Myocarditis 

Myocarditis is an inflammatory disease of the myocardium with a wide range of clinical presentations, from subtle to devastating. More specifically, it is described as "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes."^[1] Myocarditis usually manifests in an otherwise healthy person and can result in rapidly progressive (and often fatal) heart failure and arrhythmia. In the clinical setting, myocarditis is synonymous with inflammatory cardiomyopathy. It is diagnosed by established histologic, immunologic, and immunochemical criteria. (See Etiology, Clinical, and Workup.)

Lieberman further classified myocarditis as follows^[2] :

• Fulminant myocarditis - Follows a viral prodrome; distinct onset of illness consisting of severe cardiovascular compromise with ventricular dysfunction and multiple foci of active myocarditis; either resolves spontaneously or results in death
• Acute myocarditis - Less distinct onset of illness, with established ventricular dysfunction; may progress to dilated cardiomyopathy
• Chronic active myocarditis - Less distinct onset of illness, with clinical and histologic relapses; development of ventricular dysfunction associated with chronic inflammatory changes (including giant cells)
• Chronic persistent myocarditis - Less distinct onset of illness; persistent histologic infiltrate with foci of myocyte necrosis but without ventricular dysfunction (despite symptoms, eg, chest pain, palpitations)

These terms are still used to describe the clinical presentation and progression of myocarditis, particularly in the absence of ongoing histologic evaluation. (See Etiology and Clinical.)

Patient education

Patients should be advised of the current understanding of the natural history of myocarditis and the strengths and limitations of different diagnostic testing and therapeutic options. (See Etiology, Clinical, Workup, Treatment, and Medications.)

Myocarditis is probably caused by a wide variety of infectious organisms, autoimmune disorders, and exogenous agents, with genetic and environmental predisposition. Most cases are presumed to be caused by a common pathway of host-mediated, autoimmune-mediated injury, although direct cytotoxic effects of the causative agent and damages due to cytokine expression in the myocardium may play some role in myocarditis etiology. Damage occurs through the following mechanisms:

• Direct cytotoxic effect of the causative agent
• Secondary immune response, which can be triggered by the causative agent
• Cytokine expression in the myocardium (eg, tumor necrosis factor [TNF] ̶ alpha, nitric oxide synthase)
• Aberrant induction of apoptosis^[3]

Myocardial damage has 2 main phases, as follows:

• Acute phase (first 2 wk) - Myocyte destruction is a direct consequence of the offending agent, which causes cell-mediated cytotoxicity and cytokine release, contributing to myocardial damage and dysfunction; detection of the causal agent is uncommon during this stage
• Chronic phase (>2 wk) - Continuing myocyte destruction is autoimmune in nature, with associated abnormal expression of human leukocyte antigen (HLA) in myocytes (and in the case of viral myocarditis, persistence of the viral genome in myocardium)

Viral myocarditis

In viral myocarditis, viral isolates differ in tissue tropism and virulence. For example, coxsackievirus A9 is a self-limiting myocarditis, whereas coxsackievirus B3 causes severe myocarditis resulting in a high mortality rate. The induction of the coxsackie-adenovirus receptor (CAR) and the complement deflecting protein decay accelerating factor (DAF, CD55) may allow efficient internationalization of the viral genome.

Viral replication may lead to further disruption of metabolism and to perturbation of inflammation and its response. Vasospasm induced by endothelial cell viral infection may also contribute to further damage.^[4]

New evidence of dystrophin disruption by expression of enteroviral protease 2A points to yet another unique pathogenic mechanism.^[5] In contrast, some viruses (such as parvovirus B19) may focus on pericapillary depositions, contributing to diastolic dysfunction rather than to direct myocyte destruction. Regardless, viral persistence provides the necessary stimuli for autoimmune or other inflammatory responses.

Idiopathic myocarditis

Approximately 50% of the time, myocarditis is classified as idiopathic, although a report by Klugman et al found that 82% of the pediatric cases studied were considered idiopathic.^[6] The investigators also determined that 3% of cases in the study had a known bacterial or viral etiology, and that 6% of cases were related to other diseases.

In idiopathic cases, a viral etiology is often suspected but unproved, even with sophisticated immunohistochemical and genomic studies. Studies on patients with idiopathic dilated cardiomyopathy found evidence of viral particles in endomyocardial biopsy specimens in up to two thirds of the patients.^[7]

Causes

Causes of myocarditis include the following:

• Viral - Enterovirus,^[3] coxsackie B, adenovirus, influenza, cytomegalovirus, poliomyelitis, Epstein-Barr virus, HIV-1, viral hepatitis, mumps, rubeola, varicella, variola/vaccinia, arbovirus, respiratory syncytial virus, herpes simplex virus, yellow fever virus, rabies, parvovirus
• Rickettsial - Scrub typhus, Rocky Mountain spotted fever, Q fever
• Bacterial - Diphtheria, tuberculosis, streptococci, meningococci, brucellosis, clostridia, staphylococci, melioidosis, Mycoplasma pneumoniae, psittacosis
• Spirochetal - Syphilis, leptospirosis/Weil disease, relapsing fever/Borrelia, Lyme disease
• Fungal - Candidiasis, aspergillosis, cryptococcosis, histoplasmosis, actinomycosis, blastomycosis, coccidioidomycosis, mucormycosis
• Protozoal - Chagas disease, toxoplasmosis, trypanosomiasis, malaria, leishmaniasis, balantidiasis, sarcosporidiosis
• Helminthic - Trichinosis, echinococcosis, schistosomiasis, heterophyiasis, cysticercosis, visceral larva migrans, filariasis
• Bites/stings - Scorpion venom, snake venom, black widow spider venom, wasp venom, tick paralysis
• Drugs (usually causing hypersensitivity myocarditis)
• Chemotherapeutic drugs - Doxorubicin and anthracyclines, streptomycin, cyclophosphamide, interleukin-2, anti-HER-2 receptor antibody/Herceptin
• Antibiotics - Penicillin, chloramphenicol, sulfonamides
• Antihypertensive drugs - Methyldopa, spironolactone
• Antiseizure drugs - Phenytoin, carbamazepine
• Amphetamines, cocaine, catecholamines
• Chemicals - Hydrocarbons, carbon monoxide, arsenic, lead, phosphorus, mercury, cobalt
• Physical agents (radiation, heatstroke, hypothermia)
• Acute rheumatic fever
• Systemic inflammatory disease - Giant cell myocarditis, sarcoidosis, Kawasaki disease, Crohn disease, systemic lupus erythematosus, ulcerative colitis, Wegener granulomatosis, thyrotoxicosis, scleroderma, rheumatoid arthritis
• Peripartum cardiomyopathy
• Posttransplant cellular rejection

Occurrence in the United States

The frequency of myocarditis is difficult to ascertain, owing to the wide variation of clinical presentation. Incidence is usually estimated at 1-10 cases per 100,000 persons. Incidence of positive right ventricular biopsy findings in patients with suspected myocarditis is highly variable (ranging from 0-80%). According to estimates, as many as 1-5% of patients with acute viral infections may have involvement of the myocardium.

International occurrence

A population study in Finland found that, in a study of more than 670,000 healthy young male military recruits, 98 cases had myocarditis mimicking myocardial ischemia, 1 case presented as sudden death, and 9 cases presented as recent-onset dilated cardiomyopathy.^{[8, 9]}

A Japanese 20-year series of 377,841 autopsies found idiopathic, nonspecific, interstitial, or viral myocarditis in only 0.11% of individuals.^[10]

Race-, sex-, and age-related demographics

No particular race predilection is noted for myocarditis except for peripartum cardiomyopathy (a specific form of myocarditis that appears to have a higher incidence in patients of African descent).

The incidence of myocarditis is similar between males and females, although young males are particularly susceptible.

Patients are usually fairly young. The median age of patients affected with lymphocytic myocarditis is 42 years. Patients with giant cell myocarditis may be older (mean age 58 years), but this condition usually does not discriminate with respect to age, sex, or presenting symptoms.

Other susceptible groups include immunocompromised individuals, pregnant women, and children (particularly neonates).

Patients who survive fulminant myocarditis have a good prognosis. In a study of 147 cases of myocarditis monitored for an average of 5.6 years, 93% of the 15 patients with fulminant disease were alive without transplant 11 years after biopsy, compared with 45% of the 132 patients with less severe disease. Left ventricular dilation was not as severe in the fulminant cases as in the nonfulminant ones.^{[11, 12]}

Expression of soluble Fas and Fas ligands at initial presentation appears to be a good serologic marker to predict the prognosis of acute myocarditis, while antimyosin autoantibodies are associated with development of worse cardiac dysfunction in chronic myocarditis.^[13]

Predictors of death or need for heart transplantation after acute myocarditis in multivariate analyses include syncope, low ejection fraction, and left bundle-branch block, all indicators of advanced cardiomyopathy.^[14]

Morbidity and mortality

Most patients with mild symptoms recover completely without any residual cardiac dysfunction, although a third subsequently developing dilated cardiomyopathy.^{[9, 15, 16, 17]} Cardiogenic shock may occur in fulminant cases of myocarditis.

In the Myocarditis Treatment Trial, the 1-year mortality rate was 20% and the 4-year mortality rate was 56% in a population with symptomatic heart failure presentation and left ventricular ejection fraction lower than 45% at baseline.^[18] Severe heart block requiring permanent pacemaker placement occurred in 1% of patients in the trial.

In a study of patients with giant cell myocarditis, 89% of patients either died or underwent transplantation, with median survival from symptom onset to death or transplantation being only 5.5 months.^[19]

A study by Klugman et al reported a 92% survival rate among 216 pediatric patients with myocarditis.^[6] According to the investigators, nonsurviving patients were characterized by a greater severity of illness at presentation and a frequent need for extracorporeal membrane oxygenation and other intensive care unit therapies. With regard to postpartum cardiomyopathy, the mortality rate at 1 year can be as high as 50%.