Rebuttal leslie cooper

1. Debate:
All patients with clinically suspected
myocarditis shall be biopsied
YES:
Rebuttal

2. Current stateofknowledgeonaetiology,diagnosis,
management, and therapy of myocarditis:
a position statement of the European Society
of Cardiology W orking Group on Myocardial
and Pericardial Diseases
Alida L. P. Caforio1†*, Sabine Pankuweit 2†, Eloisa Arbustini3, Cristina Basso4,
Juan Gimeno-Blanes5, Stephan B. Felix6, Michael Fu7, TiinaHelio¨8, Stephane Heymans9,
Roland Jahns10, Karin Klingel11, AlesLinhart12, Bernhard Maisch2, W illiam McKenna13,
JensMogensen14, Yigal M. Pinto15, Arsen Ristic16, Heinz-Peter Schultheiss17,
Hubert Seggewiss18, Luigi Tavazzi19, Gaetano Thiene4, Ali Yilmaz20,
Philippe Charron21, and Perry M. Elliott13
1
Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 2
Universita¨tsklinikum Gießen und Marburg GmbH, Standort
Marburg, Klinik fu¨r Kardiologie, Marburg, Germany; 3
Academic Hospital IRCCSFoundation Policlinico, San Matteo, Pavia,Italy;4
Cardiovascular Pathology, Department of Cardiological
Thoracic and Vascular Sciences,University of Padua, Padova, Italy; 5
Servicio de Cardiologia, Hospital U. Virgen de Arrixaca Ctra. Murcia-Cartagena s/n, El Palmar, Spain; 6
Medizinische
Klinik B, University of Greifswald, Greifswald, Germany; 7
Department of Medicine, Heart FailureUnit,Sahlgrenska Hospital, University of Go¨teborg, Go¨teborg, Sweden; 8
Division of
Cardiology, Helsinki University Central Hospital,Heart & LungCentre, Helsinki, Finland; 9
Center for Heart FailureResearch, Cardiovascular Research Institute, University Hospital of
Maastricht, Maastricht, The Netherlands; 10
Department of Internal Medicine, Medizinische Klinik und Poliklinik I, Cardiology, Wuerzburg, Germany; 11
Department of Molecular
Pathology,University Hospital Tu¨bingen,Tu¨bingen,Germany;12
2ndDepartment ofInternal Medicine,1st School of Medicine, CharlesUniversity,Prague2,CzechRepublic;13
TheHeart
Hospital, University College, London, UK;14
Department of Cardiology, Odense University Hospital, Odense, Denmark; 15
Department of Cardiology (Heart FailureResearch Center),
Academic Medical Center, Amsterdam, The Netherlands; 16
Department of Cardiology, Clinical Center of Serbiaand Belgrade University School of Medicine, Belgrade, Serbia;
17
Department of Cardiology and Pneumology, Charite´ Centrum 11 (Cardiovascular Medicine), Charite´ –Universita¨tsmedizin Berlin, CampusBenjamin Franklin, Berlin, Germany;
18
Medizinische Klinik 1, LeopoldinaKrankenhausSchweinfurt, Schweinfurt, Germany; 19
GVM Care and Research, MariaCeciliaHospital,Cotignola, RA, Italy; 20
Robert-Bosch-
Krankenhaus, Stuttgart, Germany; and 21
UPMC Univ Paris6, AP-HP, Hoˆpital Pitie´-Salpeˆtrie`re, Centre de Re´fe´rence Maladies cardiaques he´re´ditaires, Paris, France
Received 14 December 2012; revised 19 April 2013; accepted 23 May2013
In thisposition statement of the ESC WorkingGroup on Myocardial and Pericardial Diseases an expert consensus group reviewsthe current
knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposesnew diagnostic criteriafor clinically suspected myo-
carditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to
improve management and provide acommon reference point for future registries and multicentre randomised controlled trials of aetiology-
driven treatment in inflammatory heart muscle disease.
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Keywor ds Myocarditis † Cardiomyopathy † Diagnosis † Therapy
Introduction
Myocarditisisachallengingdiagnosisduetotheheterogeneityofclinical
presentations.1–3
Theactual incidenceofmyocarditisisalso difficult to
determineasendomyocardial biopsy(EMB),thediagnosticgoldstand-
ard,1–3
isused infrequently.2,3
Studiesaddressingthe issue of sudden
cardiac death in young people report a highly variable autopsy
prevalenceof myocarditis,rangingfrom2 to 42%of cases.4,5
Similarly,
biopsy-provenmyocarditisisreportedin9–16%ofadult patientswith
unexplained non-ischaemic dilated cardiomyopathy (DCM)6,7
and in
46%ofchildrenwithanidentifiedcauseofDCM.8
Inpatientspresenting
with mild symptomsand minimal ventricular dysfunction, myocarditis
often resolves spontaneously without specific treatment.9
However,
in up to 30% of cases, biopsy-proven myocarditis can progress to
†
A.L.P.C. and S.P. contributed equally to the document.
* Correspondingauthor.Division ofCardiology,Department ofCardiological ThoracicandVascular Sciences,PaduaUniversityMedical School,Policlinico Universitario, ViaN Giustinani,
2, 35128 Padova, Italy. Tel: + 39 (0)498212348, Fax: + 39 (0)498211802, Email: alida.caforio@unipd.it
Published on behalf of the European Society of Cardiology. All rightsreserved. & The Author 2013. For permissionsplease email: journals.permissions@oup.com
Jacc 2007 Eur Heart J 2013; 34:2636-48

3. Clinical case 1
• 37 yr old male, agonist sport activity (cycling, soccer), negative family and
personal history
• March 2010: prolonged palpitation unrelated to effort
• 24 h Holter monitoring 10/2010: 4771 polymorphic VEBs, 887 in couples,
86 NSVT runs (longest 5 beats, max 120 bpm), SR, mean HR 72 (43-143)
• Negative LP, normal 2D echo, 11/2010 cardiological consultation
(EPS/ARVC specialist): arrhythmia in normal heart, ARVC excluded, starts
propafenone 150 mg tid, adviced to reduce sport activity
• December 2010: after training session, prolonged palpitation, epigastric
pain, increased with respiratory acts, admission to local hospital:normal
ECG, increased TnI, angiographically normal coronary arteries, normal
biventricular function, sporadic frequent VEBs, stable increase in TnI (2-3
ng/mL, flat curve, normal CK-MB, Reactive C Protein), suggested CMRI
• February 2011: referred to Myocarditis/cardiomyopathy OPD (Padova) as
clinically suspected myocarditis, normal coronary arteries

4. Clinical case 1
• April 2011: therapy: atenolol 100 mg, TNI high sensitivity 4,214 microg/L
(normal 0,00-0,045). Holter: Rs, mean HR 69 (46-103), 4345 VEBs, 711
couplets, 150 NSVT (longest 3 beats)
• High titre ANA (1/5000), AHA positive, AIDA positive
• Claustrophobic (refuses CMRI), 2D-echo: normal, LVEF 67%
• Young adult, good education, motivated to get a diagnosis and treatment,
2 young children
• What to do?
– f/u
– EPS
– ICD as primary prevention
– Treat with NSAIDs, colchicine?
– EMB

5. Clinical case 1
• May 2011: admitted to our hospital to get a diagnostic EMB
• CMRI: compatible with previous myocarditis, preserved biventricular
function, intramural LGE (mid septal), epicardial LGE (mid septal inferior);
T2 not diagnostic (frequent VEBs)
• Constantly abnormal TnI (4-5 microg/L, normal 0.00-0.045), normal C3,C4,
RCP
• 2D echo: mildly reduced LVEF = 50% (global hypokinesis), normal RV, no
pericardial effusion
• Coronary flow reserve on AD by 2 D echo-adenosine: normal
• while in hospital on telemetric monitoring (cardiology ward)…
– Prolonged SVT, haemodinamically stable, treated with amiodarone I.V. bolus
– Switched from beta-blocker to sotalol
• Right catheter: normal pulmonary pressures (PA mean 11 mmHg, mean
wedge 7 mmHg), normal cardiac index (3.65 ml/min/m2); performed RV
biopsy (4 samples, no complications)

7. Histology: focal
lymphomonocytic
myocarditis, initial
DCM (perinuclear
halos,dysmetric
nuclei)
ImmunoHx: focal
CD3pos, CD68 pos
and CD 20 cells
(>7/mm2) associated
with necrosis)
Negative PCR,
NT PCR for
cardiotropic
viruses:
adenov, HSV,
EBV,HHV6;
PVB19; CMV;
influenza A, B;
EV.

9. Clinical case 1• What to do?
– EPS: no, Sotalol 80 mg tid
– ICD as primary prevention: no, Loop recorder implanted
– Treat with NSAIDs, colchicine: no
– Immunosuppression (IS) (started May 2011): prednisone 1 mg/kg then taper;
Azathioprine 2 mg/Kg/d
• July 2011 (2 mo IS): TNI high sensitivity 0,47 microg/L (normal 0,00-
0,045). Holter: Rs, mean HR 66 (44-107), 1618 VEBs, 34 couplets, no NSVT
; Echo: LVEF 60%
• September 2012 (15 mo IS) during tapering: Holter: Rs, mean HR 65 (44-
105), 52 77 VEBs, 71 couplets, 6 NSVT longest 6 beats, 193 bpm; Echo:
LVEF 64%; stop IS tapering; TnI negative.
• July/2014 (36 mo IS): TnI negative, LP: no arrhythmia; Echo: LVEF 64%;
tapering IS, stop October/2014
• March 2015: TnI negative, LP: no arrhythmia; Echo: LVEF 64%; off IS

10. “There are three phases to
treatment: diagnosis,
diagnosis and
diagnosis.”
William Osler. Principles
and Practice of Medicine,
1892
Debate:
All patients with clinically suspected
myocarditis shall be biopsied:
YES

11. Clinical case 2
• 18 yr old female, agonist sport activity (canoeing), negative family and
personal history
• 12-19/06/2014: admitted to hospital, pericarditic chest pain, TnI 23,96
microg/L, negative CRP, 2D Echo: normal biventricular function, no
pericardial effusion, CMRI suggesting myocarditis, discharged with ibuprofen
600 mg tid
• 24/06: readmission to hospital, chest pain, peak TnI 18 microg/L at
admission, negative CRP, reduced TnI and second peak after few days. Echo:
preserved LVEF, septal hypokinesis, no pericardial effusion. Angio TC:
negative for CAD. New CMRI suggests increased myocarditis changes (lateral
and inferior LV walls. Discharged 4/07 TnI reduced but not normal on
Ibuprofen 800 mg tid, colchicine 1 mg day, esomeprazole 40 mg
• 02/08: readmission to hospital, chest pain, peak TnI 50 microg/L at
admission, ECG: low voltages, mild inferolateral STE, Echo: preserved
biventricular function, no pericardial effusion. In CCU short NSVT runs,
improved on bisoprolol 1.25 mg. Coronary angiography: normal, EMB (RV,
no complications).

14. Clinical case 2
• EMB Dgn: relapsing focal lymphocitic virus-negative (adeno, EBV, PVB19,
EV, CMV,influenza A, B, HHV6 weak pos), myocarditis; negative HHV6 IgM,
negative
• What to do?
– Immunosuppression (IS)?: Yes (started 15/08/2014, Prednisone 1 mg/Kg/d for 2 wks,
subsequent tapering + azathioprine 2 mg/kg)
• During medical consultation at OPD (20/08) chest pain and inverted T
waves in from V2 to V6, D1, AVL, flat inferior leads positive AVR leads,
admitted to our hospital
– 20/08 (TNI 0.20 ng /ml (normal <0.045); Eco; LVEF: 57%, hypokinesis posterior septum,
basal mid inferior wall; discharged 29/08 TnI 0.05 (normal <0.045)
– CMRI 22/9: subacute myocarditis, preserved biventricular function (LVEF 60%, Rvef
53%), no LVWMA
• Outcome
– Relapse 28/10/14: TnI 2.1; relapse 13/1/15: TnI 12, second peak 1, HHV6 DNA in blood:
detectable; ECG: neg T waves Inferolat leads; Echo: LVEF 65%
– 28/01/15 Tni neg; LVEF 65%; IVIG infusion, prednisone 25 mg (tapering), azathioprine 50
mg bid
– March 2015, TnI neg, LVEF 65%, prednisone 25 mg (tapering), azathioprine 50 mg bid,
awaiting HHV6 DNA in blood

16. T2-weighted
T1-weighted Inversion Recovery
post-Gd
Mid short-axis view: note the
epicardial bright signal in the
inferior and infero-lateral wall
due to myocardial edema (white
arrows)
Mid short-axis view: note the
epicardial Late Gadolinium
Enhancement (white arrows) in
the same region of edema. Note
the greater extent of LGE
compared to edema, due to a
subacute inflammatory process
M Perazzolo Marra

17. T1-weighted Inversion Recovery post-Gd
Long axis 4-chamber view: note the epicardial Late Gadolinium
Enhancement (white arrows) in lateral LV wall, apex and also
the right side of interventricular septum
M Perazzolo Marra

19. If: preserved LV/RV function,
normal coro’s, prolonged troponin
(weeks, months) with or without
arrhythmia: EMB
If: preserved LV/RV functions,
normal coro’s, troponin release,
patient consent (research) and
experienced tertiary centre: EMB

20. Protocol
Cardiomyopathy and Myocarditis Registry
10/June/2014
Version 1.0
Study Sponsored by the European Society of Cardiology
in conjunction with the Working Group on
Myocardial & Pericardial Disease
Coordinating centre:
EURObservational Research Programme
European Society of Cardiology
Les Templiers, 2035 Route des Colles - CS 80179 Biot
06903 Sophia Antipolis Cedex - France
Tel: +33(0)492 94 76 00
Fax: +33(0)492 94 76 29
Email: eorp@escardio.org
Chairman of the Executive Committee
Professor Perry Elliott
Protocol
Cardiomyopathy and Myocarditis Registry
10/June/2014
Version 1.0
Study Sponsored by the European Society of Cardiology
in conjunction with the Working Group on
Myocardial & Pericardial Disease
Coordinating centre:
EURObservational Research Programme
European Society of Cardiology
Les Templiers, 2035 Route des Colles - CS 80179 Biot
06903 Sophia Antipolis Cedex - France
Cardiomyopathy and Myocarditis Registry
10/June/2014
Version 1.0
Study Sponsored by the European Society of Cardiology
in conjunction with the Working Group on
Myocardial & Pericardial Disease
Coordinating centre:
EURObservational Research Programme
European Society of Cardiology
Les Templiers, 2035 Route des Colles - CS 80179 Biot
06903 Sophia Antipolis Cedex - France
Tel: +33(0)492 94 76 00
Fax: +33(0)492 94 76 29
Email: eorp@escardio.org
Chairman of the Executive Committee
Protocol
Cardiomyopathy and Myocarditis Registry
10/June/2014
Version 1.0
Study Sponsored by the European Society of Cardiology
in conjunction with the Working Group on
Myocardial & Pericardial Disease
Coordinating centre:
EURObservational Research Programme
European Society of Cardiology
Les Templiers, 2035 Route des Colles - CS 80179 Biot
06903 Sophia Antipolis Cedex - France
Tel: +33(0)492 94 76 00
Fax: +33(0)492 94 76 29
Email: eorp@escardio.org
Chairman of the Executive Committee
Professor Perry Elliott
Coordinating centre:
EURObservational Research Programme
European Society of Cardiology
Les Templiers, 2035 Route des Colles - CS 80179
06903 Sophia Antipolis Cedex - France
Tel: +33(0)492 94 76 00
Fax: +33(0)492 94 76 29
Email: eorp@escardio.org
Chairman of the Executive Committee
Professor Perry Elliott

21. Take-home message: the future
• Promote a European Myocarditis Treatment
Trial
–multicentre
–placebo-controlled
–double-blind
–randomised
–viral and autoimmune diagnosed
according to the ESC WG Task Force
criteria.

22. “There are three phases to
treatment: diagnosis,
diagnosis and
diagnosis.”
William Osler. Principles
and Practice of Medicine,
1892
Debate:
All patients with clinically suspected
myocarditis shall be biopsied:
YES

23. Thank you for your attention!