biomarqueurs du syndrome coronarien aigu
DESCRIPTION
Biomarqueurs du syndrome coronarien aigu. JP Cristol, S Badiou, AS Bargnoux, N Kuster, AM Dupuy. Biomarkers associated with various pathophysiological processes of acute coronary syndromes. Risk Factors For cardiovascular disease:. Myocardial Infarction Biomarkers. cTnI / TnT. Necrosis. - PowerPoint PPT PresentationTRANSCRIPT
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Biomarqueurs du syndrome coronarien aigu
JP Cristol, S Badiou, AS Bargnoux, N Kuster, AM Dupuy.
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Biomarkers associated with various pathophysiologicalprocesses of acute coronary syndromes.
Chan and Ng BMC Medicine 2010, 8:34
Biomarkersof ACS
Risk FactorsFor cardiovascular disease:
Myocardial Infarction Biomarkers
MPOMetalloproteinase
Leucocytes Activation
CRP , Il-6sPLA2 …
Inflammation
EndothelialActivation/
Dysfunction
AdrenomedullinEndothelin
Necrosis
cTnI / TnT
CKMB
H-FABP
AVP Axis activation
Copeptin
Biomechanicalstress
BNP NT-pro-BNP
ANP
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De l’occlusion partielle vers l’occlusion totale
Plaque fissurée
Thrombus
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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
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Stratifier le risque : Scores clinico-biologiques : Score de TIMI
Ris
que
de m
orta
lité
ou d
e co
mpl
icat
ions
gra
ves
(Antman EM, The TIMI risk score for unstable angina/non-ST elevation MI, JAMA 2000 ; 284: 835-842)
(http://www.mdcalc.com/uanstemitimiscore)
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Classification des syndromes coronariens aigus
Angorstable
SCA non ST + SCA ST +
AngorInstable :
Pas d’élévationde cTn
NSTEMI :
IDM non ST+IDM sans onde Q
cTn positive
Nécessite cinétique de cTn ou nouveaux marqueurs
STEMI :
IDM ST+
cTn positive
Désobstruction en urgence
D’après «A consensus document of The Joint European Society of Cardiology / American College of Cardiology. Eur. Heart J., 2000; 21:1502-13.
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ECG
ST + = extrême urgence médicale (H6)ST + = extrême urgence médicale (H6) Occlusion coronaireDésobstruction !! (Angioplastie, thrombolyse)
SCA ST+SCA ST+
Un sus-décalage du segment ST dans 2 Un sus-décalage du segment ST dans 2 dérivations contiguës ddérivations contiguës d’’un territoire un territoire coronairecoronaire
dd’’au moins 0,1 mV dans les dérivations au moins 0,1 mV dans les dérivations frontales (D1, D2, D3, aVL, aVF), frontales (D1, D2, D3, aVL, aVF), précordiales gauches (V4, V5, V6) ou précordiales gauches (V4, V5, V6) ou postérieures (V7, V8, V9)postérieures (V7, V8, V9)
dd’’au moins 0,2 mV dans les dérivations au moins 0,2 mV dans les dérivations droites (V1, V2, V3)droites (V1, V2, V3)
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(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)
Angioplastie
Efficacité de la désobstruction
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ECG
• Pas de ST +• Signes électriques atypiques ou ECG normal
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• 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+ ?
(European Heart Journal 2007)
Epidémiologie comparée des SCA ST + et ST -
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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))
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• Clef de voûte de la PEC• Clinique et ECG insuffisante• Marqueurs biologiques, incontournables
Stratification du risque
SCA ST+cTn élevée
Pas de marqueurs
SCA ST -Cinétique cTn Biomarqueurs
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Biomarqueurs et infarctus
cTn risecTn fall
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Classification
Spécificité
+
++
+++
CK-LDH-Myoglobine
CK-MB
cTnI ou T
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La place de la CK-MB actuellement
En discussionlors d’une suspicion d’un 2éme IDMpour évaluer la taille de l’IDMen présence d’une IRC
Suspicion de faux positifs de la cTn
National Academy of Clinical Biochemistry (NACB) en 2007dosage justifié si cTn non disponible
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La h-FABP
H-FABP ou heart-type fatty acid-binding proteinprotéine liée aux acides gras soluble de 132 acides aminésproche de la myoglobine
Les limites cardiospécificité limitée, étroitesse de la fenêtre diagnostique (20 à 30 h) élimination rénale quasi exclusive
Dosageréactif Randoximmunoturbidimétrique sur Cobas
2936 publications entre 1979-2011
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La h-FABP
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La h-FABP
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The combination of H-FABP and Tnincreased the NPV
Mc Mahon 2011
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Troponins : the corner stone of the Universal definition of myocardial infarction
ESC Guidelines for the management of acute myocardial infarction. European Heart Journal, 2012
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The spectrum of acute coronary syndromes :STEMI – NSTEMI – Unstable angina
Hamm, et al., Eur Heart J. 2011 Dec;32(23):2999-3054
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Kinetic studies with troponins :six hours to detect myocardial infarction
Myocadial infarction
cTn risecTn fall
No early change in cTn
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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
TROPONINES
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The goal for sensitive troponins :diagnosis of AMI as early as possible.
Reichlin et al. NEJM 2009
Roche TnTRoche TnT
718 Pts with acute chest painTn levels at baseline
Diagnostic accuracy of Tn at presentation according to time since onset of chest pain
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Emergence of TNT : Important issues for hs-Tn.
1) Need for a Universally Accepted Nomenclature
2) Defining Uniform Criteria for Reference Populations
3) Analytical Imprecision in Cardiac Troponin Assays
4) Ruling in / Ruling Out Acute myocardial infarction :
5) Elevated but stable hs-Tn and risk stratification
Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8
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Un passeport pour les troponines
Apple FS (2009) Clin Chem, 55(7):1303 1396
- Quelle signification :Un marqueur de SCA ?Un marqueur pronostic ?Un marqueur de remodelage ?
- Quelle troponine ? T ou I ?
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Troponine assays classified as « guideline acceptable »
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Une troponine “positive” :quelle signification ?
Seuil clinique
?
Critères d’interprétation :
-Le 99° percentile (14 ng/L pour hs-TnT)
-La valeur du delta en cinétique
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Emergence of TNT : Important issues for hs-Tn.
1) Need for a Universally Accepted Nomenclature
2) Defining Uniform Criteria for Reference Populations
3) Analytical Imprecision in Cardiac Troponin Assays
4) Ruling in / Ruling Out Acute myocardial infarction :
5) Elevated but stable hs-Tn and risk stratification
Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8
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Venge 2009
Relationship Between age and the 99% URL in Healthy Individuals
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Age-dependent TnT percentiles in Emergencing Room patients.
651 patients205 > 65446 < 65
Ola Hammarsten et al., Clinical Chemistry 58:3 (2012)
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Le 99° percentile etles facteurs de risque cardiovasculaire
Diabetesmellitus
02468
10cT
nT
-hs
(ng
/L)
(-) (+) (-) (+) (-) (+) (-) (+)
Hypertension Dyslipidemia Obesity
p<0.001 p=n.s. p=n.s. p=0.017
02468
10
cTn
T-h
s (n
g/L
)
(-) (+) (-) (+) (-) (+) (-) (+)
LVH Currentsmoking
CKD Family historyof CVD
p=0.043 p=0.004 p<0.001 p=n.s.
Otsuka T. et al., Am Heart J, 159(6): 972–8, 2010
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The Upper Reference Limitand the 99th percentile….
Apple FS, Collinson PO Clin Chem 2012;58; 58:54–61.
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 healthyquestionnaire screening, eGFR, ECG, cardiac imaging
* adequate number of individuals :300 – 500 individuals
* Should be done for each test
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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
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Le 99° Percentile dans la populaton agée ….En fonction des ATCD cardiaques
n=591
n=375
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eGFR and the 99° Percentile in elderly
n=253 n=122Stage 3a : 82 Stage 3b : 30Stage 4 : 7Stage 5 : 3
At the Emergency departement : 51% hs-cTnT > 14 ng/L(cTnI > 40 ng/L – 18%)
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The 99° Percentile in the elderly
Kuster et al., submitted
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Emergence of TNT : Important issues for hs-Tn.
1) Need for a Universally Accepted Nomenclature
2) Defining Uniform Criteria for Reference Populations
3) Analytical Imprecision in Cardiac Troponin Assays
4) Ruling in / Ruling Out Acute myocardial infarction :
5) Elevated but stable hs-Tn and risk stratification
Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8
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Great attention should be paid to analytical Imprecision in Cardiac Troponin
Assays
1) Avoiding classical interference
2) Autoantibodies to cTnI or cTnT are found in 5% to 20% of individuals and can reduce detection of cTn
3) Anticoagulant interferences
4) Avoiding lot-to-lot variations
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Implications of Adjustment of High-Sensitivity Cardiac Troponin Assay
Kuster et al., Clinical Chemistry 59:3 (2013)
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Emergence of TNT : Important issues for hs-Tn.
1) Need for a Universally Accepted Nomenclature
2) Defining Uniform Criteria for Reference Populations
3) Analytical Imprecision in Cardiac Troponin Assays
4) 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
Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8
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Rapid rule out of acute myocardial infarction using undetectable levels of hs- troponin at admission
Maria Rubini Giménez et al. International Journal of Cardiology xxx (2013) xxx–xxx
2072 consecutive patients
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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
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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 symptomsAPACE cohort : patients presented to the emergency departments in a multinational, multicenter study with symptoms suggestive of AMIhs-TnI at 0 and 2 h < 26.2 ng/l.
Cullen et al. JACC Vol. 62, No. 14, 2013
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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.
Ola Hammarsten et al., Clinical Chemistry 58:3 (2012)
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Optimal cutoff should be determined according to Reference Change Value observed in healthy
subjects
1) 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 –
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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
Healthy
Healthy
ED* patients with
chest pain
Healthy
Stable CAD§
Healthy
Healthy
Troponin level ng/LMean (SD) Median (IQR)
Hs-cTnT
12.5 (7.8-18.5)
Hs-cTnT
12.5 (7.8-18.5)
Hs-cTnT
1.53 (0.3-6.3)
Hs-cTnT
5.5
Hs-cTnT
ND
Hs-cTnT
12.7 (2)
Hs-cTnI
1.72
Hs-cTnI
2.2 (1.51-2.80)
Analytical variation
CVA , a % 2.4 2.4 53.5 7.8 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 ND ND
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
Biological variability and referencechange value in healthy subjects
Dupuy et al., Clin Chim Acta. 2013 Jul 11;425C:62-63
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Diagnostic accuracy of absolute andrelative changes
Siemens
Beckman Coulter
absolute > relative
K. Wildi et al., International Journal of Cardiology xxx (2013) xxx–xxx
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Combination of absolute and relative Changesin Cardiac Troponin (I or T) Concentrations
830 unselected patients with suspected acute myocardial infarction
Affan Irfan et al., The American Journal of Medicine (2013) 126, 781-788
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In summary : How to use hs-Tn ?
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Emergence of TNT : Important issues for hs-Tn.
1) Need for a Universally Accepted Nomenclature
2) Defining Uniform Criteria for Reference Populations
3) Analytical Imprecision in Cardiac Troponin Assays
4) Ruling in / Ruling Out Acute myocardial infarction :
5) Elevated but stable hs-Tn and risk stratification
Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8
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The increase in « positive » cTn in emergency room requires an exclusion biomarker
39%
21%
22%
16% 38% circulating cTnI
cTn-I before mai 2011 µg/L
cTnT-hs after may 2012 ng/L
33%
29%
12%
18%
5%0,2% 77% > URL
In our Institution : 120 troponins per day 3600 per month including 900 from emergency department
=> Kinetic studies
=> Kinetic studies ??
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Increase hs-Tn a marker of poor outcomein Chronic heart failure
Latini R et al Circulation 2007;116:1242-1249.
Etude VaL-HeFT
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La troponine sensible et survie….
Omland 2009
Meune 2012
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cTnT > 10
0
20
40
60
Stage 3 Stage4 Stage 5
CTnI > 70
P< 0.001
% de patients
Abbas NA et al. Clinical Chemistry 51:11; 2059–2066 (2005)
Increase hs-Tn a marker of poor outcomein Chronic kidney failure
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Les troponines en IRC : métaanalyse
Khan et al. Ciculation Circulation. 2005;112:3088-3096
cTnT – all cause mortality cTnT – cadiac death
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Biomarqueurs des syndromes coronariens aigusI) 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
II) 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
III) Quelle signification pour une troponine élevée ?- Une troponine circulante élevée (et stable) est un facteur de risque
cardiovasculaire (remodelage ?)
IV) Une stratégie multimarqueur ?
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Slides enlevées versions courtes
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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.
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Relationship between cardiac imaging and biomarkers
Truong et al. Am Heart J 2012;163:972-9.
Cardiac computed tomography in 328 patients
RWMA =Regional Wall Motion Abnormalities
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Slides non utilisées
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Quelle variabilité en dehors de l’IDM ?
The third finding in our studywas that the 97.5th percentile for change in the cTnTconcentration; 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)
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Emergence of TNT : Important issues for hs-Tn.
1) Need for a Universally Accepted Nomenclature2) Defining Uniform Criteria for Reference Populations3) Discriminating Between Acute and Non acute Causes of hs-cTn
Elevations4) 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 oxygendemand/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 Assays6) Ruling Out AMI7) Investigating the Causes of Positive Troponin Values in Non-AMI Patients8) Risk Stratifying Patients With Non acute Coronary Syndrome Conditions
Frederick K. Korley and Allan S. Jaffe, J Am Coll Cardiol 2013;61:1753–8
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Ce qui change …. Avec la cT «sensible »
DénominationTroponine 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 classiquesmise 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
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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 10 Coronarien stable, ICC, anomalies subcliniques
0.005 5 Patient sain
Twerenbold 2011