1Myocarditis

INTRODUCTION As early as 1806 , a persistent inflammatory process

following such an infection (eg, diphtheria) of the myocardium led to progressive cardiac damage and dysfunction

In 1837, the term myocarditis was first introduced as inflammation or degeneration of the heart by postmortem

Endomyocardial biopsy in 1980 allows the sampling of human myocardial tissue during life and antemortem diagnosis of myocarditis.

INTRODUCTION

Studies suggest that myocarditis is a major cause of sudden(20%), unexpected death in adults less than 40 years of age

Prospective and retrospective studies have identified myocardial inflammation in 1 to 9 percent of routine postmortem examinations.

Myocarditis

Definition: an inflammatory disease of cardiac muscle

It can be acute, subacute, or chronic, and there may be either focal or diffuse involvement of the myocardium Autopsy Endomyocardial biopsy

may provide greater insight into the pathogenesis, etiology, and treatment

CAUSATION

A large variety of infections, systemic diseases, drugs, and toxins have been associated with the development of this disease

Viruses, bacteria, protozoa, and even worms have been implicated as infectious agents.

Important Causes of Myocarditis Infection

Viral Bacterial, rickettsial, spirochetal Protozoal, Metazoal Fungal

Toxic anthracyclines, catecholamines, Interleukin-2, alpha 2

interferon, cocaine Hypersensitivity Associated with a systemic illness

granulomatous, collagen-vascular, and autoimmune diseases

2Viral Infection

Coxsackie (A, B) Echo Influenza (A, B) Polio Herpes simplex Varicella-zoster Epstein-Barr Cytomegalovirus Mumps

Rubella Rubeola Vaccinia Coronavirus Rabis Hepatitis B Arbovirus Junin virus Human immunodeficiency

Bacterial, rickettsial, spirochetal

Corynebacterium diphtheriae

salmonella typhi Beta-hemolytic streptococci Neisseria meningitidis Legionella pneumophila Listeria monocytogenes Camphylobacter jejuni Coxiella burnetii (Q fever)

Chlamydia trachomatis Mycoplasma pneumoniae Chlamydia psittaci

(psittacosis) Rickettsia rickettsii (Rocky

Mountain spotted fever) Borrelia burgdorferi (Lyme

disease) Mycobacterium

tuberculosis

Protozoal, Metazoal, Fungal

Protozoal Trypanosome cruzi

(Chagas disease) Toxoplasma gondi

Metazoal Trichinosis Echinococcosis

Fungal Aspergillosis Blastomycosis Candidiasis Coccidioidomycosis Cryptococcosis Histoplasmosis Mucormycosis

Drugs CausingHypersensitivity Myocarditis

Antibioticsamphotericin Bampicillinchloramphenicolpenicillintetracyclinestreptomycin

Sulfonamidessufadiazinesufisoxazole

Anticonvulsantsphenindionephenytoincarbamazepine

AntituberculousIsoniazidparaaminosalicylate

Anti-inflammatoryindomethacinoxyphenbutazonephenylbutazone

Diureticsacetazolamidechlorthalidonehydrochlorothiazidespironolactone

Otheramitriptylinemethyldopasulfonylureastetanus toxin

INCIDENCE

The true incidence of myocarditis is unknown because the majority of cases are asymptomatic Involvement of the myocardium has been reported

in 1-5% of patients with acute viral infections Autopsy studies have revealed varying

estimates of the incidence of myocarditis. 3.4-8.3% prevalence of active myocarditis was

reported in patients apparently healthy deceased after traumatic injuries.

RISK FACTORS

Certain groups appear to be at increased risk of virus-induced myocarditis, and the course may be hyper-acute Young males pregnant women children (particularly neonates) immunocompromised patients

3PATHOGENESIS Both direct viral-induced myocyte damage and

post-viral immune inflammatory reactions contribute to myocyte damage and necrosis

Inflammatory lesions and the necrotic process may persist for months, although the viruses only replicate in the heart for at most two or three weeks after infection

Evidence from experimental models has incriminated cytokines such as interleukin-1 and TNF, oxygen free radicals and microvascular changes as contributory pathogenic factors

Pathophysiology

Several mechanisms of myocardial damage

(1) Direct injury of myocytes by the infectious agent

(2) Myocyte injury caused by a toxin such as that from Corynebacterium diphtheriae(3) Myocyte injury as a result of infection-

induced immune reaction or autoimmunity.

Pathophysiology

Triphasic disease process

Phase I: Viral Infection and Replication

Phase 2: Autoimmunity and injury

Phase 3: Dilated Cardiomyopathy

Phase I: Viral Infection and Replication

Coxsackievirus B3 causes an infectious phase, which lasts 7-10 days, and is characterized by active viral replication

During this phase initial myocyte injury takes place, causing the release of antigenic intracellular components such as myosin into the bloodstream

Phase 2: Autoimmunity and injury

The local release of cytokines, such as interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor (TNF), and nitric oxide may play a role in determining the T-cell reaction and the subsequent degree of autoimmune perpetuation

These cytokines may also cause reversible depression of myocardial contractility without causing cell death.

Phase 2: Autoimmunity and injury

Immune-mediated by CD8 lymphocytes and autoantibodies against various myocyte components

Antigenic mimicry, the cross reactivity of antibodies to both virus and myocardial proteins

Myocyte injury may be a direct result of CD8 lymphocyte infiltration

4Phase 3: Dilated Cardiomyopathy

Viruses may also directly cause myocyte apoptosis. During the autoimmune phase, cytokine activate the

matrix metalloproteinases, such as gelatinase, collagenases, and elastases.

In later stages of immune activation, cytokines play a leading role in adverse remodeling and progressive heart failure.

Cardiomyopathy developed despite the absence of viral proliferation but was correlated with elevated levels of cytokines such as TNF.

Pathophysiology

Clinical Manifestations

Most cases of acute myocarditis are clinically silent

60% of pts had antecedent flu-like symptoms Large number identified by heart failure

symptoms 35% of pts with myocarditis and HF have chest

pain usually due to concomitant pericarditis

Clinical Manifestations Large number identified by heart failure symptoms

Since both ventricles are generally involved, patients develop bi-ventricular failure

Patients present with signs of right ventricular failure such as increased jvp, hepatomegaly, and peripheral edema

If there is predominant left ventricular involvement, the patient may present with the symptoms of pulmonary congestion: dyspnea, orthopnea, rales, and, in severe cases, acute pulmonary edema

May mimic an acute MI with ventricular dysfunction, ischemic chest pain, ECG evidence of injury or Q waves

Clinical Manifestations

May present with syncope, palpitation with AV block or ventricular arrhythmia

May cause unexpected sudden death, presumably due to ventricular tachycardia or fibrillation myocarditis found at autopsy in 20% of Air Force recruits with

sudden death*

May present with systemic or pulmonary thromboembolic disease

JAMA 1986; 256:2696-2699

5Physical examination In addition to the signs of fluid overload, the

physical examination often reveals direct evidence of cardiac dysfunction in symptomatic patients

S3 and S4 gallops are important signs of impaired ventricular function

If the right or left ventricular dilatation is severe, auscultation may reveal murmurs of functionalmitral or tricuspid insufficiency

A pericardial friction rub and effusion may become evident in patients with myo-pericarditis

Blood studies Sedimentation rate elevation 60% White count elevation 25% CK-MB elevation 12%

Immunohistologic analysis revealed evidence of myocarditis in 93% of 28 patients with elevatedcTnT levels and in 44% of 52 patients with normalcTnT

Mean cTnT levels in patients with myocarditis were 0.59 +/- 1.68

Cardiac troponin T in patients with clinically suspected myocarditis. J Am Coll Cardiol 1997 Nov 1;30(5):1354-9

Blood studies

a 4 fold rise in IgG titer over a 4-6 wk period is required to document an acute viral infection

Heart specific antibodies are nonspecific for myocarditis; also found in dilated cardiomyopathy

Electrocardiogram

sinus tachycardia is most common diffuse ST-T wave changes myocardial infarction pattern conduction delay and LBBB in 20% complete heart block causing Stokes-Adams

attacks (particularly in Japan), but rarely require a permanent pacer

supraventricular and ventricular arrhythmias: atrialor ventricular ectopic beats, high grade ventricular arrhythmias, atrial tachycardia or atrial fibrillation

Myocarditis

6Echocardiography

Useful tool in managing patients with acute myocarditis LV systolic dysfunction is common with

segmental wall motion abnormalities LV size is typically normal or mildly dilated wall thickness may be increased ventricular thrombi detected in 15%

Chest radiograph

ranges from normal tocardiomegalywith or without pulmonary congestion

Chest radiograph

ranges from normal tocardiomegalywith or without pulmonary congestion

Magnetic resonance imaging

Contrast-enhanced MRI, using gadopentate dimeglumine which accumulates in inflammatory lesions, can detect the degree and extent of inflammation

The extent of relative myocardial enhancement correlates with clinical status and left ventricular function

Laissy, J.-P. et al. Chest 2002;122:1638-1648

T1-weighted MRI of a

focal form of acute

myocarditis

Diffuse form of acute myocarditis

Laissy, J.-P. et al. Chest 2002;122:1638-1648

Focal myocarditis involving the apex

7Laissy, J.-P. et al. Chest 2002;122:1638-1648

Serial short-axis turboFLASH images obtained at 9 s (A), 18 s (B), 27 s (C),

and 54 s (D) after Gdinjection show

abnormal myocardial

enhancement of the inferior and lateral

walls of the left ventricle, with respect to the

interventricularseptum

Patient with recent episode of chest pain and fever. Slight increase in Troponin, ECG inconclusive, normal coronary arteries. At CMR evidence of small areas of Myocardial oedema(arrow). Images obtained by Triple Inversion Recovery technique.

Patient with clinical features of myocarditis in the past (10 weeks before the CMR study). Normal coronary arteries. At CMR evidence of small areas of fibro-necrosis (arrows). Images obtained using Late Gadolinium Enhancement technique.

The CMR comprehensive evaluation in patients with suspected myocarditis

Diagnostic targets for CMR include

Left Ventricle regional and global function

Morphological abnormalities such as transient increase of ventricular volumes and mass.

Pericardial effusion can be easily detected.

Oedema is an important hallmark of inflammatory cell injury and T2-weighted images sensitively detects tissue oedema.

1. CMR should not be performed too early after onset of symptoms (if this decision is clinically acceptable).

2. A negative CMR should be repeated after some days if performed within 7 days after the onset of symptoms and if the clinical features are such to indicate this diagnosis as likely.

3. A positive CMR should be repeated after at least 4 weeks after onset of symptoms.

Imaging Studies

Gallium 67 (avid for inflammation) used for screening active myocarditis

Indium 111-antimyosin monoclonal antibody (avid for injured myocardium)

sensitivity 83% specificity 53% + predictive value 92%

endomyocardial biopsy remains the diagnostic standard

Endomyocardial Biopsy

RV bioptome permit repetitive sampling Biopsy should be applied early after onset

of symptoms to maximize yield - resolution may be seen in four days on serial biopsies

Dallas criteria for active myocarditisan inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischemic changes associated with coronary artery disease

8Normal Myocardium Borderline Myocarditis

Active Myocarditis Endomyocardial Biopsy

Adenoviral myocarditis in a young man (37 years old). EMB showing lympho-monocyte inflammatory cell infiltrates associated with myocyte injury, with no viral inclusion bodies. (HE x 100)

DIAGNOSIS Acute myocarditis should be suspected

whenever a patient, especially a young male, presents with otherwise unexplained cardiac abnormalities of new onset, such as heart failure, arrhythmias, or conduction disturbances

A history of recent upper respiratory infection or enteritis may also be present

A presumptive diagnosis of myocarditis may be made on the basis of the clinical and laboratory presentations

This presumption may be strengthened if an echocardiogram is characteristic and does not reveal evidence of other forms of heart disease

A number of other tests have been used : Gallium scanning Antimyosin scans Magnetic resonance imaging

DIAGNOSIS

9 Cardiac catheterization does not yield any specific information but may be valuable in ruling out other cardiac disease, such as congenital, or ischemicheart disease

The definitive diagnosis of myocarditis can be made only by endomyocardial biopsy A negative biopsy does not rule out focal myocarditis

because of sampling error. This problem is minimized by multiple biopsies

DIAGNOSIS

Histopathologic diagnosis of a specific cause of myocarditis is occasionally possible in patients with toxoplasmosis, Chagas' disease,Lyme carditis, and trichinosis

Electron microscopic examination is only rarely contributory as with the characteristicintranuclear inclusion bodies that may be seen in CMV carditis

DIAGNOSIS

NATURAL HISTORY The majority of cases of acute myocarditis

have a benign course, the inflammatory process is self-limited without clinically overt sequelae

Some patients, however, develop heart failure, serious arrhythmias, disturbances of conduction, or even circulatory collapse

The illness may be fatal due to myocardial failure or sudden, unexpected death

Long-term outcome of patients with biopsy-proved myocarditis: comparison with DCMJ Am Coll Cardiol 1995 Jul;26(1):80-4

27 patients with myocardial biopsy-proven definite or borderline myocarditis at the Mayo Clinic between 1979 and 1988 were compared with 58 patients with idiopathic DCM who hadendomyocardial biopsy findings negative for myocarditis

There was no difference in 5-year survival rate between the myocarditis and DCM groups (56% vs. 54%, respectively)

Prognosis

SPECIFIC THERAPY There are a number causes (primarily infectious) of

myocarditis for which there is specific therapy, such as Mycoplasma or Lyme disease

Viral infection is the most common cause ofmyocarditis, with Coxsackievirus B being most frequently implicated

Antiviral therapy with ribavirin or alpha interferonhas been shown to reduce the severity of myocardial lesions as well as mortality in experimental murine myocarditis due to Coxsackie virus B3

However, this beneficial effect is seen only if therapy is started prior to inoculation or soon thereafter

The applicability of these findings to humans is therefore uncertain

Nevertheless, antiviral therapy may be considered in acute, fulminant myocarditis, in institutional outbreaks (eg, in neonates), and in laboratory-acquired cases

SPECIFIC THERAPY

10

SPECIFIC THERAPY A number of therapeutic trials in humans,

mostly uncontrolled, have suggested clinical benefit from immunosuppressive therapy withcorticosteroids, azathioprine, or cyclosporine

However, both corticosteroids andcyclosporine have been shown to exacerbatemurine myocarditis

The Myocarditis Treatment Trial Investigators

A clinical trial of immunosuppressive therapy for myocarditis.

N Engl J Med 1995 Aug 3;333(5):269-75 111 patients with a histopathological

diagnosis of myocarditis and a left ventricular ejection fraction of less than 0.45 were randomly assigned to receive conventional therapy alone or combined with a 24-week regimen of immunosuppressive therapy (prednisone with either cyclosporine or azathioprine)

The mean change in the LVEF at 28 weeks did not differ significantlybetween the group of patients who received immunosuppressive therapy and the control group

There was no significant difference in survival between the two groups

The mortality rate for the entire group was 20 % at 1 year and 56 % at 4.3 years

NONSPECIFIC THERAPY

Avoidance of exercise Physical activity should be restricted to reduce the

work of the heart during the acute phase ofmyocarditis, especially when there is fever, active systemic infection, or heart failure

Electrocardiographic monitoring Electrocardiographic monitoring can permit early

detection of asymptomatic yet potentially life-threatening arrhythmias and/or conduction defects

NONSPECIFIC THERAPY Antiarrhythmic drugs

Most antiarrhythmic drugs have negative inotropicactivity and may therefore aggravate heart failure. They should therefore be used only when the expected benefit exceeds the risk

Supraventricular arrhythmias, may induce or aggravate heart failure; these arrhythmias should be converted

High-grade ventricular ectopy should be treated cautiously with antiarrhythmic drugs

Complete heart block is an indication fortransvenous pacing. This conduction abnormality is often transient; as a result, use of a temporary pacemaker should be the first step

NONSPECIFIC THERAPY

Congestive heart failure should be treated with a low sodium diet and cautiously with digoxin, diuretics, and ACE inhibitors

The threshold for digitalis toxicity may be low Excessive reduction of preload by diuresis

may reduce ventricular filling pressures below the level needed to maintain cardiac output, possibly converting heart failure intocardiogenic shock

11

NONSPECIFIC THERAPY Anticoagulation is recommend in patients who

fulfill the following criteria: Symptomatic heart failure with a LVEF below 20% Minimal risk factors for hemorrhage A stable hemodynamic profile without evidence of

liver synthetic dysfunction The optimal degree of anticoagulation has not

been established INR between 1.5 and 2.5 is generally

recommended

PREVENTION As a result of the widespread use of

vaccination in developed countries,myocarditis secondary to measles, rubella, mumps, poliomyelitis, and influenza is now rare

Similarly, the elimination of trichinosis by meat inspection has all but eliminated this infection

It is possible that vaccines against othercardiotropic viruses may prevent viral myocarditis