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Myocarditis is an inflammatory disease of the heart muscle that may progress to dilated cardiomyopathy. The condition can manifest with a range of clinical presentations from nonspecific systemic symptoms to fulminant heart failure or sudden death. There is continued debate regarding the appropriate diagnosis, classification, and management of myocarditis. ,
Etiology
Myocarditis can have a variety of infectious and noninfectious etiologies. For most cases in routine clinical practice, a specific cause is not found. Viruses are the most common causes of acute myocarditis in North America and Western Europe. Initial studies using serologic assays implicated enteroviruses, particularly coxsackievirus B serotypes 1 through 5, as important causes. , More recent studies using polymerase chain reaction (PCR) assays of endomyocardial biopsy specimens have confirmed the importance of enteroviruses in acute myocarditis (10%–20%) and dilated cardiomyopathy (10%–30%). Other viruses that are commonly identified by PCR in the myocardium include adenovirus, parvovirus B19, Epstein-Barr virus, and cytomegalovirus. , , Recent data on parvovirus have called into question the clinical implications of molecular detection in biopsy samples or blood as latent chronic asymptomatic infection may occur more commonly than previously thought. , Myocarditis also is recognized as a complication during outbreaks of influenza, measles, mumps, and polio. Human immunodeficiency virus and hepatitis C virus have been implicated in myocarditis, although the exact role each virus plays in causing disease is unclear. , More recently SARS-CoV-2 has been noted to have significant cardiac manifestations including myocarditis in children and adults associated with the multisystem inflammatory syndrome, as well as myopericarditis associated with mRNA vaccines. ,
Bacteria cause myocarditis less frequently than viruses. Invasion of the bloodstream by a bacterial pathogen, such as Staphylococcus aureus, Neisseria meningitidis, or Salmonella species, can result in myocardial seeding and resultant microabscesses. Myocarditis or myocardial dysfunction also can be a toxin-mediated complication of tetanus or diphtheria or can be caused by other bacteria, such as Borrelia burgdorferi (occurring in up to 16% of children with early disseminated Lyme disease), Rickettsia spp. (especially scrub typhus), Mycoplasma pneumoniae, and toxin-producing staphylococci and streptococci .
Parasites are a major cause of myocarditis worldwide, with Trypanosoma cruzi (the causative agent of Chagas disease) being the principal cause in Central and South America. Many additional agents have been reported to cause myocarditis in immunocompromised hosts, most importantly cytomegalovirus, Toxoplasma gondii, T. cruzi, and Cryptococcus, Candida, and Aspergillus species.
Epidemiology
Myocarditis is diagnosed in up to 0.05% of pediatric hospitalizations in the US. Myocarditis has a slight male predominance and a bimodal age distribution that peaks in infancy and adolescence. The incidence of myocarditis can coincide with the occurrence of epidemic enterovirus infections. Enteroviruses cause approximately 10–15 million infections annually in the US and can occur in any demographic population. In the US, enterovirus activity peaks in the summer and fall, although transmission is year-round in the tropics. Chagas disease is endemic in Central and South America and is the most important cause of myocarditis in those regions.
Myocarditis has been implicated in 4%–20% of sudden cardiac deaths in autopsy series of young previously healthy adults. , Other studies using PCR techniques highlight the possible role of myocarditis in sudden infant death syndrome (SIDS). Enteroviruses, parvovirus B19, and adenoviruses are the most commonly detected viruses in cases associated with SIDS, although Epstein-Barr virus, cytomegalovirus, and T. gondii also have been detected.
Pathophysiology
Pathogenesis
The pathogenesis of myocarditis has been gleaned in large part from animal models. These models suggest that both direct myocardial infection and host immune responses are important in the pathogenesis of the disease. Viruses often initiate the process through binding to specific surface receptors on cardiac myocytes. A common coxsackievirus-adenovirus receptor has been identified on cardiac myocytes, which may in part explain the tropism of these viruses. Infection and myocardial injury induce innate immune responses, most importantly proinflammatory cytokines tumor necrosis factor-α and interleukin-1β. Mixed inflammatory cells subsequently infiltrate into the myocardium, and adaptive immune responses are activated, including antigen-specific T lymphocytes and antibodies. At this stage, most patients clear the viral infection and recover from the acute illness with minimal sequelae. However, a subset of patients experience ongoing inflammation, which can lead to cardiac remodeling, fibrosis, myocyte necrosis, and ultimately dilated cardiomyopathy. Persistent viral replication and autoimmune targeting of cardiac autoantigens are postulated mechanisms of ongoing inflammation. , Both CD4 + and CD8 + T lymphocytes are key mediators of myocardial damage and chronic inflammation. Autoantibodies directed against a variety of cardiac antigens have also been implicated in this process.
Pathologic Findings
Several standardized criteria have been developed to diagnose myocarditis using histopathology or immunohistochemistry. The Dallas pathologic criteria, initially proposed in 1986, define myocarditis as histopathologic evidence of inflammatory cellular infiltrate with or without myocyte necrosis on conventionally stained heart tissue biopsy specimens. Inflammatory infiltrates are further classified based on severity, distribution, and type (i.e., lymphocytic, eosinophilic, or granulomatous). However, follow-up studies suggest these criteria lack sensitivity, in part owing to biopsy sampling site error and variability in interobserver interpretation. The addition of immunohistochemical stains to characterize inflammatory cell infiltrates can improve diagnostic sensitivity and add prognostic value. The World Health Organization and International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies defines myocarditis as immunohistochemical evidence of mononuclear infiltrates (CD3 + T lymphocytes or CD68 + macrophages) with more than 14 cells/mm 2 on endomyocardial biopsy in addition to enhanced expression of human leukocyte antigen (HLA) class II molecules. ,
Myocarditis from bacterial, parasitic, and fungal causes can show specific findings with histologic staining. Bacterial and fungal infection result in polymorphonuclear cell infiltrates, which can be focal or organized into microabscesses. Trypanosomes can often be visualized in the biopsy specimens from patients with chronic Chagas disease. Giant cell myocarditis is a rare disorder of suspected autoimmune etiology in which multinucleated giant cells are found in the absence of granulomas.
Clinical Manifestations
Clinical manifestations of myocarditis are variable but usually arise in the setting of a systemic infection. The spectrum of cardiac manifestations ranges from subclinical cardiac dysfunction to heart failure, arrhythmia, and sudden death. A viral prodrome consisting of an influenza-like illness with fevers, myalgias, and gastrointestinal complaints often precedes cardiac involvement. This can be followed abruptly by myocarditis with hemodynamic collapse. Sudden death can be a presentation of myocarditis at any age, but particularly in infants and children.
Infants and children frequently present with nonspecific symptoms, such as respiratory distress, feeding difficulties, irritability, and constitutional symptoms. Typical findings of heart failure also can be present, including tachycardia, a new-onset heart murmur or gallop, hepatomegaly, peripheral edema, or decreased peripheral perfusion. Chest pain may be present owing to concomitant pericarditis or, occasionally, to coronary artery spasm. In a retrospective review of 31 children with biopsy-confirmed or probable myocarditis, emergency department findings included preceding “viral illness” (77%), tachypnea or other respiratory difficulty (68%), chest pain (29%), symptoms related to hypoperfusion (23%), Kawasaki-associated symptoms (10%), and gastrointestinal complaints (7%). Chest radiography abnormalities were observed in 55% of cases, and decreased ventricular function was present in 73% of cases. ST-segment or T-wave changes on electrocardiography (ECG) were also noted in 67% of cases.
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