myocarditis & inflammatory cardiomyopathy

MYOCARDITIS MYOCARDITIS & &

INFLAMMATORY CARDIOMYOPATHYINFLAMMATORY CARDIOMYOPATHY

BY Fellow: Hung Hung ChungLiehChungLieh

MYOCARDITISMYOCARDITIS: Cardiac Inflammation

Etiology1. Infectious process (Most commonly)2. Radiation3. Chemicals/Drugs 4. Physical agents5. Idiopathic (Giant-cell myocarditis)

MYOCARDITISChemicals/DrugsAnthracyclines (450-550 mg/m2)Anthracyclines combined Trastuzumab

(Anti-HER-2 receptor AB)Cocaine (Vasoconstrictor)Drug-Induced Allergic Myocarditis

(Eosinophilic infiltrate in myocardium)

VIRAL MYOCARDITISEPIDEMIOLOGY

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..etcProspective & retrospective studies: Myocardial inflammation in 1 to 9% of routine postmortem examinationsVariable incidence due to differences in methods of diagnostic evaluation

VIRAL MYOCARDITISEPIDEMIOLOGYDallas Criteria (Histological diagnosis introduced in 1986)

Use tools of Light Microscopy in endomyocardial-biopsy specimensActive Myocarditis - Infiltrating lymphocytes and myocytolysisBorderline/Ongoing Myocarditis - Infiltrating lymphocytes (+), and myocytolysis (-)Negative - Infiltrating lymphocytes (-), and myocytolysis (-)

Probably underestimate the true incidence of myocarditis due to large intraobserver variability

VIRAL MYOCARDITISMOST COMMON INFECTIVE VIRUS

Coxsackievirus B (Enterovirus)Adenoviruses in A Recent Report

VIRAL MYOCARDITISCLINICAL MANIFESTATIONS

Asymptomatic StateECG Changes (Transient Electrocardiographic ST-T-Wave Abnormalities)

ArrhythmiasFulminant Condition with ArrhythmiasHeart FailureDeath

VIRAL MYOCARDITISFULMINANT MYOCARDITIS

Rapid Progressive Cardiogenic Shock (LOS) Life-Threatening Arrhythmia (LTA)A Prominent Cause of Sudden, Unexpected deathOften Within Hours to Several Days Following A Flu-Like Illness

VIRAL MYOCARDITISPOSSIBLE PHYSICAL EXAMINATIONS

Often NormalMuffled First Heart SoundThird Heart Sound Murmur of Mitral RegurgitationPericardial Friction Rub (Associated with Pericarditis)

VIRAL MYOCARDITISDIFFERENTIAL DIAGNOSIS

Acute Myocardial InfarctionChest painECG ChangesElevated Cardiac Enzymes

VIRAL MYOCARDITISDIAGNOSIS

A 4-FOLD RISE IN NEUTRALIZING ANTIBODY TITERS IN PAIRED SERA

(over A 2 to 4-Week Period):Generally Believed to Establish A Viral PathogenesisENDOMYOCARDIAL BIOPSY:Remains The Best Standard for Diagnosis of Myocarditis

VIRAL MYOCARDITISDIAGNOSIS

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 MYOCARDITISTHERAPEUTIC STRATEGY (For Patients with CHF, Arrhythmias)

Swan-Ganz Catheter CxR, ECG, ECHOABG, Blood Count, & BCS

FULMINANT MYOCARDITIS

AOYAMA & COLLEAGUES (2001)52 Patients with Fulminant Myocarditis PCPS UsageInitial Symptoms (Flu-Like); Cardinal SymptomsSevere Myocardial Disorders, Heart Failure, Arrhythmia, Conduction System Disorders, & Cardiogenic Shock

FULMINANT MYOCARDITISCLINICAL 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%).


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%).


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 MYOCARDITISFELKER & COLLEAGUES (2000) :

TYPICAL ECHO FINDINGS

Non-dilated Left Ventricular (LV) ChambersThickened Myocardium (Suggestive of Myocardial Edema) Decreased Fractional Shortening

FULMINANT MYOCARDITISPROGNOSTIC 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 MYOCARDITISTREATMENTFulminant MyocarditisShort-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 MYOCARDITISTREATMENTFulminant MyocarditisECMO: Acker (2001)

Circulatory CollapseCardiac ArrestSevere Pulmonary Failure with HypoxemiaBridged to VADs from ECMO if Necessary

VIRAL MYOCARDITISTREATMENTFulminant MyocarditisPCPS Tapper: Duncan and colleagues (2001)

Creatinine Liver enzymesSerum Lactate

(End Organ Perfusion Marker/Perfusion Marker)

VIRAL MYOCARDITISTREATMENTFulminant Myocarditis

High-Dose Immunoglobulin Therapy: Takeda and colleagues (1998)

VIRAL MYOCARDITISPROGNOSISFulminant MyocarditisShort 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 MYOCARDITISPROGNOSISFulminant MyocarditisLong 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 MYOCARDITISETIOLOGY

UncommonA Complication of Bacterial Endocarditis (Staphylococcus Aureus and Enterococci)Myocardial Abscess Formation (Valve Rings & IVS)Diphtheritic Myocarditis in 1/4 Diphtheritic Infections

BACTERIAL MYOCARDITISMECHANISM 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 MYOCARDITISPROGNOSIS & 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' MYOCARDITISEPIDEMIOLOGYPathogen: Trypanosoma Cruzi (Transmitted

By An Insect Vector)Course: Extensive Myocarditis Typically

Evident Years after The Initial InfectionMost Common: In Central and South

America

CHAGAS' MYOCARDITISCLINICAL MANIFESTATION

Acute IllnessOnly About 1%Acute MyocarditisMyocardial Damage Years Later in About 1/3


Chronic IllnessDilatation of several cardiac chambersFibrosis and thinning of the ventricular wallAneurysm formation (especially at the left ventricular apex)Mural thrombiChronic progressive heart failure is the rule with poor survival


ECG FINDINGS1. Abnormal in most patients with cardiac

involvement2. Typically shows RBBB and LAFB3. May progress to complete AV block


ECHO FINDINGS1. A unique pattern of hypokinesis of the

posterior left ventricular wall2. Relatively preserved septal wall motion

CHAGAS' MYOCARDITISPROGNOSIS

Ventricular arrhythmias are common (especially during and after exertion) Cause of death:

Intractable congestive heart failureArrhythmiaA minority of patients dying from embolic phenomena.

CHAGAS' MYOCARDITISTREATMENT

Oral Amiodarone appears to be particularly effective in treating VTsCHF treatment strategy

HIV MYOCARDITISMany cardiac disease has also been associated with HIV-1HIV-I RNA has been detected in heart tissue from patients with AIDSDCM 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 myocardiumBoth HCV positive & negative-strand RNA was noted in DCM

HIV MYOCARDITISSome cases appears to be due to infiltration of the myocardium by the virus itselfIn 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)


Host Factors That Influence Susceptibility to Viral Myocarditis

Murine viral infection is increased by:MalnutritionExerciseSex & sex hormonesAgeGenetic factors (Immune States)


Host Factors That Influence Susceptibility to Viral Myocarditis

Susceptibility to viral infection may be regulated primarily by:1. MHC2. H-2 complex,

in each strain of inbred mice.


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.


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 CARDIOMYOPATHYAcute 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 CARDIOMYOPATHYSubacute Phase of Viral Myocarditis (Days 4 to 14)1. NK Cells: The first wave of infiltrating cells in the

heart2. 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 CARDIOMYOPATHYSubacute 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


NK Cells, PerforinIFN 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 protectiveNO induced by IFN is important in enterovirus

infection


IFNNK 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 CARDIOMYOPATHYSubacute 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 CARDIOMYOPATHYSubacute Phase of Viral Myocarditis (Days 4 to 14)Cell-Mediated Immune PathogenicityInfiltrating T lymphocytes are seen in the myocardium

as the 2nd wave of cells, important in:Limiting viral replicationIn 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 CARDIOMYOPATHYSubacute 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 spleenLyt 2-positive cells (suppressor/cytotoxic): Greatly increased in the myocardium on days 7 to 14

FROM MYOCARDITIS TO CARDIOMYOPATHYSubacute Phase of Viral Myocarditis (Days 4 to 14)Cell-Mediated Immune Pathogenicity

B lymphocytes (10-20% of infiltrating lymphocytes) in the myocardium on day 7-14Thereafter, they increased gradually with reciprocal T cells counts drop over 1-3 months

FROM MYOCARDITIS TO CARDIOMYOPATHYSubacute Phase of Viral Myocarditis (Days 4 to 14)Cell-Mediated Immune PathogenicityCell-Mediated immune mechanisms play a pivotal role

in the ongoing destruction of cardiac tissueCytotoxic 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 CARDIOMYOPATHYSubacute Phase of Viral Myocarditis (Days 4 to 14)Cell-Mediated Immune PathogenicityPerforin Particles on Virus-specific CTLs caused

myocardial injuryMechanism

Cellular ContactAdhesion of Myocytes (ICAM-1 by TNF-α, IFN-γ, CD40, B7-1, B7-2 ) to T Lymphocytes (CD40L, CD28)

OutcomeViral MyocarditisDCM

FROM MYOCARDITIS TO CARDIOMYOPATHYSubacute Phase of Viral Myocarditis (Days 4 to 14)Myocardial Injury in T-Cell-Depleted MiceMonoclonal 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 CARDIOMYOPATHYSubacute Phase of Viral Myocarditis (Days 4 to 14)Myocardial Injury in T-Cell-Depleted MiceNo Significant Virus Titrations in Myocardium &

Serum Abs:Viral clearance from the myocardium is controlled by B lymphocytesT cell Lymphocytes mediated the severity & development of myocarditis


Chronic Phase of Viral Myocarditis (Days 15 to 90)Persistent Evolutional Myocardial InjuryLV Cavity Dimentions Enlargement, Myocardial

Fibrosis (Inner 2/3 of LV Wall)No Inflammatory Cells Infiltration In This StageIL-1 Associated?Absence of Culturable Virus/Viral Capsid Proteins

NotedCell-Mediated Autoimmune Mechanism Possible

FROM MYOCARDITIS TO CARDIOMYOPATHYChronic Phase of Viral Myocarditis (Days 15 to 90)Persistent Viral RNAIn situ hybridization & PCR: viral RNA detection in

heart 3 weeks later EMCV-inoculationT-cell lymphocytes hypothesis

Altered Manner or Restricted Manner in viral replication possible?Carrier State Infection (Extracardiac Organ in Immunocompromised status)?Hepatitis C Role?


Chronic Phase of Viral Myocarditis (Days 15 to 90)Persistent Viral RNAHCV Involvement


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


Chronic Phase of Viral Myocarditis (Days 15 to 90)Apoptosis

Early shrinkage, Disintegration of nucleolus, Rapid phagocytosis, Total absence of InflammationJames et al (Arrhythmias including sudden unexpected death, cardiomyopathy, arrhythmogenic right ventricular dysplasia Uhl’s anomaly..etc)Partial role from acute viral myocarditis to DCMVirus triggered mechanism


From Myocarditis to CardiomyopathyMechanism

1. Direct Virus-induced Myocytes Injury2. Immune-mediated Mechanism3. Persistent Viral RNA in Myocardium4. Apoptosis


THERAPY-Hemodynamic PortionSupportive care is the first line of therapyCHF Stage:

Diuretics..To lower ventricular filling pressuresACEI..To decrease vascular resistanceß-Blocker..Once clinical stability achievedPotent IVD Vasodilators..Esp. in severe filling pressures

Aggressive control of vascular filling pressures might minimize immune activation by preventing endotoxin in the gut


THERAPY-Hemodynamic PortionMicrovascular Spasm Theory?-> Calcium Blocker/α1-Blocker: Also effectiveAmlodipine

Inhibit NO productionProlonged survival and reduced myocardial damageImproved survival of patients with non-ischemic DCM

AmiodaroneBeneficialInhibition of TNF- α, IL-6


THERAPY-Antiviral AgentsRibavirin (Virazole), synthetic nucleoside analogue:

Against RNA, DNA VirusesHuman amnion study in vitro/ Mice myocardial study is beneficial

Recombinant human leukocyte IFN- α A/D:Inhibit viral replication/Reduce inflammatory process in Mice modelIt should be used before or simultaneously used with viral inoculation


THERAPY-Antiviral AgentsCombined Usage of Ribavirin/ IFN- α:

May decreased the effective dosageMinimize side effectsSynergic effects ….in Mice model

FROM MYOCARDITIS TO CARDIOMYOPATHYTHERAPY-Immunosuppressive AgentsSteroids:Inhibits ABs synthesisAggravated the course of Murine MyocarditisWorth further study


THERAPY-Immunosuppressive AgentsCyclosporine:Preferentially inhibit helper T-cell functionsInhibition of IL-2 productionGreater mortality/CHF when administered early/later

during myocarditis in MurineDecreased Thy 1.2+ (pan T) & L3T4+ (activated helper

T) in blood/thymusNo reduction in serum neutralizing ABs titers


THERAPY-Immunosuppressive AgentsFK-506At least 10-fold stronger than Cyclosporine in vivoAlmost total depletion of T- & B-cell functions in

MiceHigher mortality rate, higher virus titer & low serum

ABs


THERAPY-Immunosuppressive AgentsCyclophosphamideInhibit 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

mortalityTreatment in the late stage had no effect


THERAPY-Immunosuppressive AgentsSUMMARYThe importance in the ABs production in the host for

the treatment of viral myocarditisABs production is not affected by the absence of T

cellsNo distinct benefit for patients with myocarditis in

Prednisolone with either Cyclosporine/ Azathioprine in recent biopsy –proven trials


THERAPY-Immunosuppressive AgentsAnti-Monoclonal ABs (Against total T cells) in Mice model

Decreased mortality during the viremic stage Less myocardial cellular infiltration & necrosisNo significant changes in ABs titers/virus replications

High-dose Immunoglobulin/γ-GlobulinEffective in the treatment of Mice/Human myocarditis

High-dose γ-GlobulinEffective in myocarditis 2nd to Kawasaki Dz


THERAPY-Immunosuppressive AgentsLevamisole (In Mice Study)

A promising immunopotentiating drugIncreased the number of myocarditis lesions

Recombinant human TNFMore severe myocarditis in Mice

Exogenous IL-1 or IL-2Restored myocarditis susceptibility in Mice


THERAPY-Immunosuppressive AgentsAnti-B7-1 Monoclonal AB Alone or Combined with

Anti-CD40L Monoclonal ABObviously suppressed myocardial injuries in Murine

viral myocarditis

myocarditis & inflammatory cardiomyopathy

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