Debate endomyocardial biopsy aldia

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

Current stateofknowledgeonaetiolo
management, and therapy of myocar
a position statement of the European
of Cardiology W orking Group on My
and Pericardial Diseases
Alida L. P. Caforio1†*, Sabine Pankuweit 2†, Eloisa Arbustini3, Cr
Juan Gimeno-Blanes5, Stephan B. Felix6, Michael Fu7, TiinaHelio¨
Roland Jahns10, Karin Klingel11, AlesLinhart12, Bernhard Maisch
JensMogensen14, Yigal M. Pinto15, Arsen Ristic16, Heinz-Peter Sc
Hubert Seggewiss18, Luigi Tavazzi19, Gaetano Thiene4, Ali Yilma
Philippe Charron21, and Perry M. Elliott13
1
Division of Cardiology, Department of Cardiological Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 2
Universita¨tsk
Marburg,Klinik fu¨r Kardiologie,Marburg, Germany;3
Academic Hospital IRCCSFoundationPoliclinico, SanMatteo,Pavia,Italy;4
Cardiov
Thoracic and Vascular Sciences, University of Padua, Padova, Italy; 5
Servicio deCardiologia,Hospital U.Virgen de ArrixacaCtra. Murc
European Heart Journal (2013) 34,2636–2648
doi:10.1093/eurheartj/eht210

Debate:
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:
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 Cardiology
Working Group on
Myocardial & 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 is
your 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 is
your 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

presentation (TnI, 20 μg/L) preserved LVEF, normal coro’s

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
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
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

Debate:
YES: Why?
3) Is EMB dangerous for the patient?
NO

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.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
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

Debate:
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

Marker
Adenovirus
Cytomegalovirus
Epstein-Barrvirus
InfluenzavirusA/B
ParvovirusB19
Enterovirus
Paramixovirus
Marker
Adenovirus
Cytomegalovirus
Epstein-Barrvirus
HerpesSimplexvirus
InfluenzavirusA/B
ParvovirusB19
Enterovirus
Paramixovirus
HepatitisCvirus
*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

Etiological forms of biopsy-proven myocarditis
Current stateof
management, an
a position statem
of Cardiology W
and Pericardial D
Alida L. P. Caforio1†*, Sabin
Juan Gimeno-Blanes5, Steph
10
European Heart Journal
doi:10.1093/eurheartj/eht210
European Heart

Debate:
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
ProportionSurviving
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
ProportionSurviving
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:
YES: Why?
7) Do biopsy data change clinical
management? YES

Hemodinamically unstable myocarditis

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 Cardiology
Working Group on
Myocardial & Pericardial Diseases
Newsletter Issue 34 – April 2011

ACUTE MYOCARDITIS: DIAGNOSTIC AND MANAGEMENT PROTOCOL
Clinically Suspected Myocarditis
Haemodynamically stable
PreservedLV 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:
myocarditis shall be biopsied:
YES

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

Debate endomyocardial biopsy aldia

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