Melissa A. Lyle

Lori A. Blauwet

Leslie T. Cooper


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


The true incidence of myocarditis is difficult to quantify given the wide range of clinical presentations; however, in 2019, an estimated 820,000 incident cases of myocarditis occurred in men and 608,000 cases in women. The overall global incidence of myocarditis during 2019 was estimated at 1.4 million or 19 per 100,000 population.7 As a percentage of heart failure prevalence, the myocarditis burden varies from 0.5% to 4.0%. From 1990 to 2015, the death rate from myocarditis and cardiomyopathy together was approximately 5 per 100,000.8 Based on autopsy and clinical case series, myocarditis is thought to be one of the leading causes of sudden cardiac death.9 There is a bimodal distribution by age. Notably, the prevalence of myocarditis as a cause of cardiomyopathy is high in the first year of life. The increased rate and more fulminant presentation in infants can be attributed to an immature immune system. Myocarditis is responsible for approximately 2% of infant sudden cardiovascular deaths.2 The prevalence of myocarditis relative to all heart failure declines between ages 1 and 12 years, then the risk again increases after puberty. The mean age of adults with most forms of myocarditis ranges between 20 and 51 years,10 while the mean age of patients with giant cell myocarditis (GCM) is 42 years.11

Most case studies of myocarditis illustrate a male predominance, which is strongly influenced by sex hormones. In mice, estrogenic hormones protect against viral infection of cardiomyocytes and decrease the myocardial inflammatory response. Testosterone exerts a deleterious effect through inhibition of regulatory components and promotion of inflammasome-mediated, profibrotic pathways.12 The severity of disease as assessed by the degree of delayed gadolinium enhancement on magnetic resonance imaging (MRI) is greater in men with myocarditis than women. In patients with severe myocarditis requiring mechanical circulatory support, female sex predicts a higher likelihood of bridge to recovery.13


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.

Infectious Etiologies


From the 1950s to 1990s, enterovirus species, specifically coxsackievirus, were the most frequently identified viruses in patients with myocarditis. Enteroviruses are nonenveloped, lytic viruses with a single, positive-strand RNA genome of approximately 7.4 kb. Molecular studies during the late 1980s and 1990s utilizing polymerase chain reaction (PCR) identified an enterovirus genome in heart biopsies of 15% to 30% of patients with acute myocarditis.


Adenoviruses are nonenveloped, double-stranded DNA viruses that cause myocarditis in a common rat model. The incidence of adenovirus in myocarditis patients varies between a high of 23% and a low of 2%. In the past decade, the prevalence of enteroviruses and adenoviruses detected in the myocardium of patients with myocarditis has decreased to the single digits. The most commonly detected viral genomes on endomyocardial biopsy samples are now parvovirus B19 (B19V) and human herpesvirus 6.

B19V of the Genus Erythrovirus

B19V of the genus Erythrovirus is a nonenveloped, nonlytic virus with a single-strand, positive-strand DNA genome, and parvoviruses do not cross species. Its primary receptor is globoside, known as group P antigen. Group P antigen is found primarily on erythroid progenitors, erythroblasts, megakaryocytes, and endothelial cells. This tropism translates to a reported association with the relatively common clinical syndrome of chest pain because of microvascular dysfunction. The B19V genome has been identified by PCR studies in 11% to 56% of patients with myocarditis and in 10% to 51% of patients with DCM. Because of a high prevalence of B19V in heart tissue from subjects without apparent heart conditions, B19V may often have a bystander role, particularly in subjects with low copy numbers detected on endomyocardial biopsy (EMB) samples.23 Studies that demonstrated a correlation of much higher viral loads with more acute myocarditis support this conclusion.

Human Immunodeficiency Virus (HIV)

HIV is associated with myocarditis and DCM, either through direct toxicity of the gp120 protein or through secondary viral infections. Myocarditis is the most common cardiac pathologic finding at autopsy in patients with severe HIV.1 The incidence of myocarditis, in addition to cardiomyopathy and pericardial disease, correlates with the severity of HIV infection as measured by a low CD4+ count or high-viral titers. Since the introduction of highly active antiretroviral therapy (HAART), the incidence of myocarditis in HIV-infected patients has dramatically decreased in developed countries. In regions with limited availability to HAART, HIV-associated myocarditis remains clinically important.24

Influenza A and B

Influenza A and B viruses are known causes of myocarditis, with H1N1 having a particularly severe clinical syndrome. The incidence of myocarditis in severe influenza A infections may be as high as 5% with reports of electrocardiographic changes suggestive of subclinical cardiac involvement as high as 11%. Some cases of influenza A resulted in fulminant myocarditis with a high rate of recovery after supportive medical care. If myocardial tissue is obtained in the course of ventricular assist device (VAD) placement, histopathologic examination illustrates a cellular inflammatory infiltrate.25


In the setting of the COVID-19 pandemic, it has been demonstrated that patients admitted to the hospital with COVID-19 infection had a 13% to 41% incidence of myocardial injury, but classic lymphocytic myocarditis was relatively uncommon. Further research will be needed to clearly define the mechanism of cardiac injury and risk of myocarditis following infection with SARS-CoV2.

Nonviral Pathogens (Bacteria and Parasites)

Nonviral pathogens, including bacteria and parasites, can also affect the heart and incite an immune reaction resulting in myocarditis. Globally, bacterial- and protozoal-related myocarditis is much less common than viral myocarditis. Important bacterial infections associated with myocarditis include Corynebacterium diphtheriae that causes heart block and group A streptococcus species that cause poststreptococcal valvulitis and myocarditis. The tick-borne spirochete Borrelia burgdorferi causes Lyme disease, which usually begins with the characteristic rash of erythema chronicum migrans, followed by neurologic, joint, and cardiac involvement. Lyme carditis, frequently characterized by a heart block, is an uncommon manifestation, complicating only 1.1% of patients with Lyme disease.26 In central and northern South America, infections involving the protozoa Trypanosoma cruzi (ie, Chagas disease) is a common cause of cardiomyopathy. Occasionally helminths, including Echinococcus granulosus and Trichinella spiralis, can result in clinical myocarditis, sometimes with profound eosinophilia.

Noninfectious Etiologies

A variety of noninfectious causes, including toxic and autoimmune reactions, can damage the heart with an inflammatory infiltrate and myocyte necrosis. Causes with specific treatments include adverse drug hypersensitivity reactions, systemic disorders such as eosinophilic granulomatosis with polyangiitis, cancer, and hypereosinophilic syndrome. These are associated with specific forms of eosinophilic myocarditis. Checkpoint inhibitor chemotherapeutic drugs are a recently described cause for severe and frequently fatal myocarditis.

Drug Toxicity

Adverse drug reactions manifest as a direct toxic effect on the heart or hypersensitivity myocarditis. Drug-induced hypersensitivity typically occurs within 8 weeks of initiation of the drug. Common offenders include antiepileptics, antimicrobials, and sulfa-based drugs. The inotrope dobutamine, often used for additional hemodynamic support in patients with cardiogenic shock or end-stage heart failure, is associated with eosinophilic
myocarditis. Because of adverse outcomes associated with dobutamine-associated hypersensitivity myocarditis, this agent should be discontinued when significant eosinophilia occurs in association with an otherwise unexplained decline in ventricular function. The antipsychotic drug clozapine has also been associated with myocarditis, with reported rates as high as 1% to 10% of patients. Myocarditis can occur anytime during treatment but usually is diagnosed within the first 2 months after initiation of clozapine.

Chemotherapeutic Agents

Chemotherapeutic agents, including anthracyclines, can cause cardiac toxicity and sometimes myocardial inflammation. Immune checkpoint inhibitors are newer chemotherapeutic agents that have substantially improved the outcome of several cancers by releasing restrained antitumor immune responses; however, they can be associated with myocarditis in up to 1% of patients. Ipilimumab, an anticytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, and nivolumab, an antiprogrammed death-1 (PD-1) antibody, improve survival in patients with melanoma and can be used in combination to augment antitumor activity. The prevalence of myocarditis associated with immune checkpoint inhibitors is 1.14%, with a median onset time of 34 days after initiation of therapy. Myocarditis after immune checkpoint inhibitor therapy can result in a fulminant process, which may respond to corticosteroids as initial treatment.27 Fulminant myocarditis may be more common in patients who receive more than one checkpoint inhibitor, as it occurs in 0.27% of patients treated with a combination of ipilimumab and nivolumab.28

Giant Cell Myocarditis and Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

Idiopathic GCM is a rare, autoimmune form of myocarditis histologically defined by the presence of multinucleated giant cells, lymphocytic inflammatory infiltrate, and myocyte necrosis.1 GCM is thought to be autoimmune given the association with other autoimmune disorders. Usually occurring in young adults, GCM carries a high risk of death without cardiac transplantation. Plakoglobin remodeling at cardiac myocyte junctions is known to occur in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD) but is also seen in GCM with ventricular arrhythmias.29 Occasionally, myocarditis and ARVD can coexist or myocarditis can mimic ARVD or acute left ventricular dysplasia (ALVD). Greater than 50% of ARVD patients have associated desmosomal gene mutations. Nondesmosomal gene mutations have also been identified in association with ARVD. Lopez-Ayala et al identified seven patients with acute myocarditis, four with ALVD, and two with classic ARVD. All patients had defined gene mutations, and microsatellite analysis identified that they were all relatives or had a common ancestor, providing evidence for familial distribution of myocarditis. In this study, there appeared to be a higher incidence of myocarditis in desmoplakin mutation carriers, illustrating that signs of acute myocarditis should raise the possibility of ARVD, particularly if the pattern occurs in patient’s relatives.29

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May 8, 2022 | Posted by in CARDIOLOGY | Comments Off on Myocarditis
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