Myocarditis is collection of diseases of infectious, toxic, and autoimmune etiologies characterized by inflammation of the heart. Subsequent myocardial destruction can lead to dilated cardiomyopathy. Myocarditis is an elusive illness to study, diagnose, and treat because the clinical presentation may range from nearly asymptomatic to overt heart failure requiring transplantation; a myriad of causes exist, and it is occasionally the unrecognized culprit in cases of sudden death. Pathophysiology Myocarditis is defined as inflammatory changes in the heart muscle and is characterized by myocyte necrosis. Animal models of viral myocarditis have lead to a much greater understanding of the pathophysiology of acute, severe myocarditis and correlate with the findings in susceptible patients who apparently uptake viral RNA and develop a cytotoxic necrosis and rapid (1-2 d) cell death without the appearance of the interstitial infiltrate usually associated with myocarditis. Over 4-14 days, those cells that survive the initial insult, in response to macrophage activation and cytokine expression, develop the classic, histologically apparent infiltration of mononuclear cells. In this subacute viral-clearing phase, natural killer cells target myocardium expressing viral RNA and continue myocyte necrosis. Tumor necrosis factor is also involved in rapidly clearing virus, but its involvement results in the further recruitment of inflammatory cells, activates endothelial cells, and has negative inotropic effects. In the latter stages of the subacute process, cytotoxic T lymphocytes infiltrate the myocardium and direct lysis of cardiocytes, which present virus fragments via the histocompatibility complex on the surface of myocyte membrane. Neutralizing antiviral antibodies also develop to assist in the clearing of virus. In the chronic phases, the deleterious effects of either inadequate or inappropriately abundant immune response can lead to the unfortunate long-term sequelae of dilated cardiomyopathy and heart failure. In animal models of insufficient immune response, viral replication can continue and cause chronic destruction of myocytes. Biopsy results of patients with acute myocarditis who develop dilated cardiomyopathy demonstrate changes consistent with those seen in polymerase chain reaction (PCR) amplifying RNA from enteroviruses. On the opposite spectrum of immune activity, overabundant T cells may continue activity into the chronic phase and also may cause tissue destruction and heart failure. Frequency United States The true incidence of myocarditis is unknown because many cases are asymptomatic, and some symptoms related to significant morbidity may not be appropriately credited. One major urban US medical examiners office attributed 1.3% of sudden and unexpected deaths to myocarditis1, consistent with other autopsy studies that demonstrate evidence of myocardial inflammation in 1-1.5% of deaths. In the United States, viral and medication-related cases are the most commonly identified causes. International Internationally other etiologies (ie, Chagas disease, diphtheria) play a greater role than in the United States, and true frequency of disease is even more difficult to appreciate. Mortality/Morbidity Because of its difficulty in diagnosis, the large number of cases that likely never come to medical attention, and its previously underappreciated role in sudden dysrhythmic death, morbidity and mortality data are difficult to construct. Rarely, acute myocarditis is fulminant and leads rapidly to death. Mortality for clinically significant and biopsy proven myocarditis varies widely. Recent studies have demonstrated death to be as low as 4% of cases for patients without heart failure and with no persistent viral genome expression. On the opposite end of the spectrum, in patients with persistent viral genome expression, myocarditis related mortality may be as high as 25%. The appropriate delicate balance of the immune response to viral invasion of myocytes indicates that a certain number of individuals, perhaps with genetic predispositions, will advance to dilated cardiomyopathy and heart failure, the most common long-term sequelae in those patients who do not recover completely. Sex The male-to-female ratio is 1.5:1. Age The average age of patients with myocarditis is 42 years. It is a prominent cause of sudden cardiac death in young adults, accounting for 8-12% of such deaths. Clinical History Many patients present with a nonspecific illness characterized by fatigue, mild dyspnea, and myalgias. A few patients present acutely with fulminant congestive heart failure (CHF) secondary to widespread myocardial involvement. Small and focal areas of inflammation in electrically sensitive areas may be the etiology in patients whose initial presentation is sudden death. Most cases of myocarditis are subclinical; therefore, the patient rarely seeks medical attention during acute illness. These subclinical cases may have transient ECG abnormalities. An antecedent viral syndrome is present in more than one half of patients with myocarditis. The appearance of cardiac-specific symptoms occurs primarily in the subacute virus-clearing phase; therefore, patients commonly present 2 weeks after the acute viremia. Fever is present in 20% of patients. Other symptoms include fatigue, myalgias and arthralgias, and malaise. Chest pain Chest discomfort is reported in 35% of patients. The pain is most commonly described as a pleuritic, sharp, stabbing precordial pain. It may be substernal and squeezing and, therefore, difficult to distinguish from that typical of ischemic pain. Dyspnea on exertion is common. Orthopnea and shortness of breath at rest may be noted if CHF is present. Palpitations are common. Syncope in a patient with a presentation consistent with myocarditis should be carefully approached because it may signal high-grade atrioventricular (AV) block or risk for sudden death. Pediatric patients, particularly infants, present with nonspecific symptoms, including the following: Fever Respiratory distress Poor feeding or, in cases with CHF, sweating while feeding Cyanosis in severe cases Physical Physical findings can range from nearly normal examination findings to signs of fulminant CHF. Patients with mild cases of myocarditis have a nontoxic appearance and simply may appear to have a viral syndrome. Tachypnea and tachycardia are common. Tachycardia is often out of proportion to fever. More acutely ill patients have signs of circulatory impairment due to left ventricular failure. A widely inflamed heart shows the classic signs of ventricular dysfunction including the following: Jugular venous distention Bibasilar crackles Ascites Peripheral edema S3 or a summation gallop may be noted with significant biventricular involvement. Intensity of S1 may be diminished. Cyanosis may occur. Hypotension caused by left ventricular dysfunction is uncommon in the acute setting and indicates a poor prognosis when present. Murmurs of mitral or tricuspid regurgitation may be present due to ventricular dilation. In cases where a dilated cardiomyopathy has developed, signs of peripheral or pulmonary thromboembolism may be found. Diffuse inflammation may develop leading to pericardial effusion, without tamponade, and pericardial and pleural friction rub as the inflammatory process involves surrounding structures. Causes The causes of myocarditis are numerous and can be roughly divided into infectious, toxic, and immunologic etiologies, with viral etiologies most common in North America. Amongst the infectious causes, viral acute myocarditis is by far the most common. Identification of the coxsackie-adenovirus receptor protein explains the prevalence of these viruses as a frequent cause. The receptor is the common target of coxsackievirus B of the enterovirus family and serotypes 2 and 5 of the adenovirus family. Other viruses implicated in myocarditis include influenza virus, echovirus, herpes simplex virus, varicella-zoster virus, hepatitis, Epstein-Barr virus, and cytomegalovirus. Hepatitis C, in particular, is becoming a major focus of research. Human immunodeficiency virus (HIV) deserves special mention because it seems to function differently than other viruses. Although some evidence indicates that HIV directly invades myocytes, HIV genomes can be amplified from patients without histologic signs of inflammation. In addition, in patients who are infected with HIV, T-cell mediated immune suppression increases the risk of contracting myocarditis due to other infectious causes. Nonviral infectious causes are numerous and varied. Worldwide the most common bacterial cause is diphtheria, and, in South America, the protozoal Chagas disease is a common entity. Streptococcal and staphylococcal species and Bartonella, Brucella, Leptospira, and Salmonella species can spread to the myocardium as a consequence of severe cases of endocarditis. Borrelia burgdorferi, the spirochete agent in Lyme disease, is also a known cause of myocarditis. Parasitic myocarditis from trypanosomiasis; trichinosis; and, in the immunocompromised host, toxoplasmosis have been identified. Toxic myocarditis has a number of etiologies including both medical agents and environmental agents. Among the most common drugs that cause hypersensitivity reactions are clozapine, penicillin, ampicillin, hydrochlorothiazide, methyldopa, and sulfonamide drugs. This syndrome is associated with peripheral eosinophilia, fever, and rash in patients who have biopsy findings of an eosinophilic infiltrate of the myocardium. Numerous medications (eg, lithium, doxorubicin, cocaine, numerous catecholamines, acetaminophen) may exert a direct cytotoxic effect on the heart. Zidovudine (AZT) has been associated with myocarditis. Environmental toxins include lead, arsenic, and carbon monoxide. Cases have been attributed to Chinese sumac. Wasp, scorpion, and spider stings Radiation therapy may cause a myocarditis with the development of a dilated cardiomyopathy. Immunologic etiologies of myocarditis encompass a number of clinical syndromes and include the following: Connective tissue disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, and dermatomyositis that can often result in a dismal prognosis Idiopathic inflammatory and infiltrative disorders such as Kawasaki disease, sarcoidosis, and giant cell arteritis Rejection of the post transplant heart may present as inflammatory myocarditis.