Post on 21-Jul-2020
Carsten Tschöpe, Berlin
Kardiologie, Charite, CVK
Grippe und Kardiomyopathie
„A. zieht nach Berlin für ein Praktikum.
48 Stunden später ist er tot,
gestorben an einer Herzmuskelentzündung,
obwohl er hier noch
zwei Rettungsstellen und einen Arzt aufsuchte.“
Der Tagesspiegel VOM 19.04.2014
„Herz und Versagen“
German register of
sport-related sudden deaths
Bohm et al Eu J Precv Cardiol 2016
Pathogenesis of
inflammatory cardiomyopathies
Trachtenberg et al Circ Res. 2017;121:803-818
Blauwet L et al, Pro Cardiovascu Dis 2010
Pathogenesis of viral myocarditis
Ammirati et al Circulation 138:1088-1099; 2018
Impaired prognosis of
complicated Myocarditis
Complicated:
Changes in EF
or
Abnormal ECG
or
Trop T pos
or
hemodynamically compromised
54%
recover
* No specific
treatment
due to viral
persistence
19,4%
stay at risk
27%
Defect
healing
Kühl et al
Spontaneous Course of biopsy proven MC/DCMi *
(clinical mean follow-up: 30 months, n=922)
Despite HF standard therapy
45% will patients with MC/DCMi will not recover
ESC Recommendations
Caforio et al, Eur Heart J 2013
Chronic Viral Cardiomyopathy versus Controls (n=669)
negative EV PVB19 HHV6 PVB/HHV
260 54 210 89 56
Infection 48% 45% 49% 35% 42%
Tiredness 69% 82% 72% 59% 82%
Angina pectoris ( atypical ) 40% 10% 47% 36% 40%
Dyspnoe on exertion 55% 50% 60% 64% 77%
Pericardial effusion 6% 2% 7% 5% 13%
Impaired contractility (global) 68% 71% 68% 69% 69%
Impaired contractility (region.) 43% 24% 31% 44% 25%
Rhythm disturbances 46% 50% 51% 38% 62%
SVES 7% 9% 11% 4% 6%
VES 23% 9% 24% 19% 18%
Atrial fibrillation 19% 25% 16% 18% 23%
Ventricular tachycardia 9% 0% 13% 4% 7%
Charite - CBF
No viral specfic symptoms in patients
with suspected myocarditis
Diagnostics
• ECG
• hsTroponin, CRP
• No virusserology
• Echocardiography
• MRI (Lake-Louise Criteria)
• Endomyocardial biopsy
Caforio et al, Eur Heart J 2013
Myocarditis
Mimicking Acute Myocardial Infarction
Kühl et al Circulation 2003
6 months later
Shahid et al JACC 2016
Diagnostics
• ECG
• hsTroponin, CRP
• No virus serology
• Echocardiography
• MRI (Lake-Louise Criteria)
• Endomyocardial biopsy
Caforio et al, Eur Heart J 2013
Diagnostics
• ECG
• hsTroponin, CRP
• No virus serology
-> To excude a systemic infection
(Herpesvirus, Hepatitis C, Parvovirus B19)
-> anti bodies (IgMs) do not reflect the cardiac disease
Caforio et al, Eur Heart J 2013
Diagnostics
• ECG
• hsTroponin, CRP
• No virusserology
• Echocardiography
• MRI (Lake-Louise Criteria)
• Endomyocardial biopsy
Caforio et al, Eur Heart J 2013
Wall oedema
Echocardiography
EchocardiographyWall oedema
EchocardiographyPericardial Effusion
MCpEF
Echocardiography
Myocarditis with preserved ejection Fraktion
Escher et al 2013 Kasner et al IJC 2016
MCpEF
Echocardiography
Myocarditis with preserved ejection Fraktion
Escher et al 2013 Kasner et al IJC 2016
Fibrosis and MRI in MCpEF
Aquaro et al JACC 2017
2nd y
Diagnostics
• ECG
• hsTroponin, CRP
• No virusserology
• Echocardiography
• MRI (Lake-Louise Criteria)
• Endomyocardial biopsy
Caforio et al, Eur Heart J 2013
Indicate myocarditis, if 2 out of 3 criteria are positive
quantitative
Yes/no
T2 – ER ≥ 2
quantitative
T1 – gRE ≥ 4
qualitative
LGE T2W
Yes/no
T1W
Friedrich et al JACC 2009
MRT Lake – Louise Kriterien
zur Diagnostik der Myokarditis
MRT Lake Louise Kriterien zur
akuten und chronischen MyokarditisLurz P et al.: JACC 2012
= acute myocarditis
Moderen MRI:
T1-, T2-Mapping
von Knobelsdorff-Brenkenhoff et al. Circ Cardiovasc Imaging. 2017
New MRI – Louise criteria for
acute but not chronic Myocarditis
Ferreira et al JACC 72:3158-3176; 2018
Lurz P et al.: JACC 2016
New MRI – Louise criteria for
acute but not chronic Myocarditis
Kindermann et al. Circulation 2008
Immunohistology criteria –
have a prognostic significance
MRI and virus presence
Gutberlet et al 2008 Friedrich JACC CVI 2008 (Review)
T1 und T2 Mapping zur Verlaufsbeurteilung einer
Myokarditis
Bohnen et al Eu Heart J Cardiovasc Imaging 2017
Diagnostics
• ECG
• hsTroponin, CRP
• No virusserology
• Echocardiography
• MRI (Lake-Louise Criteria/T1/T2) – a negative result
does not exclude a myocarditis – a positive does
not clarify the viral situation
• Endomyocardial biopsy - Goldstandard
Caforio et al, Eur Heart J 2013
Ammirati et al Circulation 138:1088-1099; 2018
Impaired prognosis of
complicated Myocarditis
Complicated:
Changes in EF
or
Abnormal ECG
or
Trop T pos
or
hemodynamically compromised
Bio
psie
MR
T
Ammirati et al Current Cardiology Reports 2018
MRI or Biopsy
in suspected myocarditis
A RV-Biopsy in 20 sec ?
„ Get it ! „
The requirement for a specific treatment strategy for
myocarditis is a comprehensive diagnostic by an
endomyocardial biopsy
Coxsackie
Caforio et al, Eur Heart J 2013
Noutsias et al 2011
Histology Immuno-
Histology
Molecular-
biology
Flow diagram illustrating clinical scenarios described in
AHA/ACC/ESC Scientific Statement.
Francis et al heartjnl-2017
Class 1
Eosinophilic
Myocarditis
(EF: 30%,)
Fulminant
Myocarditis
(EF: 32%) (EF: 32%)
Giant cell
Myocarditis
Moderate
Prognosis
Poor
Prognosis
Poor
Prognosis
Severe unexplained acute new onset HF
Initial defect size and
type of inflammatory response
Flow diagram illustrating clinical scenarios described in
AHA/ACC/ESC Scientific Statement.
Francis et al heartjnl-2017
Class I
Class IIA
Immunosuppression in virus-negative DCMi:
6 months Follow-up – TIMIC Study
Randomized, double-blind, placebo-
controlled study
n=85 patients
Placebo: n= 42 patients
Immunosuppression: n= 43 patients
Prednisone / Azathioprine
* P<0.05
Immunosuppres. placebo
Immunosuppres. placebo
Frustaci et al. Eur Heart J 2009
Empfehlungen zur TherapieImmunsuppression in virus-negativer komplizierter Myokarditis
Merken et al Circ Heat Fail 2018
Dominguez F et al, Rev. Esp Cardiol 2016
Current Therapeutic Options in
Chronic forms of myocarditis
After Exclusion of
viral persistence
Viral genomes epidemiology
Dominguez et al, Rev Esp Cardiol 2015
Shauer et al, IMAJ 2013
Can
be cleared
Cannot
be cleared
Coxsackievirus B3 and Adenovirus
Yoder et al, J of Virol 2012
Pankuweit et al, Heart Failure Rev 2013
- Single stranded (ss) RNA
- Nonenveloped, icosahedral
- 6 serotypes of CVB: 1, 3 & 5 cardiotropic
- Clear association with MC
- Infects cardiomyocytes
- Double-stranded (ds) DNA
- Nonenveloped, icosahedral
- Human 51 serotypes: 2 & 5 cardiotropic
- Clear association with MC
- Infects among others cardiomyocytes
Zhang et al, J of Virology 2005; McCarthy et al, J of Virology 2014
Blailock et al, Exp & Molec Pathol 1968
Coxsackievirus B3 Adenovirus
Kühl et al JACC, 2012
Enterovirus
Cardiac Coxsacki virus
persistence and prognosis
50%
EV Spontan-
elimination
ß-Interferon in Chronic Adeno Viral
Cardiomyopathy: RCT Phase II – BICC Study
Schultheiss et al CRC 2016
Viral genomes epidemiology
Dominguez et al, Rev Esp Cardiol 2015
Shauer et al, IMAJ 2013
Hepatitis C virus and restrictiveCardiomyopathy
Fall in BNP
Drop in PAP
improvement
in NAYH
Poller et al Clin Card 2017
45 % of patients with HCV have HF
Effect of DAA –Therapy on HCV copies
IIyas et al Viral Immunol 2017
Hepatitis C virus and Myocarditis
Viral genomes epidemiology
Dominguez et al, Rev Esp Cardiol 2015
Shauer et al, IMAJ 2013
EBV CMV HHV-6
Life-long latency X X X
Reactivation in
immunocompromised
patients/geriatrics
X X X
Cardio/vasculotropism X X X
Treatment Foscarnet Gancyclovir Acyclovir/
Ganclovir
Herpes viruses
Herpes viruses
Cardiotropism
Long-life (latent) persistence - > Bystanders
-> no specific treatment / not to clear
-> in doubt: treat inflammation
Re-activatable
–> Antiviral treatment target in severe HF with and cardiac
inflammation
-> Antiviral therapy in ciHHV-6 with high copy numbers
Viral genomes epidemiology
Dominguez et al, Rev Esp Cardiol 2015
Shauer et al, IMAJ 2013
22.07% Virus negative0.34% CVB369.31% PVB191.03% EBV2.24% HHV60.17% CMV0.52% CVB3/PVB190.52% HHV6/PVB193.45% EBV/PVB190.17% HHV6/PVB19/EBV0.17% CVB3/PVB19/EBV
69.3% PVB19
22.1% Virus negative
Distribution of viral genomes 2015-2019
Charite – Campus Virchow
Tschöpe et al 2019, unpublished
N = 580
Adamson-Small LA et al, Virus Research 2014
Persistent B19V DNA in non-erythroid tissues:
possible role in inflammatory and disease process
Parvovirus B19 in Endomyocardial Biopsy of Patients
With Idiopathic Dilated Cardiomyopathy
Hjalmarsson, C., et al. (2019). J Card Fail 25(1): 60-63.
B19V-DNA is a common finding in both patients
with IDCM and in healthy donor hearts,
not affecting prognosis
CAPACITY Trial
Cortison in PVB positive DCMi
Tschöpe et al EJHF 2019
Improved
EF
Reduced
Inflammation
No change
In viral load
Cardiac viruses:
To be a bystander or not be a bystander
Adenovirus Coxsackie virus B3
Virulent Cardiotropic
PVB19
HCV
HCV positive with HF – treat, independent of
EMB result
HHV-6/ciHHV6EBV
Latent; undetectable DNA in EMB;
no Inflammation
DNA+ EMB; active: needs to be treated
in ciHHV-6 or in severe HF
Inactive persistent; DNA (<500 copies/µg);
no inflammation
High copy numbers/systemic viraemia
Bystander
Virluent
Bystander
Virluent
Virluent
Virluent
Influenza-associated Myocarditis
58 reported cases of myocarditis associated with H1N1
2009 pandemic in Japan
Ukimura, A., et al. (2012). Influenza Res Treat 2012: 351979.
Influenza-associated Myocarditis
• Acute fulminant form of myocarditis.
• The true prevalence remains unknown.
• Influenza A virus–associated fulminant
myocarditis is rare.
• The treatment is based on hemodynamic and
ventilatory support beside neuraminidase
inhibitors.
Zusammenfassung der Therapie
bei Myokarditis
1. Symptomatische Therapie
2. Kausale Therapie
Tschöpe et al 2019
Zusammenfassung der Therapie
bei Myokarditis
1. Symptomatische Therapie
2. Kausale Therapie
Tschöpe et al 2019
1. ACEI/ARB/ARNI
2. Beta Blocker
3. MRA (EF <35%)
4. Diuretics
5. Ivabradine (HF > 74 bpm)
6. No Sport (for 6 months)
7. Devices
Chronic phase: GL
2015 ESC Guidelines:
Conventional
standard therapy
Zusammenfassung der Therapie
bei Myokarditis
1. Symptomatische Therapie
2. Kausale Therapie
Tschöpe et al 2019
Inflammation negative
Virus negative
EMB-
results
Differential
diagnosis
Therapy
options
Post MC
DCM
HF therapy
Risk adjusted therapy
Proposal for Biopsy- guided therapy options in viral
– induced myocarditis 2019
Tschöpe et al 2019
Inflammation positive
Virus negative
Inflammation negative
Virus negative
EMB-
results
Differential
diagnosis
Therapy
options
Post MC
DCM
HF therapy
Risk adjusted therapy
Lymphocytic MC
Giant Cell MC
Sarcoid
Eosinophilic MC
Immuno-
suppression
Proposal for Biopsy- guided therapy options in viral
– induced myocarditis 2019
Tschöpe et al 2019
Inflammation positive
Virus positive
Inflammation positive
Virus negative
Adenovirus Enterovirus Immunmodulation**
Inflammation negative
Virus negative
EMB-
results
Differential
diagnosis
Therapy
options
Post MC
DCM
HF therapy
Risk adjusted therapy
Lymphocytic MC
Giant Cell MC
Sarcoid
Eosinophilic MC
Immuno-
suppression
Herpesvirus, HIV, HCV,
Ifluenza
Parvovirus B19
Antiviral***
Immunosuppression*
Proposal for Biopsy- guided therapy options in viral
– induced myocarditis 2019
Tschöpe et al 2019
Zusammenfassung
Inflammatorische Kardiomyopathien
Diagnostik
-> neue MRT Kriterien zur akuten Myokarditis
-> Biopsie-geführte Diagnose bei V. a. chronische oder
„komplizierter“ Myokarditis (> 30 Tage / Schock)
Therapie
-> Prognose Verbesserung durch Immunsuppression
bei virus-negativen kardialen Entzündungen
-> Spezielle Therapie Ansätze bei Viruspersistenz
Prognose -> Meist gut unter konservativer Therapie und Schonung