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2/6/2015
MyocardialInfarction‐
Classification,Diagnosis
andUseofTroponins
Arun Rao , MD
Objectives
• Describe the recent updates to the Universal definition of Myocardial infarction.
• Understand the different troponin assays and their various cutoff values ,limits and limitations . • Review the pathophysiology of the Type 1 and Type 2 Myocardial Infarction and the implications for management. WhichpatienthadaTypeI
acuteMI?
• A 70 year old male with edema and dyspnea at rest . EF 20% one month ago. Troponin 0.7 now . It was 0.6 one month ago.
• A 40 year old male with severe chest pain , minimal ECG changes & troponin of 7 .Cath showed normal coronaries.
• A patient present with rapid AF and hypotension . A troponin
is 2.1 . • A 50 year old male with chest pain, troponin of 0.4 , no ECG changes on standard leads and a cath showing thrombus in OM1 artery.
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Whatisthecauseoftroponin
rise?
• Patient is a 74 year old white female in ICU with urosepsis .She has prior history of coronary artery bypass surgery . She is hypotensive requiring pressors . Creatinine is normal . ECG shows 1 mm ST depression in inferior leads . Echo shows EF of 40% with hypokinetic anterior wall . Troponin I level is 0.8 .She denies chest pain . • The rise in troponin is due to –
1. Type 1 Inferior MI –NSTEMI.
2. Type 2 MI .
3. Indeterminate cause .
4. The high troponin is probably an artifact. OutlineofPresentation
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The Basics of coronary physiology .
The Basics of laboratory testing.
Definition and Classification of Myocardial Infraction.
Interpretation and use of troponins.
High‐sensitivity Troponin. Practical tips for management. CoronaryCirculation‐Supply
• Coronary flow is about 250 ml/minute (5% of cardiac output).
• The majority of cardiac tissue perfusion occurs during diastole
• The systolic time is fixed at 200 msec.The diastolic time depends upon the heart rate . • Coronary flow is auto‐regulated (like cerebral flow) at mean aortic pressures of 40‐140 mm Hg.
• Vasomotor function, endothelial function, Coronary stenosis and collateral circulation all affect coronary flow.
• The O2 extraction is about 80%.
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Whatismyocardialinfarction?
• It is myocardial cellular injury/necrosis due to ischemia . • Myocardial ischemia is defined as tissue anemia due to poor inflow at the capillary level. • It can be supply (arterial flow ) ischemia or demand (increased oxygen consumption ) ischemia . • Myocardial necrosis can be of different types from a pathologist point of view (coagulation, contraction band, cytolysis ,border zone etc).
• It has different connotation to a pathologist ,biochemist, ECG reader , cardiac imaging specialist or an angiographer . ECGdetectionofacuteMI
• New ST elevation in two contiguous leads with cut‐points >0.1mV in all leads except V2‐V3 where the following cut‐
points apply‐0.2 mV in men >40, 0.25 mV in men < 40 and 0.15 mV in all females.( to account for early repolarization).
• New horizontal or down‐sloping ST depression >0.05 mv or T inversion greater than 0.1 mV in two contiguous leads with prominent R waves or R/S ratio greater than 1 .
• Initial non‐diagnostic ECG in symptomatic patients should prompt repeat ECG’s in 15‐30 minutes.
• Consider right precordial leads and posterior leads.
• Pitfalls of ECG diagnosis of MI includes LBBB, LVH ,Pericarditis and Ventricular Paced Rhythms.
PreviousDefinitions‐
• WHO definition(1971) Chest pain & ECG changes .
• WHO definition(1979) Chest pain, ECG changes and positive biomarkers.
• ACC/ESC Joint task force (2000) –Central role of troponin ,99th
percentile rule , <10% coefficient of variation (standard deviation divided by mean ) .
• Universal Definition (2007)‐Different types of MI, diagnosis with imaging .
• Third Universal Definition (2012)‐Role of angiographic evidence of thrombus in diagnosis .
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DiagnosisofMI‐ latestupdate
• Detection of rise and/or fall of a cardiac biomarker with one value>99th percentile upper reference limit and with atleast one of the following –
1. Symptoms of cardiac ischemia.
2. New or presumed new significant ST‐T changes or new LBBB.
3. Development of pathologic Q waves on ECG (>0.1 mV and >0.02 sec or QS V2,V3,I,II,avL,avF or V4‐V6).
4. Imaging evidence of new loss of viable myocardium.
5. Identification of intracoronary thrombus.
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Abriefhistoryofbiomarkers
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SGOT and isoforms ‐
LDH and isoforms ‐
CPK and CPK‐MB – 1972/1980 Troponin – 1990/ 1996 reported in ng/ml ( or mcg/L).
Troponin hs – 2008/2014 reported in ng/L ( or pcg/ml) Whatarecardiactroponins?
• The Tn protein complex is immobilized on the thin filament of the contractile apparatus. It consists of Tn C , TnI and TnT all encoded by different genes .
• A small amount may exist in the cytoplasm.
• Proteolysis of cTnI and cTnT occurs in myocardium in response to ischemia and others forms of insults. Its release from myocytes probably denotes irreversible injury to the myocytes . Small amount may indicate tissue wear and tear . This is being debated . • It is released within 2‐12 hours of myocardial injury and peaks at about 24 hours . It may be present up to 7 days.
Whatisapositivetroponin?
Keyclinicalconcepts
• The 99th percentile rule‐ In 2007 ,The National Academy of Biochemistry stated “in presence of clinical history of ACS ,the following is indicative of myocardial necrosis ‐
max concentration of cTn >99th percentile (for a reference control group)”.
• A positive troponin is a biomarker of myocardial injury/necrosis ,not necessarily of atherosclerotic coronary artery disease. • A rise and/or fall (20%) is more indicative of MI. Mild, chronic elevations can be seen in CHF.
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Type1
• Spontaneous – related to atherosclerotic plaque rupture and/or intra‐coronary thrombus.
• STEMI or NSTEMI. • ECG essential for reperfusion protocol ( Time is Muscle ).
• Core measure for STEMI is Door to Balloon Time <90 minutes for STEMI. Type2
• It is related to Supply/Demand mismatch and is unrelated to plaque rupture or thrombosis .
• The incidence is about 1/4 of all MI’s.
• Approximately 50% will not have significant CAD (based upon limited data ) .Ref – Thygesen et al .Am J of Med . Sept ,2013 . • Severe Anemia ,Severe Hypoxemia and Shock are common causes of decreased O2 supply . • Tachyarrhythmias and hypertensive urgencies are common instances of increased myocardial O2 demand . MyocardialOxygenDemand
Heart Rate
Wall stress BP MVO2
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Type3
• Diagnosed at autopsy due to presence of intracoronary thrombus or advanced CAD . • It is useful for population records . Type4– afterPCI
• PCI‐related MI with increase in troponin >5 times the 99th
percentile during the first 48 hours after PCI plus either chest pain or ischemic ST‐T changes/Q waves or TIMI 1 flow or imaging evidence.
• The cutoff level is arbitrary , to improve specificity . • In patients with baseline elevated levels , a 50% rise is the consensus criteria.
Type5‐afterCABGS
• Increase in troponin > 10 times the 99th percentile during first 48 hours with new ECG changes or new native or graft occlusion or new imaging evidence. 7
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MultifactorialorIndeterminate
Causes
Stress Cardiomyopathy (Takotsubo)
Severe Pulmonary Embolism Sepsis Acute neurologic disease resulting in rush of catecholamines
( deep T wave inversions ).
• VT with ICD shocks .
• Atrial fibrillation or SVT with rapid rates but not hypotensive or hypertensive .
The level of troponin may be indicative of the presence or absence of true MI in these cases . •
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MIintheICUsetting
• Diagnosis of MI in the ICU can be challenging . A increased troponin should prompt use of ECG and imaging techniques to diagnose a true ischemic event .
• Clinical circumstances should lead to diagnosis between type 1 vs type 2 event. • An elevated troponin alone is not an independent predictor of in‐hospital mortality but a diagnosis of MI has a two fold increased risk of hospital mortality . Appropriate medical therapy is recommended ( ASA ,beta‐blockers,statins ) along with risk stratification for conservative vs invasive management. IV Heparin if Type I MI suspected. • No current guidelines .
• An elevated troponin may reflect increased risk long term. Definitionofassays&limits‐
• 99th percentile limit– corresponds to the 3rd standard deviation from the mean of the reference population .It is the recommended cutoff for decision making for troponins ( recommended level of imprecision or co‐efficient of variation <10%). For most tests it is >95% and 20% CV.
• Limit of detection – the lowest concentrate which can be distinguished from 0.
• Limit of Quantitation ‐ the lowest concentration which can be measured with co‐efficient of variation <20% . ( CV = standard deviation divided by the mean for tests from one sample) .
• Contemporary sensitivity – current assays . • High sensitivity troponins – levels detectable in atleast 50% of normal individuals ( 95% in the latest generation ) . 8
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CurrentassaysatHVH
• Troponin I by Roche‐
current reference range =0.00 ‐ 0.3 ng/ml which is the limit of quantitation . Sensitivity at this level is 84% and Specificity is 94% . 99th
percentile level is 0.16 ng/ml. AbbottPOCassay
• Lowest level of detection‐ 0.02 ng/ml for Abbott I‐STAT .
• 99th percentile‐( 99% of the reference population will be below this limit )‐ 0.08ng/ml (with cv of 16%).
• 10% CV (coefficient of variation) level‐ (Limit of Quantitation) 0.1ng/ml .
• Current reference range = 0.00 ‐0.09 ng/ml.
Troponin levels
10% CV
99th
percentile
Current Reference Troponin HVH
0.3
0.18
0.3 ng/ml
Troponin POC 0.01 ng/ml
0.08 ng/ml ?
0.1 ng/ml
0.1 ng/ml
Hs‐troponin I
.006 ng/ml
.023ng/ml
23 ng/L
Limit of Detection .0013 ng/ml
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HighSensitivityTroponins
• The definition is detectable levels in atleast 50% of the reference population . • In the ARISTOTLE study for use of apixaban for stroke prevention , 14821 patients with AF participated in a side study. Hs‐troponin I (>1.3ng/L) was detectable in 98.5%. It was greater than 99th percentile (>23 ng/L) in 9.2%. Ref‐
Wallentin L, Circulation Feb 11 , 2014 . Theproblemswithclinical
diagnosis–
• Typical chest pain is present in only 50% of MI .
• ECG is non‐specific in over 80% of NSTEMI.
• Measurement of reliable biomarkers with good sensitivity and specificity is helpful but their positive predictive value depends on the prevalence in the population (Bayes theorem). P(H/D)= P(D/H) x P (H) / P(D) . “The doctrine of chances” . “The theory that refuses to die” .
• But, Time is Muscle and early treatment/perfusion decreases the extent of infarction and improves mortality .
Theother“realities”
• Chest pain is the one of the most common reason for a ER visit . Approximately 20% of chest pain visits have MI.
• A positive biomarker indicates myocardial injury but does not indicate the pathophysiology of MI or presence/severity of coronary artery disease in the major vessels of the heart .
• Biomarkers are often drawn for a possibility of MI in a patient with a non‐ACS presentation but “abnormal” ECG and/or high risk presentation . • Cardiac troponins are reliable prognostic indicators in stable and decompensated CHF , AF , Stroke , OSA ,Cardiac Transplant and Cancer Chemotherapy . There appears to be a continuum of risk. The exact mechanism is unknown. 10
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From: ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of
Troponin Elevations: A Report of the American College of Cardiology Foundation Task Force on Clinical
Expert Consensus Documents
J Am Coll Cardiol. 2012;60(23):2427-2463. doi:10.1016/j.jacc.2012.08.969
Figure Legend:
Relation Between Pre-Test And Post-Test Probability According to Bayes' Theorem for Troponin Test With 100% Sensitivity
The curves are shown for a specificity of 60% (lowermost) to 90% (uppermost). See text for further discussion.
Date of download:
1/27/2015
Copyright © The American College of Cardiology.
All rights reserved.
Triageofelevatedtroponinwithout
ACS.
• Causes of secondary cardiac ischemia (type 2 MI) –
due to supply/demand mismatch ‐ rapid arrhythmias associated with hypotension or hypertension,shock
,hypoxemia etc.
• Non‐ischemic causes (direct insults) – cardiac contusion, myocarditis ,cardiotoxic agents (anthracyclines,CO poisoning ), rhabdomyolysis with cardiac involvement, severe burns (>30%) .
From: ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents
J Am Coll Cardiol. 2012;60(23):2427‐2463. doi:10.1016/j.jacc.2012.08.969
Figure Legend:
Conceptual Model for Clinical Distribution of Elevated Troponin
ACS = acute coronary syndrome; AMI = acute myocardial infarction; CAD = coronary artery disease; CHF = congestive heart failure; CM = cardiomyopathy; CT = cardiothoracic; PCI = percutaneous coronary intervention; PE = pulmonary embolism; STEMI = ST‐segment elevation myocardial infarction.
Date of download: 7/6/2014
Copyright © The American College of Cardiology. All rights reserved.
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Othersfactorshelpfulin
decisionmaking
• A early rise and fall after an acute event . • A reason for low‐level elevation ( increased LVEDP) . • Temporal relation known to be associated with either Type 1 or Type 2 MI. • Identifying (and reporting ) the altered variable in the supply/demand balance . If none identified , unlikely to be type 2 MI. • If a patient with MI has angiographically “normal” coronaries and has no significantly altered variable in the supply/demand balance , then searching for other etiologies such as myocarditis with cardiac MRI may be helpful . • In short , identify the mechanism if not ACS . Inform lab if no cause/mechanism identified at all . TakeHomePoints
• Cardiac Troponins are central to the diagnosis of MI but clinical co‐relation is warranted .
• Criteria for a positive test is at or near the 99th percentile for the reference population and it is different for each assay.
• A positive test does not indicate the pathophysiology.
• ECG is an integral part of workup .
• Risk stratification (clinical and imaging ) , the right decision making models and guideline directed pathways (when applicable) are key for optimal care of patients with chest pain and patients with MI.
• Thanks for listening .
• Please e‐mail me with questions and comments ‐>[email protected].
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References
• 1. Third Universal Definition of Myocardial Infarction‐ Expert Consensus Document‐ Thygesen et al, JACC 2012 ;60 :1097.
• 2. Early Diagnosis of Myocardial Infarction –NEJM Aug 27 , 2009 .
• 3. Cardiac Troponins and High sensitivity cardiac troponin assays – Conrad MJ , Clinics in Laboratory Medicine 34 (2014) 59‐73. • 4. Methodologies for Measurement of Cardiac Markers – Sluss PM , Clinics in Laboratory medicine 34 (2014) 167‐185. • 5. Cardiac troponin I elevation in hospitalized patients without acute coronary syndromes. Blich M et al, Am J of cardiology May 15,2008 . • 6. Supply/demand Type 2 MI . Apple FS et al ; JACC May 27 , 2014 . • 7. ACCF 2012 Expert Consensus Document on Practical Considerations in the Interpretation of Troponin Elevations‐ JACC Dec 2012.
MoreReferences
• Clinical Decision Making in Cardiology – chapter 3 by J.sanford schwartz in Braunwald’s heart disease .7th edition . • The role of cardiac MRI in patients presenting with chest pain ,raised troponin and unobstructed coronary arteries . Assomul RG, Eur Heart J 2007;28,1242.
• Hs‐troponin in stable CHF – Heart 2010 ;98:1778 .
• Hs‐troponin in decompensated CHF‐ JACC May 10,2010 • Hs‐troponin in stable CAD – PEACE study‐ JACC 61(12),2013.
• Hs Troponin in Stroke –JACC 61(10) 2013 .
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