U N I V E R S I T Ä T S M E D I Z I N B E R L I N CBF KARDIOLOGIE

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1 U N I V E R S I T Ä T S M E D I Z I N B E R L I N

2 I have nothing to disclose.

3 Case 2 A Case of acute heart failure 54 year old female

4 Patient with acute heart failure and ventricular tachycardia 53 year old female patient February 2007 ventricular fibrillation left ventricular decompensation, ICD March 2007 ( send to our hospital ) LVEF: 35% Heart failure medication

5 Biopsy: Yes? No?

6 AHA/ACC/ESC Joint Scientific Statement Indication for endomyocardial biopsy in cardiovascular disease Charite Presentation history clinical presentation class evidence Acute HF < 2 weeks - LV normal oder dilated, I B impaired LV-function Acute HF 2-12 weeks - DCM, ventrikular arrhythmias, AVB II-III I B or no response to standard HF treatment Chronic HF > 3 months - ventricular dilatation and new ahrrhytmias IIa C or no response to standard HF treatment independent - DCM (allergic/eosinophilic) IIa C - toxic (e.g. antrazyklin) IIa C - idiopathic DCM in children IIa C - unclear restricitv CM IIa C - suspected myocardial cancer IIa C Acute HF 2-12 weeks - acute DCM without arrhythmias IIb B response on medical therapy Chronic HF > 3 months - DCM without arrhythmias IIb C response on medical therapy independent - Heart failure in unclear hypertrophy IIb C - suspected ARVD IIb C - unclear ventricular arrhythmias IIb C

7 A case of acute heart failure 45 year old male Which diagnosis would we expect from endomyocardial biopsy? 1. Active myocarditis (including giant cell myocarditis)? 2. Inflammatory cardiomyopathy? 3. Dilated cardiomyopathy? 4. Virus-associated heart disease with/without inflammation?

8 A 53 year old female with recurrence of giant cell myocarditis Biopsy diagnosis: giant cell myocarditis

9 A 53 year old female with recurrence of giant cell myocarditis Medical treatment: - heart failure medication - immunosuppressive therapy: Ciclosporin 150mg/day Prednisolon 80mg/day

10 Patient with acute heart failure and ventricular tachycardia 53 year old female patient Mai 2007 improvement of left ventricular function (LVEF: 45%) clinical improvement (NYHA II/III) control biopsy: no GCM, ongoing myocarditis immunosuppressive therapy Ciclosporine 150 mg/day Prednisolone 40 mg/day

11 Patient with acute heart failure and ventricular tachycardia 53 year old female patient December 2007 Normal left ventricular function (LVEF: 64%) further clinical improvement (NYHA II) control biopsy: no GCM, healed myocarditis

12 What would you do? Reduce / stop immunosupression

13 Patient with acute heart failure and ventricular tachycardia 53 year old female patient December 2007 Normal left ventricular function (LVEF: 64%) further clinical improvement (NYHA II) control biopsy: no GCM, healed myocarditis immunosuppressive therapy was reduced Ciclosporine 80 mg/day Prednisolone 20 mg/day

14 Patient with acute heart failure and ventricular tachycardia 53 year old female patient February 2008 Normal left ventricular function (LVEF: 64%) NYHA II pro BNP 600 pg/ml immunosuppressive therapy Ciclosporine 80 mg/day Prednisolone reduced to 5 mg/day within 3 months

15 Patient with acute heart failure and ventricular tachycardia 53 year old female patient July 7, 2008 fever 39 C, no history of viral infection, sore throat LVEF: 52%, Troponin T: 0.6, probnp: 14,000 pg/ml no infectious focus Tazobac 13.5 g/day ( ) July 17,2008 VT, appropriate ICD shock pro-bnp: 26,000 pg/ml LVEF 35% immunosuppressive therapy Ciclosporine 100 mg/day Methylprednisolone 5 mg/day

16 What would you do? Biopsy again: Yes? No?

17 Patient with acute heart failure and ventricular tachycardia 53 year old female patient July 17, 2008 Control biopsy ( n = 9 ) PCR: no viral infection ( 3 biopsies ) Histology: focal lymphocytic myocarditis ( 3 biopsies ) no GCM, no eosinophils IHS: lymphocytic infiltration ( 3 biopsies ) Evg, x100 H&E, x100 IHS CD3+, x200

18 A 53 year old female with recurrence of giant cell myocarditis Histology ( n = 3 ): Active myocarditis Immunohistological staining ( n = 3 ): CD3, x200 Mac 1,x200 CD45ro, x200 no giant cells

19 What now? Treatment if yes: how? or Biopsy again?

20 Patient with acute heart failure and ventricular tachycardia 53 year old female patient July 23, 2008 LVEF: 19% pro-bnp: >35,000 pg/ml

21 Patient with acute heart failure and ventricular tachycardia 53 year old female patient 2. Control biopsy: Histology: 8 biopsies Diagnosis: GCM (only seen in 2 out of 8 biopsies) mixed cell myocarditis some eosinophiles

22 A 53 year old female with recurrence of giant cell myocarditis now : giant cells detectable but only in 2 out of 8 biopsies biopsy 1 biopsy 2 biopsy 3 biopsy 4 biopsy 5 biopsy 6 biopsy 7 biopsy 8

23 Patient with acute heart failure and ventricular tachycardia 53 year old female patient July 23, 2008 LVEF: 19% Treatment: Muromonab 5 g/10 days Prednisolone 10 mg/kg BW/3 days Ciclosporine 150 mg/day

24 A 53 year old female with recurrence of giant cell myocarditis left ventricular ejection fraction Left ventricular function under medical treatment 55% 50% 45% Start of treatment with Orthoclone OKT3, Anti-CD3 Start of treatment with Orthoclone OKT3, Anti-CD3 40% 35% Control biopsy 30% 25% 20% 15% time

25 Patient with acute heart failure and ventricular tachycardia Muromonab-CD3 5g/d (10 days) Ciclosporin trough level ng/ml, ongoing Prednisolon 10 mg/kg ( 3 d) 1.0 mg/kg ( 4 d) 0,5 mg/kg ( 1 week) 0,25 mg/kg ( 1 week) 0,10 mg/kg 0,05 mg/kg (since week 48) LVEF % % % (NYHA II) % (NYHA II) % (NYHA II) % (NYHA II)

26 Differential Therapy of Inflammatory Heart Disease Charite Disease Pathogenesis Clinical Phenotype Standard Therapy Additional Therapy in Severe / Refractory Cases No Virus Inflammation + Heart Failure HF Therapy + Immunsuppression Immunoadsorption Recomb. Immunmodulatory Proteins Chemokine/Chemokine Receptor Modulators Anti-Inflammatory RNA-Interference Cardiac Inflammation Eosinophilic Cardiomyopathy Heart Failure HF Therapy + Immunsuppression Giant Cell Myocarditis Heart Failure HF Therapy + Immunsuppression + Ciclosporin OKT3 (anti-cd3-mab)

27 Lassner, Schultheiss et al, submitted Detection of giant cell myocarditis by gene profiling % Immunohistological staining of granulomateous myocarditis by CD 11a (LFA-1). brown: activated inflammatory cells negative: multinucleated giant cells (GC). Detection of suspicious giant cells by highly upregulated genes without pathohistological proof on paraffin sections.

28 GCM Treatment Trial Average histologic scores by blinded analysis at baseline and day 30 Cooper et al. Am J Cardiol 2008

29 GCM Treatment Trial Change in ejection fraction baseline and after 30-day Cooper et al. Am J Cardiol 2008

30 GCM Treatment Trial Conclusion Immunosuppressive treatment with the combinations of agents used in this study resulted in relatively low 1-year mortality. Further, abrupt withdrawal of immunosuppression can result in recurrent, fatal GCM. They observed a marked improvement in the inflammatory infiltrate accompanied by an increase in fibrosis after 4 weeks of treatment. Cooper et al. Am J Cardiol 2008

31 Thank You for your attention U N I V E R S I T Ä T S M E D I Z I N B E R L I N

32 Acute Myocarditis Case 1

33 A 53 year old female with recurrence of giant cell myocarditis May 2007 June 2008 Improvement of left ventricular function ( EF : 56% ) and further clinical improvement (NYHA II) Control biopsies ( June 2008 ): no giant cells, healing myocarditis, no viral infection Reduction of immunosuppressive therapy: Ciclosporin 100mg/day Prednisolon 5 mg/day

34 A 53 year old female with recurrence of giant cell myocarditis July 2008: Fever 39 C, NYHA III VT, appropropriate ICD shock Troponin T : 0.6 probnp: 35,000 pg/ml Left ventricular function: EF 19% Again: myocardial biopsy

35 A 53 year old female with recurrence of giant cell myocarditis Control biopsy after OKT3 treatment: EF: 52% - no giant cells, - continuance of healing myocarditis Immunohistological staining CD3: x200 Mac1: x200 CD45ro: x200

36 mrna analysis to relative controls Specific distribution pattern of inflammatory factors in giant cell myocarditis * * * * * P< CCL20 CCR6 IL6 TLR3 TLR4 * TLR5 * TLR9 TNF controls MCA GCM * P<0.001 n=10

37 A Case of acute heart failure 45 year old male

38 A case of acute heart failure 45 year old male History May 2002 flue-like infection angina at rest mild dyspnea on exertion (persistent since 3 weeks) June 2002 Physical exam. normal ECG: minimal ST elevations (II, III, avf, V 4-6 ) Troponin T negative

39 A case of acute heart failure 45 year old male June Echocardiography LVEDD 62 mm LVESD 45 mm EF 43% - Angiography no CAD - MRI reduced LV-EF (45%) no inflammation - Laboratory tests normal - Medication ACE inhibitor, β-blocker, diuretics

40 A case of acute heart failure 45 year old male Which diagnosis would we expect from endomyocardial biopsy? 1. Active myocarditis (including giant cell myocarditis)? 2. Inflammatory cardiomyopathy? 3. Dilated cardiomyopathy? 4. Virus-associated heart disease with/without inflammation?

41 A case of acute heart failure 45 year old male Which diagnosis can we expect from endomyocardial biopsy? 1. Active myocarditis (including giant cell myocarditis)? 2. Inflammatory cardiomyopathy? 3. Dilated cardiomyopathy? 4. Virus-associated heart disease with/without inflammation? All answers are correct

42 A case of chronic myocarditis 45 year old male Analysis of endomyocardial biopsies Histology: IHS: PCR: regular cardiac tissue mild inflammation enterovirus positive Diagnosis: Enteroviral heart disease with mild myocardial inflammation

43 A case of chronic myocarditis 45 year old male November 2002 Echocardiography LVEDD 63mm LVESD 40mm LVEF 58% March 2003 Echocardiography LVEF 60% Control Biopsy? Yes? No?

44 A case of chronic myocarditis 45 year old male March 2003 Angiography: LVEF 60% follow-up biopsy: npcr IHS Histology 8 biopsies enterovirus positive 1 out of 6 biopsies no inflammation normal tissue, no fibrosis

45 A case of chronic myocarditis 45 year old male What are the suggestions for diagnosis and further management of this patients at 2003? 1. Healing enterovirus myocarditis; echocardiographic follow-up? 2. Mildly dilated cardiomyopathy; echocardiographic follow-up? 3. Enteroviral cardiomyopathy; follow-up biopsy if symptomatic? 4. Enteroviral cardiomyopathy; antiviral treatment?

46 A case of chronic myocarditis 45 year old male What are the suggestions for diagnosis and further management of this patients at 2003? 1. Healing enterovirus myocarditis; no follow-up until symptomatic? 2. Healing enterovirus myocarditis; echocardiographic follow-up? 3. Mildly dilated cardiomyopathy; echocardiographic follow-up? 4. Enteroviral cardiomyopathy; follow-up biopsy if symptomatic? 5. Enteroviral cardiomyopathy; follow-up biopsy? 6. Enteroviral cardiomyopathy; antiviral treatment?

47 A case of chronic myocarditis 45 year old male What are the suggestions for diagnosis and further management of this patients at 2003? 1. Healed enterovirus myocarditis; no follow up until symptomatic? 2. Healing enterovirus myocarditis; echocardiographic follow-up? 3. Mildly dilated cardiomyopathy; echocardiographic follow-up? 4. Enteroviral cardiomyopathy; follow-up; biopsy if symptomatic! 5. Enteroviral cardiomyopathy; follow-up biopsy? 6. Enteroviral cardiomyopathy; antiviral treatment?

48 A case of chronic myocarditis 45 year old male What are the suggestions for diagnosis and further management of this patients at 2003? 1. Healed enterovirus myocarditis; no follow up until symptomatic? 2. Healing enterovirus myocarditis; echocardiographic follow-up? 3. Mildly dilated cardiomyopathy; echocardiographic follow-up? 4. Enteroviral cardiomyopathy; follow-up; biopsy if symptomatic! 5. Enteroviral cardiomyopathy; follow-up biopsy? 6. Enteroviral cardiomyopathy; antiviral treatment?

49 A case of chronic myocarditis 45 year old male August 2003 no cardiac complaints patient stopped all medication September 2003 Echocardiography LVEDD 63mm LVESD 39mm LV-EF 69%

50 A case of chronic myocarditis 45 year old male January 2005 progressive heart failure Echocardiography LVEDD 67mm LVESD 58mm LV-EF 19%

51 A case of chronic myocarditis 45 year old male EF 69% EF 19% September 2003 January 2005

52 A case of chronic myocarditis follow-up biopsy 45 year old male npcr IHS histology EV positive moderate, focal inflammation DCM, fibrosis x200 CD3+ lymphocytes

53 Enteroviral Myocarditis follow up Myocardial biopsy March 2003 Myocardial biopsy Feb Myokardbiopsie Februar 2005 Clinical follow up: heart transplantation

54 Enteroviral Myocarditis chronic course EF 70 June 2002: clinically suspected myocarditis Ø endomyocardial biopsy mild focal lymphocytic infiltration (CD8 + ) June 02 March 03 Feb 05 CD3 + coxsackievirus B3 positive March 2003 (healed myocarditis) Ø endomyocardial biopsy healed myocarditis coxsackievirus B3 positive Patient, male, 45 years now listed for HTX) Feb 2005 (clinical diagnosis: DCM) Ø endomyocardial biopsy dilated cardiomyopathy ( EF 19% ) (interstitial fibrosis/scars) coxsackievirus B3 positive June 02

55 Inflammatory Cardiomyopathy (Influence of enteroviral persistence on survival, n = 96) p =

56 Identification of Novel Noncoding RNA Targets Poller, Kühl, Schultheiss, 2012 submitted

57 Identification of Novel Noncoding RNA Targets Q1: Does blockade of a Type I mir reduce antiviral capacity? Q2: Reasons for blockade of Type I mir expression? Epigenetic? Q3: Does blockade of a Type II mir enhance antiviral capacity? Q4: Reasons for induction of Type II mir expression? Q5: What blocks the normal response of Type III mirs = reduction upon viral infection and turns it to the contrary?

58 Pathogenesis of viral/inflammatory Cardiomyopathy Viral infection antiviral Cytokines Myocardial inflammation Innate/adaptive immune response antiviral Cytokines Virus clearance resolved inflammation Minor myocardial damage Severe myocardial damage Virus clearance persistent inflammation Minor myocardial damage Severe myocardial damage Virus persistence ± persistent inflammation Healed Myocarditis Dilated Cardiomyopathy Chronic Myocarditis Inflammatory Cardiomyopathy Chronic viral Cardiomypopathy clinical picture like Dilated Cardiomyopathy

59 Prognostic relevance of clinical and aetiopathogenetic features at diagnosis Caforio, EHJ 2007

60 A case of acute heart failure 45 year old male June 2002 Suspected Diagnosis : viral myocarditis Yes? No? Biopsy: Yes? No?

61 Patient with acute heart failure and ventricular tachycardia 53 year old female patient February 2007 ventricular fibrillation left ventricular decompensation, ICD March 2007 ( send to our hospital ) LVEF: 35% Heart failure medication Biopsy: diagnosis: GCM