BIOMARKERS IN ACS

DR.RAVI KANTHASSISTANT PROFESSOR

CARDIOLOGY

Acute Coronary SyndromeDefinition:

The spectrum of acute ischemia related syndromes ranging from

UA to MI with or without ST elevation that are secondary to acute plaque

rupture or plaque erosion.

[----UA---------NSTEMI----------STEMI----]

•The risk of death and the benefit from early revascularization are highest

within the first hours; therefore early diagnosis is critical.

• Cardiac biomarkers have had a major impact on the management of this

disease and are now the cornerstone in its diagnosis and prognosis.

DEFINITION

• A biomarker is a substance used as an

indicator of a biologic state. It is a

characteristic that is objectively measured

and evaluated as an indicator of normal

biologic processes, pathogenic processes, or

pharmacologic responses to a therapeutic

intervention.

• Biomarkers complement clinical assessment and the 12-lead

ECG in the diagnosis, risk stratification, triage, and

management of patients with suspected ACS.

The diagnosis of acute myocardial infarction (AMI) can be

made with the detection of a rise/fall of cardiac troponin (at

least one value above the 99 th percen-tile of the upper

reference limit) and one of 1) symptoms of ischaemia,

2) electrocardiogram (ECG) changes of new ischaemia,

3) new pathological Q waves or

4) imaging evidence of new loss of viable myocardium.

CRITERIA FOR A TRUE BIOCHEMICAL MARKER OF MYOCARDIAL INJURY

1. It should be myocardial tissue specific and its concentration in the myocardium

should be high but should be absent in non-myocardial tissues.

2. It should be detectable in blood soon after the myocardial injury i.e. the

sensitivity should be high.

3. It should remain elevated in blood for several days of the onset of damage so

that it can be detected in patients coming to the hospital quite late after myocardial

infarction.

4. It could be assayed by simple and quick method i.e. the turn-around time (TAT)

should be low because the first few hours of myocardial infarction are crucial for

medical intervention.

Thus the appearance of these markers in the blood stream and their measurable life in the blood

following ischaemia depends on :

1. Their intracellular location or compartmentation – The molecules present in cytosol are released

first when myocardial damage occurs whereas the structurally bound molecules are released later.

2. Their molecular weight – The larger molecules diffuse at a slower rate than the smaller molecules.

3. Their rate of elimination from the blood – The smaller molecules are eliminated rapidly as

compared to larger molecules.

4. Blood flow in the necrotic region – The difference in the circulation of blood in the infarcted area

leads to differences in the release of cytosolic proteins from the necrotic region while the release of

structurally bound proteins are independent of the blood flow in the infarcted region.

PATHOPHYSIOLOGY BASIS OF BIOMARKERS

Biomarkers of inflammation . C-reactive protein. Myeloperoxidase (MPO) Soluble fragment CD40 ligand (sCD40L)

Biomarkers of plaque instability/disruption. Pregnancy-associated plasma protein A (PAPP-A) Choline Placental growth factor MMP-9 Myeloperoxidase (MPO)

Biomarkers of myocardial ischemia . Ischemia-modified albumin (IMA) Free fatty acids unbound to albumin (FFAu) Heart-type fatty acid binding protein (H-FABP) (PRE NECROSIS)

Myocardial necrosis Tn , CK-MB

Pump failure,myocardiac stress Nt-PROBNP,GDF-15,ST-2,ET-1

Acute coronary syndrome biomarkers associated with the underlying myocardial events.

Interdependence of Cardiac Biomarkers

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

Progression of Biomarkers in ACS

ACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non–ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction

Adapted from: Apple Clinical Chemistry March 2005

STEMIUA/NSTEMISTABLE CAD PLAQUE RUPTURE

MPOCRPIL-6

MPO ICAMsCD40LPAPP-A

MPOD-dimerIMAFABP

TnITnTMyoglobinCKMB

Inflammation has been linked to the development of vulnerable plaque and to plaque rupture

TIME LINE OF MARKERS OF MYOCARDIAC 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]

ESTABLISHED AND OLD BIOMARKERS

• The use of biomarkers in the diagnosis of acute myocardial

infarction (AMI) begins in 1954 when Karmen et al. first reported

elevation of aspartate aminotransferase (AST) in the serum of

patients with AMI

• Later, limitations of AST as a biomarker were recognized due to its

lack of specificity for myocardial tissue.

• One year later,Wroblewski proposed the use of lactate

dehydrogenase (LDH) in the diagnosis of AMI

CREATINE KINASE (CK) AND ITS ISOENZYME MB (CKMB)

• CK has three isoenzymes namely CKBB, CKMB and CKMM each consisting of

two subunits named according to main tissue of occurrence : B (brain) and

M(skeletal muscles).

• Myocardium contains 60% CKMB and 40% CKMM along with traces of

mitochondrial CK (macro CK type II) .

• Being highest in proportion in myocardium CKMB has been used as the

biochemical marker in patients with suspected acute myocardial infarction

(AMI).

• The ratio of the CK-MB / total CK has also been proposed for the diagnosis of

the origin of raised CK-MB by some authors.

It begins to increase between 3-5 hours after the onset of

infarction and peaking at 16-20 hours.

• The CKMB mass assay has a diagnostic sensitivity of 50% at 3

hours and 80% at 6.

Despite all these advantages of CKMB mass assay it has two main limitations :

(1) it is not perfectly specific to cardiac injury with increases occurring in large amounts in skeletal muscle and increased levels found in muscular dystrophy , hypothyroidism , hypothermia alcoholism , cerebrovascular accidents and a variety of myopathies make it unsuitable as a marker of myocardial injury

(2) the early release pattern limits its use for the late MI diagnosis.

Other uses;-

• But it has a definite place for the diagnosis of reinfarction and has

prognostic value in patients with unstable angina .

• Its potential as an aid in

– non-invasive detection of coronary recanalization following thrombolytic

therapy and also as a

– sensitive marker in detecting myocardial necrosis following percutaneous

coronary intervention has also been shown

MYOGLOBINMyoglobin, a 18 KD cytosolic protein, appears in blood earliest after

myocardial injury than any other marker available so far.The detectable levels of myoglobin in the blood are found as early as 2

to 3 hours after the onset. Its peak value is obtained at 6 – 12 hours after the onset of the

symptoms and then it normalizes over the next 24 hours. However, it is not cardiac specific as its release from the skeletal

muscles cannot be distinguished from that released due to cardiac injury severe renal insufficiency and in alcohol binges .

Several studies have compared the diagnostic utility of serum myoglobin

with other markers like CKMB, CKMB mass, CKMB isoforms and cardiac

Troponins but the results have been controversial .

The high negative predictive value of serum myoglobin for excluding early

infarction has encouraged its use along with more specific markers such as

CKMB and cardiac troponin and this two – marker approach has improved

the diagnosis of MI .

HISTORY: TROPONIN

• Troponin I first described as a biomarker specific

for AMI in 19871; Troponin T in 1989

• Now the biochemical “gold standard” for the

diagnosis of acute myocardial infarction via

consensus of ESC/ACC.•

Cardiac troponin• sensitive biomarkers of myocardial damage

• plays a critical role in the regulation of excitation–contraction

coupling in the heart

• Detection of cTn in peripheral blood indicates and quantifies

cardiomyocyte damage

• low sensitivity at the time of patient presentation

• requiring serial sampling for 6–9 h in a significant number of

patients

TROPONINS

Troponin is a protein complex located on the thin filament of striated muscles consisting of the three subunits namely Troponin T (TnT), Troponin I (TnI) and Troponin C (TnC) each having different structure and function. Of the three troponins,

TnT and TnI are being used as the biochemical markers for the diagnosis of myocardial injury.

The troponins found in cardiac tissue (cTn) have a different amino acid sequence than that present in troponin of skeletal muscles.

This makes cTnT and cTnI more specific for the diagnosis of myocardial injury.

These cardiac troponins (cTns) appear in the blood as early as 3-4 hours of the acute episode and remain elevated for 4-14 days.

The pattern of release of troponin may be monophasic or biphasic.

This release kinetics is related to the distribution of these proteins within the myocardial cell.

About 94-97% of these troponins is bound to myofibril and only 3% of cTnI and 6% of cTnT is free in the cytoplasm

When the myocardial damage occurs the cytosolic troponins reach the blood stream quickly resulting in a rapid peak of serum troponin observed during the first few hours.

This is followed by the release of structurally bound troponin resulting in a second peak lasting for several days.

• Studies have shown that cardiac troponins should replace CKMB The reasons being :

– 1. Troponins are highly cardiospecific especially the TnI (100%).– 2. The prolonged elevation (4-14 days) make it a good marker for

patients admitted to the hospital after several days of MI.– 3. cTns have greater sensitivity for minor degrees of myocardial

injury due to the cardiospecificity and their very low concentration in serum of normal individuals.

– 4. These are excellent prognostic indicator in patients with unstable angina and is a very useful parameter for stratifying risk in acute coronary syndrome(ACS).

5. A single measurement of serum cTnT at the time corresponding to the slow

continuous release after AMI (~72 hours after onset) can be used as a convenient

and cost effective non-invasive estimate of infarct size whereas CKMB requires

repetitive sampling

6. The early serial measurements of cTnI are a more accurate predictor of

early coronary artery reperfusion after thrombolytic therapy as compared

to CKMB and myoglobin and it also identifies a subgroup of patients with

unstable coronary syndrome in whom prolonged antithrombotic treatment

with low-molecular weight heparin can improve the prognosis.

• 7.cTn typically increases more than 20 times above the upper limit of the reference range

in myocardial infarction as compared to creatine kinase-myocardial band (CK-MB)

which usually increases 10 times above the reference range.

8.This provides an improved signal - to - noise ratio, enabling the detection of even

minor degree of necrosis with troponin. The cTn begins to elevate 3 h from the onset of

chest pain in MI. Because of the continuous release, cTn elevation persists for days

(cTnI: 7-10 days, cTnT: 10-14 days).

9. According to U.S. National Academy of Clinical Biochemistry (NACB) and Joint

European Society of Cardiology and American College of Cardiology (ESC/ ACC)

guidelines cTns are the most specific and sensitive biochemical markers.

cTnT Versus cTnI

Both cTnT and cTnI are almost equally good markers and it is difficulty to say which is better because both have some positive and negative points.

cTnI is 100% cardiospecific and it is not elevated in trauma and skeletal muscle disease.

The overall diagnostic specificity and efficiency of cTnI is better than cTnT and it (cTnI) is proved to be the most sensitive marker in detecting myocardial necrosis following percutaneous intervention .

Both cTns undergo posttranslational modifications such as phosphorylation, oxidation, reduction, proteolysis and form complex with other troponins.

cTnI is more prone to these modifications and these modification may prevent some antibodies used in the assay system from binding to the molecules and thereby diminishing the signal.

The other advantage of cTnI may be its greater specificity in patients of

ESRD.

However, the important advantage of cTnT is that due to international patent

restrictions there is only one assay for its measurement, thus cTnT

demonstrates a high degree of precision at the low end of measurement range

and a relatively uniform cut-off concentration.

In contrast, at least 18 different commercial assays for cTnI are available

leading to considerable variation in the cut-off concentrations in the definition

of a myocardial infarction by cTnI values.

Thus, a clinician should be aware of the cTnI cut-off values specifically

associated with the particular assay used by the laboratory.

• The life-time of cTnT in blood (5- 14 days) is some what more than that of

cTnI (4-10 days).

• Although cardiac troponins are extremely specific for myocardial necrosis,

they do not discriminate between ischaemic and non-ischaemic etiologies of

myocardial injury.

• Combining troponin with other cardiac biomarkers may offer complimentary

information on the underlying pathobiology and prognosis in an individual

patient .

• The recommended time course for collection of blood samples for cTn is at

hospital admission, 6 and 12 hours later but when it is used along with an

early marker like myoglobin (two-marker strategy) then at hospital admission,

4,8 and 12 hours later is used.

WASH-OUT PHENOMENON. Patients with ST-segment elevation myocardial infarction who achieve an

effective reperfusion have a greater and earlier peak plasma concentration of troponin, followed by a faster return to normal – the so-called “wash-out phenomenon” – compared with those patients having no significant reperfusion.

In this event, two blood samples should be collected – at the time of the patient's admission to hospital, and 90 min later – and the enzyme plasma concentrations compared.

The ratio between the concentrations at these two points can be used to discriminate between successful and unsuccessful reperfusion. In general, the greater the ratio (at least 5), the more likely it is that reperfusion has occurred.

If reperfusion has indeed occurred, estimation of infarct size using peak biomarker concentration may be not reliable..

The 12-hour wait for the levels to peak remains the Achilles heel of this bio-marker.

ESTIMATION OF INFARCT SIZE

AFTER CABG

Increase more than 5 x 99 percentile URL during first 72 hrs

Tn IN ESRD The cardiac troponin especially cTnT pose diagnostic challenges in patients of chronic

renal failure. Frequent cTnT elevations (30 to 70% of end stage renal disease (ESRD) patients

compared with <5% in similar patients of cTnI) are seen in patients of renal failure in the absence of clinical suspicion of ACS .

The putative mechanisms for chronic elevation of troponin in chronic renal disease patients include endothelial dysfunction, acute cardiac stretch, microinfarction and left ventricular hypertrophy.

However, it is important to understand that in the setting of acute coronary syndrome these patients should be treated as if renal failure were not present as the short term prognostic value of troponin T for cardiovascular event is similar in patients with and without renal failure

– Increasing evidence suggests that chronically elevated troponin levels

indicate a worse long-term prognosis for cardiovascular outcomes in this

patient population

– False positives have been reported with use of troponin-T in ESRD

patients but not as much with troponin-I

– CK: plasma concentrations are elevated in 30-70% of dialysis patients at

baseline, likely secondary to skeletal myopathy, intramuscular injections

and reduced clearance.

– CK-MB: 30-50% of dialysis patients exhibit an elevation in the MB

fraction >5% without evidence of myocardial ischemia

– Therefore, the most specific marker for suspected AMI in ESRD patients

is Troponin-I with an appropriate sequential rise of atleast 20% after 6 hrs.

Sensitive and high-sensitivitycardiac troponin assays,

• Sensitive (detection of cTn in 20–50% of healthy individuals) and high-

sensitivity cTn (hs-cTn, detection of cTn in 50–90% of healthy individuals)

assays have two differentiating features from conventional cTn assays

• (i) detection of cTn in a substantial number of healthy persons and

• (ii) a more precise definition of what is ‘normal’ (¼the 99th percentile) with

a precision of the assay expressed as the coefficient of variability which

should be ,20% and preferably ,10%.• increase the accuracy of the diagnosis of AMI at the time of presentation to

the ED.• allows a more rapid rule-in and rule-out.

Concerns and pitfalls withhigh-sensitivity cardiac troponin

• increased detection of patients with cardiomyocyte damage from causes

other than AMI.

• incorrect interpretation of hs-cTn results.

High-sensitivity cardiac troponin:timing of serial measurements and

the ESC guidelines

• time interval to the second measurement of hs-cTn can be significantly

shortened.

• clinical advantage

- substantial reduction in time to decision

- total treatment costs in the ED

• 3h rule-out protocol is not based on hs-cTn levels only, but also requires

patients to be pain-free and to have a GRACE score below 140.

• AMI may ruled out without a second measurement once hs-

cTn levels are normal if chest pain onset > 6 h prior to ED

presentation.

• a significant rise and/or fall in cTn is an important criterium

to differentiate AMI from chronic causes of cardiomyocyte

injury.

Rapid rule-out and rule-in protocols

Rule-in of AMI can be at presentation(0 h) in patients with unequivocal ST-elevations, with elevations in cardiac troponin (cTn) in the measurement performed at presentation.at 7 h if the first cTn is normal and the elevation at second measurement performed after 6 h. Rule-out requires a normal second cTn level and therefore 7 h. According to the 2011 ESC NSTEMI guidelines,AMI can be ruled-out at 4 h if a (h)s-cTn assay is used. Recent research has indicated that (h)s-cTn assays may allow even earlierrule-out and rule-in if assay-specific algorithms are used or if applied in combination with copeptin.

Algorithm for the use of high-sensitivity cardiac troponin levels

• lower the level, higher the negative

predictive value (NPV) for the

presence of AMI.

• In contrast, the higher the level, the

higher the positive predictive value

(PPV) for the presence of AMI

• mild elevations of cTn with levels just

above the 99th percentile have a broad

differential diagnosis and therefore a

rather low PPV for AMI of only 50 %

• Heart-type fatty-acid binding protein• involved in the transportation of long-chain fatty acids into the

cardiomyocyte,

• released rapidly into the circulation in response to cardiomyocyte injury

• regarded as an early sensitive marker of AMI.

• Ongoing research is therefore focusing on the use of h-FABP in patients

presenting very early (,1–2 h since chest pain onset).

• Copeptin• c-terminal part of the vasopressin prohormone• appears to be able to identify AMI very early after symptom onset, even

when cTn is still negative.• The added value of copeptin when used in combination with sensitive cTnI

or hs-cTnT seems to be smaller.• greatest appeal to clinicians is its use within a dual-marker strategy for

very early rule-out of AMI.• Patients with acute chest pain presenting to the ED with initial negative

values (below the 99th percentile) of either sensitive cTn or hs-cTn and also low levels of copeptin do have a very high negative predictive value (around 99%)forAMI and seem to be appropriate candidates for rapid discharge from the ED without the need for serial cTn testing.

Copeptin

copeptin seems to be the ideal marker to

compensate for the sensitivity deficit of

conventional cTn assays in early

presenter

added value of copeptin regarding

diagnostic accuracy at presentation is

substantial

Other complimentary prognosticbiomarkers

• Natriuretic peptides, midregional pro-adrenomedullin, and

GDF-15

• powerful predictors of mortality in patients with suspected or

established ACS, but do not seem to provide added diagnostic

information

Biomarkers associated with plaqueinstability

• markers of plaque instability including myeloperoxidase, myeloid-related

protein 8/14, pregnancy-associated plasma protein-A, and C-reactive

protein have very low diagnostic accuracy and therefore are not helpful in

the early diagnosis of AMI.

HSCRP (HIGH-SENSITIVITY C-REACTIVE PROTEIN)

C-reactive protein is a nonspecific inflammatory marker

that is released by the liver in response to the acute phase

injury.

CRP can be measured by multiple assays in acceptable

precisions down to or below 0.3 mg/l and most give

comparable results (designated as high-sensitive CRP or

hsCRP).

In terms of the association of CRP and ACS it is

important to distinguish cases without (unstable angina)

and with necrosis (acute MI).

In cases of AMI, CRP release is triggered as an acute

phase reactant secondary to necrosis and levels of CRP

are much higher and these have been correlated with

infarct size.

Though infarct size is the major determinant of long term

prognosis after AMI; mortality has been shown to be

related to CRP levels independent of left ventricular

systolic function.

Suleiman M, Aronson D, Reisner SA, Kapelovich MR, 21. Admission C-

reactive protein levels and 30-day mortality in patients with acute

myocardial infarction. Am J Med 2003; 115 : 695-701.21,22.

The RISCA (recurrence and inflammation in the acute coronary syndromes) study.

J Am Coll Cardiol 2008; 51 : 2339-46.

• In the absence of infarction, CRP levels correlate to the extent of

atherosclerosis and some studies have shown that it predicts coronary

events in patients of unstable angina independent of troponin levels .

• However, a more recent large prospective study showed only a weak

association of CRP levels and future coronary events in patients of

ACS and even this disappeared once adjusted for other common

clinical variables.

• This study included about two-thirds of AMI patients and one-third

unstable angina patients.

CRP is elevated post-acute coronary syndrome almost exclusively

in the setting of myocardial necrosis indicating the level of

myocardial inflammation

• One study found that CRP measurements (taken between 12

and 24 hours post event) predicted occurrence of

– heart failure (HR = 2.6, P = 0.04) and

– death (HR = 2.7, P = 0.02) post-MI [89].

– Elevated peak CRP in the early phase of MI was related to

early mechanical complications, cardiac rupture , ventricular

aneurysm and thrombus formation..

CRP levels post-MI peak at two to four days, then take 8 to 12 weeks to subside

to baseline levels.

Interestingly, CRP levels post acute MI do not predict re-infarction.

Additional acute coronary events can only be predicted after CRP levels have

receded to baseline levels (after about 12 weeks).

One of the difficulties with CRP is that it is non-specific in the presence of other

inflammatory conditions

rheumatoid arthritis,

malignancy,

vasculitis.

GDF-15 antihypertrophic effect, prognosticdeath , HF

ST2 death , HF

C-reactive protein. HF,death,infarct size,atherosclerotic burden

MPO oxidative stress, plaque rupture, death

PAPP-P plaque rupture, death,recurrent MI

MYOGLOBIN negative predictive value

MMP-9 plaque instability, and ventricular remodeling after cardiac injury.

sCD40L destabilization of the plaquedeath and recurrent MI

CHOLINE coronary plaque destabilization and tissue ischemia. death or cardiac arrest, cardiac arrhythmias, heart failure, and coronary angioplasty

PLACENTAL GROWTH FACTOR plaque instability, myocardial ischemia, and prognosis

IMA early marker of the occurrence and indicator of the severity

UNBOUND FREE FATTY ACIDS early indication of cardiac ischemia

H-FABP Earlier diagnosis of MI death, myocardial infarction and heart failure

CYSTATIN C prognostic marker in heart failure Renal failure

POINT-OF-CARE TESTING (POCT)

Diagnostic Accuracy of Point-of-care Testing for Acute Coronary Syndromes, in Primary

Care

A Cluster-Randomised Controlled Trial Yuki Tomonaga; Felix Gutzwiller; Thomas F

Lüscher; Walter F Riesen; Markus Hug; Albert Diemand; Matthias Schwenkglenks;

POC tests are a simple, rapid and relatively inexpensive means for reducing hospital

stay, complications and improving adherence to treatment.

• The use of POC tests can lead to a reduction in test ordering, sample transport to

laboratories and data reporting.

• Decreased TAT(Turn Around Time) is the central issue in POC testing.

Several automated systems have enabled the introduction of a wide range of tests to be

performed simply (no requirement for highly trained personnel) and quickly (without the

need for laboratory processing) implementation.

The two main types of POC testing formats available in the clinical setting include-

small bench-top analysers and - hand-held devices.

Small bench-top analysers- are basically a miniaturised version of the mainframe

central lab equipment, except with essential modifications to prevent operator error

and provid rapid, reproducible results.

Hand-held devices- are developed using state-of-the-art microfabrication

techniques, which essentially integrate several key analytical steps i.e. sample

clean-up, separation, analysis and data reporting.

Devices for cardiac biomarker POC testing are predominantly based upon

immunoassay methods.

New Development in Biomarker Discovery

• The traditional approach of biomarker discovery, which usually

focuses on one or a few potential candidates at a time, has been

ineffective and led to a low rate of biomarker discovery with clinical

utility.

• The pathophysiologic changes in ACS are influenced by many

factors, including genetic and environmental factors.

• The complete sequencing of human genome and recent advances in

genomic, transcriptomic, proteomic, lipidomic, metabolomic, and

bioinformatics technologies offer tremendous opportunities for novel

biomarker discovery.

Early Risk Stratification

JACC. September 23, 2014.

Cardiac Biomarkers

JACC. September 23, 2014. Accepted Manuscript

EARLY RISK STRATIFICATION

• Class I 1. Patients with suspected ACS should undergo early risk stratification

based upon an integrated assessment of symptoms, physical exam findings, ECG findings, and biomarkers.

2. A cardiac troponin is the preferred marker for risk stratification and, if available, should be measured in all patients with suspected ACS. In patients with a clinical syndrome consistent with ACS, a maximal concentration exceeding the 99th percentile of values for a reference control group (with acceptable precision) should be considered indicative of increased risk of death and recurrent ischemic events.

3. Blood should be obtained for testing on hospital presentation followed by serial sampling with timing of sampling based on the clinical circumstances. For most patients, blood should be obtained for testing at hospital presentation, at 6 to 9 hours, and again at 12 –24 hours if the earlier samples are negative and the clinical index of suspicion is high.

• Class IIa • 1. Measurement of hs-CRP may be useful, in addition to a cardiac troponin,

for risk assessment in patients with a clinical syndrome consistent with ACS. The benefits of therapy based on this strategy remain uncertain.

• 2. Measurement of B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) may be useful, in addition to a cardiac troponin, for risk assessment in patients with a clinical syndrome consistent with ACS. The benefits of therapy based on this strategy remain uncertain.

• 3. Early repeat sampling of cardiac troponin (e.g. 2 to 4 hours after presentation) may be appropriate if tied to therapeutic strategies.

• Class IIb • 1. In patients with a high clinical probability of ACS, maximal concentrations

of cardiac troponin exceeding the 99th percentile (without stringent requirements for precision) may be recognized as indicative of increased risk of death or recurrent ischemic events.

2. Measurement of markers of myocardial ischemia, in addition to cardiac troponin and ECG, may aid in the short-term risk stratification of patients with suspected ACS, and in excluding ACS in patients with a low clinical probability of myocardial ischemia.

3. A multi-marker strategy that includes measurement of two or more pathobiologically diverse biomarkers in addition to a cardiac troponin, may aid in enhancing risk stratification in patients with a clinical syndrome consistent with ACS. BNP and hs-CRP are the biomarkers best studied using this approach. The benefits of therapy based on this strategy remain uncertain.

• Class III Biomarkers of necrosis should not be used for routine screening of

patients with low clinical probability of ACS.

USE OF BIOCHEMICAL MARKERS IN THE MANAGEMENT OF NSTE ACS

A. Clinical decision-making Class I • Among patients with a clinical history consistent with ACS, an

increased concentration of cardiac troponin should prompt application of ACS management guidelines for patients with indicators of high risk.

Class III • 1. Application of management guidelines for ACS

should not be based solely upon measurement of natriuretic peptides.

• 2. Application of management guidelines for ACS should not be based solely upon measurement of C-reactive protein.

Biochemical marker measurement after the diagnosis of acute MI

• Class I

1. Once the diagnosis of acute MI is ascertained, testing of

biochemical markers of injury at a reduced frequency is valuable

to qualitatively estimate the size of the infarction, and to detect the

presence of complications such as re-infarction.

• Class IIa

2. CK-MB is the preferred marker for detection of re-infarction early

after the index event when the concentration of cardiac troponin is

still increased.

THANK U