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Debate:
All patients with clinically suspected
myocarditis shall be biopsied
YES Alida LP Caforio, MD, PhD, FESC
Dept Cardiological ,Thoracic and Vascular Sciences
University of Padova, Italy
E-mail: alida.caforio@unipd.it
ESC REPORT
Current stateofknowledgeonaetiology,diagnosis,
management, and therapy of myocardit is:
a posit ion statement of the European Society
of Cardiology W orking Group on Myocardial
and Pericardial Diseases
Alida L. P. Cafor io1†*, Sabine Pankuweit 2†, Eloisa Arbust ini3, Cr ist ina Basso4,
Juan Gimeno-Blanes5, Stephan B. Felix6, Michael Fu7, TiinaHelio8, Stephane Heymans9,
Roland Jahns10, Kar in Klingel11, AlesLinhart 12, Bernhard Maisch2, W illiam McKenna13,
JensMogensen14, Yigal M. Pinto15, Arsen Rist ic16, Heinz-Peter Schultheiss17,
Hubert Seggewiss18, Luigi Tavazzi19, Gaetano Thiene4, Ali Yilmaz20,
Philippe Charron21, and Perry M. Elliot t 13
1Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 2UniversitatsklinikumGießen und Marburg GmbH, Standort
Marburg,Klinik fur Kardiologie,Marburg, Germany; 3Academic Hospital IRCCSFoundation Policlinico, San Matteo, Pavia, Italy; 4Cardiovascular Pathology,Department of Cardiological
Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 5Servicio de Cardiologia, Hospital U. Virgen de ArrixacaCtra. Murcia-Cartagena s/n, El Palmar, Spain; 6Medizinische
Klinik B, University of Greifswald, Greifswald, Germany; 7Department of Medicine, Heart Failure Unit, Sahlgrenska Hospital, University of Goteborg, Goteborg, Sweden; 8Division of
Cardiology, Helsinki University Central Hospital, Heart & LungCentre, Helsinki, Finland; 9Center for Heart Failure Research, Cardiovascular Research Institute, University Hospital of
Maastricht, Maastricht, The Netherlands; 10Department of Internal Medicine, Medizinische Klinik und Poliklinik I, Cardiology, Wuerzburg, Germany; 11Department of Molecular
Pathology,University Hospital Tubingen,Tubingen,Germany; 122ndDepartment of Internal Medicine, 1st School of Medicine, CharlesUniversity, Prague2,CzechRepublic; 13TheHeart
Hospital,University College, London, UK;14Department of Cardiology, Odense University Hospital,Odense, Denmark; 15Department of Cardiology (Heart FailureResearch Center),
Academic Medical Center, Amsterdam, The Netherlands; 16Department of Cardiology, Clinical Center of Serbiaand Belgrade University School of Medicine, Belgrade, Serbia;17Department of Cardiology and Pneumology, Charite Centrum 11 (Cardiovascular Medicine), Charite–Universitatsmedizin Berlin, CampusBenjamin Franklin, Berlin, Germany;18Medizinische Klinik 1, LeopoldinaKrankenhaus Schweinfurt, Schweinfurt, Germany; 19GVM Care and Research, MariaCeciliaHospital, Cotignola, RA, Italy; 20Robert-Bosch-
Krankenhaus, Stuttgart, Germany; and 21UPMC Univ Paris6, AP-HP, Hopital Pitie-Salpetriere, Centre de Reference Maladiescardiaques hereditaires, Paris, France
Received 14 December 2012; revised 19 April 2013;accepted 23 May2013; online publish-ahead-of-print 3 July2013
In thisposition statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviewsthe current
knowledge on clinical presentation, diagnosisand treatment of myocarditis, and proposesnew diagnostic criteria for 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.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywor ds Myocarditis † Cardiomyopathy † Diagnosis † Therapy
Int roduct ion
Myocarditisisachallengingdiagnosisduetotheheterogeneityofclinical
presentations.1–3Theactual incidenceofmyocarditisisalso difficult to
determineasendomyocardial biopsy(EMB),thediagnosticgoldstand-
ard,1–3 isused infrequently.2,3 Studiesaddressing the issue of sudden
cardiac death in young people report a highly variable autopsy
prevalenceof myocarditis, rangingfrom2 to 42%of cases.4,5Similarly,
biopsy-provenmyocarditisisreported in9–16%of adult patientswith
unexplained non-ischaemic dilated cardiomyopathy (DCM)6,7 and in
46%ofchildrenwithanidentifiedcauseofDCM.8Inpatientspresenting
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.DivisionofCardiology,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 rights reserved. & The Author 2013. For permissionsplease email: journals.permissions@oup.com
European Heart Journal (2013) 34,2636–2648
doi:10.1093/eurheartj/eht210
at Univ
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Debate:
All patients with clinically suspected
myocarditis shall be biopsied
YES: Why?
1) Can we reach the
diagnosis of certainty
without a biopsy? NO
What is myocarditis?
• Definition (Circulation, 1995 WHO/ISFC classification; Eur Heart J, 1999; AHA statement 2006; ESC 2008)
– Myocarditis is an inflammatory disease of the myocardium and is diagnosed by established histological, immunological and immunohistochemical criteria
• Histological features (Dallas criteria on EMB)
• Myocarditis forms
– idiopathic,
– Infectious (mainly viral) and/or autoimmune
Debate:
All patients with clinically suspected
myocarditis shall be biopsied
YES: Why?
2) Do we have a typical clinical presentation? NO
Myocarditis:clinical presentation
• Mild symptoms • Palpitation, atypical chest pain, SOB
• Minor ECG abnormalities • Conduction disturbances, ST-T changes
• Major arrhythmia • SVT, complete A-V block, VT-VF
• Syncope, sudden cardiac death
• Cardiogenic shock • Fulminant myocarditis
• Unexplained heart failure with or without DCM features
• Onset of symptoms: days or up to several years
• Peri-partum
• Infarct-like with normal coronary arteries
Chimenti et al, JACC 2004; 43: 2305
EMB in 30 pts with sporadic ARVC and similar clinical, ECG, Echo,
angiographic and MRI findings differentiates ARVC (fatty tissue and myocyte%
area) from myocarditis
30% ARVC 70%
Myocarditis
Miocarditis mimicking ARVC
CD45
B 021150 I BEM
• Active Autoimmune Myocarditis (T Lymphocytes, few B cells)
• Virus negative by PCR
•AHA pos
Z.V. 32 F, (peri-partum DCM,
cardiogenic shock )
CD45
Suspected myocarditis in a 36-year woman with acute DCM, normal coro’s www.escardioorg
European Society of CardiologyWorking Group onMyocardial & Pericardial Diseases
Newsletter Issue 34 – April 2011
Presented by: ^Martina Perazzolo Marra, MD, PhD *Marny
Fedrigo, PhD and ^Alida LP Caforio, MD, PhD
The clinical case of the month: What isyour diagnosis?
Biopsy-proven giant cell myocarditis in a 36-year woman with acute DCM, normal coro’s
Cooper LT, 2013 Heart Fail Rev
CD68
Courtesy of Prof A Angelini, Cardiac
Pathology, University of Padova, Italy
The clinical case of the month: What isyour diagnosis?
Caforio et al, Eur J Heart Fail 2009
Caforio et
al, Eur J
Heart Fail
2009
Myocarditis, mimicking Takotsubo cardiomyopathy
a, b:
inflammation
and necrosis
(HE);
c,d=positive T
lymph.
activated
(CD45RO);
f=positive
cytotoxic T
lymph
Caforio et al,
Eur J Heart
Fail 2009
Myocarditis, mimicking Takotsubo cardiomyopathy
Suspected myocarditis, 65 yr, male, pseudo-infarct
presentation (TnI, 20 μg/L) preserved LVEF
Suspected myocarditis, 65 yr, male, pseudo-infarct
presentation (TnI, 20 μg/L) preserved LVEF, normal coro’s
Suspected myocarditis, 65 yr, male, pseudo-infarct
presentation, preserved LVEF, normal coro’s: 3-D echo at
discharge
65 yr, male, pseudo-infarct presentation, normal LVEF and
coro’s, biopsy-proven autoimmune eosinophilic myocarditis
Cardiovascular Pathology, University of Padua A B
A: eosinophilic infiltrate, B: Thrombus
Table 3 Possible presentations in clinically suspected myocarditis
Caforio et al. Eur Heart J 2013; 34:2636-48
Clinical presentations*:
1) acute chest pain, pericarditic or pseudo-ischaemic
2 ) 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
3 ) 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
4 ) palpitation, and/or unexplained arrhythmia symptoms and/or syncope, and/or aborted sudden
cardiac death
5) unexplained cardiogenic shock
Table 3 Diagnostic criteria for clinically suspected myocarditis
Caforio et al. Eur Heart J 2013; 34:2636-48
Diagnostic criteria:
I. ECG/Holter/stress test features
1) newly abnormal 12 lead ECG and/or Holter and/or stress testing, any of the following: I to III
degree atrioventricular block, or bundle branch block, ST/T wave change (ST elevation or non
ST elevation, T wave inversion), sinus arrest, ventricular tachycardia or fibrillation and asystole,
atrial fibrillation, reduced R wave height, intraventricular conduction delay (widened QRS
complex), abnormal Q waves, low voltage, frequent premature beats, supraventricular
tachycardia
II. Myocardiocytolysis markers
2 ) elevated TnT/TnI by local criteria (high-sensitivity assay, where available)
III. Morphofunctional abnormalities at cardiac imaging (echo/angio/CMR)
3) new, otherwise unexplained LV and/or RV structure and function abnormality (including
incidental finding finding in apparently asymptomatic subjects): regional wall motion or global
systolic or diastolic function abnormality, with or without ventricular dilatation, with or without
increased wall thickness, with or without pericardial effusion, with or without endocavitary
thrombi.
IV. Tissue characterization by CMR
oedema and/or LGE of classical myocarditic pattern (see text)
Table 3 Diagnostic criteria for clinically suspected myocarditis
Caforio et al. Eur Heart J 2013; 34:2636-48
Clinically suspected myocarditis if >1 clinical presentation and >1 diagnostic criteria from
different categories, in the absence of: - 1) angiographically detectable coronary artery disease
(coronary stenosis ≥ 50%) –2) known pre-existing cardiovascular disease or extra-cardiac causes that
could explain the syndrome (e.g. valve disease, congenital heart disease, hyperthyroidism, etc.) (see
text). Suspicion is higher with higher number of fulfilled criteria. *If the patient is asymptomatic >2
diagnostic criteria should be met.
Diagnostic criteria and proposed diagnostic approach for clinically suspected myocarditis
Caforio et al. Eur Heart J 2013; 34:2636-48
Debate:
All patients with clinically suspected
myocarditis shall be biopsied
YES: Why?
3) Is EMB dangerous for the patient?
NO
ESC REPORT
Current stateof knowledgeonaet iology,diagnosis,
management, and therapy of myocardit is:
a posit ion statement of the European Society
of Cardiology W orking Group on Myocardial
and Pericardial Diseases
Alida L. P. Cafor io1†*, Sabine Pankuweit 2†, Eloisa Arbust ini3, Cr ist ina Basso4,
Juan Gimeno-Blanes5, Stephan B. Felix6, Michael Fu7, T iinaHelio8, Stephane Heymans9,
Roland Jahns10, Kar in Klingel11, Ales Linhart 12, Bernhard Maisch2, W illiam McKenna13,
JensMogensen14, Yigal M. Pinto15, Arsen Rist ic16, Heinz-Peter Schultheiss17,
Huber t Seggewiss18, Luigi Tavazzi19, Gaetano Thiene4, Ali Yilmaz20,
Philippe Charron21, and Perry M. Elliot t 13
1Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 2Universitatsklinikum Gießen und Marburg GmbH, Standort
Marburg, Klinik fur Kardiologie, Marburg, Germany; 3Academic Hospital IRCCSFoundation Policlinico, San Matteo, Pavia, Italy; 4Cardiovascular Pathology, Department of Cardiological
Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 5Servicio de Cardiologia, Hospital U. Virgen de Arrixaca Ctra. Murcia-Cartagena s/n, El Palmar, Spain; 6Medizinische
Klinik B, University of Greifswald, Greifswald, Germany; 7Department of Medicine, Heart FailureUnit, Sahlgrenska Hospital, University of Goteborg, Goteborg, Sweden; 8Division of
Cardiology, Helsinki University Central Hospital, Heart & LungCentre, Helsinki, Finland; 9Center for Heart Failure Research, Cardiovascular Research Institute, University Hospital of
Maastricht, Maastricht, The Netherlands; 10Department of Internal Medicine, Medizinische Klinik und Poliklinik I, Cardiology, Wuerzburg, Germany; 11Department of Molecular
Pathology,University Hospital Tubingen, Tubingen, Germany;122nd Department of Internal Medicine,1st School of Medicine, CharlesUniversity, Prague2,CzechRepublic; 13TheHeart
Hospital, University College, London, UK;14Department of Cardiology, Odense University Hospital, Odense, Denmark; 15Department of Cardiology (Heart FailureResearch Center),
Academic Medical Center, Amsterdam, The Netherlands; 16Department of Cardiology, Clinical Center of Serbia and Belgrade University School of Medicine, Belgrade, Serbia;17Department of Cardiology and Pneumology, Charite Centrum 11 (Cardiovascular Medicine), Charite–Universitatsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany;18Medizinische Klinik 1, LeopoldinaKrankenhaus Schweinfurt, Schweinfurt, Germany; 19GVM Care and Research, Maria CeciliaHospital, Cotignola, RA, Italy; 20Robert-Bosch-
Krankenhaus, Stuttgart, Germany; and 21UPMC Univ Paris6, AP-HP, Hopital Pitie-Salpetriere, Centre de Reference Maladies cardiaques hereditaires, Paris, France
Received 14 December 2012; revised 19 April 2013; accepted 23 May2013
In thisposition statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviewsthe current
knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposesnew diagnostic criteria for 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.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywor ds Myocarditis † Cardiomyopathy † Diagnosis † Therapy
Int roduct ion
Myocarditisisachallengingdiagnosisdueto theheterogeneityofclinical
presentations.1–3Theactual incidenceofmyocarditisisalso difficult to
determineasendomyocardial biopsy(EMB), thediagnosticgold stand-
ard,1–3 is used infrequently.2,3 Studies addressing the issue of sudden
cardiac death in young people report a highly variable autopsy
prevalenceof myocarditis, rangingfrom 2 to 42%of cases.4,5Similarly,
biopsy-provenmyocarditisisreported in9–16%ofadult patientswith
unexplained non-ischaemic dilated cardiomyopathy (DCM)6,7 and in
46%ofchildrenwithanidentifiedcauseofDCM.8Inpatientspresenting
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 rights reserved. & The Author 2013. For permissions please email: journals.per missions@oup.com
European Heart Journal
doi:10.1093/eurheartj/eht210
European Heart Journal Advance Access published July 3, 2013
by
gu
est o
n Ju
ly 4
, 20
13
http
://eurh
eartj.o
xfo
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Jacc 2007 Eur Heart J 2013; 34:2636-48
Debate:
All patients with clinically suspected
myocarditis shall be biopsied
YES: Why?
4) Do we have a common aetiology
and similar treatment? NO
5) Do we have non-invasive
alternative tools to identify
aetiology? NO
Etiology of human myocarditis
INFECTIOUS IMMUNE-MEDIATED TOXIC
Bacterial Allergens: e.g. penicillin Drugs: e.g
catecholamine
cocaine
Spirochetal
Fungal Alloantigens: e.g. heart-
transplant rejection
Heavy
metals
Protozoal
Parasitic Physical
agents
Rickettsial
Viral: coxsackievirus, cytomegalovirus, dengue
virus, echovirus, encephalomyocarditis, Epstein–
Barr virus, hepatitis A, hepatitis C virus, herpes
simplex virus, herpes zoster, HIV, influenza A and
B, Junin virus, lymphocytic choriomeningitis,
measles, mumps, parvovirus, poliovirus, rabies,
respiratory syncytial, rubella, rubeola, vaccinia,
varicella–zoster, variola, and yellow fever virus
Autoantigens: e.g. myosin
in giant-cell myocarditis and
in virus-negative myocarditis ,
myocarditis associated to
organ and non-organ-specific
autoimmune diseases
Various
Agents, e.g
sting bites
Caforio A and McKenna WJ, Drugs 1996
From Task Force on Myocarditis-WG Position Statement, Eur Heart J 2013
Mar
ker
Aden
ovir
us
Cyto
meg
alovir
us
Epst
ein
-Bar
r vir
us
Infl
uen
za v
irus
A/B
Par
vovir
us
B19
Ente
rovir
us
Par
amix
ovir
us
Mark
er
Adenov
irus
Cyto
megalo
vir
us
Epst
ein
-Barr
vir
us
Herp
es
Sim
ple
x v
irus
Infl
uen
za v
irus
A/B
Parv
ovir
us
B19
Ente
rovir
us
Para
mix
ov
irus
Hepati
tis
C v
irus
*Calabrese et al.,Diagn Mol Pathol 2002; 11(4):212-21
Organ-specific (O-S) AHA and AIDA
Positive diffuse O-s and AIDA
pattern on human myocardium
(X40)
Negative pattern on human
skeletal muscle (X40)
Caforio et al. J Am Coll Cardiol 1990; 15 : 1527-34; Heart 2010; 96:779-84
Caforio et al. Eur Heart J 2013; 34:2636-48
Etiological forms of biopsy-proven myocarditis
ESC REPORT
Current stateofknowledgeonaetiology,diagnosis,
management, and therapy of myocardit is:
a posit ion statement of the European Society
of Cardiology W orking Group on Myocardial
and Pericardial Diseases
Alida L. P. Cafor io1†*, Sabine Pankuweit 2†, Eloisa Arbust ini3, Cr ist ina Basso4,
Juan Gimeno-Blanes5, Stephan B. Felix6, Michael Fu7, TiinaHelio8, Stephane Heymans9,
Roland Jahns10, Karin Klingel11, AlesLinhart 12, Bernhard Maisch2, W illiam McKenna13,
JensMogensen14, Yigal M. Pinto15, Arsen Rist ic16, Heinz-Peter Schultheiss17,
Hubert Seggewiss18, Luigi Tavazzi19, Gaetano Thiene4, Ali Yilmaz20,
Philippe Charron21, and Perry M. Elliot t 13
1Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 2Universitatsklinikum Gießen und Marburg GmbH, Standort
Marburg, Klinik fur Kardiologie, Marburg, Germany; 3Academic Hospital IRCCSFoundation Policlinico, San Matteo,Pavia, Italy; 4Cardiovascular Pathology, Department of Cardiological
Thoracic and Vascular Sciences,University of Padua, Padova, Italy; 5Servicio de Cardiologia, Hospital U. Virgen de ArrixacaCtra. Murcia-Cartagena s/n, El Palmar, Spain; 6Medizinische
Klinik B, University of Greifswald, Greifswald, Germany; 7Department of Medicine, Heart Failure Unit, Sahlgrenska Hospital, University of Goteborg, Goteborg, Sweden; 8Division of
Cardiology, Helsinki University Central Hospital,Heart & LungCentre, Helsinki, Finland; 9Center for Heart Failure Research, Cardiovascular Research Institute, University Hospital of
Maastricht, Maastricht, The Netherlands; 10Department of Internal Medicine, Medizinische Klinik und Poliklinik I, Cardiology, Wuerzburg, Germany; 11Department of Molecular
Pathology,UniversityHospital Tubingen,Tubingen,Germany;122ndDepartment of Internal Medicine,1st School ofMedicine, CharlesUniversity,Prague2,CzechRepublic;13TheHeart
Hospital, University College, London, UK;14Department of Cardiology, Odense University Hospital, Odense, Denmark; 15Department of Cardiology (Heart FailureResearch Center),
Academic Medical Center, Amsterdam, The Netherlands; 16Department of Cardiology, Clinical Center of Serbiaand Belgrade University School of Medicine, Belgrade, Serbia;17Department of Cardiology and Pneumology, Charite Centrum 11 (Cardiovascular Medicine), Charite–Universitatsmedizin Berlin, CampusBenjamin Franklin, Berlin, Germany;18Medizinische Klinik 1, LeopoldinaKrankenhaus Schweinfurt, Schweinfurt, Germany; 19GVM Care and Research, MariaCeciliaHospital,Cotignola, RA, Italy; 20Robert-Bosch-
Krankenhaus, Stuttgart, Germany; and 21UPMC Univ Paris6, AP-HP, Hopital Pitie-Salpetriere, Centre de Reference Maladies cardiaques hereditaires, Paris, France
Received 14 December 2012; revised 19 April 2013; accepted 23 May2013
In thisposition statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviewsthe current
knowledge on clinical presentation, diagnosisand treatment of myocarditis, and proposesnew diagnostic criteria for 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.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywor ds Myocarditis † Cardiomyopathy † Diagnosis † Therapy
Int roduct ion
Myocarditisisachallengingdiagnosisduetotheheterogeneityofclinical
presentations.1–3Theactual 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.4,5Similarly,
biopsy-provenmyocarditisisreported in9–16%ofadult patientswith
unexplained non-ischaemic dilated cardiomyopathy (DCM)6,7 and in
46%ofchildrenwithanidentifiedcauseofDCM.8Inpatientspresenting
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.DivisionofCardiology,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 rights reserved. & The Author 2013. For permissionsplease email: journals.permissions@oup.com
European Heart Journal
doi:10.1093/eurheartj/eht210
European Heart Journal Advance Access published July 3, 2013
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://eu
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Caforio et al. Eur Heart J 2013; 34:2636-48
Debate:
All patients with clinically suspected
myocarditis shall be biopsied
YES: Why?
6) Are biopsy data are prognostically
relevant? YES
AM: Actuarial survival
and PCR result
AM: Actuarial survival
and histology type
0 20 40 60 80 100
Follow up (months)
0,0
0,2
0,4
0,6
0,8
1,0
Pro
po
rtio
n S
urv
ivin
g
PCR result
PCR negative
PCR positive
P= 0.02
0 100 200 300
Follow up (months)
0,0
0,2
0,4
0,6
0,8
1,0
Pro
po
rtio
n S
urv
ivin
g
Histological type
Active lymphocytic
Borderline myocarditis
Giant cell myocarditis
Others
P= 0.004
P= 0.004
Caforio et al, Eur Heart J 2007; 28:1326-33
Figure 3. Unadjusted survival free from cardiac death and heart transplantation according to the findings of endomyocardial biopsy.
Kindermann I et al. Circulation 2008;118:639-648
Copyright © American Heart Association
Debate:
All patients with clinically suspected
myocarditis shall be biopsied
YES: Why?
7) Do biopsy data change clinical
management? YES
Hemodinamically unstable myocarditis
Caforio et al. Eur Heart J 2013; 34:2636-48
Major Criteria of Autoimmune Disease
• Mononuclear cell infiltrate and abnormal HLA expression in the target organ (organ-specific disease) or in various organs (nonorgan-specific disease) in the absence of infectious agents
• Circulating autoantibodies (Abs) and/or autoreactive lymphocytes in patients (pts) and family members
• Abs and/or autoreactive lymphocytes within the affected organ
• Identification and isolation of autoantigen(s) (Ags) involved
• Disease induction in animals after immunization with Ags and/or passive transfer of serum, Abs and/or lymphocytes
• Efficacy of immunosuppression/immunomodulation in pts
• Autoimmune disease= fullfillment of 2 or more major criteria
Witebsky E, Rose NR
ESC recommendations for immunosuppression in myocarditis
European Society of CardiologyWorking Group onMyocardial & Pericardial Diseases
Newsletter Issue 34 – April 2011
Caforio et al. Eur Heart J 2013; 34:2636-48
ACUTE MYOCARDITIS: DIAGNOSTIC AND MANAGEMENT PROTOCOL
Clinically Suspected Myocarditis
Haemodynamically stable
Preserved LV function
No eosinophilia
No significant rhythm or conduction disturbances
Not associated with systemic immune disease#
History, Examination, ECG, Echo, Laboratory tests: Troponin, CRP, ESR, Blood Cell Count, BNP,
CMR; if Available, Serum Cardiac Autoantibodies
Consider coronary angiography and EMB
No coronary disease
General Supportive Therapy
Haemodynamically
unstable, Decreased LV
Function,
Cardiogenic Shock
Pharmacological & if needed
Mechanical support (ECMO,
LVAD/Bi-VAD, Bridge to heart
transplant or to recovery)
Lymphocytic Giant cell, Eosinophilic,
Sarcoidosis (acute
decompensation)
General Supportive Therapy
Immunosuppression if
unresponsive & virus negative
EMB
Immunosuppression if
infection negative EMB
# If myocarditis is associated with systemic immune disease exacerbation, therapy overlaps with treatment of the background disease (usually immunosuppression).
“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
ESC REPORT
Current stateof knowledgeonaet iology,diagnosis,
management, and therapy of myocardit is:
a posit ion statement of the European Society
of Cardiology W orking Group on Myocardial
and Pericardial Diseases
Alida L. P. Cafor io1†*, Sabine Pankuweit 2†, Eloisa Arbust ini3, Cr ist ina Basso4,
Juan Gimeno-Blanes5, Stephan B. Felix6, Michael Fu7, T iinaHelio8, Stephane Heymans9,
Roland Jahns10, Kar in Klingel11, Ales Linhart 12, Bernhard Maisch2, W illiam McKenna13,
JensMogensen14, Yigal M. Pinto15, Arsen Rist ic16, Heinz-Peter Schultheiss17,
Huber t Seggewiss18, Luigi Tavazzi19, Gaetano Thiene4, Ali Yilmaz20,
Philippe Charron21, and Perry M. Elliot t 13
1Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 2Universitatsklinikum Gießen und Marburg GmbH, Standort
Marburg, Klinik fur Kardiologie, Marburg, Germany; 3Academic Hospital IRCCSFoundation Policlinico, San Matteo, Pavia, Italy; 4Cardiovascular Pathology, Department of Cardiological
Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 5Servicio de Cardiologia, Hospital U. Virgen de Arrixaca Ctra. Murcia-Cartagena s/n, El Palmar, Spain; 6Medizinische
Klinik B, University of Greifswald, Greifswald, Germany; 7Department of Medicine, Heart FailureUnit, Sahlgrenska Hospital, University of Goteborg, Goteborg, Sweden; 8Division of
Cardiology, Helsinki University Central Hospital, Heart & LungCentre, Helsinki, Finland; 9Center for Heart Failure Research, Cardiovascular Research Institute, University Hospital of
Maastricht, Maastricht, The Netherlands; 10Department of Internal Medicine, Medizinische Klinik und Poliklinik I, Cardiology, Wuerzburg, Germany; 11Department of Molecular
Pathology,University Hospital Tubingen, Tubingen, Germany;122nd Department of Internal Medicine,1st School of Medicine, CharlesUniversity, Prague2,CzechRepublic; 13TheHeart
Hospital, University College, London, UK;14Department of Cardiology, Odense University Hospital, Odense, Denmark; 15Department of Cardiology (Heart FailureResearch Center),
Academic Medical Center, Amsterdam, The Netherlands; 16Department of Cardiology, Clinical Center of Serbia and Belgrade University School of Medicine, Belgrade, Serbia;17Department of Cardiology and Pneumology, Charite Centrum 11 (Cardiovascular Medicine), Charite–Universitatsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany;18Medizinische Klinik 1, LeopoldinaKrankenhaus Schweinfurt, Schweinfurt, Germany; 19GVM Care and Research, Maria CeciliaHospital, Cotignola, RA, Italy; 20Robert-Bosch-
Krankenhaus, Stuttgart, Germany; and 21UPMC Univ Paris6, AP-HP, Hopital Pitie-Salpetriere, Centre de Reference Maladies cardiaques hereditaires, Paris, France
Received 14 December 2012; revised 19 April 2013; accepted 23 May2013
In thisposition statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviewsthe current
knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposesnew diagnostic criteria for 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.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywor ds Myocarditis † Cardiomyopathy † Diagnosis † Therapy
Int roduct ion
Myocarditisisachallengingdiagnosisdueto theheterogeneityofclinical
presentations.1–3Theactual incidenceofmyocarditisisalso difficult to
determineasendomyocardial biopsy(EMB), thediagnosticgold stand-
ard,1–3 is used infrequently.2,3 Studies addressing the issue of sudden
cardiac death in young people report a highly variable autopsy
prevalenceof myocarditis, rangingfrom 2 to 42%of cases.4,5Similarly,
biopsy-provenmyocarditisisreported in9–16%ofadult patientswith
unexplained non-ischaemic dilated cardiomyopathy (DCM)6,7 and in
46%ofchildrenwithanidentifiedcauseofDCM.8Inpatientspresenting
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 rights reserved. & The Author 2013. For permissions please email: journals.per missions@oup.com
European Heart Journal
doi:10.1093/eurheartj/eht210
European Heart Journal Advance Access published July 3, 2013
by
gu
est o
n Ju
ly 4
, 20
13
http
://eurh
eartj.o
xfo
rdjo
urn
als.org
/D
ow
nlo
aded
from
Jacc 2007 Eur Heart J 2013; 34:2636-48
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
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
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)
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.
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
“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
Thank you for your attention!
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