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

2 Progression to MI Troponin released follows necrosis MI - Thrombus completely blocking vessel Fatty Streak Ruptured plaque with thrombosis

3 Troponin I or T ACS Overview Plaque Accumulation Fatty streaks Acute Coronary Syndromes AGE

4 Classification of different types of MI Major Focus in Emergency Department

Acute Coronary Syndromes Evidence 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 5

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

WHO criteria MI CK-MB Mass cTnI in MI cTnI/cTnT Risk Stratification Redefinition of MI cTnI Standardization AST in MI CK isoenzymes LD & CK in MI Electrophoresis CK and LD Myoglobin RIA CK-MB in MI CK-MB RIA cTnT in MI Necrosis Biomarkers Timeline Guidelines sensitive cTn Assays Highly sensitive cTn Assays

8

Myoglobin Characteristics 9 NPV = 96% (95%CI: 94.9% to 96.8%) Sensitivity = 90% (95%CI: 87.8% to 93.1%)

10 M Epitope 1 Epitope 2 B M M Skeletal Muscle B B Brain M B Hybrid M B Creatine + Phosphate Creatine Phosphate ACTIVITY ASSAY MASS ASSAY

11 = Cardiac isoforms in blood When troponin is increased think heart

12 Universal Definition of Myocardial Infarction Joint ESC/ACCF/AHA/WHF Task Force Circulation Nov 27;116(22): Joint ESC/ACCF/AHA/WHF Task Force

3. What is the difference between clinical performance of CK-MB and cardiac troponin? 13

14 CK-MB mass Metaanalysis

Comparison of CK-MB and Cardiac Troponin ACS indicates acute coronary syndrome Circulation 2003;108:

Single Biomarker Test for MI 16

17 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 ACS 2007 Clin Chem and Circulation Class I

18 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 ACS 2007 Clin Chem and Circulation Class I

19 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  ) 20 Thygesen K, et al, JACC 2000;36: 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) Clin Chem and Circulation Class I

22 Universal Definition of Myocardial Infarction Joint ESC/ACCF/AHA/WHF Task Force Circulation Nov 27;116(22): Joint ESC/ACCF/AHA/WHF Task Force RISE AND/OR FALL OF CARDIAC BIOMARKERS (PREFERALY TROPONIN)

23 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 24

cTn at Presentation 25

6. What are the differences in performance for the between cardiac troponin methods? 26

Are All Cardiac Troponin Assays Created Equal? 27 NO 1000 NO

Single Biomarker Test for MI 28

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 29 Class I (Level of Evidence C) 2007 Clin Chem and Circulation

30 cTnT cTnI cTnC Epitope 1 Epitope 2 Six commercial (Hytest) mAbs evaluated for use in a 1 x 1 “reference “immunoassay mAb M18mAb 3C7 mAb 19C7 mAb 560 mAb 267 mAb MF4

31 Company/platform/assay (generation)LoD µg/L99 th centile µg/L 10% CV µg/LEpitopes recognized by antibodies Abbott AxSYM ADV (2 nd ) C 87-91, 41-49; D Abbott Architect C 87-91, 24-40: D: Abbott i-STAT # 0.10C: 41-49, 88-91; D: 28-39,62-78 Beckman Access AccuTnI (2 nd ) C; 41-49; D: BioMerieux Vidas TnI-Ultra (2 nd ) 0.01 NA Innotrac Aio! C: 41-49, ; D: Inverness Biosite Triage0.05<0.05NAC: NA; D: Mitsubishi Chemical NAC: 41-49; D:71-116, Ortho Vitros ECi (2 nd ) C 24-40, 41-49; D Response Biomedical0.03< NA Roche* E170 (4 th ) 0.01< C: ; D: Roche* Elecsys 2010 (4 th ) 0.01< C: ; D: Siemens Centaur TnI-Ultra (2 nd ) C; 41-49, 87-91; D: Siemens Dimension RxL (2 nd ) C: 27-32; D: Siemens Immulite 2500 STAT C: 87-91:D: Siemens Immulite 1000 Turbo0.15NA0.64C: 87-91:D: Siemens Stratus CS (2 nd ) C: 27-32; D: Siemens VISTA (2 nd ) C: 27-32; D: Tosoh AIA 21 (2 nd ) 0.06< NA From IFCC Website: Accessed Analytical characteristics of commercial cardiac troponin I and T assays as stated by manufacturer (version October 2008) 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 32 Class I (Level of Evidence C) 2007 Clin Chem and Circulation

Recommended Precision of Troponin Assays at 99th Percentile Cutoff CV  10% 33 J Am Coll Cardiol 2000;36;

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 34 Class I (Level of Evidence C) 2007 Clin Chem and Circulation

7. Are there other conditions where cardiac troponin is clinically useful? 35

36 Acute Infarction (Hours) Infarct Expansion (Hours to Days) Global Remodeling (Days to Months) Adapted from: Atlas of Heart Failure, 2 nd Edition, Current Science, Inc, Philadelphia, PA

Heart Failure is Huge Healthcare Issue  Most common discharge Dx in patients > 65 years  400, ,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 37

Incidence of detectable troponin in acute and chronic HF 38

39 <3.00 ng/L >12.94 ng/L Categories

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. 40 (J Am Coll Cardiol 2010;56:1071–8)