfarct size/prognosis Intra/post-operative MI Intra/post-operative MI

(non-cardiac/cardiac surgery).(non-cardiac/cardiac surgery).