Hội Tim mạch học Việt Nam

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Some points updated on myocarditis Nguyen Ngoc Quang, MD, FASCC Dept of Cardiology, Hanoi Medical University Vietnam National Heart Institute Epidemiology ✓ True incidence of myocarditis in community is unknown ✓ Greatest burden of myocarditis (chronic DCM, then die or require orthotopic heart transplantation) may not be apparent for 6-12 years after diagnosis 50 Underlying Causes and Long-Term Survival in Patients with Initially Unexplained Cardiomyopathy Felker GM, et al N Engl J Med 2000; 342:1077-1084 IDCM Myocarditis Ischemic 4 3 Infiltrative Peripartum HTN HIV CTD Abuse A B C Symptom threshold Active myocarditis Left ventricular function Normal Poor Clinical syndrome of heart failure Severe Normal Time Years In Review, Lancet, 2009 Etiology ✓ Viral & postviral myocarditis: major causes of acute and chronic dilated cardiomyopathy ✓ Spectrum of viruses (EMB samples) shifted from coxsackievirus B to adenovirus to parvovirus B19 and other viruses ✓ Less frequent viruses: hepatitis C, EBV, CMV and HIV Coxsackie B Coxsackie A 1948 Other Many Adenovirus Enterovirus Uncommon HCV Viruses Enteroviruses HHV6 EBV PVB19 2010 Non-Enteroviruses Many injuries can cause myocarditis • • • • • • • Viruses- changing spectrum Toxins- Doxorubicin Radiation Hypersensitivity Reactions Drugs, Vaccines Bacterial, fungal, protozoal Infections Genetic predisposition in 20% or more Some special etiology ✓ Hypersensitivity myocarditis: anticonvulsants, antibiotics, and antipsychotics ✓Eosinophilic myocarditis: Churg–Strauss syndrome, Loffler’sendomyocardial fibrosis, cancer, and parasitic, helminthic, or protozoal infections and with vaccination for several diseases, including smallpox ✓ Giant-cell myocarditis (acute dilated cardiomyopathy): thymoma, autoimmune disorders, ventricular tachycardia, or high-grade heart block Major causes of myocarditis ✓ Infectious causes ✓ Noninfectious causes ✓ Viral ✓ Cardiotoxins: ✓ Bacterial ✓Catecholamines, Anthracyclines, Cyclophosphamide, ✓ Spirochetal Heavy metals (copper, lead, iron), Arsenic, ✓ ✓ Mycotic ✓ Alcohol, Cocaine, Carbon monoxide,Methysergide ✓ Rickettsial ✓ Hypersensitivity reactions: ✓ Protozoal ✓ Helminthic ✓ Antibiotics, Diuretics, Dobutamine; Lithium; Tetanus toxoid; Clozapine; Methyldopa ✓ Insect bites (bee, wasp, spider, scorpion, Snake) ✓ Systemic disorders ✓ Collagen-vascular diseases, Sarcoidosis, Celiac disease, Kawasaki disease, Hypereosinophilia, Wegener's granulomatosis, Thyrotoxicosis ✓ Inflammatory bowel disease (Crohn's disease, ulcerative colitis) ✓ Radiation Pathophysiology Progression from acute injury to chronic DCM: 3-stage process: ✓ Acute injury leads to cardiac damage (myocyte death) within hours of viral cell entry, results from direct viral damage tomyocytes ✓ Exposure of intracellular antigens (cardiac myosin) and an innate immune response comprised of altered regulatory T cell function, NK cells, interferon gamma, nitric oxide… ✓ Heart specific immune response characterized by antibodies to pathogen, host cardiac proteins and autoreactive T cells Most recover with few consequences, a minority die from arrhythmias or progress onto chronic HF Immune Pathogenesis of Chronic DCM Acute Myocarditis Innate Immunity/TLRs Anti-viral response Cytokines (TH1/TH2/TH17) Autoimmunity T and B cell Mimicry Recognition of Myosin by Immune System Chronic Myocarditis Autoreactive T cells and Autoantibodies Antibody Mediated Cell Signaling in the Heart Relapsing and Remitting Autoimmunity Epitope Spreading Dilated Cardiomyopathy Pathogenesis of DCM After Enteroviral Infection Coxsackie B virus Myocyte infection Days “Normal heart” Necrosis Apoptosis Innate immunity Myocyte cytoskeletal damage Direct cytopathic effect Myocyte cell death Weeks • Autoantibodies • Autoreactive • T lymphocytes ? Acute dilated cardiomyopathy Months to years Sequestered viral genome Hemodynamic remodeling Neurohumoral activation Cooper LT, Gersh BJ Am J Card, 2002 Apoptosis Chronic dilated cardiomyopathy CP1184045-6 Consensus Criteria on the CMR Diagnosis of Myocarditis Endorsed by SCMR Myocardial Inflammation Requires of IR prepared T2 weighted images (body coil), the regional or global intensity ratio of myocardium to skeletal muscle exceeds 2SD (1.9) T1 global enhancement ratio is greater than 2SD (4.5) T1 “Late enhancement” post-contrast has at least one focal lesion with non-ischemic distribution Friedrich, M., Presented ESC September 2008, JACC 2009 CMR in Acute Myocarditis Triple-inversion-recovery T2 weighted Spin echo CMR T1 weighted fast spin echo T1 inversion recovery Skouri et al: JACC 48(10):2085, 2006 Antimyosin and Gallium Imaging in Rheumatic Carditis Indium-111 Antimyosin Aschoff Nodule, 10x, 40x Gallium-67 Enteroviral Infection & Clinical Outcome Mortality in Myocarditis/ DCM Patients (%) Proportion Surviving Enterovirus negative 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 25 25 20 P=0.02 P=0.02 15 10 Enterovirus positive 0 12 16 20 24 28 Enteroviral RNA+ Enteroviral RNA- Months Detection of enteroviral RNA in pt with myocardial disease is associated with an adverse prognosis and is an independent predictor of outcome Why HJ: Circ, 1994 Terasaki F: J Card Surg, 1999 Recent Predictors of Outcome in Patients with Myocarditis Freedom from cardiac death and HTx Viral Genome Detection 1.0 Virus negative 0.8 Virus positive 0.6 0.4 P=0.893 0.2 0.0 42 83 125 Months after biopsy Kindermann et al: Circ 118:639, 2008 CP1324648-3 β1-AR Antibodies Predict Mortality in DCM N=105 Stork, Am Heart J 2006 Treatment ✓ Supportive therapy for LV dysfunction: mainstay of treatment ✓ Antiviral therapy ✓ Benefit in acute viral myocarditis (?) dute to late prognosis ✓ IV Ig routine use for acute myocarditis: not recommended (Intervention in Myocarditis and Acute Cardiomyopathy trial) ✓ Interferon beta: maybe effective in viral persistence chronic, stable DCM ✓ Immunosuppression ✓ Routine immunosuppression not beneficial in acute lymphocytic myocarditis ✓ Cyclosporine and steroids: prolong transplant-free survival in giant-cell myocarditis (unlike lymphocytic myocarditis) ✓ Heart transplantation ✓ Recent Treatment Strategies for Chronic Dilated Cardiomyopathy • Targeted cytokine blockade- Negative RCT • Statins- Negative RCT (2008) • Immune Modulation- Negative RCT (2007) • Immunosuppression- positive RCT (2001) • IVIG- positive RCT (2001) • Immunoadsorption• Case Control Series, RCT underway • Antiviral Therapy- Interferon β, Pleconaril Interferon β1b for Chronic Viral Cardiomyopathy BICC Trial • IFN treatment was associated with lower viral load/elimination (p=.049) • Improved NYHA class at 12 weeks (p= 013; 38.6% vs 18.6% > I class) • EF data were not presented Schultheiss, H-P AHA November 11th, 2008 Protein A Immunoadsorption Sepharose matrix • Staph protein A • High affinity to fc of IgG, subclasses 1, 2, • Lower affinitiy to IgG3, IgA and IgM Immunosuppression improves LV function in virus-negative inflammatory cardiomyopathy Changes in LV measurements following immunosuppressive therapy End point Baseline mo LVEF (%) 26.4 48.0 LVEDD (mm) 68.6 52.8 Randomized 85 patients with active lymphocytic myocarditis Immunosuppression (prednisone mg/kg daily * weeks, followed by 0.33 mg/kg daily dose for five months) + azathioprine (2 mg/kg daily for six months) versus control Frustaci A ESC Congress 2008; Munich, Germany Thank you very much for your attention Conclusion ✓ Imaging modalities: CMRI replace EBM ✓ Immunopression vs Immunostimulation ... echo T1 inversion recovery Skouri et al: JACC 48(10):2085, 2006 Antimyosin and Gallium Imaging in Rheumatic Carditis Indium-111 Antimyosin Aschoff Nodule, 10x, 40x Gallium-67 Enteroviral Infection... Autoreactive • T lymphocytes ? Acute dilated cardiomyopathy Months to years Sequestered viral genome Hemodynamic remodeling Neurohumoral activation Cooper LT, Gersh BJ Am J Card, 2002 Apoptosis Chronic dilated... with VT or AVB ✓ Fulminant heart failure after viral syndrome: better prognosis but require hemodynamic support ✓ Chest pain: good prognosis Diagnostic procedures ✓ Troponin I: specificity 89%,