Biomarqueurs du syndrome coronarien aigu JP Cristol, S Badiou, AS Bargnoux, N Kuster, AM Dupuy. First at al, I would like to thank the organizers of this symposium, to invite me to discuss with you about biomarkers of acute coronary syndrome

Biomarkers associated with various pathophysiological processes of acute coronary syndromes. Risk Factors For cardiovascular disease: Myocardial Infarction Biomarkers Necrosis cTnI / TnT CKMB H-FABP MPO Metalloproteinase Leucocytes Activation AVP Axis activation Copeptin Biomarkers of ACS CRP , Il-6 sPLA2 … Inflammation Novel Biomarkers representent an important contribution to the stratification of cardiovascular risk. A first group of biomarkers could identify non traditional risk factors for cardiovascular disease, for exemple, Myeloperoxidase or metaloproteinase are associated to leucocytes activation. Inflammation, which is recognise as an important feature in CVD, could be investigated by C reactive protein or iL-6. Endothelial dysfonction could be monitored by adrenomoduline or endothelin. On the other hand, some biomarkers could be used to perform timely diagnosis of myocardial infarction or to predict outcome. Increase in troponins, creatinine kinase from muscle and brain, or heart fatty acid binding protein indicate mocardial cell necrosis. In adition, myocardial inarction could result in an vascular stress which activate the arginine vasopressine axis with increase in copeptin levels. Finally, myocadial dysfunction could result in a biomechanical stress leading to natriuretic peptide release. Biomechanical stress BNP NT-pro-BNP ANP Endothelial Activation/ Dysfunction Adrenomedullin Endothelin Chan and Ng BMC Medicine 2010, 8:34

De l’occlusion partielle vers l’occlusion totale Thrombus Plaque fissurée

De l’occlusion partielle vers l’occlusion totale : Du SCA vers l’IDM ST+ Artère coronaire non complètement occluse Risque évolutif à court terme vers SCA ST+ ou mort subite SCA ST+ cTn élevée SCA ST - Cinétique cTn ? Normale ou élevée 4

Stratifier le risque : Scores clinico-biologiques : Score de TIMI Risque de mortalité ou de complications graves (Antman EM, The TIMI risk score for unstable angina/non-ST elevation MI, JAMA 2000 ; 284: 835-842) (http://www.mdcalc.com/uanstemitimiscore)

Classification des syndromes coronariens aigus Angor stable SCA non ST + SCA ST + Angor Instable : Pas d’élévation de cTn NSTEMI : IDM non ST+ IDM sans onde Q cTn positive STEMI : IDM ST+ cTn positive Désobstruction en urgence Nécessite cinétique de cTn ou nouveaux marqueurs D’après «A consensus document of The Joint European Society of Cardiology / American College of Cardiology. Eur. Heart J., 2000; 21:1502-13. 6

ECG ST + = extrême urgence médicale (H6) SCA ST+ Un sus-décalage du segment ST dans 2 dérivations contiguës d’un territoire coronaire d’au moins 0,1 mV dans les dérivations frontales (D1, D2, D3, aVL, aVF), précordiales gauches (V4, V5, V6) ou postérieures (V7, V8, V9) d’au moins 0,2 mV dans les dérivations droites (V1, V2, V3) ST + = extrême urgence médicale (H6) Occlusion coronaire Désobstruction !! (Angioplastie, thrombolyse)

Efficacité de la désobstruction Angioplastie (The GUSTO Angiographic Investigators. The effects of tissue plasminogen acti-vator, streptokinase, or both on coronary-artery patency, ventricular function and survival after acute myocardial infarction. N Engl J Med 1993; 329: 1615-1622) 9

ECG Pas de ST + Signes électriques atypiques ou ECG normal

Epidémiologie comparée des SCA ST + et ST - USA en 2004 > 1million de SCA non ST+ recensés (European Heart Journal 2007) La fréquence de l’IDM alors que SCA non ST+ 1/3 des DT répond aux critères diagnostics de SCA non ST+ L’évolution à long terme est moins favorable que SCA ST+ ? 12

Pronostic à long terme Mortalité hospitalière des SCA non ST+ < ST+ Mortalité à 6 mois idem et > à long terme (Keth AA Fox, BMJ, Prediction of risk of death and myocardial infarction in the 6 months after presentation ACS, prospective multinational observational study (GRACE))

Stratification du risque Clef de voûte de la PEC Clinique et ECG insuffisante Marqueurs biologiques, incontournables SCA ST+ cTn élevée Pas de marqueurs SCA ST - Cinétique cTn Biomarqueurs 14

Biomarqueurs et infarctus cTn rise cTn fall However, it is well known that troponin rise is quite slow following inarction reaching maximal value in 24 hours. Importantly, during the first hours, classical troponin remain undetectable. Thus, in order to rule out or rule in myocardial infarctio, it is recommanded to monitor troponin levels for a least 6 hours. It has been suggested that increasing troponin sensitivity could result in a shortened kinetic study.

Classification Spécificité + ++ +++ CK-LDH-Myoglobine CK-MB cTnI ou T

La place de la CK-MB actuellement En discussion lors d’une suspicion d’un 2éme IDM pour évaluer la taille de l’IDM en présence d’une IRC Suspicion de faux positifs de la cTn National Academy of Clinical Biochemistry (NACB) en 2007 dosage justifié si cTn non disponible

La h-FABP H-FABP ou heart-type fatty acid-binding protein protéine liée aux acides gras soluble de 132 acides aminés proche de la myoglobine Les limites cardiospécificité limitée, étroitesse de la fenêtre diagnostique (20 à 30 h) élimination rénale quasi exclusive Dosage réactif Randox immunoturbidimétrique sur Cobas 2936 publications entre 1979-2011

La h-FABP

La h-FABP

The combination of H-FABP and Tn increased the NPV H-FABP is anoter potential exclusion biomarker. As you can see, the association of HFABP and Copeptine leads to a NPV of 98 %. Mc Mahon 2011

Troponins : the corner stone of the Universal definition of myocardial infarction Troponins remain the corner stone of the universal definition of myocardial inarction. Indeed, myocardial infarction should be defined by a rise o fall of cadiac biomarker, preferably troponin, with at least one value above the ççth percentile of the uppe reference limit associated with clinical sympoms and/or electric changes. It is important to underline that this definition include 2 main points : A kinetic analysis and the definition of the 99th percentile. ESC Guidelines for the management of acute myocardial infarction. European Heart Journal, 2012

The spectrum of acute coronary syndromes : STEMI – NSTEMI – Unstable angina According to these definitions it will be possible to analyse, in the emergency room, all the spectrum of acte coronary syndrome and it will be possible to distinguish STEMI, non STEMI, and unstable angina; Among the patients presenting with chaist pain, ECG could rapidely identify pateint with an ST elevation, indicate a myocardial infarction. These STEMI patients could be directly reaed without waiting results of biomarkers kinetics. By contrast, in patients without typical electrical changes, troponin kinetic will be of crucial importance. Changes in troponin levels indicate a NST elevation infactus, whyle stable troponin indicate an unstable angina. Hamm, et al., Eur Heart J. 2011 Dec;32(23):2999-3054 24

Kinetic studies with troponins : six hours to detect myocardial infarction No early change in cTn Myocadial infarction cTn rise cTn fall However, it is well known that troponin rise is quite slow following inarction reaching maximal value in 24 hours. Importantly, during the first hours, classical troponin remain undetectable. Thus, in order to rule out or rule in myocardial infarctio, it is recommanded to monitor troponin levels for a least 6 hours. It has been suggested that increasing troponin sensitivity could result in a shortened kinetic study.

TROPONINES TnIc et TnTc sont des composant des myocytes Libérées dans le sang lors de la lésion des cellules myocardiques: ischémie, nécrose , inflammation, traumatisme, toxique Spécificité et sensibilité ++++ Aucun intérêt dans les 2 à 3 premières heures de la douleur augmente 4 à 6h après le début de la symptomatologie (2ème dosage à réaliser entre 6-12h si 1er négatif

The goal for sensitive troponins : diagnosis of AMI as early as possible. Roche TnT Roche TnT 718 Pts with acute chest pain Tn levels at baseline Diagnostic accuracy of Tn at presentation according to time since onset of chest pain Thus, Diagnosis of acute myocardial infarction as early as possible is clearly te goal for igly sensitiv troponin. Indeed as you can see on this slides, troponin levels, above the 99 th percentile i necessary to myocardial infaction diagosis. In addition if the sensitivity of the test is inceasing, the accuracy of troponin at presentation is enhnaced. Using ROC curve (), the area under curve is progressively increasing according to the time since onset of chest pain. By contrast, a quite perfect diagnosis with area under the curve between 90 and 95 % is obtained as early than 2 hours. These promising results conduct to the developpment of new hs-troponin assays. Reichlin et al. NEJM 2009

Emergence of TNT : Important issues for hs-Tn. Need for a Universally Accepted Nomenclature Defining Uniform Criteria for Reference Populations Analytical Imprecision in Cardiac Troponin Assays Ruling in / Ruling Out Acute myocardial infarction : Elevated but stable hs-Tn and risk stratification However at least 6 important issues have been higlighte in a ecent reviw by Korley and Jaffe. The first quesion is to have an universally accepted nomenclature. Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8

Un passeport pour les troponines Apple has proposed a scorecard for hs-troponins according to analtical chaacteristic and detection in healthy population. In order to be guidelin acceptable, an hsTn migh have a otal imprecision lower than 10% a the 99th percentile. In addition, an hs-Tn should detect circulatin troponin in more than 50% of healthy individuals. - Quelle signification : Un marqueur de SCA ? Un marqueur pronostic ? Un marqueur de remodelage ? - Quelle troponine ? T ou I ? Apple FS (2009) Clin Chem, 55(7):1303 1396

Troponine assays classified as « guideline acceptable »

Une troponine “positive” : quelle signification ? Critères d’interprétation : Le 99° percentile (14 ng/L pour hs-TnT) La valeur du delta en cinétique Seuil clinique ?

Emergence of TNT : Important issues for hs-Tn. Need for a Universally Accepted Nomenclature Defining Uniform Criteria for Reference Populations Analytical Imprecision in Cardiac Troponin Assays Ruling in / Ruling Out Acute myocardial infarction : Elevated but stable hs-Tn and risk stratification Since the 99th pecentile is a critical point, the second impotant issue is to defin an unifom criteria for reference populations. Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8

Relationship Between age and the 99% URL in Healthy Individuals Venge 2009

Age-dependent TnT percentiles in Emergencing Room patients. 205 > 65 446 < 65 This slide illustrates the age-dependent TnT pecentile in emegency room patients. As you can see the 99 percentile remains quite stable until 60 years old but dramaticall increase after 65 years old an could reach values as hight as 100. Ola Hammarsten et al., Clinical Chemistry 58:3 (2012)

Le 99° percentile et les facteurs de risque cardiovasculaire Diabetes mellitus 2 4 6 8 10 cTnT-hs (ng/L) (-) (+) Hypertension Dyslipidemia Obesity p<0.001 p=n.s. p=0.017 LVH Current smoking CKD Family history of CVD p=0.043 p=0.004 Otsuka T. et al., Am Heart J, 159(6): 972–8, 2010

The Upper Reference Limit and the 99th percentile…. How to select a reference population ? * Young individuals or age-matched patients ? recommendation of a 2n fold approach in which both younger (< 30 YO) and older (> 30 YO; median 60 to be representative of the ages of cardiac patients) * Apparently healthy questionnaire screening, eGFR, ECG, cardiac imaging * adequate number of individuals : 300 – 500 individuals * Should be done for each test The main question is how to define a reference population. The first question is about age. Should we select young population or age-matched patients ? According to recent review, upper reference limit should be performed in a two fold approach in which both younger people and older could be selected. It is thought that the older population with a median age of 60 will be representative to pateints with cardiac disease. The second question is how to define and healthy population ? We can use only a questionnaire with medical history, or adding creatinine and GFR measuremen, or adding an ECG or adding a cardiac imaging. Of course this inceasing criteria dramatically change he uppe reference value. It is recommanded to perform this detemination in an adequate number of individuals between 3 and 5 hundreds individuals. Finally the uppe reference value should be peformed for each new assay. Apple FS, Collinson PO Clin Chem 2012;58; 58:54–61.

Relationship Between Patient Characteristics and the 99% URL in Healthy Individuals Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8

Le 99° Percentile dans la populaton agée …. En fonction des ATCD cardiaques n=591 n=375

eGFR and the 99° Percentile in elderly Stage 3a : 82 Stage 3b : 30 Stage 4 : 7 Stage 5 : 3 In addition, in these elderly patients we observed a clear schift according to the GFR. Indeed, the 99th percentile is around 50 in patients without kidney fonction impairemern but is near 100 in patients with a GFR lower than 60 ml/min. In conclusion these data strongly suggest that the URL should be determined in a matched population. These observations are supported by the previous reports showing optimal level fo acute myocardial infarction for hs-TnT is closed to 50 and not to 14. At the Emergency departement : 51% hs-cTnT > 14 ng/L (cTnI > 40 ng/L – 18%)

The 99° Percentile in the elderly According to these data we decide to explore the 99th percentile in a cohort of x ambulatory elderly patients. In addition we are able to normlize the 99th percentile for kidney fonction and comorbidity. As you can see, the 99th percentile increase linearly according to age in males (at right) and females (at left) from 23 ng/L to 116 ng/L Kuster et al., submitted

Emergence of TNT : Important issues for hs-Tn. Need for a Universally Accepted Nomenclature Defining Uniform Criteria for Reference Populations Analytical Imprecision in Cardiac Troponin Assays Ruling in / Ruling Out Acute myocardial infarction : Elevated but stable hs-Tn and risk stratification The third point is the analytical imprecision in cardiac troponin assays Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8

Great attention should be paid to analytical Imprecision in Cardiac Troponin Assays Avoiding classical interference Autoantibodies to cTnI or cTnT are found in 5% to 20% of individuals and can reduce detection of cTn Anticoagulant interferences Avoiding lot-to-lot variations Analytical imprecision shoul take into acciount the classical interernee such as lipids, hemolyis, but also anticoagulant. In addition, Autoantibodies to troponins are found in 5 to 20 percent of individuals and can reducedetection of cTn. Finally, since sensibility is a major point of hs-troponin, manufacturer should avoid lot to lot variation.

Implications of Adjustment of High-Sensitivity Cardiac Troponin Assay Adjustement or recalibration of troponin assay could have important implications, specially for low levels. As you can see here, the recalibration beween 2 hs-Tnt lot, leads to an important variation of Tnt levels lower than 50. Kuster et al., Clinical Chemistry 59:3 (2013)

Emergence of TNT : Important issues for hs-Tn. Need for a Universally Accepted Nomenclature Defining Uniform Criteria for Reference Populations Analytical Imprecision in Cardiac Troponin Assays Ruling in / Ruling Out Acute myocardial infarction : Rule out by undetectable hs-Tn at presentation ? Kinetic studies remain necessary to rule in … Very short, short or long kinetic studies? What is the optimal delta change ? 5) Elevated but stable hs-Tn and risk stratification The fourth issue is to Rule in or Rule out vely, a ernati. It has been proposed that undetectable hs-TN at présentation could exclude AMI. However, in emergency room, onl few patiens have undetectable levels, since using an hs-Tn, between 50% and 90% of healty subject have detectable troponins. Thus, kinetic studies remain necessary to rule in Acute myocardial infarction. Two questions are of crucial importance in kinetic studies : first: what is the optimal kinetic, very short, short or long kinetic study. Second, what is the optimal delta change ? Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8

Rapid rule out of acute myocardial infarction using undetectable levels of hs- troponin at admission 2072 consecutive patients Maria Rubini Giménez et al. International Journal of Cardiology xxx (2013) xxx–xxx

Stratification by time from onset Rapid rule out of acute myocardial infarction using undetectable levels of hs- troponin Stratification by time from onset Maria Rubini Giménez et al. International Journal of Cardiology xxx (2013) xxx–xxx

Accelerated diagnostic protocol (ADP) for excluding major adverse cardiovascular events (MACE) using clinic data and hs-cTnI ADAPT cohort : patients with at least 5 min of possible cardiac symptoms APACE cohort : patients presented to the emergency departments in a multinational, multicenter study with symptoms suggestive of AMI hs-TnI at 0 and 2 h < 26.2 ng/l. Very sfort kinetic studies, less than 3 hous, have been proposed to exclusion of acute myocardial infarction. In addition, it has been suggested that accelerated diagnosis protocol, not only rule ou myocardial infction but also exclude major adverse cardiovascular events. Indeed, if we combine clinical data and c-TnI lower than the upper reference value we can exclude with an excellent negative predictive value adverse effect 30 days after the presentation. Cullen et al. JACC Vol. 62, No. 14, 2013

Short kinetic studies should be used with caution An interesting finding in this study was that a conservative estimate of the 1st percentile of cTnT in NSTEMI patients remained below 12 ng/L until 8.5 h after onset of symptoms, and 6 h after arrival at the ER. However, short kinetic studies should be use with caution. Hammarsten has clearly shown, that patients with low hs-Tn values at presentation could have a late increase in hs-Tn value. In these patients with STEMI, circulating Tn could remain below the 99th percentil until _ hours after the onset of symptoms and 6 hours after arrival in the emergency room. Ola Hammarsten et al., Clinical Chemistry 58:3 (2012)

Optimal cutoff should be determined according to Reference Change Value observed in healthy subjects Reference Change Values (RCV) - The “reference change value” is the modification in level that would be expected due to inherent sources of variation. - In order to decide whether a change is due to the patient improving or deteriorating, the observed variation must be greater than the “reference change value” . - The RCV depend on probability [Z], analytical [CVA] and within-subject biological [CVI] variation, if pre-analytical variation is minimized – The second question is bout the optimal cut off. This cutof should be determined according to the reference change value observed in healthy individuals and should be geater than this reference change value. Reference change value is defined as the modification in level that would be expected due to inhrent souces of variation. The RCV depends on analytical CV and within subject biological variation.

Biological variability and reference change value in healthy subjects Variables Very short term (0-1h) Short term (0-3h) Vasile et al. 2010 Scharnhorst et al. 2012 Frankenstein et al. 2012 Nordenskjold et al. 2012 Wu et al. 2009 Vasile et al. 2011   Population Healthy ED* patients with chest pain Stable CAD§ Troponin level ng/L Mean (SD) Median (IQR) Hs-cTnT 12.5 (7.8-18.5) 1.53 (0.3-6.3) 5.5 ND 12.7 (2) Hs-cTnI 1.72 2.2 (1.51-2.80) Analytical variation CVA , a % 2.4 53.5 7.8 4 8.3 3.5 Biological variation CVI , a % 6.3 (2-16.4) 6.2 (1-18.8) 48.2 11 15 7 9.7 3.4 RCV, c % Normal d 12.4 (1-37) 11.3 (4-32) 84.6 38 47 23 Log-normal e 19, -16 (0.6) 19, -16 (1.5) 58; -57.5 46; -32 64; -39 26; -21 +46; -32 45.2; -15.8 Reference value has been evalated for hsnT and hs TnI. As you can see on this slide, both analytical CV and biolological variation are low when the troponin levels are between the limit of detection and the 99 percentile. By contrast, Vasille observe large variations but for value lower tan the detection limit. We have obsrved he same result in very short term and short term kinetic for levels around the ççth percentile. As a result, the reference change value range from 5% to 50 %, suggesting that the optimal cutoff will be between 20 and 30%. Dupuy et al., Clin Chim Acta. 2013 Jul 11;425C:62-63

Diagnostic accuracy of absolute and relative changes Siemens D absolute > D relative Beckman Coulter K. Wildi et al., International Journal of Cardiology xxx (2013) xxx–xxx

Combination of absolute and relative Changes in Cardiac Troponin (I or T) Concentrations 830 unselected patients with suspected acute myocardial infarction Furthermore it has been recommanded using a combination of absolute and relative changes in cardiac troponin to dignosis AMI. Indeed for s-TnT, the relative change is about 30 % and the absolute change is abou 7. Th combined approch lead to and aea under curve of 98% For hs-TnI, the relative change is 80 and te absolute change is 10. Here again, the combined approach leads to an area under curve of 96 or 97 Affan Irfan et al., The American Journal of Medicine (2013) 126, 781-788

In summary : How to use hs-Tn ? In sumary, what are the recommandations to th use of sTn in acute myocardail infarction ? First at all, biomarkers should be used in combination to clinical data. Secondly, kinetic study should be performed, at least for 3 hours and 6 hours will be optimal for high risk patients. The cut off could be diffeetn according to the troponin level at presentation. If the troponin level is lower that the URL, teh cutoof will be at least 50 % of increase. If the ltroponin level at pesentation is greater than the upper reference limit, the relative change could be 20%.

Emergence of TNT : Important issues for hs-Tn. Need for a Universally Accepted Nomenclature Defining Uniform Criteria for Reference Populations Analytical Imprecision in Cardiac Troponin Assays Ruling in / Ruling Out Acute myocardial infarction : Elevated but stable hs-Tn and risk stratification The last questions will concern the usefullness of an elevated but stable troponin in stratification of patients with non acue coronary sndrome. Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8

The increase in « positive » cTn in emergency room requires an exclusion biomarker In our Institution : 120 troponins per day 3600 per month including 900 from emergency department 16% 38% circulating cTnI => Kinetic studies cTn-I before mai 2011 µg/L 22% 21% 39% 5% 77% > URL 0,2% 18% => Kinetic studies ?? In fac, the increase in positive troponins in emergency room requires an exclusion biomarkers In our institution in Montpellier, we performed about 120 troponins determination per day, thus about 3600 pe moth including 900 fromemergency department. Using classical troponin I we observed 38 % of positive value leading to exploration vit kinetic studies. In may 2012, we change from TnI to a hs-TnT and we observed 77% of troponins upper thant the 99th percentile. Are all these patients requiring a kinetic study ? In order to select patient who realy need a kinetic study we need an exclusion marker with very short term kinetic such as copeptin or HFABP 12% cTnT-hs after may 2012 ng/L 29% 33%

Increase hs-Tn a marker of poor outcome in Chronic heart failure Etude VaL-HeFT In fact it has been clarly shown that in chroic eart failure, an increase in tn value is a marke of poor outcome. Latini R et al Circulation 2007;116:1242-1249.

La troponine sensible et survie…. Omland 2009 Meune 2012

Increase hs-Tn a marker of poor outcome in Chronic kidney failure % de patients cTnT > 10 60 CTnI > 70 P< 0.001 40 20 Similarly, it has been shown that both tnI and tnT increase in end stage renal disease and that bot biomakers are associated with an increase in mortality. Thus it could be suggested that a patient with stable positive Tn should be addressed to cardiology for exploration may be via stress test. Stage 3 Stage4 Stage 5 Abbas NA et al. Clinical Chemistry 51:11; 2059–2066 (2005)

Les troponines en IRC : métaanalyse cTnT – cadiac death cTnT – all cause mortality Khan et al. Ciculation Circulation. 2005;112:3088-3096

Biomarqueurs des syndromes coronariens aigus Les biomarqueurs permettent le diagnostic d’IDM devant SCA sans élévation du segment ST: La troponine est la pierre angulaire de la démarche diagnostique La myoglobine peut-être un marqueur d’exclusion Les autres marqueurs ne sont plus indiqués Les hs-Tn Doivent répondre à un CV < 10% au 99° percentile Doivent détecter plus de 50 % des valeurs dans une population « normale » Le « seuil » du 99° percentile doit prendre en compte l’âge et les comorbidités ? L’infarctus doit être défini sur une variation relative et absolu Les cinétiques courtes doivent être utilisées avec prudence Quelle signification pour une troponine élevée ? Une troponine circulante élevée (et stable) est un facteur de risque cardiovasculaire (remodelage ?) Une stratégie multimarqueur ?

Slides enlevées versions courtes

Multi-marker strategy enhances ACS diagnosis (AMI and UA) in emergency department. The “Rule Out Myocardial Infarction using Computer Assisted Tomography” (ROMICAT) trial. Truong et al. Am Heart J 2012;163:972-9.

Relationship between cardiac imaging and biomarkers Cardiac computed tomography in 328 patients RWMA = Regional Wall Motion Abnormalities Truong et al. Am Heart J 2012;163:972-9.

Slides non utilisées

Quelle variabilité en dehors de l’IDM ? The third finding in our study was that the 97.5th percentile for change in the cTnT concentration; i.e., the upper reference limit, was 51%– 67% in actual coronary care unit patients without MI. Ola Hammarsten et al., Clinical Chemistry 58:3 (2012)

Emergence of TNT : Important issues for hs-Tn. Need for a Universally Accepted Nomenclature Defining Uniform Criteria for Reference Populations Discriminating Between Acute and Non acute Causes of hs-cTn Elevations Distinguishing Between Type 1 and Type 2 AMI Type 1 AMI is caused by a primary coronary event, usually plaque rupture. Type 2 AMI typically evolves secondary to ischemia from an oxygen demand/supply mismatch such as severe tachycardia and hypo- or hypertension and the like, with or without a coronary abnormality. For now, clinical judgment is recommended 5) Analytical Imprecision in Cardiac Troponin Assays 6) Ruling Out AMI 7) Investigating the Causes of Positive Troponin Values in Non-AMI Patients 8) Risk Stratifying Patients With Non acute Coronary Syndrome Conditions Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8

Ce qui change …. Avec la cT «sensible » Dénomination Troponine I ultra sensible = TnI–us Troponine T hyper sensible = TnT–hs Sensibilité analytique + basse Présence de troponines chez le sujet « normal » Hypothèses: renouvellement physiologique (sport, âge…) giannoni 2009 faux positifs classiques mise en cause du 99th percentile panteghini 2009 mise en cause des AC : leur spécificité, leur imonuréactivité avec les isoformes, interférences avec AC lippi 2009 facteurs génétiques pour la TnI et la TnT lippi 2009 Proposition d’un passeport pour les critères hs troponines apple 2009

Relation taux et sévérité… Niveau de cTnT-hs en µg/l Niveau de cTnT-hs en ng/l 10 10 000 IDM très étendu, myocardite 1 1000 IDM étendu, myocardite, tako-tsubo, embolie pulmonaire 0.100 100 IDM peu étendu, IDM précoce, myocardite, Tako-Tsubo, EP, choc, ICC, poussée hypertensive 0.050 50 Micro-IDM, IDM précoce, myocardite, Tako-Tsubo, EP, choc, ICC, poussée hypertensive, coronarien stable 0.014 14 99th percentile 0.010 Coronarien stable, ICC, anomalies subcliniques 0.005 5 Patient sain Twerenbold 2011