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• 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.

• 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.

• 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

• 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

Viral 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 Causing Hypersensitivity Myocarditis
Anticonvulsants Diuretics Antibiotics phenindione acetazolamide amphotericin B phenytoin chlorthalidone ampicillin carbamazepine hydrochlorothiazide chloramphenicol Antituberculous spironolactone penicillin Isoniazid tetracycline Other paraaminosalicylate streptomycin amitriptyline Anti-inflammatory methyldopa Sulfonamides indomethacin sulfonylureas sufadiazine oxyphenbutazone tetanus toxin sufisoxazole phenylbutazone

• 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

• 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

• 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.

• 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

• 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 infectioninduced immune reaction or autoimmunity.

• 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

Phase 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.


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

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

• May present with systemic or pulmonary thromboembolic disease
JAMA 1986; 256:2696-2699

Physical 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 functional mitral or tricuspid insufficiency • A pericardial friction rub and effusion may become evident in patients with myo-pericarditis

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

• Immunohistologic analysis revealed evidence of myocarditis in 93% of 28 patients with elevated cTnT levels and in 44% of 52 patients with normal cTnT • 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
• • • • •

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


• 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 to cardiomegaly with or without pulmonary congestion

Chest radiograph Magnetic resonance imaging
– ranges from normal to cardiomegaly with or without pulmonary congestion
– 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

Focal myocarditis involving the apex

Diffuse form of acute myocarditis

T1weighted MRI of a focal form of acute myocarditis

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

Laissy, J.-P. et al. Chest 2002;122:16381648

Serial short-axis turboFLASH images obtained at 9 s (A), 18 s (B), 27 s (C), and 54 s (D) after Gd injection show abnormal myocardial enhancement of the inferior and lateral walls of the left ventricle, with respect to the interventricular septum

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

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.

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. 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.
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 myocarditis “an inflammatory infiltrate of the myocardium with necrosis
and/or degeneration of adjacent myocytes not typical of the ischemic changes associated with coronary artery disease”

Normal 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)

• 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

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

• 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 characteristic intranuclear inclusion bodies that may be seen in CMV carditis

• 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

• 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 had endomyocardial biopsy findings negative for myocarditis • There was no difference in 5-year survival rate between the myocarditis and DCM groups (56% vs. 54%, respectively)
Long-term outcome of patients with biopsy-proved myocarditis: comparison with DCM J Am Coll Cardiol 1995 Jul;26(1):80-4

• 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 of myocarditis, with Coxsackievirus B being most frequently implicated • Antiviral therapy with ribavirin or alpha interferon has 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

• A number of therapeutic trials in humans, mostly uncontrolled, have suggested clinical benefit from immunosuppressive therapy with corticosteroids, azathioprine, or cyclosporine • However, both corticosteroids and cyclosporine have been shown to exacerbate murine 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 significantly between 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

• Avoidance of exercise
– Physical activity should be restricted to reduce the work of the heart during the acute phase of myocarditis, especially when there is fever, active systemic infection, or heart failure

• Electrocardiographic monitoring
– Electrocardiographic monitoring can permit early detection of asymptomatic yet potentially lifethreatening arrhythmias and/or conduction defects

• Antiarrhythmic drugs
– Most antiarrhythmic drugs have negative inotropic activity 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 for transvenous pacing. This conduction abnormality is often transient; as a result, use of a temporary pacemaker should be the first step

• 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 into cardiogenic shock

• 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

• 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 other cardiotropic viruses may prevent viral myocarditis

• The optimal degree of anticoagulation has not been established • INR between 1.5 and 2.5 is generally recommended