MYOCARDITISMYOCARDITIS && INFLAMMATORYINFLAMMATORY CARDIOMYOPATHYCARDIOMYOPATHY

BY Fellow: HungHung ChungLiehChungLieh MYOCARDITIS MYOCARDITIS: Cardiac Inflammation „ Etiology 1. Infectious process (Most commonly) 2. Radiation 3. Chemicals/Drugs 4. Physical agents 5. Idiopathic (Giant-cell myocarditis) MYOCARDITIS Chemicals/Drugs Anthracyclines (450-550 mg/m2) Anthracyclines combined Trastuzumab (Anti-HER-2 receptor AB) Cocaine (Vasoconstrictor) Drug-Induced Allergic Myocarditis (Eosinophilic infiltrate in myocardium)

VIRAL MYOCARDITIS EPIDEMIOLOGY „ Post mortem studies suggested myocarditis is a major cause of sudden, unexpected death (20%) in adults less than 40 years, young athlets, US Air Force Recruits..etc „ Prospective & retrospective studies: Myocardial inflammation in 1 to 9% of routine postmortem examinations „ Variable incidence due to differences in methods of diagnostic evaluation VIRAL MYOCARDITIS EPIDEMIOLOGY Dallas Criteria (Histological diagnosis introduced in 1986) „ Use tools of Light Microscopy in endomyocardial-biopsy specimens „ Active Myocarditis - Infiltrating lymphocytes and myocytolysis „ Borderline/Ongoing Myocarditis - Infiltrating lymphocytes (+), and myocytolysis (-) „ Negative - Infiltrating lymphocytes (-), and myocytolysis (-) Probably underestimate the true incidence of myocarditis due to large intraobserver variability VIRAL MYOCARDITIS MOST COMMON INFECTIVE VIRUS „ Coxsackievirus B (Enterovirus) „ Adenoviruses in A Recent Report VIRAL MYOCARDITIS CLINICAL MANIFESTATIONS „ Asymptomatic State „ ECG Changes (Transient Electrocardiographic ST- T-Wave Abnormalities) „ Arrhythmias „ Fulminant Condition with Arrhythmias „ Heart Failure „ Death VIRAL MYOCARDITIS FULMINANT MYOCARDITIS „ Rapid Progressive Cardiogenic Shock (LOS) „ Life-Threatening Arrhythmia (LTA) „ A Prominent Cause of Sudden, Unexpected death „ Often Within Hours to Several Days Following A Flu-Like Illness VIRAL MYOCARDITIS POSSIBLE PHYSICAL EXAMINATIONS „ Often Normal „ Muffled First Heart Sound „ Third Heart Sound „ Murmur of Mitral Regurgitation „ Pericardial Friction Rub (Associated with Pericarditis) VIRAL MYOCARDITIS DIFFERENTIAL DIAGNOSIS „ Acute Myocardial Infarction Chest pain ECG Changes Elevated Cardiac Enzymes VIRAL MYOCARDITIS DIAGNOSIS „ A 4-FOLD RISE IN NEUTRALIZING ANTIBODY TITERS IN PAIRED SERA (over A 2 to 4-Week Period): Generally Believed to Establish A Viral Pathogenesis „ ENDOMYOCARDIAL BIOPSY: Remains The Best Standard for Diagnosis of Myocarditis VIRAL MYOCARDITIS DIAGNOSIS „ DIAGNOSIS SHOULD NOT BE BASED ON HISTOLOGIC FINDINGS ALONE 1. The potential discord between clinical and histologic features of myocarditis; 2. Inherent limitation of histologic diagnosis; 3. Newer, less invasive modalities of diagnosing myocarditis in develop. VIRAL MYOCARDITIS THERAPEUTIC STRATEGY (For Patients with CHF, Arrhythmias)

„ Swan-Ganz Catheter „ CxR, ECG, ECHO „ ABG, Blood Count, & BCS FULMINANT MYOCARDITIS

AOYAMA & COLLEAGUES (2001) „ 52 Patients with Fulminant Myocarditis „ PCPS Usage „ Initial Symptoms (Flu-Like); Cardinal Symptoms „ Severe Myocardial Disorders, Heart Failure, Arrhythmia, Conduction System Disorders, & Cardiogenic Shock FULMINANT MYOCARDITIS CLINICAL FINDINGS ON ADMISSION (1) „ VITAL SIGNS: Systolic blood pressure <90 mmHg (50%), tachycardia, or bradycardia (60%). „ CHEST X-RAY: Slight dilatation (increased cardiothoracic ratio: 55%), congestion (70%). FULMINANT MYOCARDITIS CLINICAL FINDINGS ON ADMISSION (2) „ ECG: Sinus tachycardia (40%), complete atrioventricular block (C-AVB) (35%), ST-T abnormality (100%), abnormal Q wave (80%), low voltages (60%), poor r-wave progression (95%). „ ECHO: Diffuse left ventricular hypokinesis (90%), slight hypertrophy (65%), pericardial effusion (90%), nondilated left atrium (85%) or left ventricle (90%). FULMINANT MYOCARDITIS CLINICAL FINDINGS ON ADMISSION (3) „ ABG: Respiratory compensation of metabolic acidosis (50%). „ BLOOD CELLS: Leukocytosis (60%). „ BIOCHEMICAL EXAMINATION: Elevation of creatine kinase (90%), renal dysfunction (55%), hyponatremia (60%), elevated C-reactive protein (CRP) (95%). FULMINANT MYOCARDITIS

MORGERA & COLLEAGUES (1992) : POOR PROGNOSIS in ECG

„ Abnormal QRS Complexes „ Left Bundle Branch Block FULMINANT MYOCARDITIS FELKER & COLLEAGUES (2000) : TYPICAL ECHO FINDINGS

„ Non-dilated Left Ventricular (LV) Chambers „ Thickened Myocardium (Suggestive of Myocardial Edema) „ Decreased Fractional Shortening FULMINANT MYOCARDITIS PROGNOSTIC SEROLOGIC MARKERS

„ Serum Levels of Soluble Fas (sFas) & Soluble Fas Ligand (sFasL) (Fuse et al, 2000) „ Cardiac Isoform of Troponin-I (cTnI) (Briassoulis et al, 2000) „ CRP (Kaneko et al, 2000) VIRAL MYOCARDITIS TREATMENT Fulminant Myocarditis Short-Term PCPS (VADs/ECMO) Indications: Duncan and colleagues/Aoyama and colleagues (2001) „ Cardiogenic Shock induced by LOS or LTA despite maximal medical therapy (Drugs & IABP) „ Increasing Inotropic Requirements: Unlikely VIRAL MYOCARDITIS TREATMENT Fulminant Myocarditis ECMO: Acker (2001) „ Circulatory Collapse „ Cardiac Arrest „ Severe Pulmonary Failure with Hypoxemia „ Bridged to VADs from ECMO if Necessary VIRAL MYOCARDITIS TREATMENT Fulminant Myocarditis PCPS Tapper: Duncan and colleagues (2001) „ Creatinine „ Liver enzymes „ Serum Lactate (End Organ Perfusion Marker/Perfusion Marker) VIRAL MYOCARDITIS TREATMENT Fulminant Myocarditis „ High-Dose Immunoglobulin Therapy: Takeda and colleagues (1998) VIRAL MYOCARDITIS PROGNOSIS Fulminant Myocarditis Short Term Prognosis „ Aoyama and Colleagues (2001): 32 (57.5%) of 52 treated with PCPS survived and returned to normal life „ Acker (2001): Overall success rates of 50-70% with mechanical ventricular support VIRAL MYOCARDITIS PROGNOSIS Fulminant Myocarditis Long Term Prognosis „ McCarthy and Colleagues (2000): 93% were alive without having received a heart transplant 11 years after biopsy „ Aoyama Colleagues (2001): Readmission rate of 10%, an exacerbation rate 3.3%, and mortality of 10% during the follow-up period of 962 ± 780 days post PCPS BACTERIAL MYOCARDITIS ETIOLOGY „ Uncommon „ A Complication of Bacterial Endocarditis (Staphylococcus Aureus and Enterococci) „ Myocardial Abscess Formation (Valve Rings & IVS) „ Diphtheritic Myocarditis in 1/4 Diphtheritic Infections BACTERIAL MYOCARDITIS MECHANISM OF CARDIAC DAMAGE „ Liberation of Toxin: 1. Inhibits protein synthesis; 2. Leads to a dilated, flabby, hypocontractile heart. „ Conducting System: Frequently involved as well. BACTERIAL MYOCARDITIS PROGNOSIS & TREATMENT „ Cardiomegaly & Severe Congestive Heart Failure: Typically appear after the first week of illness; „ Prompt therapy with antitoxin is crucial; „ Antibiotic therapy is also indicated but is of less urgency. CHAGAS' MYOCARDITIS EPIDEMIOLOGY Pathogen: Trypanosoma Cruzi (Transmitted By An Insect Vector) Course: Extensive Myocarditis Typically Evident Years after The Initial Infection Most Common: In Central and South America CHAGAS' MYOCARDITIS CLINICAL MANIFESTATION „ Acute Illness Only About 1% Acute Myocarditis Myocardial Damage Years Later in About 1/3 CHAGAS' MYOCARDITIS CLINICAL MANIFESTATION „ Chronic Illness Dilatation of several cardiac chambers Fibrosis and thinning of the ventricular wall Aneurysm formation (especially at the left ventricular apex) Mural thrombi Chronic progressive heart failure is the rule with poor survival CHAGAS' MYOCARDITIS CLINICAL MANIFESTATION „ ECG FINDINGS 1. Abnormal in most patients with cardiac involvement 2. Typically shows RBBB and LAFB 3. May progress to complete AV block

CHAGAS' MYOCARDITIS CLINICAL MANIFESTATION „ ECHO FINDINGS 1. A unique pattern of hypokinesis of the posterior left ventricular wall 2. Relatively preserved septal wall motion CHAGAS' MYOCARDITIS PROGNOSIS „ Ventricular arrhythmias are common (especially during and after exertion) „ Cause of death: Intractable congestive heart failure Arrhythmia A minority of patients dying from embolic phenomena. CHAGAS' MYOCARDITIS TREATMENT „ Oral Amiodarone appears to be particularly effective in treating VTs „ CHF treatment strategy HIV MYOCARDITIS

„ Many cardiac disease has also been associated with HIV-1 „ HIV-I RNA has been detected in heart tissue from patients with AIDS „ DCM was evident in 80% of a large group of asymptomatic HIV-Positive patients, 83% of whom had myocarditis „ Overt clinical involvement is seen in 10% of HIV patients „ Most common finding is left ventricular dysfunction HCV MYOCARDITIS

„ HCV also is able to replicate in myocardium „ Both HCV positive & negative-strand RNA was noted in DCM HIV MYOCARDITIS

„ Some cases appears to be due to infiltration of the myocardium by the virus itself „ In others, heart is affected by opportunistic infections common in AIDS, such as toxoplasmosis, or cardiac metastases in Kaposi's sarcoma, other 2nd viral myocarditis from CMV, Adenovirus FROM MYOCARDITIS TO CARDIOMYOPATHY „ Higher incidence of neutralizing antibodies to CVB in patients with cardiomyopathy (than in age-, sex-, race-, and living district- matched control subjects) has prompted the theory of a viral cause underlying the pathogenesis of cardiomyopathy

(From Myocarditis to Cardiomyopathy: Circulation. 1999;99:1091-1100) FROM MYOCARDITIS TO CARDIOMYOPATHY Host Factors That Influence Susceptibility to Viral Myocarditis Murine viral infection is increased by: „ Malnutrition „ Exercise „ Sex & sex hormones „ Age „ Genetic factors (Immune States) FROM MYOCARDITIS TO CARDIOMYOPATHY Host Factors That Influence Susceptibility to Viral Myocarditis Susceptibility to viral infection may be regulated primarily by: „ 1. MHC „ 2. H-2 complex, in each strain of inbred mice. FROM MYOCARDITIS TO CARDIOMYOPATHY Sequential Pathological Changes in Murine Viral Infection (EMCV or CVB)

After inoculation of mice with a virus, 2 principal pathogenic mechanisms are implicated in the destruction of myocardial tissue: 1. The direct viral mechanism; 2. Immunocyte-mediated pathogenic mechanism. FROM MYOCARDITIS TO CARDIOMYOPATHY

Sequential Pathological Changes in Murine Viral Infection

Acute Phase of Viral Myocarditis (Days 0 to 3) Subacute Phase of Viral Myocarditis (Days 4 to 14) Chronic Phase of Viral Myocarditis (Days 15 to 90) Flow diagram indicating temporal changes in murine myocytes inoculated with virus covering days 0 to 90. Large solid arrow indicates beneficial effect; dashed arrow, detrimental effect; small solid arrow, induced, produced, or activated; and NT, neutralizing antibody titer. FROM MYOCARDITIS TO CARDIOMYOPATHY Acute Phase of Viral Myocarditis (Days 0 to 3)

1. Virus-Induced Cytotoxicity (Focal Necrotic Myofibers in the absence without inflammatory cells infiltrate) 2. Cytokine mRNA (IL-1ß, TNF-α, IFN-γ) already induced 3 days after inoculation FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) 1. NK Cells: The first wave of infiltrating cells in the heart 2. Cytokine mRNA (IL-1ß, TNF-α, IFN-γ, IL-2) are produced and persisted as long as 80 days after inoculation: Beneficial VS Deleterious Effects 3. Circulating levels of cytokines also elevated in patients with Acute myocarditis, DCM, CHF 4. The role of NO FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) NK Cells, Perforin, & IFN

1. NK Cells (IL-2 Activated) have protective effects against viral invasion by limiting replication 2. Perforin Molecules Formation with Myocardial Injury (NK-like large granular lymphocytes, GM1 Positive cells) 3. NK also damage virus-infected myofibers FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) NK Cells, Perforin, & IFN „ NK Cells, Perforin IFN administration (Exogenous) before, immediately with, or within 24 hours of inoculation with EMCV or CVB3 can be effective in viral myocarditis Native IFN is not fully protective NO induced by IFN is important in enterovirus infection FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) NK Cells, Perforin, & IFN „ IFN NK Cells, Perforin, & IFN IL-1ß, TNF-α, IFN-γ each induce inducible NO Synthase (iNOS) IL-1ß + IFN-γ: Contractile dysfunction in the presence of insulin in adult rate ventricular myocytes TGF-ß decreases iNOS activity, protein content, and mRNA at cardiac microvascular endothelial cells FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) Viral Titers & Neutralizing Antibody (AB) Viral titers in the myocardium were maximal on day 4 after EMCV inoculation in NALB/c mice, but rapidly decreased & disappeared after day 10 Neutralizing ABs elevated rapidly on day 8 & 10 & reached the highest level on day 14 Infiltrating mononuclear cells (NK, Macrophage), which appear in the heart 5 to 10 days after viral infection, also play a definite role in suppressing viral infection FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) Cell-Mediated Immune Pathogenicity Infiltrating T lymphocytes are seen in the myocardium as the 2nd wave of cells, important in: „ Limiting viral replication „ In eliminating infected myocardial cells They peaked on day 7 to 14 after viral inoculation, coinciding the most severe acute pathological damage in the myocardium FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) Cell-Mediated Immune Pathogenicity „ Lyt 1-positive cells (helper/inducer): In the same extent as they were in the peripheral blood & the spleen „ Lyt 2-positive cells (suppressor/cytotoxic): Greatly increased in the myocardium on days 7 to 14 FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) Cell-Mediated Immune Pathogenicity „ B lymphocytes (10-20% of infiltrating lymphocytes) in the myocardium on day 7-14 „ Thereafter, they increased gradually with reciprocal T cells counts drop over 1-3 months FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) Cell-Mediated Immune Pathogenicity Cell-Mediated immune mechanisms play a pivotal role in the ongoing destruction of cardiac tissue „ Cytotoxic T lymphocytes have been shown to lyse virus-infected myocytes in vitro (Figure 4) „ Recent study raises the possibility that: 1. Anti-TCR Abs or; 2. Vaccine with synthetic TCR V- regionpeptides to prevent T-cell-mediated myocardial damage after viral infection FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) Cell-Mediated Immune Pathogenicity Perforin Particles on Virus-specific CTLs caused myocardial injury Mechanism „ Cellular Contact „ Adhesion of Myocytes (ICAM-1 by TNF-α, IFN-γ, CD40, B7-1, B7-2 ) to T Lymphocytes (CD40L, CD28) Outcome „ Viral Myocarditis „ DCM FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) Myocardial Injury in T-Cell-Depleted Mice Monoclonal ABS, Antithymocyte serum: „ Induced marked reduction in myocardial damage (CVB3 in Mice) BALB/c-nu/nu (T-cell-depleted Mice): „ Less prominent myocardial pathological changes BALB/c-nu/+ : „ Markedly severe, prominent mononuclear cells infiltration, cavity enlargement FROM MYOCARDITIS TO CARDIOMYOPATHY Subacute Phase of Viral Myocarditis (Days 4 to 14) Myocardial Injury in T-Cell-Depleted Mice No Significant Virus Titrations in Myocardium & Serum Abs: „ Viral clearance from the myocardium is controlled by B lymphocytes „ T cell Lymphocytes mediated the severity & development of myocarditis FROM MYOCARDITIS TO CARDIOMYOPATHY Chronic Phase of Viral Myocarditis (Days 15 to 90) Persistent Evolutional Myocardial Injury LV Cavity Dimentions Enlargement, Myocardial Fibrosis (Inner 2/3 of LV Wall) No Inflammatory Cells Infiltration In This Stage IL-1 Associated? Absence of Culturable Virus/Viral Capsid Proteins Noted Cell-Mediated Autoimmune Mechanism Possible FROM MYOCARDITIS TO CARDIOMYOPATHY Chronic Phase of Viral Myocarditis (Days 15 to 90) Persistent Viral RNA In situ hybridization & PCR: viral RNA detection in heart 3 weeks later EMCV-inoculation T-cell lymphocytes hypothesis „ Altered Manner or Restricted Manner in viral replication possible? „ Carrier State Infection (Extracardiac Organ in Immunocompromised status)? „ Hepatitis C Role? FROM MYOCARDITIS TO CARDIOMYOPATHY Chronic Phase of Viral Myocarditis (Days 15 to 90) Persistent Viral RNA HCV Involvement FROM MYOCARDITIS TO CARDIOMYOPATHY

Chronic Phase of Viral Myocarditis (Days 15 to 90) Persistent Viral RNA „ Heart specific autoantibodies (Anti-sarcolemma Abs in CVB-Induced Murine myocarditis) „ Cross-Reactivity to CVB3 Capsid Proteins (40% Identity shared with Myosin in Amino Acid Sequence ) „ Myocardiogenic Epitopes located in the cardiac myosin rod or in the head portion FROM MYOCARDITIS TO CARDIOMYOPATHY Chronic Phase of Viral Myocarditis (Days 15 to 90) Apoptosis „ Early shrinkage, Disintegration of nucleolus, Rapid phagocytosis, Total absence of Inflammation „ James et al (Arrhythmias including sudden unexpected death, cardiomyopathy, arrhythmogenic right ventricular dysplasia Uhl’s anomaly..etc) „ Partial role from acute viral myocarditis to DCM „ Virus triggered mechanism FROM MYOCARDITIS TO CARDIOMYOPATHY From Myocarditis to Cardiomyopathy Mechanism

1. Direct Virus-induced Myocytes Injury 2. Immune-mediated Mechanism 3. Persistent Viral RNA in Myocardium 4. Apoptosis FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Hemodynamic Portion Supportive care is the first line of therapy CHF Stage: „ Diuretics..To lower ventricular filling pressures „ ACEI..To decrease vascular resistance „ ß-Blocker..Once clinical stability achieved „ Potent IVD Vasodilators..Esp. in severe filling pressures Aggressive control of vascular filling pressures might minimize immune activation by preventing endotoxin in the gut FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Hemodynamic Portion Microvascular Spasm Theory? -> Calcium Blocker/α1-Blocker: Also effective Amlodipine „ Inhibit NO production „ Prolonged survival and reduced myocardial damage „ Improved survival of patients with non-ischemic DCM Amiodarone „ Beneficial „ Inhibition of TNF- α, IL-6 FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Antiviral Agents Ribavirin (Virazole), synthetic nucleoside analogue: „ Against RNA, DNA Viruses „ Human amnion study in vitro/ Mice myocardial study is beneficial Recombinant human leukocyte IFN- α A/D: „ Inhibit viral replication/Reduce inflammatory process in Mice model „ It should be used before or simultaneously used with viral inoculation FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Antiviral Agents Combined Usage of Ribavirin/ IFN- α: „ May decreased the effective dosage „ Minimize side effects „ Synergic effects ….in Mice model FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Immunosuppressive Agents Steroids: Inhibits ABs synthesis Aggravated the course of Murine Myocarditis Worth further study FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Immunosuppressive Agents Cyclosporine: Preferentially inhibit helper T-cell functions Inhibition of IL-2 production Greater mortality/CHF when administered early/later during myocarditis in Murine Decreased Thy 1.2+ (pan T) & L3T4+ (activated helper T) in blood/thymus No reduction in serum neutralizing ABs titers FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Immunosuppressive Agents FK-506 At least 10-fold stronger than Cyclosporine in vivo Almost total depletion of T- & B-cell functions in Mice Higher mortality rate, higher virus titer & low serum ABs FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Immunosuppressive Agents Cyclophosphamide Inhibit mainly the B-cell region in lymphoid organs at low dose (30 mg. kg-1.d-1) Total cellular depletion of the B/T-cell regions (300 mg. kg-1.d-1) High dose in the early stage resulted in an increased mortality Treatment in the late stage had no effect FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Immunosuppressive Agents SUMMARY The importance in the ABs production in the host for the treatment of viral myocarditis ABs production is not affected by the absence of T cells No distinct benefit for patients with myocarditis in Prednisolone with either Cyclosporine/ Azathioprine in recent biopsy –proven trials FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Immunosuppressive Agents Anti-Monoclonal ABs (Against total T cells) in Mice model „ Decreased mortality during the viremic stage „ Less myocardial cellular infiltration & necrosis „ No significant changes in ABs titers/virus replications High-dose Immunoglobulin/γ-Globulin „ Effective in the treatment of Mice/Human myocarditis High-dose γ-Globulin „ Effective in myocarditis 2nd to Kawasaki Dz FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Immunosuppressive Agents Levamisole (In Mice Study) „ A promising immunopotentiating drug „ Increased the number of myocarditis lesions Recombinant human TNF „ More severe myocarditis in Mice Exogenous IL-1 or IL-2 „ Restored myocarditis susceptibility in Mice FROM MYOCARDITIS TO CARDIOMYOPATHY THERAPY-Immunosuppressive Agents Anti-B7-1 Monoclonal AB Alone or Combined with Anti-CD40L Monoclonal AB Obviously suppressed myocardial injuries in Murine viral myocarditis