1. What is the acute coronary syndrome? How big a health

problem is the acute coronary syndrome?

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2

Progression to MITroponin released follows necrosis

MI - Thrombus completely blocking vessel

Fatty Streak

Ruptured plaque with thrombosis

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Troponin I or T

ACS Overview

Plaque AccumulationFatty streaks

Acute Coronary Syndromes

AGE

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Classification of different types of MIMajor Focus in Emergency Department

Acute Coronary SyndromesEvidence of a Major Health Problem

• 500,000 CHD deaths per year• 250,000 sudden deaths per year• 700,000 hospitalized MIs per year• 1.25 million MIs per year• 6 million patients with CHD

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2. What is the preferred test for diagnosis of myocardial infarction?

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1950 1960 1970 1980 1990 2000 2010

WHO criteria MI

CK-MB Mass cTnI in

MI

cTnI/cTnT Risk Stratification

Redefinition of MI

cTnIStandardizationAST in

MI CKisoenzymes

LD & CK in MI Electrophoresis

CK and LDMyoglobin RIACK-MB

in MI

CK-MB RIA

cTnT in MI

Necrosis Biomarkers TimelineNecrosis Biomarkers TimelineGuidelinessensitivecTn Assays Highly

sensitivecTn Assays

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Myoglobin Characteristics

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NPV = 96% (95%CI: 94.9% to 96.8%)

Sensitivity = 90% (95%CI: 87.8% to 93.1%)

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M

Epitope 1

Epitope 2

B

MMSkeletal Muscle

BBBrain

M BHybrid

M BCreatine

+Phosphate

Creatine

Phosphate

ACTIVITYASSAY

MASSASSAY

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=

Cardiac isoforms in blood

When troponin is increased think heart

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Universal Definition of Myocardial InfarctionJoint ESC/ACCF/AHA/WHF Task Force

Circulation. 2007 Nov 27;116(22):2634-53.

3. What is the difference between clinical performance of CK-MB and

cardiac troponin?

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CK-MB mass Metaanalysis

Comparison of CK-MB and Cardiac Troponin

ACS indicates acute coronary syndrome

Circulation 2003;108:2543-2549

Table 5. Studies of CK-MB and Troponin (cTn) Comparison

Positive CK-MB Positive cTn % cTnCharacteristics n (%) n (%) cTn/CK-MB

Acute myocardial ischemia admissions 216 (27) 289 (36) + 34%

Possible myocardial ischemia in emergency ward 15 (5) 34 (12) + 127%

MI discharge diagnosis plus biomarker, ECG and pain

algorithm 4157 (28) 4661 (32) + 12%All ACS admissions 373 (22) 430 (25) + 15%

All ACS admissions except with diagnostic ECG of MI 23 (29) 32 (40) + 39%

Single Biomarker Test for MI

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1. A Cardiac troponin is the preferred marker for the diagnosis of MI. CK-MB by mass assay is an acceptable alternative when cardiac troponin is not available (Level of Evidence: A).

2. In patients with a clinical syndrome consistent with ACS, a maximal (peak) concentration exceeding the 99th percentile of values for a reference control group should be considered indicative of increased risk of death and recurrent ischemic events (Level of Evidence: A).

NACB Clinical Guidelines for ACS2007 Clin Chem and Circulation

Class I

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1. Patients with suspected ACS should undergo early risk stratification based upon an integrated assessment of symptoms, physical exam findings, ECG findings, and biomarkers (Level of Evidence: C).

2. 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, and at 6 to 9 hours (Level of Evidence: B).

NACB Clinical Guidelines for ACS2007 Clin Chem and Circulation

Class I

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4. How should cardiac troponin be interpreted for diagnosis of myocardial infarction

“Definition of MI. Criteria for acute, evolving or recent MI.”

Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers for myocardial necrosis with at least one of the following:– Ischemic symptoms– Development of pathologic Q waves on ECG– ECG changes indicative of ischemia (ST or

ST)

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Thygesen K, et al, JACC 2000;36:959-969. Note: Joint ESC/ACC Consensus Committee.

NACB Clinical Guidelines for ACS

1. 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 (peak) concentration exceeding the 99th percentile of values for a reference control group should be considered indicative of increased risk of death and recurrent ischemic events (Level of Evidence: A).

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2007 Clin Chem and Circulation

Class I

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Universal Definition of Myocardial InfarctionJoint ESC/ACCF/AHA/WHF Task Force

Circulation. 2007 Nov 27;116(22):2634-53.

RISE AND/OR FALL OF CARDIAC BIOMARKERS (PREFERALY TROPONIN)

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5. What are some of the diagnostic specificity problems with cardiac troponin?

Elevated Troponin in Patients without ACS or Heart Failure

• Acute Disease• Cardiac and Vascular• Acute Aortic dissection• Cerebrovascular accident• Ischemic Stroke• Intracerebral Hemorrhage• Subarachnoid Hemorrhage• Medical ICU Patients• Gastrointestinal bleeding• Respiratory• Acute pulmonary embolism• ARDS• Cardiac Inflammation• Endocarditis• Myocarditis • Pericarditis• Muscular Damage• Infectious• Sepsis• Viral Ilness• Other Acute Causes of Troponin Elevation• Kawasaki disease• Apical ballooning syndrome• TTP• Rhabdomyolysis• Birth Complications in Infants• Extreme Low Birth Weight• Preterm Delivery• Acute Complications of • Inherited Disorders• Neurofibromatosis• Duchenne Muscular Dystrophy• Klippel-Feil syndrome• Environmental Exposure• Carbon Monoxide• Hydrogen Sulfide• Colchicine exposure

• Chronic Disease• ESRD• Cardiac infiltrative disorders • Amyloidosis• Sarcoidosis • Hemochromatosis• Scleroderma• Hypertension• Diabetes• Hypothyroidism

• Iatrogenic• Invasive Procedures • Heart Transplantation• Congenital defect repair• Radio Frequency Catheter Ablation• Lung Resection• ERCP• Non-Invasive Procedures • Cardioversion• Lithotripsy • Pharmacologic sources• Chemotherapy• Other Medications

• Myocardial Injury• Blunt Chest Injury• Endurance athletes• Envenomation• Snake• Jellyfish• Spider• Centipede• Scorpion

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cTn at Presentation

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6. What are the differences in performance for the between

cardiac troponin methods?

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Are All Cardiac Troponin Assays Created Equal?

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NO1000

NO

Single Biomarker Test for MI

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NACB Analytical Guidelines for ACS

Identification of antibody/epitope recognition sites for each biomarker.

Assays for cardiac biomarkers should strive for a total imprecision (%CV) of <10% at the 99th percentile reference limit.

Cardiac biomarker assays must be characterized with respect to potential interferences, including rheumatoid factors, human anti-mouse antibodies, and heterophile antibodies.

Stability (over time and across temperature ranges) for each acceptable specimen type

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Class I (Level of Evidence C)

2007 Clin Chem and Circulation

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cTnT

cTnI

cTnC

Epitope 1

Epitope 2

Six commercial (Hytest) mAbs evaluated for use in a 1 x 1 “reference “immunoassay

A D G S S D A A R E P R P A P A P I R R R S S N Y R A Y A T E P H A K K K S K I S A S R K L Q L K T1 50

L L L Q I A K Q E L E R E A E E R R G E K GR A L S T R C Q P L E L A G L G F A E L Q D L C R Q L H51 100

A R V D K V D E E R Y D I E A K V T K N I T E I A D L T Q K I F D L R G K F K R P T L R R V R I S A101 150

D A MM Q A L L G A R A K E S L D L R A H L K Q V K K E D T E K E N R E V GDWR K N I D A L S GM151 200

E G R K K K F E S201 209

mAb M18 mAb 3C7 mAb 19C7

mAb 560

mAb 267 mAb MF4

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Company/platform/assay (generation) LoD µg/L 99thcentile µg/L

10% CV µg/L Epitopes recognized by antibodies

Abbott AxSYM ADV (2nd) 0.02 0.04 0.16 C 87-91, 41-49; D 24-40

Abbott Architect 0.009 0.012 0.032 C 87-91, 24-40: D: 41-49

Abbott i-STAT 0.02 0.08# 0.10 C: 41-49, 88-91; D: 28-39,62-78

Beckman Access AccuTnI (2nd) 0.01 0.04 0.06 C; 41-49; D: 24-40.

BioMerieux Vidas TnI-Ultra (2nd) 0.01 0.01 NA NA

Innotrac Aio! 0.012 0.023 0.036 C: 41-49,190-196; D: 137-149

Inverness Biosite Triage 0.05 <0.05 NA C: NA; D: 27-40

Mitsubishi Chemical 0.008 0.029 NA C: 41-49; D:71-116, 163-209

Ortho Vitros ECi (2nd) 0.012 0.034 0.034 C 24-40, 41-49; D 87-91

Response Biomedical 0.03 <0.01 0.21 NA

Roche* E170 (4th) 0.01 <0.01 0.03 C: 125-131; D: 136-147

Roche* Elecsys 2010 (4th) 0.01 <0.01 0.030 C: 125-131; D: 136-147

Siemens Centaur TnI-Ultra (2nd) 0.006 0.04 0.03 C; 41-49, 87-91; D: 27-40

Siemens Dimension RxL (2nd) 0.04 0.07 0.14 C: 27-32; D: 41-56

Siemens Immulite 2500 STAT 0.1 0.2 0.42 C: 87-91:D: 27-40

Siemens Immulite 1000 Turbo 0.15 NA 0.64 C: 87-91:D: 27-40

Siemens Stratus CS (2nd) 0.03 0.07 0.06 C: 27-32; D: 41-56

Siemens VISTA (2nd) 0.015 0.045 0.04 C: 27-32; D: 41-56

Tosoh AIA 21 (2nd) 0.06 <0.06 0.09 NA

From IFCC Website: Accessed 7-15-09<http://www.ifcc.org/index.asp?cat=Scientific_Activities&scat=Committees&suba=Standardisation_of_Markers_of_Cardiac_Damage_(C-SMCD)&zip=1&dove=1&numero=53 >

Analytical characteristics of commercial cardiac troponin I and T assays as stated by manufacturer (version October 2008)

41-49 AA region =11/16 = 68%

81-93 AA region =8/16 = 50%

NACB Analytical Guidelines for ACS

Identification of antibody/epitope recognition sites for each biomarker.

Assays for cardiac biomarkers should strive for a total imprecision (%CV) of <10% at the 99th percentile reference limit.

Cardiac biomarker assays must be characterized with respect to potential interferences, including rheumatoid factors, human anti-mouse antibodies, and heterophile antibodies.

Stability (over time and across temperature ranges) for each acceptable specimen type

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Class I (Level of Evidence C)

2007 Clin Chem and Circulation

Recommended Precision of Troponin Assays at 99th Percentile Cutoff

CV 10%

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J Am Coll Cardiol 2000;36;959-969

NACB Analytical Guidelines for ACS

Identification of antibody/epitope recognition sites for each biomarker.

Assays for cardiac biomarkers should strive for a total imprecision (%CV) of <10% at the 99th percentile reference limit.

Cardiac biomarker assays must be characterized with respect to potential interferences, including rheumatoid factors, human anti-mouse antibodies, and heterophile antibodies.

Stability (over time and across temperature ranges) for each acceptable specimen type

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Class I (Level of Evidence C)

2007 Clin Chem and Circulation

7. Are there other conditions where cardiac troponin is clinically

useful?

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Acute Infarction (Hours)

Infarct Expansion (Hours to Days)

Global Remodeling (Days to Months)

Adapted from: Atlas of Heart Failure, 2nd Edition, Current Science, Inc, Philadelphia, PA

Heart Failure is Huge Healthcare Issue

Most common discharge Dx in patients > 65 years

400,000 - 700,000 new cases yearly 10% of individuals over 65 years 4.7 million patients 50% of patients are asymptomatic 11 million office visits each year 3.5 million hospitalizations 250,000 deaths Cost exceeds 56 billion dollars

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Incidence of detectable troponin in acute and chronic HF

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<3.00 ng/L

>12.94 ng/L

Categories1. <3.00 2. 3.00 - 5.44 3. 5.44 - 8.16 4. 8.17 – 12.94 5. >12.94

Conclusions

As investigators begin to understand the relationship of detectable cTn to HF outcome… more insight may be gained into….the transition from chronic compensated to acute decompensated HF. Ultimately, this information might allow physicians to guide therapy… and improve HF outcomes.

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(J Am Coll Cardiol 2010;56:1071–8)