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1 Acute Myocarditis - Unusual Causes of HF - 성균관의대순환기내과 삼성서울병원, 심장혈관센터 전은석

2 Case Summary initial presentation CC) Palpitation and DOE for 5 days 39 세여자 Local 입원하여심초음파상 pericardial effusion cardia tamponade 소견으로전원 심전도 : 동성빈맥, low voltage 심초음파도 ) pericardial effusion- 심낭천자 10 cc 2

3 Echocardiography 3

4 Pathology 4

5 Laboratory Findings 08/03 08/16 Day 1 Day 14 BP 90/60 110/80 LVID s/d M d t i di l ff i 30/53 Moderate pericardial effusion with tampone physiology EF 68% WBC Eosinophils 5.0% 20%(1690) Total IgE 220 (0-200) CK-MB/TnI 17.71/ /0.911 NT-proBNP No specific medication Except pericardiocentesis / 퇴원시 Pd 30 mg Losartan Carvedilol 5

6 Myocarditis; Inflammatory Heart Disease Department of Medicine, Sungkyunkwan University School of Medicine, Eun-Seok Jeon, MD, PhD

7 Definition of Myocarditis an INFLAMMATION INFILTRATE and by INJURY to the adjacent myocardial cell that is not typical of INFARCTION Despite clear-cut definition, Classcification, diagnosis and treatment continue to debate. Dallas Criteria (1986) inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocardium not typical of the ischemic damage associated with coronary artery disease 7

8 Inflammations Dallas Criteria Active vs borderline inflammation cell infiltration with or w/o myocardial necrosis or injury Inflammatory infiltrates; lymphocytic, eosinophillic, granulomatous Amount of inflammation Mild, moderate, severe Distribution of inflammation Focal, confluent, diffuse Circulation 2006;113:876 8

9 Dallas Criteria Inflammations Active vs borderline inflammation cell infiltration with or w/o myocardial necrosis or injury Circulation 2006;113:876 9

10 Dallas Criteria Inflammatory infiltrates lymphocytic eosinophillic granulomatous H&E x 400 H&E x 1000 H&E x

11 Biopsy at day 5 : Patchy interstitial and perivascular lymphoplasma cell infiltration ti with multifocal l myocyte damage; consistent with lymphocytic myocarditis 춘계심장학회심부전심포지움 11

12 Pathology Interstitial eosinophilic and lymphocytic infiltration with focal myocyte damage; consistent with eosinophilic myocarditis; suggestive of hypersensitivity myocarditis 12

13 Pathology 13

14 14

15 Etiologic Agents of Myocarditis Infectious Agents Toxic Agents Immunological Syndromes Virus Coxsackievirus(A,B) Adenovirus HIV HCV Bacteria : mycobacterial / streptococcal mycoplasma pneumoniae Treponema pallidum Metazoa : Trichinosis, Echinococcosis Protozoa : Trypanozoma cruzi Fungus : Aspergillosis, Cadidiasis... Anthracyclines Catecholamines Interleukin-2 Coccaine Hypersensitivity sulfonamide cephalosporin diuretics/digoxin TCA dobutamine Chug-Strauss infl bowel dis Sarcoidosis diabetes Sarcoidosis SLE Takayasus Thyrotoxicosis Wegener s PSS / MCTD 15

16 Incidence of Viral Genomes in Myocardium 16

17 Coxsackievirus Type B3 (CVB3) 7.4 Kb ssrna picornavirus i highly cardiotropic induces myocarditis progress to cardiomyopathy 17

18 Diagnostic evaluation 1.Endomyocardial di biopsy 2. Cardiac biomarkers Troponin I; sensitivity 34%, specificity 89% CK, CK-MB;low predictive value 3. Immunologic Approaches Immunohistochemical staining for Lc MHC expression chronic for of myocarditis 4. Myocardial imaging Circulation 2006;113:876 18

19 Endomyocardial Biopsy Histological myocarditis in 25% of samples >5 biopsies, two thirds are (+) For accurate Dx, Needs >17 samples in >80% of patients Agreement of 7 pathologists in 16 DCM specimen Fibrosis i (25-69%), Hypertrophy (19-88%) Nuclear changes (31-94%), LC counts on HPF (0-38%) Myocarditis associated with HIV/AIDS, ischemia, Inflammations- sarcoidosis, SLE etc Otherwise primary (postviral) Circulation 2006;119:593 19

20 Neutralization test with serial sera 120% Cell survival ATCC B4 Day 주은숙 1 NT( ) Day 15 Day 30 Control serum 100% 80% 60% 40% 20% 0% C C+ 20

21 PFU assay from tissue with HeLa Viable virus was isolated from frozen left atrial tissue at day 1. The final concentration of virus was 1.5 x 10 4 PFU/ml 21

22 Detection of enteroviral Genome by in situ Hybridization in CVB2 myocarditis Badorff C. Med Microbiol Immunol (Berl) Aug 12 22

23 Detection of enteroviral capsid protein VP1 by immunohistochemistry A : fatal myocarditis B : D-CMP C: Chronic myocarditis D : Negative control with IgG2a x200 : A, B1, C1, D x600 : B2, C2 Circulation 2000;101:231 23

24 Virus without inflammation Virus can exist in the myocardium (even in a replicative form) in the absence of myocardial inflammation adequate to meet Dallas criteria. Clinical l myocarditis (36 pts) viral pathogen (+) 26 pts viral pathogen (-) 10 pts Inflammation (+) 13 pts Inflammation (-) 13 pts Circulation 2006;119:593 24

25 Dystrophin Enteroviral VP1 X 400 Maisch, Curr Opi Cardiol,

26 Pathologic findings Inflammation and fibrosis depends on the timing of biopsy H&E x 400 H&E x 400 H&E x 200 At day 1 in patients 1 At day 5 in patients 6 At day 25 in patients 2 Anti-enteroviral VP1-alkaline MT x 400 Phosphatase x100 H&E x

27 Endomyocardial biopsy: Day 7 vs Day 24 X

28 Diagnosis 4. Myocardial imaging Echocardiography RI imaging - Gallium scan for inflammation - In111 labeled anti-myosin RI scan for necrosis Contrast enhanced MRI Circulation 2006;113:876 28

29 2007/08/ /08/16 29

30 Diagnostic evaluation Contrast enhanced MRI At day 2 At day 14 Circulation 1998;97:

31 Host Responses after Viral Infection Viremia (Acute phase) within 3 hour to day 3 maximum virus titer in Heart : day 3-4 to day 7-10 Inflammation (Subacute phase) from day 3, peak day 5-10 mononuclear cell infiltration : macrophage, NK cell cytotoxic T lymphocytes : 7-14 days Serum Ab titer IgM from day 2, peak day 4 IgG from day 6, peak day 15 31

32 Time Course of Viral Myocarditis N Engl J Med 2000;343:

33 Clinical Presentation & Evolution 33

34 Types and causes of AHF Acute de novo HF Decompensated chronic HF Myocardial infarction Arrhythmia Valve destruction Myocarditis Hypertension crisis Cardiac surgery Pulmonary edema Low CO HF (Congection) Cardiogenic shock Myocardial ischemia Arrhythmia Malcompliance Infections Salt overload Hypertension 34

35 Chest PA At day 10 At day 1 35

36 Clinical Presentation & Evolution 36

37 Definition of FM Lieberman (JACC 1991;18:1617) Patients with FM become acutely ill after a distinct viral prodrome, have severe cardiovascular compromise, multiple foci of active myocarditis by histologic study and ventricular dysfunction that either resolves spontaneously or results in death. 37

38 Definition of FM McCarthy (NEJM 2000;342:690) : FM should have 1. severe hemodynamic compromise requiring >5 mg of dopamine or dobutamine /kg/min) or LVAD 2. histopathologically borderline or active myocarditis 3. at least two of the following clinical features 1) fever 2) distinct onset of symptoms of heart failure (fatigue, dyspnea on exertion or at rest, or edema that could be dated specifically to a one-to-two-day period) 3) history consistent t with the presence of a viral illness within the two weeks before hospitalization 38

39 FM has different clinical Manifestations estato s Better Survival Rate ( Lieberman EB 1991, JACC) ) Though more severely ill at presentation. More likely to recover left ventricular function than acute myocarditis. Excellent long-term prognosis (McCarthy RE III et al. NEJM 2000) Fulminant: non-fulminant = 93 % : 45 % Aggressive hemodynamic support is warranted. 39

40 Clinical Presentation & Evolution 40

41 Case Summary initial presentation A 14-year-old boy was admitted with anterior chest pain for a day. Three days earlier, he had had flu-like symptoms. The patient had a positive troponin I ( ng/ml) result and an elevated level of CK-MB (98.27 ng/ml) A coronary angiogram showed no thrombus and no clinically significant stenosis. 41

42 Case Summary Hospital course His ejection fraction at ER was over 50% Eight hours after admission, complete AV block was developed and IV isoproterenol was started for heart rate control. After then, various ventricular arrhythmias were developed and treated with DC version. Shock and urine output decreased and treated with dopamine and dobutamine. He was transferred to SMC after temporary pacemaker insertion and with amiodarone infusion (day 0). 42

43 Case Summary Hospital course Ventilation support were started due to hypoxia. At day 1, shock and pulmonary edema progressed, and urine output was decreased and EF was < 20%. Mechanical circulatory support was started with EBS (Terumo, CAPIOX SP101, Tokyo, Japan). Urine output and dbp were maintained with EBS and inotropics. CPS: Continuous flow Cardiology Division, SKKU Samsung Medical Center 43 16

44 Case Summary Hospital course After 56 hours of mechanical support with EBS, leftventricular-wall motion was restored and her ejection fraction was 45 % on echocardiography. The EBS was removed and he was discharged at hospital day 17 without any symptoms of heart failure. H&E x 200 MT x 200 H&E x

45 Indications for Device support 1. Cardiogenic Shock 2. Heart failure dependent on intravenous inotropic i support 3. Outpatients with symptomatic heart failure functional class IV 4. Uncontrolled ventricular arrhythmia 5. Cardiac allograft dysfunction and/or cardiac allograft vasculapathy 6. Fulminant myocarditis Consensus Conference Report, JACC 2001;37:340 45

46 Circulatory Assist Device Ventricular Assistant Device Counterpulsation device (IABP) Ventricular assist device (VAD) Cardiopulmonary assist device (CPS) Abiomed biventricular system (BVS) 5000i. Cardiology Division, SKKU Cardiology Division, SKKU Samsung Medical Center 13 Samsung Medical Center 15 Intra-aortic balloon pump CPS: Continuous flow mmhg 120 Augmented diastolic pressure Increased coronary artery perfusion Reduced pre-systolic pressure Reduced myocardial oxygen Demand Cardiology Division, SKKU Maisch, Cardiology Curr Opi Division, Cardiol, SKKU Samsung Medical Center 14 Samsung Medical Center 16

47 Contraindications of PCPS 1. Significant AR 2. Severe peripheral artery disease 3. Bleeding diathesis 4. Recent CVA or head trauma 5. Irreversible or end-stage underlying illness Maisch, Curr Opi Cardiol,

48 Emergency Bypass System ( EBS,Terumo, Japan ) Quick / Compact / Simple / Safe Console Drive motor Oxygenator Flow sensor Gas Pump FA Heater Controller Priming RA 48

49 EBS continuous flow Arterial cannula Venous drainage cannula Centrifugal Pump Oxygenator 49

50 Benefits of mechanical support 1. Decrease cardiac strain and work load 2. Increase subendocardial blood flow 3. Normalize histologic changes fiber orientation Cardiac ac hypertrophy y Decrease myocyte wavy fibers and contraction-band necrosis 4. Decrease chamber size 5. Increase mitochondria energy metabolism 6. Inactivation of neurohumoral factors (RAAS, Sympathetic nervous system) Consensus Conference Report, JACC 2001;37:340 50

51 Therapeutic Guideline of Fulminant Myocarditis Circ J 2002;66:133 51

52 Guidelines of PCPS for acute fulminate myocarditis (1) Circ J 2002;66:133 52

53 Guidelines of PCPS for acute fulminate myocarditis (2) Circ J 2002;66:133 53

54 Guidelines of PCPS for acute fulminate myocarditis (3) Circ J 2002;66:133 54

55 Factors Influencing Prognosis Important factors concerning the prognosis were 1) the severity and grade of cardiac and renal dysfunction 2) the adjusted support flow rate to enable recovery from circulatory failure 3) prevention of circulatory disturbances of the legs and multiple organ failure directly associated with PCPS. Long-term prognosis of patients treated with PCPS 1. the readmission rate was 10% 2. the exacerbation rate was 3.3% 3. mortality was 10% during the average follow-up pperiod of 962 days. Optimal management of the mechanical cardiopulmonary support and curative treatment for the myocarditis further improve the outcome of this disease. Circ J 2002;66:133 55

56 Coxsackieviral protease 2A cleaves dystrophin Badorff, Nat Med 5:320,

57 Serial histological and immunohistochemical analyses of left appendage showed the enteroviral VP1 capsid proteins over the entire heart (A, day 1, 100; B, day 6, 400), with scant lymphocytes observed at day 5. C, Hematoxylin and eosin stain, 400. Focal areas of myocardium displayed a loss of the sarcolemmal staining pattern for dystrophin using antidystrophin Ab (NCLDYSA) that colocalized with enteroviral capsid protein (D, merged image for serial sections, 200). Lee YT, Jeon ES. Circulation 2006;113;

58 Case Summary (F/39) CC) Syncope 2WA, fever for 5 days 4 DA, chest discomfort, palpitation, dizziness (+) syncope ER EKG: ant ST elevation / Cardiac enzyme / ant wall-hypokinesia r/o anterior STEMI 로 CAG 시행했으나정상 CAG 시행중에 VT(polymorphic) with shock 발생 Cardioversion & Mg replacement 시행 Refractory VT SMC ER transfer 58

59 HD1 ECMO insertion HD4 MV thrombus(+) HD5 valve thrombectomy(+) t & Bx HD6 biopsy- viral protein(+) Giant cell myocarditis on pathology HD10 heart transplantation HD12 expired 59

60 Endomyocardial biopsy findings done at hospital day 5 H&E x 100 H&E x 200 H&E x 400 H&E x

61 Endomyocardial biopsy findings done at hospital day 5 H&E x 40 Enterovirus VP1 x40 Enterovirus VP1 x40 w/o 1 Ab Enterovirus VP1 x400 in H3 infected mice day 7 61

62 Pathology of explanted heart (day 10) LV x 200 x 400 x 1000 RV 62

63 Viral Capsid protein VP0 Western blot Lane 1 : H3 infected mouse heart at day 3 Lane 2 : Control mouse heart Lane 3 : LA Lane 4: LV Lane 5 : RA Lane 6 : RV 63

64 Case Summary (M/37) 1WA chest pain 발생한후감기몸살같은증상 ( 열, 근육통, 등 ) 있어며칠간일을거르고 self medication Sx aggravation 되어순천성가롤로병원방문 wide QRS, AV dissociation on EKG / CAG: normal Hypotension 발생하여 SMC ER refer BP 60/40, altered mentality intubation and PCPS insertion 후 CCU adm 64

65 Case Summary Hospital course Ventilation support were started due to hypoxia. At day 1, ECMO inserted. At HD 23, Loss of brain stem sign 65

66 Endomyocardial biopsy findings done at hospital day 8 (H&E) X 200 X

67 Autopsy findings at day 24 (H&E) X 200 X400 67

68 Immunohistochemistry with enteroviral VP1 Ab at day 8 X 200 without Ab X 200 with Ab 68

69 vp1 GAPDH vp1 GAPDH vp1 GAPDH LA LV RA RV Patient other 69

70 Clinical Presentation & Evolution 70

71 Laboratory findings 3/22 4/4 5/19 10/06 LV 74/81 76/81 74/82 46/62 EF(%) LA NT-proBNP

72 H & E, x400 IHC, x100 IHC, x100 IHC, x100, control IHC with anti-enteroviral Ab 72

73 Persistent Viral Infection in Chronic Phase Clinical Evidences Viral gemones (+) in DCMP : CVB3, CMV, Adeno, HCV Experimental Evidence EMC genome (+) 80 days after infection (Matsumori, Circulation 1996:94) Replication defective cdna of CVB3 (Wessely, Circulation 1998:98) Transgenic animal with replication defective CVB3 cdna (Wessely, J Clin Invest 1998:102) 73

74 Prognosis and viral RNA 1. JACC 1995;25:1170 Better TPL free survival rate in CVB3 (+) than (-) in heart (95% vs 55%) 2. Circulation 1994;89:2582 Actuarial survival at 24 months RNA(+) vs (-) = 92 vs 68% 3. Circulation 2003;107:857 In LC myocarditis, immunosuppressive nonresponder 85% had viral genome 74

75 Immune Models of Myocarditis Autoimmune Model Rat or mice immunized with myosin (Kodama, Circ Res 75: 1994) Cell mediated Model : SCID mice Adoptive transfer of immunized Lc Human Lc transfer of to SCID mice (Schwimmbeck, Circ Res 75: 1994) 75

76 Myocarditis Treatment Trial Inclusion Criteria CHF not d/t VHD, CAD LVEF <45% by RI angio Symptom duration < 2 years Patients enrolled : 2233 pts (Oct ) Endomyocardial biopsy : 214(10%) pts - final 111 pts Drugs : Azathioprine + Prednisolone for 6 months Cyclosporine + Prednisolone for 6 months Mason, NEJM 333:269,

77 Myocarditis Treatment Trial Results : No significant effects of immunosuppression on NYHA FC, LVEF, Survival, PWP, LV dimension Mason, NEJM 333:269,

78 Treatment 1. Supportive care Hemodynamic stabilization 2. ACC/AHA guideline for LV dysfunction β-adrenergic blocker / ACEI for all Aldosterone antagonist in NYHA FC III-IV 3. Immunosuppressive agents Circulation 2006;113:876 78

79 Immuosuppression in myocarditis Supportive care Immunosuppressive agents Intravenous immuno- globulin Inter feron Fulminant yes??? Eosinophillic yes yes?? Giant cell yes yes Yes? Lympho cytic Virus(+) yes?? + Virus(-) yes??? 79

80 Acknowledgement Samsung Medical Center 권기영교수 ( 해부병리 ) 윤수현 / 송현미 / 주은선 University California, San Diego Byung-Kwan Lim Kirk Knowlton 80

Cytokine Gene Therapy in Viral Myocarditis

Cytokine Gene Therapy in Viral Myocarditis - VAD in treatment of Fulminant Myocarditis - Definition of Myocarditis an INFLAMMATION INFILTRATE and by INJURY to the adjacent myocardial cell that is not typical of INFARCTION Dallas Criteria (1986)