Myocarditis refers to inflammation of the myocardium and incorporates a broad spectrum of clinical and histopathologic presentations.¹ Acute myocarditis results from either an external event or an endogenous trigger. External causes include viruses, bacteria, parasites, drugs, and direct toxins, while internal triggers are associated with host autoantigen-mediated myocarditis. The initial cardiac injury precipitates an immunologic response, which results in cardiac inflammation. This chapter focuses on the diagnosis and management of common causes of acute and chronic myocarditis. The diagnosis and management of cardiac sarcoidosis are covered elsewhere.

The clinical presentation can range from subclinical disease to fulminant myocarditis that requires inotropic or mechanical circulatory support.² The host immune response can downregulate after clearance of damage with little scar or result in more persistent or extensive inflammation that permanently damages heart tissue. Usually the process is self-limited, but if the immune response persists, then cardiac remodeling can lead to chronic dilated cardiomyopathy (DCM). Up to 20% of patients with myocarditis develop chronic DCM.¹,³

The Dallas criteria, proposed in 1986, defined acute myocarditis as an inflammatory cellular infiltrate with associated myocyte necrosis or degeneration of adjacent myocytes, noted on conventionally stained myocardial tissue sections.⁴ However, these criteria have been criticized because of interreader variability and low sensitivity. Immunohistologic criteria, which rely on cell-specific immunoperoxidase stains for surface antigens including anti-CD3 (T lymphocytes), anti-CD68, and class I and II human leukocyte antigens, are thought to have greater sensitivity and better prognostic value.⁵ Myocarditis accounts for 10% of initially unexplained DCM when the Dallas criteria are used. The rate of myocarditis increases from 20% to 30% when immunohistology establishes the diagnosis.⁶

Current understanding of cellular and molecular pathogenesis of acute myocarditis as being caused by an inciting event, such as a viral infection or a primary immunologic abnormality, is based mostly on animal models. Viral infection is one of the most common causes of myocarditis, and most of our understanding regarding the pathophysiology of viral myocarditis is specifically derived from mouse models with heightened autoimmunity with or without enteroviral infection. The pathogenesis of viral myocarditis may be conceptualized into overlapping phases of viral infection and replication, an immunologic response including innate and adaptive immune responses, and chronic cardiac remodeling. Viruses can enter the host via the gastrointestinal or respiratory systems and subsequently undergo replication in host organs such as the liver,
spleen, and pancreas. Enteroviruses eventually reach the heart by hematogenous or lymphatic spread. At the cellular level, viruses are internalized after binding to a cell surface receptor leading to viral genome and proteome interaction with host cellular machinery. The mechanism varies by virus with coxsackieviruses and adenoviruses using a transmembrane molecule known as the coxsackievirus-adenovirus receptor (CAR), which triggers receptor-associated kinases such as p56lck, Fyn, and Abl to facilitate viral entry.¹⁴ In immature cardiomyocytes, CAR is found on the entire surface of cardiac myocytes, which could partly explain the apparent susceptibility of infants to coxsackievirus B3-mediated myocarditis.¹⁵ A recent study involving inducible CAR knockout mice illustrated that elimination of CAR prevented virus entry into myocytes and subsequent signs of inflammatory cardiomyopathy.¹⁶ After entry of the enterovirus into the cell, the positive, single-strand RNA is released from the icosahedral capsid and translated using host translational mechanisms. Enteroviruses such as coxsackievirus B produce protease 2A, which can then cleave dystrophin and damage cytoskeletal components such as the dystrophin-sarcoglycan complex with disruption of the sarcolemmal membrane. Thus, viral proteases can cause cardiomyopathy in the absence of enteroviral replication.

Innate and antigen-specific immunity both play an important role in the pathogenesis of viral and autoimmune myocarditis. An antigen-independent tissue repair mechanism is initiated within days of enteroviral infection and serves to contain viral replication. During the innate immunity phase, multiple inflammatory markers—including cytokines, histamine, inducible nitric oxide, and complement components—are rapidly upregulated or released. Damage receptors, such as the toll-like receptor (TLR), signaling through the NLRP3 inflammasome are one of the earliest innate immune pathways. Damage receptors recognize pathogen motifs, such as double-stranded RNA, and activate cytosolic and nuclear signaling mechanisms, thereby increasing master proinflammatory cytokines such as interferon-1β. The downstream molecules activated by TLR signaling, specifically myeloid differentiation factor-88 (MyD88), which binds to toll-like receptor 4, play an important role in myocarditis, particularly viral infections. Mice with global knockout of MyD88 are noted to have decreased susceptibility to viral infections, indicating that the absence of MyD88 offers a degree of host protection from myocarditis.¹⁷ Some viruses continue to replicate at a low level, causing ongoing direct myocardial injury. Viral proteases can inhibit host cell protein synthesis, induce apoptosis, and cleave dystrophin, resulting in cardiomyocyte injury and cardiomyopathy.

Antigen-specific, cell-mediated immunity begins 4 to 5 days after viral infection. Acquired immunity is an antigen-specific response directed to a single antigen, mediated by T and B cells. T cells are targeted to danger signals and attempt to limit infection by destroying the host cell and secreting cytokines. T-cell mediated immunity is important for limiting viral replication but can have detrimental effects on the host organ. Helper T cell types 1 and 2 (Th1 and Th2) secrete tumor necrosis factor (TNF) and interleukins, which are associated with resultant autoimmune cardiomyopathy. Helper T cells that produce interleukin 17 (TH17) can result in a higher rate of chronic DCM.

Cardiac injury associated with myocarditis may be caused by the virus directly entering the endothelial cells (as in parvovirus B19) and myocytes (enterovirus). In the majority of patients with viral myocarditis, the specific pathogen is cleared and removed, with the immune system being subsequently downregulated. However, in a minority of patients, the virus is not cleared and there is persistent myocyte infection. Cytokines such as TNF α can also cause cellular dysfunction without acute or persistent infection. As noted previously, up to 20% of myocarditis patients develop chronic DCM, with some due to persistent viral infection.³ Treatments that regulate steps in pathogenesis, including the mechanism of viral entry and replication, components of innate and acquired immunity, and integrity of the sarcolemmal membrane are under investigation as detailed here.

Host factors can affect susceptibility to myocarditis. Genetic susceptibilities, including HLA-DQB1* polymorphisms, can increase the risk of progressive inflammatory cardiomyopathy. There has been speculation that microbial components contribute to this process as well. A recent study using a mouse model of spontaneous autoimmune myocarditis illustrated that progression of myocarditis depended on cardiac myosin-specific T helper cells imprinted in the intestine by a Bacteroides species peptide mimic. This study found that distinct bacterial communities, particularly Bacteroides, provide mimic peptides that can activate MYH6-specific CD4⁺ T cells. Modification of the microbiome by antibiotic treatment reduced cardiac inflammation and prevented lethal cardiomyopathy.¹⁸ Other environmental factors can modify the cardiac immune response to injury in murine models. For example, the endocrine disrupter bisphenol A (BPA), commonly found in plastic water bottles and plastic food storage containers, increases myocardial inflammation. Bruno et al found that exposure to BPA dissolved in water at a high-human relevant dose (5 µg BPA/kg body weight) administered to adult female BALB/c mice increased the severity of coxsackievirus B3 (CVB3) myocarditis and pericarditis. The BPA exposure increased the estrogen receptor β (ERβ) expression in the heart, which has been previously found to promote other cardiovascular diseases.¹⁹,²⁰ BPA also increased the number of T cells, mast cells, proinflammatory cytokines such as IFNγ, IL-1β, and IL-17A, and the TLR/caspase-1 signaling pathway. Additionally, BPA that leaked from the plastic bottles, with no additional BPA added to the water, activated cardiac mast cells, and increased cardiac fibrosis.¹⁹ Other environmental factors, including low levels of selenium and high levels of mercury, can also increase myocardial damage in viral myocarditis.²¹,²² Finally, in a clinical study of checkpoint inhibitor myocarditis, chronic use of prednisone at doses greater than 20 mg per day increases the severity of disease.