myocarditis – new onset dilated cardiomyopathy · 2017-05-27 · eur j heart failure 2005, june...
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Stamatis Adamopoulos, MD, PhD (Imperial College)
Heart Failure-Transplant Unit
Onassis Cardiac Surgery Center, Athens, Greece
Myocarditis – New Onset Dilated Cardiomyopathy
Current State of Knowledge on Aetiology, Diagnosis and Therapy of Myocarditis: Time for a National Registry
Thessaloniki, May 2017
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Evolution of Acute Viral Myocarditis
R Dennert et al, Eur Heart J 2008, July 9
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R Dennert et al, Eur Heart J 2008, July 9
Persistent or Increasing Cardiac Dysfunction
Proposal of Diagnostic Approach for Patients with Suspected Myocarditis
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New Echo Findings Correlate with Intramyocardial Inflammation in EMB of Patients with Acute Myocarditis and Inflammatory Cardiomyopathy
F Escher et al, Mediators Inflamm
2013
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R Dennert et al, Eur Heart J 2008, July 9
Persistent or Increasing Cardiac Dysfunction
Proposal of Diagnostic Approach for Patients with Suspected Myocarditis
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✓ Clinical scenario 1 EMB should be performed in the setting of unexplained new-onset HF of <2 weeks’ duration associated with normal-sized or dilated left ventricle in addition to hemodynamic compromise (dd: lymphocytic vs GCM vs necrotizing eosinophilic) (Class I, Evidence B)
✓ Clinical scenario 2 EMB should be performed in the setting of unexplained new-onset HF of 2 weeks’ to 3 months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, Mobitz type II 2nd- or 3rd-degree AV heart block, or failure to respond to usual care within 1 to 2 weeks (exclude GCM) (Class I, Evidence B)
The Role of Endomyocardial Biopsy in the Management of Cardiovascular DiseaseAHA/ACC/ESC scientific statement, Eur Heart Journal 2007, October 24
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Diagnosis, Treatment, and Outcome of Giant-Cell Myocarditis in the Era of Combined Immunosuppression
R Kandolin et al, Circ Heart Fail 2013,
Januaryimmunosuppression
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✓ Clinical scenario 3 EMB is reasonable in the clinical setting of unexplained HF of >3 months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, Mobitz type II 2nd- or 3rd-degree AV heart block, or failure to respond to usual care within 1 to 2 weeks (exclude cardiac sarcoidosis) (Class IIa, Evidence C)
✓ Clinical scenario 4 EMB is reasonable in unexplained HF associated with a DCM of any duration with suspected allergic reaction in addition to eosinophilia (Class IIa, Evidence C)
The Role of Endomyocardial Biopsy in the Management of Cardiovascular DiseaseAHA/ACC/ESC scientific statement, Eur Heart Journal 2007, October 24
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Sequential Cardiac Magnetic Resonance Imaging of Acute Eosinophilic MyocarditisBNP 1,031 pg/mL, troponin I 2.99 ng/mL and blood eosinophils 13,800/µL
M Kimura et al, Intern Med 2013
Day 14
Day 42
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✓ Clinical scenario 1 EMB should be performed in the setting of unexplained new-onset HF of <2 weeks’ duration associated with normal-sized or dilated left ventricle in addition to hemodynamic compromise (dd: lymphocytic vs GCM vs necrotizing eosinophilic) (Class I, Evidence B)
✓ Clinical scenario 2 EMB should be performed in the setting of unexplained new-onset HF of 2 weeks’ to 3 months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, Mobitz type II 2nd- or 3rd-degree AV heart block, or failure to respond to usual care within 1 to 2 weeks (exclude GCM) (Class I, Evidence B)
✓ Clinical scenario 3 EMB is reasonable in the clinical setting of unexplained HF of >3 months’ duration associated with a dilated left ventricle and new ventricular arrhythmias, Mobitz type II 2nd- or 3rd-degree AV heart block, or failure to respond to usual care within 1 to 2 weeks (exclude cardiac sarcoidosis) (Class IIa, Evidence C)
✓ Clinical scenario 4 EMB is reasonable in unexplained HF associated with a DCM of any duration with suspected allergic reaction in addition to eosinophilia (Class IIa, Evidence C)
✓ Clinical scenario 9 EMB may be considered in the setting of unexplained, new-onset HF of 2 weeks’ to 3 months’ duration associated with a dilated LV, without new ventricular arrhythmias, Mobitz type II 2nd- or 3rd-degree AV heart block that responds to usual care within 1 to 2 weeks (Class IIb, Evidence B)
The Role of Endomyocardial Biopsy in the Management of Cardiovascular DiseaseAHA/ACC/ESC scientific statement, Eur Heart Journal 2007, October 24
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Clinical presentations
▪ Acute chest pain, pericarditic, or pseudo-ischaemic ▪ New-onset (days up to 3 months) or worsening of: dyspnoea at rest or exercise, and/or fatigue, with or without left and/or right heart failure signs ▪ Subacute/chronic (>3 months) or worsening of: dyspnoea at rest or exercise, and/or fatigue, with or without left and/or right heart failure signs ▪ Palpitation, and/or unexplained arrhythmia symptoms and/or syncope, and/or aborted sudden cardiac death ▪ Unexplained cardiogenic shock
Diagnostic criteria
I. ECG/Holter/stress test features II. Myocardiocytolysis markers Elevated TnT/TnI III. Functional and structural abnormalities on cardiac imaging (echo/angio/CMR) New, otherwise unexplained LV and/or RV structure and function abnormality (including incidental finding in apparently asymptomatic subjects) IV. Tissue characterization by CMR Oedema and/or LGE of classical myocarditic pattern
Diagnostic Criteria for Clinically Suspected Myocarditis
Clinically suspected myocarditis if ≥1 clinical presentation and ≥1 diagnostic criteria from different categories
AL Caforio et al, Eur Heart J 2013, September
ESC Position Statement
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Probability for Myocarditis Patients of Remaining Free from Death or Transplantation According to Clinical and Histological Presentation
ALP Caforio et al, Eur Heart J 2007;28:1326-1333
Giant cell Active lymphocytic Borderline
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U Kühl et al, Circulation 2005,
February 22
S Adamopoulos et al, Int J Cardiol 2013, September
P Lurz et al, JACC Cardiovasc Imaging 2012, May
High Prevalence of Viral Genomes and Multiple Viral Infections in the Myocardium of Adults with “Idiopathic” Left Ventricular Dysfunction
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Viral Persistence in the Myocardium is Associated with Progressive Cardiac DysfunctionU Kühl et al, Circulation 2005;112:1965-1970
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I Kindermann et al, Circulation 2008, August 5
Predictors of Outcome in Patients with Suspected Myocarditis
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Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper
MG Friedrich et al, J Am Coll Cardiol 2009, April 28
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Diagnostic Performance of CMR Imaging Compared with EMB in Patients with Suspected Myocarditis
P Lurz et al, JACC Cardiovasc Imaging 2012, May
Acute ≤14 days
Chronic > 14 days
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T1-Mapping for the Diagnosis of Acute Myocarditis using CMR Comparison of T2-Weighted and Late Gadolinium Enhanced Imaging
VM Ferreira et al, JACC Cardiovascular Imaging 2013,
October
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Long-Term Follow-Up of Biopsy-Proven Viral Myocarditis
Predictors of Mortality and Incomplete Recovery
S Grün et al, JACC 2012, May 1
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Predictors of Outcome
Parvovirus B19 Endomyocardial Biopsy
S Greulich et al, Clin Res Cardiol 2016
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The Progression from Acute Injury to Chronic Dilated Cardiomyopathy May Be Simplified into a Three-Stage Process
Pathogenesis of MyocarditisI Kindermann et al, JACC 2012, February 28
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A Clinical Trial of Immunosuppressive Therapy for Myocarditis
J Mason et al, New Engl J Med 1995, August 3 for The Myocarditis Treatment Trial Investigators
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Immunosuppressive Therapy for Active Lymphocytic Myocarditis
Virological and Immunologic Profile of Responders vs Nonresponders
A Frustaci et al, Circulation 2003, February 18
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HP Schultheiss et al, EHJ 2011, June 23
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Frustaci A et al, Eur Heart J 2009, August
Randomized Study on the Efficacy of Immunosuppressive Therapy in Patients with Virus-Negative Inflammatory Cardiomyopathy: the TIMIC Study
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Long-term Outcome of Patients with Virus-Negative Chronic Myocarditis or Inflammatory Cardiomyopathy
Immunosuppresive Therapy
F Escher et al, Clin Res Cardiol 2016
114 pts, 6 months prednizone+azathioprine
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Successive Ιmmunosuppressive Τreatment of Fulminant Myocarditis that is Refractory to Mechanical Circulatory Support
H Nakashima et al, Am J Case Rep 2013 V Manins et al, J Heart & Lung Transpl 2009, Nov
Corticosteroids ATG
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Chromosomally Ιntegrated Ηuman Ηerpesvirus-6 in Ηeart Failure: Prevalence and Treatment
U Kühl et al, Eur Heart J 2015, January
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Pathogen-Driven Treatment Strategy in New Onset Dilated Cardiomyopathy: Impact on Ventricular Function and Clinical Outcome
LVEF non-fatal complications
fatal and non-fatal complications
A Gkouziouta et al, Int J Cardiol 2016, April 15
Herpes-Chlamydiae
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Roles of MicroRNAs Involved in Myocarditis
S Heymans et al, JACC 2016, November 29
ProtectivePro-inflammatory
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MicroRNA Profiling Identifies MicroRNA-155 as an Adverse Mediator of Cardiac Injury and Dysfunction during Acute Viral Myocarditis
MF Corsten et al, Circ Res 2012, August 3
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IL-1 Effects on Heart Function
Van Tassell et al, 2015; Curr Heart Fail Rep
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Formation of the Inflammasome in Acute Myocarditis
S Toldo et al, Intern J Cardiol 2104
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IL-1 Receptor Blockade in Experimental Myocarditis Model
A - C: Coxsackie infected control group
D - F: Coxsackie infected mice with blocked IL-1 receptor
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Anakinra as Treatment Option in MyocarditisAD Choi et al, Intern J Cardiol 2014
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Clinical Trial of Anakinra in Myocarditis
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M Pauschinger et al, Eur J Heart Failure 2005, June
Carvedilol Improves Left Ventricular Function in Murine Coxsackievirus-Induced Acute Myocarditis
Carvedilol attenuated over-expression of myocardial TGF-β1, IL-1β and MMP-8 mRNA expression significantly and induced a relevant IL-10 mRNA expression in the infected mice
CD4-T-lymphocytes
CD8-T-lymphocytes
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➢ Eplerenone improved survival, reduced inflammation and suppressed expression of genes related to fibrosis and remodeling
Xiao et al, Eur J Heart Fail 2009
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www.emeka.org.gr/databases
Myocarditis National Registry200 patients recruited and…counting!
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Ελληνική Καταγραφή (Registry) Μυοκαρδιτίδων
✓Ποιές παράµετροι από την CMR ή/και την ηχωκαρδιογραφία ή/και τον ιολογικό έλεγχο ή/και τον ορολογικό έλεγχο έχουν την µεγαλύτερη προγνωστική αξία
✓Ποια είναι η χρησιµότητα της ΕΜΒ στην διάγνωση, πρόγνωση και θεραπεία της µυοκαρδίτιδας? Πιθανή διεύρυνση ενδείξεων σε κατηγορίες ασθενών πέραν από τις προβλεπόµενες από τις κατευθυντήριες οδηγίες (π.χ. υποτροπιάζουσα µυοκαρδίτιδα)
✓Ποιές υποοµάδες ασθενών θα µπορούσαν να ωφεληθούν από στοχευµένη αντιϊκή ή ανοσοκατασταλτική θεραπεία? Ποια είναι η βέλτιστη διάρκεια της θεραπείας αυτής?
✓Πότε και πως θα διακόψουµε την κλασσική θεραπεία καρδιακής ανεπάρκειας στους ασθενείς που αποκαθιστούν πλήρως την καρδιακή τους λειτουργία?
✓Αρχίζουµε θεραπεία ΚΑ σε ασθενείς µε καλή καρδιακή λειτουργία?
Στόχοι: Διαγνωστικοί- Θεραπευτικοί
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Greek Myocarditis Registry A Preliminary Analysis
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Demographicsmedian (IQR)
Sex male (%) 81.94%
Age years 29.7 (20.45 - 37.75)
Smoking (%) 29.86%
Hypertension (%) 4.86%
Dyslipidemia (%) 10.42%
Family history (%) 13.89%
Diabetes (%) 0.69%
Obesity (%) 5.56%
BMI kg/m2 25.08 (23.19 - 28.34)
Chronic drugs (%) 9.72%
Recent drugs (%) 13.19%
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Acute
Chronic
MJ Coronado et al,Am J Physiol Heart Circ Physiol 2012,
February 10
Testosterone and Interleukin 1β Increase Cardiac Remodeling during Coxsackievirus B3 Myocarditis via Serpin A 3n
Myocarditis and DCM occurmore frequently in men than in women
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MYKKE Registry - Children and Adolescents
Male: 66.4%, female: 33.6% (n = 149)
DR Messroghli et al, Am Heart J 2017, May
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Demographics
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Infections
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Symptoms
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Echocardiography
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CMR findings
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CMR findings
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CMR findings
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Treatment
p = 0.0001548
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TnI change to LVEF change
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Ευχαριστούμε τα κέντρα που συμμετείχανΩνάσειο Καρδιοχειρουργικό Κέντρο
Πανεπιστηµιακό Νοσοκοµείο Αλεξανδρούπολης
Mediterraneo 251 Γενικό Νοσοκοµείο Αεροπορίας
ΑΧΕΠΑ Ασκληπιείο Βούλας
Νοσοκοµείου Ρίου Β’ Πανεπιστηµιακή Καρδιολογική Κλινική
ΓΝΑ “Γεννηµατάς” Α’ Πανεπιστηµιακή Καρδιολογική Κλινική
ΕΛΠΙΣ ΓΝΑ “Σισµανόγλειο - Αµαλία Φλέµινγκ”
ΓΝΑ Ιπποκράτειο ΓΝ Βόλου
Νοσοκοµείο Χαλκίδας Νοσοκοµείο Έδεσσας
ΠεΠαΓΝΗ Νοσοκοµείο Καβάλας
Κωνσταντοπούλειο Γενικό Νοσοκοµείο
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✓ 13/05/2015 ! περικογχικό οίδηµα Χωρίς άλλη συµπτωµατολογία Χορήγηση αντιισταµινικών και έπειτα προσθήκη κορτιζόνης (στις 18/05/2015)
✓ 23/05/2015 ! εισαγωγή στο Γ.Ν. Χαλκίδας Εµπύρετο µε ρίγος ↑ µυοκαρδιακών ενζύµων Λεµφαδενοπάθεια Toxoplasma: IgM (-) IgG (-) CMV: IgM (-) Monotest (-) Wright (-)
ΙΣΤΟΡΙΚΟ Γυναίκα 32 ετών
IgG (+)
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Με απόφαση της ασθενούς µεταφορά στο Γ.Ν. Λαϊκό
✓ ↑↑↑ µυοκαρδιακών ενζύµων (cTnI > 9,000 ng/mL) ✓ ↑ BNP ✓ ΗΚΓ ! χαµηλά δυναµικά ✓ Ηχωκαρδιογραφική µελέτη
❖ LVEF ≈ 40% ❖ ↓ συσπαστικότητας κυρίως ΜΚΔ – κορυφής ❖ Μικρού βαθµού περικαρδιακή συλλογή ≈ 0.9 cm στο οπίσθιο τοίχωµα
✓ Αγωγή Tb Lopresor 100mg ¼ x 2 iv Lasix amp 20mg 1 x 2 Διακοπή Στεροειδών
Διακοµιδή στο ΩΚΚ για περαιτέρω διερεύνηση (4/6/2015)
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Ηχωκαρδιογραφική µελέτη (04/06/2015) ❖ LVEF ≈ 45% ❖ Αριστερή κοιλία φυσιολογικών διαστάσεων µε οριακό πάχος τοιχωµάτων
1η ΝΟΣΗΛΕΙΑ ΩΚΚ
❖ Ικανοποιητική λειτουργικότητα δεξιάς κοιλίας µε SRV = 11 cm/s ❖ Μικρή/µέτρια περικαρδιακή συλλογή χωρίς επιπωµατισµό ❖ Χωρίς αξιόλογες βαλβιδικές ανεπάρκειες ❖ Κατά την διάρκεια της µελέτης ! ναυτία και εφίδρωση ! επεισόδιο ασυστολίας ! ΚΑΡΠΑ ! άµεση ανταπόκριση και αποκατάσταση ρυθµού
Ζωτικά σηµεία εισόδου ❖ 110/70 mmHg ❖ 102 bpm ❖ 12 αναπνοές/min ❖ 35.9 oC
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Ηχωκαρδιογραφική µελέτη (08/06/2015) ✓ Οίδηµα µυοκαρδίου µε διατήρηση ικανοποιητικής λειτουργικότητας ✓ LVEF ≈ 50 – 55% ✓ Δεξιά κοιλία µε καλή λειτουργικότητα ✓ Μικρή περικαρδιακή συλλογή
Νευρολογική εκτίµηση ✓ Σηµαντικού βαθµού τετραπάρεση ✓ Μυϊκή ισχύς άνω/κάτω άκρων ! 3/5 κατά MRC ✓ Μυαλγίες ✓ Τενόντια αντανακλαστικά νωθρά ✓ Δυσκαταποσία ✓ CPK ≈ 4,000 – 5,000 IU/L ✓ Πιθανή µυοσίτιδα ! Συνιστάται ΗΜΓ 4 άκρων και βιοψία µυός
1η ΝΟΣΗΛΕΙΑ ΩΚΚ
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04/06 05/06 06/06 07/06 08/06 09/06 10/06
WBC k/µL 25.9 22.5 22.3 19.0 16.5 12.9 8.1CPK IU/L 4,476 4,009 5,066 4,994 4,529 4,240 3,325CK-MB ng/mL 176.3 137.2 157.2 151.1 132.5 128.4 73.0
cTnI ng/mL 8.32 6.74 4.39 2.39 1.08 0.70 0.49CRP mg/L 25.8 - 38.1 31.9 - - 12.4
NT-proBNP
pg/mL 7,729 - - - - - -
✓ Αιµατολογικός – Βιοχηµικός έλεγχος
1η ΝΟΣΗΛΕΙΑ ΩΚΚ
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Γ.Ν. Λαϊκό (10/06/2015 – 19/06/2015) ✓ Σταδιακή βελτίωση µε έναρξη φυσικοθεραπείας και κινητοποίησης ✓ 19/06/2015 ! βιοψία µυός ! µυοσίτιδα
Αγωγή εξόδου Tb Lopresor 100mg ¼ x 2 Tb Lonarid N επί πόνου Tb Augmentin 1g 1 x 2 για πέντε ηµέρες
Follow-up
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Νέα εισαγωγή Γ.Ν. Λαϊκό (02/07/2015) ✓ Συµπτώµατα
❖ Πυρετός ❖ Προκάρδιο άλγος ❖ Ήπια δύσπνοια ❖ Εύκολη κόπωση
✓ Ηχωκαρδιογραφική µελέτη LVEF ≈ 35% Μικρή/µέτρια περικαρδιακή συλλογή
✓ Υποτροπή περιµυοκαρδίτιδας
Διακοµιδή στο ΩΚΚ (03/07/2015) για βιοψία µυοκαρδίου και περαιτέρω αντιµετώπιση
Επανεµφάνιση συµπτωµάτων
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Ζωτικά σηµεία εισόδου ✓90/60 mmHg υπό ινότροπη υποστήριξη (iv Dobutamine 15 mL/h) ✓118 bpm ✓14 αναπνοές/min ✓36.6 oC
Κλινική εξέταση ✓Μείωση αναπνευστικού ψιθυρίσµατος δεξιού µέσου και κάτω λοβού ✓Ήπιοι τρίζοντες
ΗΚΓ ! αρνητικά T V4 – V6
2η ΝΟΣΗΛΕΙΑ ΩΚΚ
04/07/2015 ! βιοψία µυοκαρδίουΔιάχυτη οξεία νεκρωτική µυοκαρδίτιδα
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05/07/2015 ! κοιλιακή ταχυκαρδία + απώλεια συνείδησης ! ΚΑΡΠΑ ! ΜΕΘ ✓ Πολλαπλά επεισόδια κοιλιακής ταχυκαρδίας – κοιλιακής µαρµαρυγής ! ΚΑΡΠΑ + IABP + Διασωλήνωση ✓ Χορήγηση κορτιζόνης και ATG ✓ Χειρουργείο – υποστήριξη µε ECMO ! η ασθενής σταθεροποιείται αιµοδυναµικά και ηλεκτρικά
2η ΝΟΣΗΛΕΙΑ ΩΚΚ
Ηχωκαρδιογραφική µελέτη υπό ECMO (06/07/2015) ❖ LVEF < 10% ❖ Διάταση αµφοτέρων κοιλιών µε σηµεία βραδείας ροής ❖ SRV = 2 cm/s ❖ MR 2+, TR 3 – 4+, AR 2+
10/07/2015 ! βιοψία γραµµωτού µυός ❖ Λίγες εστίες ινώσεως και αποτιτανώσεως ❖ Δεν διαπιστώνονται σηµεία µυοσίτιδας
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2η ΝΟΣΗΛΕΙΑ ΩΚΚ
14/07/2015 ! χειρουργείο αντικατάστασης ECMO µε BiVAD
✓ Διαπιστώνονται πρόσφατοι θρόµβοι σε όλες τις καρδιακές κοιλότητες εν είδει εκµαγείου µε επέκταση στις πνευµονικές φλέβες ✓ Επιµελής αφαίρεση των θρόµβων από όλες τις καρδιακές κοιλότητες και τις πνευµονικές φλέβες ✓ Σύνδεση του BiVAD ! αδύνατη η υποστήριξη λόγω ηπατώσεως των πνευµόνων άµφω ✓ Διακοπή της υποστήριξης µετά από ενηµέρωση των συγγενών ! ✓ Θάνατος
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✓ Βιοψία µυοκαρδίου – δείγµα από χειρουργείο (14/07/2015) ❖ Διάχυτη νεκρωτική γιγαντοκυτταρική πανκαρδίτιδα
2η ΝΟΣΗΛΕΙΑ ΩΚΚ