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Brociek, E.; Tymińska, A.; Giordani, A.S.; Caforio, A.L.P.; Wojnicz, R.; Grabowski, M.; Ozierański, K. Myocarditis. Encyclopedia. Available online: (accessed on 19 June 2024).
Brociek E, Tymińska A, Giordani AS, Caforio ALP, Wojnicz R, Grabowski M, et al. Myocarditis. Encyclopedia. Available at: Accessed June 19, 2024.
Brociek, Emil, Agata Tymińska, Andrea Silvio Giordani, Alida Linda Patrizia Caforio, Romuald Wojnicz, Marcin Grabowski, Krzysztof Ozierański. "Myocarditis" Encyclopedia, (accessed June 19, 2024).
Brociek, E., Tymińska, A., Giordani, A.S., Caforio, A.L.P., Wojnicz, R., Grabowski, M., & Ozierański, K. (2023, June 20). Myocarditis. In Encyclopedia.
Brociek, Emil, et al. "Myocarditis." Encyclopedia. Web. 20 June, 2023.

Myocarditis is an inflammatory disease of the myocardium caused by infectious or non-infectious agents. It can lead to serious short-term and long-term sequalae, such as sudden cardiac death or dilated cardiomyopathy. Due to its heterogenous clinical presentation and disease course, challenging diagnosis and limited evidence for prognostic stratification, myocarditis poses a great challenge to clinicians. As it stands, the pathogenesis and etiology of myocarditis is only partially understood.

myocarditis inflammatory cardiomyopathy heart failure dilated cardiomyopathy immunosuppressive therapy

1. Introduction

Myocarditis is defined as an inflammatory disease of the myocardium diagnosed by established histological, immunological and immunohistochemical criteria [1]. The etiopathogenesis of myocarditis is complex as it is caused by a variety of infectious (i.e., viruses, bacteria, fungi, parasites) and non-infectious (i.e., organ-specific or systemic immune-mediated disease, drugs, vaccines, toxins) factors [2].
Management of myocarditis poses a major challenge to clinicians due to the heterogeneity in clinical presentation, infrequent use of endomyocardial biopsy (EMB), which is the diagnostic gold standard, and limited treatment options supported by suboptimal evidence [2]. The understanding of myocarditis has greatly improved in recent years, but many questions still remain to be answered. As it stands, it is unclear why some patients progress to DCM, while others spontaneously recover. The therapeutic significance and prognostic utility of etiopathogenesis, patients’ genetic background and mechanisms participating in the immune response are still not entirely understood. Such data, however, are essential for accurate prognosis, risk assessment and personalized care. Moreover, a deep understanding of mechanisms governing the onset and progression of the disease is necessary for the development of novel therapeutic strategies.

2. Clinical Presentation, Diagnostic Approach and Assessment of Disease Etiology

2.1. Clinical Presentation

Myocarditis has a heterogenous clinical presentation, as it can range from mild symptoms (e.g., chest pain, palpitations) to life-threatening acute HF, cardiogenic shock and ventricular arrhythmias [2][3][4]. It occurs most frequently in young males; however, females more often have a complicated clinical presentation [5]. Based on registry data, chest pain appears to be the most common patient complaint, with dyspnea being the second [5][6][7]. Fever is also present in over half of patients. In the largest registry to date, 26.6% of patients had presentation complicated by left ventricular systolic dysfunction, ventricular arrhythmias or cardiogenic shock, and 57.5% had ST-segment elevations on electrocardiogram (ECG), which is considered to be the most common ECG abnormality among patients with myocarditis [5].Therefore, it should be noted that patients with myocarditis can mimic acute myocardial infarction or acute pericarditis at presentation. In up to 80.5% of cases, patients present with prodromal symptoms, frequently suggestive of respiratory or gastrointestinal tract infections [5].

2.2. Utility of Diagnostic Tests

Current HF guidelines of the European Society of Cardiology (ESC) state that a 12-lead ECG, laboratory tests (e.g., troponins, natriuretic peptides, full blood count), echocardiography and cardiac magnetic resonance (CMR) are mandatory in all patients with suspected myocarditis [8]. ECG and laboratory tests are frequently abnormal in myocarditis, but the abnormalities are neither specific nor sensitive, and their absence cannot rule out the disease [2][3][5][6][7][8][9]. Echocardiography is also neither highly specific nor sensitive; however, it plays a significant role in the differential diagnosis of the patient (e.g., to rule out structural heart disease). Similarly, invasive coronary angiography or computed tomography angiography may be used to rule out coronary artery disease.
Out of non-invasive diagnostic tests, CMR is the preferred one, as it possesses the ability to assess inflammation and cardiac fibrosis, making it highly sensitive when using the 2018 modified Lake Louise Criteria [10][11][12]. However, its sensitivity varies depending on the extent of cell necrosis and clinical presentation, making it not entirely reliable in every clinical situation [13]. Moreover, CMR does not possess the ability to confirm or rule out the presence of infectious agents in the myocardium and cannot characterize immune cell infiltrates, which are the key to patient’s prognosis and management. Therefore, EMB still remains the diagnostic gold standard as it allows clinicians to establish a definitive myocarditis diagnosis in every clinical presentation, enables the assessment of the presence of infectious factors in the myocardium (most importantly viral genomes) and permits the characterization of immune cell infiltrates [2][3].

3. Viral and Virus-Induced Immune-Mediated Myocarditis

3.1. Overview of Viruses Associated with Myocarditis

Viruses are widely considered to be a key factor in the pathogenesis of myocarditis due to the widespread presence of viral genomes in EMB samples collected from patients with myocarditis [14]. Studies report presence of viral genomes in the myocardium of almost 70% of patients with idiopathic DCM, and in nearly 30% of such patients, multiple viral agents were present [15]. Viral myocarditis is diagnosed in the presence of histological evidence of myocarditis and concurrent presence of viral genome in cardiac tissue samples, confirmed by positive polymerase chain reaction (PCR) [2]. However, available evidence suggests that viruses can also induce myocarditis in the absence of direct cardiotoxicity, doing so instead via virus-mediated inflammatory response during infection (autoimmune myocarditis) with no viral genome present in EMB [10].
Despite the fact viruses are the most studied etiological agents in myocarditis, clear evidence on the exact pathological mechanisms is lacking. This is due in large part to the variety of infectious agents that contribute to the disease and their heterogenous characteristics (e.g., different cell tropism), resulting in many putative pathological processes [16]. Available evidence suggests that Parvovirus B19 (B19V), which has an endothelial cell tropism, is the most frequently identified species in active myocarditis or DCM on EMB [15][17][18][19]. Other commonly found viruses include the following: Enteroviruses and Adenoviruses, cardiotropic; human herpesvirus type 6 (HHV-6), Epstein–Barr Virus (EBV) and Cytomegalovirus (CMV), lymphotropic; Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and Influenza viruses, cardiotoxic [10][15][20].

3.2. Virus-Mediated Myocardial Injury

Because of the complex nature and variability between different etiopathogeneses of viral myocarditis, they need to be discussed in multiple steps. While phase 2 and 3 of the triphasic model remain challenging to elucidate, phase 1 (i.e., infection of the cardiac tissue and direct virus-mediated damage) has been better investigated using animal models and human data. The process causing direct virus-induced myocardial injury appears to mostly consist of cardiomyocyte infection, subsequent replication in the infected cells and ultimately cell death. Such behavior is exhibited by adenoviruses and coxsackieviruses, which have been associated with myocarditis for decades, and both utilize the coxsackievirus-adenovirus receptor (CAR) to infect cardiomyocytes [19][21][22]. The relevance of CAR in myocarditis is highlighted by the fact that CAR-deficient mice are protected from Coxsackievirus B3-induced myocarditis and pancreatitis [23]. A large portion of experimental data regarding the pathogenesis of viral myocarditis are derived from Coxsackievirus B3 (CVB3)-infected mouse models, which have demonstrated the ability of CVB3 to induce cytopathic effects potentially leading to necrosis or apoptosis of infected cells [24][25][26].
On the other hand, B19V is a member of the erythroparvovirus genus that replicates in erythroid progenitor cells [27][28]. However, the infection of endothelial cells has also been demonstrated, and available evidence suggests that endothelial cell dysfunction plays a central role in B19V-induced myocarditis [17][27][29][30][31]. Coronary arterioles, venules and capillaries are lined with endothelium, and therefore, their infection is possible, given the concurrent presence of globoside (blood group antigen P) which acts as a B19V receptor, with required co-receptors in the form of α5 β1-integrin and Ku80 on the cell surface [32][33][34][35]. After cell entry, the mechanisms that lead to endothelial dysfunction appear intricate. In vitro studies have shown that the non-structural protein (NS1) increases the expression of pro-inflammatory cytokines, is potentially cytotoxic and induces apoptosis [36][37][38][39]. Furthermore, viral capsid protein (VP1) is thought to modulate the immune response after cell infection, induce endothelial dysfunction, as well as possibly facilitate cell proliferation [34][40][41]. VP1 may also be responsible for the facilitation of cell entry by binding to a coreceptor [40]. Persistent inflammation of the endothelium and subsequent endothelial dysfunction lead to the impairment of microcirculation and subsequent cardiomyocyte necrosis [16]. Crucially, B19V is also found in non-inflamed hearts, and therefore, its role as a bystander and possible etiological agent causing myocarditis remains uncertain and is yet to be fully understood [17]
The exact mechanisms behind myocardial injury induced by other viruses are not well understood. The presence of herpesviruses is not uncommon in patients with myocarditis or DCM [14][15][20]. This is not surprising, considering their ability to cause latent infections and high prevalence among adults [42][43]. Currently, limited data are available from mouse models infected with murine gamma herpesvirus-68 (MHV-68) and murine cytomegalovirus (MCMV). Interestingly, BALB/c mice infected with MHV-68 showed signs of myocardial necrosis, while C57BL/6 mice, as well as B- and T-cell-deficient B6-(Rag1)™ mice, did not, despite the presence of very high viral loads in B6-(Rag1)™ [44][45]
SARS-CoV-2 has been recognized as a cause of myocardial injury; however, due to very limited histological data, the exact processes involved in this phenomenon remain unknown [46][47][48]. It is important to note that myocarditis is a different entity to myocardial injury, and since both may appear during a viral infection, differential diagnosis should be made carefully following international guidelines [49]

3.3. Immune Response to the Viral Infection

Immune response to the viral infection and its mechanisms implicated in the persistence and severity of myocarditis remain only partially described. The most common immune infiltrate observed in viral myocarditis is lymphocytic, and it almost always also includes macrophages [50]. At the beginning, immune response involves innate mechanisms, since natural killer cells followed by macrophages are usually the first to be recruited to the injured myocardium. Lymphocytes arrive later, and their infiltration is most pronounced at 7–14 days, which corresponds with the most severe phase of the disease. Using CVB3-infected models, Opavsky et al. have demonstrated that CD4−/− CD8−/− mice, as well as TCRβ−/− mice, had much better survival than control mice, confirming the notion of the importance of T cell response in host susceptibility [51]. Response against autoantigens as well as molecular mimicry between infectious agents’ antigens and cardiac tissue antigens are thought to play a role in the development of the disease [52].

3.4. Clinical Implications of Viral Etiology

Clinical implications of viral presence in the myocardium remain not entirely understood, since conflicting reports exist regarding the prognostic role of the presence of viral genomes in EMB samples. Moreover, their applicability in the context of myocarditis is limited since some reports included patients with diagnoses different from myocarditis, such as DCM [20][53][54][55]. The best available evidence so far comes from a study by Kindermann et al., which suggests that the presence of viruses is not related to poor patient outcomes [20].
Antiviral therapy in viral myocarditis remains controversial, and so far, interferon-β (IFN-β) has received the most attention as a potential candidate for such use. However, IFN-β use for viral myocarditis treatment is not endorsed by international guidelines, as data supporting such therapy are very limited and based on cohorts without active myocarditis, thereby making its applicability doubtful in the acute setting [2][3][4][56][57][58]. The routine use of intravenous immunoglobulin (IVIG) is also not supported by robust evidence, as the results of available meta-analyses are conflicting, and the patients included in the studies were not always diagnosed using EMB or CMR [59][60][61]. Therefore, it is not routinely recommended by international societies [2][3][4].
According to the 2013 Position Statement of the ESC, a positive viral PCR on EMB is a major contraindication to immunosuppression [2]. The 2021 HF guidelines of the ESC highlight that immunosuppressive therapy should not be routinely used in acute myocarditis without evidence of autoimmune disease [8]. However, in cases of high suspicion of immune-mediated myocarditis, empirical administration of intravenous corticosteroids may be taken into consideration before the results of EMB become available, especially in presence of complications such as acute HF, malignant arrhythmias and/or high degree atrioventricular (AV) block (i.e., fulminant myocarditis). 

4. Myocarditis in the Course of Parasitic Infections

4.1. Parasitic Involvement in Cardiac Disease

Myocarditis can be caused by a wide range of protozoa and helminths, with Trypanosoma spp. appearing as the most relevant etiological agents [62]. Trypanosomiasis in cardiovascular disease is mostly associated with Chagas’ disease (also referred to as ‘American trypanosomiasis’), which is a zoonosis caused by Trypanosoma cruzi, a protozoan, obligate intracellular parasite. It is a neglected tropical disease that is endemic in all Latin American countries; however, with increasing population mobility, cases in non-endemic regions are also being reported [63]. As it stands, it is estimated that 6–7 million people are infected with T. cruzi worldwide, and up to 30% of them will develop Chagas’ cardiomyopathy which is associated with HF, arrhythmia, stroke, thromboembolism and sudden death [63][64].

4.2. Pathogenesis and Clinical Picture of Chagas’ Disease

The pathogenesis of Chagas’ disease has been extensively studied in animal models and clinical observation. Since myocarditis constitutes only one particular aspect of the systemic syndrome and not the totality of Chagas’ disease, it is important to consider cardiac involvement in the context of the entire natural course of the disease. T. cruzi infections are usually divided into two consecutive stages referred to as acute and chronic Chagas’ disease [65]. The acute phase, is associated with parasitemia observable in direct examination of the blood and subsequent chronic phase, is characterized at first by lack of symptoms and, later, by severe gastrointestinal and cardiac manifestations [63]. T. cruzi is transmitted by Triatomine vector species (‘kissing bugs’), but importantly, it can also spread through blood transfusions or congenital infection. At first, trypomastigotes replicate near the inoculation site and subsequently spread throughout the body [66]. Trypomastigotes enter the cell where they differentiate into amastigotes and divide through binary fission [67]. Thereafter, amastigotes differentiate into trypomastigotes and disrupt the cell to infect surrounding cells. Alternatively, amastigotes can disrupt a cell prematurely, thus leading to their release, and reinvade cells through phagocytosis. While the parasite can infect any nucleated cell, it exhibits tropism towards cardiac and skeletal muscle cells. Experimental data suggest that such tropism may be related to well-developed plasma membrane repair mechanisms which facilitate cell entry of trypomastigotes [67]. T. cruzi infection of myocardial fibers results in visible cell damage and is associated with mononuclear cell infiltration. These infiltrates consist primarily of T cells and macrophages but can also include other immune cell types such as lymphocytes, eosinophils, neutrophils or plasma cells [66]. During the acute phase, the disease is often characterized by mild symptoms (i.e., splenomegaly, fever, malaise) [63][65].

4.3. Management of Patients with Chagas’ Cardiomyopathy

The current evidence suggests that the prognosis of patients with Chagas’ cardiomyopathy remains worse than in the case of other etiologies [68][69][70]. Antitrypanosomal medication, i.e., benznidazole (first-line treatment) and nifurtimox, is recommended for all patients with acute Chagas’ disease [65]. The benefits of such therapy are less clear in the indeterminate stage of the disease, and the current Scientific Statement of the AHA does not recommend the routine use of antitrypanosomal agents in these patients, but rather it highlights that it could be offered. Benznidazole also did not show any significant effect on clinical outcomes in patients with established Chagas’ cardiomyopathy [71]. Therefore, AHA recommends that the management of patients with Chagas’ cardiomyopathy should be based on treatment regimens analogous to those observed in other HF etiologies; however, their efficacy in this condition is unknown [8][72].

4.4. Cardiac Involvement in Other Parasitic Diseases

While Chagas’ disease remains notorious for cardiac involvement, in HAT, neurological problems dominate the clinical picture [73]. T. brucei gambiense and T. brucei rhodesiense are transmitted by tsetse flies (Glossina spp.), but similarly to T. cruzi, congenital and transfusional modes of transmission are also possible [62]. Cardiac disease in HAT has been studied much less extensively than in Chagas’ disease; however, studies have shown evidence of myocarditis in patients infected with T.b. gambiense and T.b. rhodesiense [74][75]. Moreover, Blum and colleagues noticed ECG abnormalities in 71% of HAT patients [76].

5. Bacterial Myocarditis

Bacteria are considered to be an uncommon cause of myocarditis and even if there are case reports of such infections, a recent study has shown that many of these reports do not rely on autopsy/EMB histology, and a large portion of them do not even include CMR [77]. Therefore, their credibility is questionable, and no clear clinical guidelines regarding such cases are available due to the scarcity of data. Nevertheless, it is important to consider the possibility of myocarditis triggered by bacterial species (e.g., Borrelia spp., Corynebacterium spp., Streptococcus spp., Staphylococcus spp.) [77][78]. Carditis in the course of Lyme disease appears to be more common, as its estimated incidence in patients with Lyme disease is 0.3–4% [79]. Myocarditis during diphtheria is also assumed to be more common in countries without widespread immunization [78]

6. Autoimmune Myocarditis and Drug-Induced Myocarditis

6.1. Overview

Autoimmune myocarditis is diagnosed in the presence of immunohistological evidence of myocarditis with negative viral PCR, with or without serum anti-heart antibodies [2]. These patients present yet another heterogenous group, because autoimmune myocarditis can occur with exclusive cardiac involvement as well as in the course of an immune-mediated disease such as sarcoidosis, systemic sclerosis (SSc), systemic lupus erythematosus (SLE) or eosinophilic granulomatosis with polyangiitis (EGPA) [80]. It can also be induced by exposure to various substances (e.g., drugs, alcohol, vaccines) [10]. Moreover, as has been previously described, virus-induced myocarditis appears to possess a significant autoimmune component, which may not resolve after viral clearance and present as autoimmune myocarditis.

6.2. Pathogenesis and Genetic Predisposition to Autoimmune Myocarditis

In many patients with autoimmune myocarditis, the exact trigger and molecular interactions underlying the disease are unknown [81]. However, it appears that a lack of balance in T cell populations may be responsible for this owing to a disturbed balance of pro- and anti-inflammatory activity of the immune system. This hypothesis is consistent with mice models that exhibit susceptibility to the development of experimental autoimmune myocarditis. In a study by Chen et al., a more susceptible mouse strain was shown to have higher percentage of CD4+ T cells along with a tendency to differentiate into the Th17 phenotype and a lower frequency of Treg cells when compared to a less susceptible strain [82]. Interestingly, in experimental models of autoimmune myocarditis, the Th17 response has been implied to play a critical role in autoimmune driven progression of myocarditis to DCM [83][84]. Genetic features are also thought to play a role in predisposing to autoreactivity. These include both genes related to the major histocompatibility complex (MHC) as well as genes independent of the MHC [81]. What is important to note is that autoimmune myocarditis appears much more heterogenous when it comes to the characteristics of cellular infiltrates present in the myocardium when compared to viral myocarditis. These include giant cell myocarditis (GCM) and eosinophilic myocarditis [83].

6.3. Pathogenesis of Drug-Associated Myocarditis

Involvement of drugs in myocarditis is complex, and definitions are not clear. The 2020 AHA Expert Consensus Document defines drug-induced myocarditis as caused by direct cytotoxic effect of the drug [3]. This, however, is not the only mode of drug involvement in myocarditis, as hypersensitivity reactions and more complex mechanisms such as those relating to immune checkpoint inhibitor (ICI)-associated myocarditis or vaccine-induced myocarditis are also to be considered.
Hypersensitivity reactions to drugs and drug reaction with eosinophilia and systemic symptoms (DRESS) are a possible cause of eosinophilic myocarditis [3]. They can be caused by exposure to medications such as clozapine, carbamazepine, minocycline, β-lactam antibiotics and even vaccination.
Special attention should be given to ICI-associated myocarditis as it is considered to be the most frequent immune-related adverse event during ICI treatment and carries high mortality [85]. ICIs are a group of monoclonal antibodies which enhance the host immune response against cancer cells by inhibiting key immunoregulatory mechanisms (i.e., checkpoints) [86]. Such drugs can target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 receptor (PD-1) and its ligand (PD-L1) and lymphocyte-activation gene 3 (LAG-3). While the pathophysiology of ICI-associated myocarditis is still poorly understood, some work has been conducted to identify the putative mechanisms behind this etiology. EMB findings appear to be consistent and show lymphocytic infiltrates, while the main risk factor appears to be combination ICI therapy (e.g., anti-CTLA-4 and anti-PD-1) [85][87][88].
Vaccine-associated myocarditis has gathered a lot of attention because of its reports in association with COVID-19 vaccines. As described previously, hypersensitivity is one of the possible pathophysiological mechanisms behind adverse cardiovascular effects of vaccines, and there are reports of histologically documented cases of eosinophilic myocarditis following mRNA vaccination against COVID-19 [89]. The characteristics of infiltrates are, however, heterogenous, and histological investigation has so far shown many possible presentations of myocarditis following COVID-19 vaccination, such as GCM or lymphocytic myocarditis [90][91]. It has been demonstrated that myocarditis is more common in younger men and after sequential doses of COVID-19 vaccine, while its risk is highest after a second dose of the mRNA-1273 vaccine [92]. The mechanisms responsible for myocarditis following mRNA vaccination against COVID-19 are unknown, but current hypotheses imply maladaptive immune response possibly modified by immune-genetic background, age, sex and hormonal differences [93]. Circulating spike protein was found to be present in patients with post-COVID-19 mRNA vaccine myocarditis, giving a possible hint into the underlying cause of this adverse reaction [94]. Available evidence does not suggest that molecular mimicry plays a significant role [95]. Aberrant cytokine-driven lymphocyte cytotoxicity and profibrotic myeloid cell response appear to be key in the immunopathogenesis of vaccine-associated myocarditis [96].

6.4. Clinical Implications of Autoimmune and Drug-Associated Myocarditis

GCM and eosinophilic myocarditis have the worst prognosis, but it is important to remember that lymphocytic myocarditis also can have a fulminant presentation [4][83][97][98][99]. In case of virus-negative myocarditis or complicated clinical presentation and high-suspicion of immune-mediated disease, immunosuppressive treatment can be considered in addition to standard guideline-directed medical therapy for HF [2][3][8]. However, routine use of corticosteroids before obtaining a definitive diagnosis is not endorsed by either ESC or AHA. Some randomized trials reported promising improvements in LVEF with the best response in virus-negative patients [100][101][102][103][104].
Immunosuppressive therapy should be modulated on the histological type of myocarditis. Currently, for lymphocytic virus-negative myocarditis, the use of prednisone and azathioprine is supported by the best available evidence. As such, corticosteroid therapy combined with the use corticosteroid-sparing agent is the most used first-line therapy regimen and should be tailored depending on patient characteristics (e.g., underlying autoimmune disease) [80]. There are ongoing clinical trials that may provide randomized multicenter evidence for the use of immunosuppressive treatment in the future [105].
Giant cell and eosinophilic myocarditis are rare, but rapidly progressing myocarditis histotypes may, and may in turn, provide the most dramatic improvement of prognosis if the diagnosis is made early and aggressive immunosuppression is started. The treatment of GCM, which has a dramatic clinical presentation that includes progressive HF, cardiogenic shock and ventricular arrythmias, is based on the prompt initiation of combination immunosuppressive therapy [99][106][107]. It should involve intravenous corticosteroids and at least one, and most often two, other immunosuppressive agents, such as azathioprine and cyclosporine [99]. The decision on how to stop therapy, in case of remission, is still not defined and needs to be individualized for each case [108]

7. Conclusions

Diagnosis, management and prognostic stratification of myocarditis patients remain difficult. Even with progress being made in experimental and clinical research, underlying mechanisms of the disease are still only partially understood. Current evidence suggests that myocarditis is not only heterogenous in its clinical presentation but also in processes governing its pathogenesis depending on etiology. A thorough understanding of these issues is needed in order to optimize patient care, implement new therapeutic strategies as well as to better understand factors that influence clinical presentation, patient outcomes and response to treatment. This requires the development of new animal models and further experimental research that will examine the role of host (e.g., genetic, immunity-related) and environmental (e.g., infectious) factors in myocarditis.


  1. Richardson, P.; McKenna, W.; Bristow, M.; Maisch, B.; Mautner, B.; O’Connell, J.; Olsen, E.; Thiene, G.; Goodwin, J.; Gyarfas, I.; et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996, 93, 841–842.
  2. Caforio, A.L.; Pankuweit, S.; Arbustini, E.; Basso, C.; Gimeno-Blanes, J.; Felix, S.B.; Fu, M.; Heliö, T.; Heymans, S.; Jahns, R.; et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur. Heart J. 2013, 34, 2636–2648.
  3. Ammirati, E.; Frigerio, M.; Adler, E.D.; Basso, C.; Birnie, D.H.; Brambatti, M.; Friedrich, M.G.; Klingel, K.; Lehtonen, J.; Moslehi, J.J.; et al. Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy. Circ. Heart Fail. 2020, 13, e007405.
  4. Kociol, R.D.; Cooper, L.T.; Fang, J.C.; Moslehi, J.J.; Pang, P.S.; Sabe, M.A.; Shah, R.V.; Sims, D.B.; Thiene, G.; Vardeny, O. Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association. Circulation 2020, 141, e69–e92.
  5. Ammirati, E.; Cipriani, M.; Moro, C.; Raineri, C.; Pini, D.; Sormani, P.; Mantovani, R.; Varrenti, M.; Pedrotti, P.; Conca, C.; et al. Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry. Circulation 2018, 138, 1088–1099.
  6. Aquaro, G.D.; Perfetti, M.; Camastra, G.; Monti, L.; Dellegrottaglie, S.; Moro, C.; Pepe, A.; Todiere, G.; Lanzillo, C.; Scatteia, A.; et al. Cardiac MR With Late Gadolinium Enhancement in Acute Myocarditis With Preserved Systolic Function: ITAMY Study. J. Am. Coll. Cardiol. 2017, 70, 1977–1987.
  7. White, J.A.; Hansen, R.; Abdelhaleem, A.; Mikami, Y.; Peng, M.; Rivest, S.; Satriano, A.; Dykstra, S.; Flewitt, J.; Heydari, B.; et al. Natural History of Myocardial Injury and Chamber Remodeling in Acute Myocarditis. Circ. Cardiovasc. Imaging 2019, 12, e008614.
  8. McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Bohm, M.; Burri, H.; Butler, J.; Celutkiene, J.; Chioncel, O.; et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2021, 42, 3599–3726.
  9. Klingel, K.; Hohenadl, C.; Canu, A.; Albrecht, M.; Seemann, M.; Mall, G.; Kandolf, R. Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: Quantitative analysis of virus replication, tissue damage, and inflammation. Proc. Natl. Acad. Sci. USA 1992, 89, 314–318.
  10. Tschöpe, C.; Ammirati, E.; Bozkurt, B.; Caforio, A.L.P.; Cooper, L.T.; Felix, S.B.; Hare, J.M.; Heidecker, B.; Heymans, S.; Hübner, N.; et al. Myocarditis and inflammatory cardiomyopathy: Current evidence and future directions. Nat. Rev. Cardiol. 2021, 18, 169–193.
  11. Friedrich, M.G.; Sechtem, U.; Schulz-Menger, J.; Holmvang, G.; Alakija, P.; Cooper, L.T.; White, J.A.; Abdel-Aty, H.; Gutberlet, M.; Prasad, S.; et al. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J. Am. Coll. Cardiol. 2009, 53, 1475–1487.
  12. Ferreira, V.M.; Schulz-Menger, J.; Holmvang, G.; Kramer, C.M.; Carbone, I.; Sechtem, U.; Kindermann, I.; Gutberlet, M.; Cooper, L.T.; Liu, P.; et al. Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations. J. Am. Coll. Cardiol. 2018, 72, 3158–3176.
  13. Francone, M.; Chimenti, C.; Galea, N.; Scopelliti, F.; Verardo, R.; Galea, R.; Carbone, I.; Catalano, C.; Fedele, F.; Frustaci, A. CMR sensitivity varies with clinical presentation and extent of cell necrosis in biopsy-proven acute myocarditis. JACC Cardiovasc. Imaging 2014, 7, 254–263.
  14. Bowles, N.E.; Ni, J.; Kearney, D.L.; Pauschinger, M.; Schultheiss, H.P.; McCarthy, R.; Hare, J.; Bricker, J.T.; Bowles, K.R.; Towbin, J.A. Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults. J. Am. Coll. Cardiol. 2003, 42, 466–472.
  15. Kühl, U.; Pauschinger, M.; Noutsias, M.; Seeberg, B.; Bock, T.; Lassner, D.; Poller, W.; Kandolf, R.; Schultheiss, H.P. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation 2005, 111, 887–893.
  16. Klingel, K.; Sauter, M.; Bock, C.T.; Szalay, G.; Schnorr, J.J.; Kandolf, R. Molecular pathology of inflammatory cardiomyopathy. Med. Microbiol. Immunol. 2004, 193, 101–107.
  17. Bock, C.T.; Klingel, K.; Kandolf, R. Human parvovirus B19-associated myocarditis. N. Engl. J. Med. 2010, 362, 1248–1249.
  18. Sagar, S.; Liu, P.P.; Cooper, L.T.J. Myocarditis. Lancet 2012, 379, 738–747.
  19. Schultheiss, H.P.; Baumeier, C.; Aleshcheva, G.; Bock, C.T.; Escher, F. Viral Myocarditis-From Pathophysiology to Treatment. J. Clin. Med. 2021, 10, 5240.
  20. Kindermann, I.; Kindermann, M.; Kandolf, R.; Klingel, K.; Bültmann, B.; Müller, T.; Lindinger, A.; Böhm, M. Predictors of outcome in patients with suspected myocarditis. Circulation 2008, 118, 639–648.
  21. Pauschinger, M.; Phan, M.D.; Doerner, A.; Kuehl, U.; Schwimmbeck, P.L.; Poller, W.; Kandolf, R.; Schultheiss, H.P. Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis. Circulation 1999, 99, 889–895.
  22. McManus, B.M.; Chow, L.H.; Wilson, J.E.; Anderson, D.R.; Gulizia, J.M.; Gauntt, C.J.; Klingel, K.E.; Beisel, K.W.; Kandolf, R. Direct myocardial injury by enterovirus: A central role in the evolution of murine myocarditis. Clin. Immunol. Immunopathol. 1993, 68, 159–169.
  23. Kallewaard, N.L.; Zhang, L.; Chen, J.W.; Guttenberg, M.; Sanchez, M.D.; Bergelson, J.M. Tissue-specific deletion of the coxsackievirus and adenovirus receptor protects mice from virus-induced pancreatitis and myocarditis. Cell Host Microbe 2009, 6, 91–98.
  24. Garmaroudi, F.S.; Marchant, D.; Hendry, R.; Luo, H.; Yang, D.; Ye, X.; Shi, J.; McManus, B.M. Coxsackievirus B3 replication and pathogenesis. Future Microbiol. 2015, 10, 629–653.
  25. Yuan, J.P.; Zhao, W.; Wang, H.T.; Wu, K.Y.; Li, T.; Guo, X.K.; Tong, S.Q. Coxsackievirus B3-induced apoptosis and caspase-3. Cell Res. 2003, 13, 203–209.
  26. Colston, J.T.; Chandrasekar, B.; Freeman, G.L. Expression of apoptosis-related proteins in experimental coxsackievirus myocarditis. Cardiovasc. Res. 1998, 38, 158–168.
  27. Young, N.S.; Brown, K.E. Parvovirus B19. N. Engl. J. Med. 2004, 350, 586–597.
  28. Landry, M.L. Parvovirus B19. Microbiol. Spectr. 2016, 4.
  29. Bültmann, B.D.; Klingel, K.; Sotlar, K.; Bock, C.T.; Baba, H.A.; Sauter, M.; Kandolf, R. Fatal parvovirus B19-associated myocarditis clinically mimicking ischemic heart disease: An endothelial cell-mediated disease. Hum. Pathol. 2003, 34, 92–95.
  30. Bültmann, B.D.; Sotlar, K.; Klingel, K. Parvovirus B19. N. Engl. J. Med. 2004, 350, 2006–2007.
  31. Zakrzewska, K.; Cortivo, R.; Tonello, C.; Panfilo, S.; Abatangelo, G.; Giuggioli, D.; Ferri, C.; Corcioli, F.; Azzi, A. Human parvovirus B19 experimental infection in human fibroblasts and endothelial cells cultures. Virus Res. 2005, 114, 1–5.
  32. Brown, K.E.; Anderson, S.M.; Young, N.S. Erythrocyte P antigen: Cellular receptor for B19 parvovirus. Science 1993, 262, 114–117.
  33. Munakata, Y.; Saito-Ito, T.; Kumura-Ishii, K.; Huang, J.; Kodera, T.; Ishii, T.; Hirabayashi, Y.; Koyanagi, Y.; Sasaki, T. Ku80 autoantigen as a cellular coreceptor for human parvovirus B19 infection. Blood 2005, 106, 3449–3456.
  34. Verdonschot, J.; Hazebroek, M.; Merken, J.; Debing, Y.; Dennert, R.; Brunner-La Rocca, H.P.; Heymans, S. Relevance of cardiac parvovirus B19 in myocarditis and dilated cardiomyopathy: Review of the literature. Eur. J. Heart Fail. 2016, 18, 1430–1441.
  35. Weigel-Kelley, K.A.; Yoder, M.C.; Srivastava, A. Alpha5beta1 integrin as a cellular coreceptor for human parvovirus B19: Requirement of functional activation of beta1 integrin for viral entry. Blood 2003, 102, 3927–3933.
  36. Duechting, A.; Tschöpe, C.; Kaiser, H.; Lamkemeyer, T.; Tanaka, N.; Aberle, S.; Lang, F.; Torresi, J.; Kandolf, R.; Bock, C.T. Human parvovirus B19 NS1 protein modulates inflammatory signaling by activation of STAT3/PIAS3 in human endothelial cells. J. Virol. 2008, 82, 7942–7952.
  37. Fu, Y.; Ishii, K.K.; Munakata, Y.; Saitoh, T.; Kaku, M.; Sasaki, T. Regulation of tumor necrosis factor alpha promoter by human parvovirus B19 NS1 through activation of AP-1 and AP-2. J. Virol. 2002, 76, 5395–5403.
  38. Hsu, T.C.; Tzang, B.S.; Huang, C.N.; Lee, Y.J.; Liu, G.Y.; Chen, M.C.; Tsay, G.J. Increased expression and secretion of interleukin-6 in human parvovirus B19 non-structural protein (NS1) transfected COS-7 epithelial cells. Clin. Exp. Immunol. 2006, 144, 152–157.
  39. Lupescu, A.; Geiger, C.; Zahir, N.; Aberle, S.; Lang, P.A.; Kramer, S.; Wesselborg, S.; Kandolf, R.; Foller, M.; Lang, F.; et al. Inhibition of Na+/H+ exchanger activity by parvovirus B19 protein NS1. Cell. Physiol. Biochem. 2009, 23, 211–220.
  40. Dorsch, S.; Liebisch, G.; Kaufmann, B.; von Landenberg, P.; Hoffmann, J.H.; Drobnik, W.; Modrow, S. The VP1 unique region of parvovirus B19 and its constituent phospholipase A2-like activity. J. Virol. 2002, 76, 2014–2018.
  41. Lupescu, A.; Bock, C.T.; Lang, P.A.; Aberle, S.; Kaiser, H.; Kandolf, R.; Lang, F. Phospholipase A2 activity-dependent stimulation of Ca2+ entry by human parvovirus B19 capsid protein VP1. J. Virol. 2006, 80, 11370–11380.
  42. Cohen, J.I. Herpesvirus latency. J. Clin. Investig. 2020, 130, 3361–3369.
  43. Lan, K.; Luo, M.H. Herpesviruses: Epidemiology, pathogenesis, and interventions. Virol. Sin. 2017, 32, 347–348.
  44. Häusler, M.; Sellhaus, B.; Scheithauer, S.; Gaida, B.; Kuropka, S.; Siepmann, K.; Panek, A.; Berg, W.; Teubner, A.; Ritter, K.; et al. Myocarditis in newborn wild-type BALB/c mice infected with the murine gamma herpesvirus MHV-68. Cardiovasc. Res. 2007, 76, 323–330.
  45. Pankuweit, S.; Klingel, K. Viral myocarditis: From experimental models to molecular diagnosis in patients. Heart Fail. Rev. 2013, 18, 683–702.
  46. Gluckman, T.J.; Bhave, N.M.; Allen, L.A.; Chung, E.H.; Spatz, E.S.; Ammirati, E.; Baggish, A.L.; Bozkurt, B.; Cornwell, W.K., III; Harmon, K.G.; et al. 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee. J. Am. Coll. Cardiol. 2022, 79, 1717–1756.
  47. Lala, A.; Johnson, K.W.; Januzzi, J.L.; Russak, A.J.; Paranjpe, I.; Richter, F.; Zhao, S.; Somani, S.; Van Vleck, T.; Vaid, A.; et al. Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection. J. Am. Coll. Cardiol. 2020, 76, 533–546.
  48. Basso, C.; Leone, O.; Rizzo, S.; De Gaspari, M.; van der Wal, A.C.; Aubry, M.C.; Bois, M.C.; Lin, P.T.; Maleszewski, J.J.; Stone, J.R. Pathological features of COVID-19-associated myocardial injury: A multicentre cardiovascular pathology study. Eur. Heart J. 2020, 41, 3827–3835.
  49. Collet, J.P.; Thiele, H.; Barbato, E.; Barthélémy, O.; Bauersachs, J.; Bhatt, D.L.; Dendale, P.; Dorobantu, M.; Edvardsen, T.; Folliguet, T.; et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur. Heart J. 2021, 42, 1289–1367.
  50. Pollack, A.; Kontorovich, A.R.; Fuster, V.; Dec, G.W. Viral myocarditis—Diagnosis, treatment options, and current controversies. Nat. Rev. Cardiol. 2015, 12, 670–680.
  51. Opavsky, M.A.; Penninger, J.; Aitken, K.; Wen, W.H.; Dawood, F.; Mak, T.; Liu, P. Susceptibility to myocarditis is dependent on the response of alphabeta T lymphocytes to coxsackieviral infection. Circ. Res. 1999, 85, 551–558.
  52. Caforio, A.L.; Marcolongo, R.; Jahns, R.; Fu, M.; Felix, S.B.; Iliceto, S. Immune-mediated and autoimmune myocarditis: Clinical presentation, diagnosis and management. Heart Fail. Rev. 2013, 18, 715–732.
  53. Kühl, U.; Pauschinger, M.; Seeberg, B.; Lassner, D.; Noutsias, M.; Poller, W.; Schultheiss, H.P. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005, 112, 1965–1970.
  54. Figulla, H.R.; Stille-Siegener, M.; Mall, G.; Heim, A.; Kreuzer, H. Myocardial enterovirus infection with left ventricular dysfunction: A benign disease compared with idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 1995, 25, 1170–1175.
  55. Why, H.J.; Meany, B.T.; Richardson, P.J.; Olsen, E.G.; Bowles, N.E.; Cunningham, L.; Freeke, C.A.; Archard, L.C. Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy. Circulation 1994, 89, 2582–2589.
  56. Schultheiss, H.-P.; Piper, C.; Sowade, O.; Waagstein, F.; Kapp, J.-F.; Wegscheider, K.; Groetzbach, G.; Pauschinger, M.; Escher, F.; Arbustini, E.; et al. Betaferon in chronic viral cardiomyopathy (BICC) trial: Effects of interferon-β treatment in patients with chronic viral cardiomyopathy. Clin. Res. Cardiol. 2016, 105, 763–773.
  57. Kühl, U.; Lassner, D.; von Schlippenbach, J.; Poller, W.; Schultheiss, H.-P. Interferon-Beta Improves Survival in Enterovirus-Associated Cardiomyopathy. J. Am. Coll. Cardiol. 2012, 60, 1295–1296.
  58. Kühl, U.; Pauschinger, M.; Schwimmbeck, P.L.; Seeberg, B.; Lober, C.; Noutsias, M.; Poller, W.; Schultheiss, H.P. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003, 107, 2793–2798.
  59. McNamara, D.M.; Holubkov, R.; Starling, R.C.; Dec, G.W.; Loh, E.; Torre-Amione, G.; Gass, A.; Janosko, K.; Tokarczyk, T.; Kessler, P.; et al. Controlled Trial of Intravenous Immune Globulin in Recent-Onset Dilated Cardiomyopathy. Circulation 2001, 103, 2254–2259.
  60. Huang, X.; Sun, Y.; Su, G.; Li, Y.; Shuai, X. Intravenous Immunoglobulin Therapy for Acute Myocarditis in Children and Adults A Meta-Analysis. Int. Heart J. 2019, 60, 359–365.
  61. Yen, C.-Y.; Hung, M.-C.; Wong, Y.-C.; Chang, C.-Y.; Lai, C.-C.; Wu, K.-G. Role of intravenous immunoglobulin therapy in the survival rate of pediatric patients with acute myocarditis: A systematic review and meta-analysis. Sci. Rep. 2019, 9, 10459.
  62. Hidron, A.; Vogenthaler, N.; Santos-Preciado, J.I.; Rodriguez-Morales, A.J.; Franco-Paredes, C.; Rassi, A.J. Cardiac involvement with parasitic infections. Clin. Microbiol. Rev. 2010, 23, 324–349.
  63. Ribeiro, A.L.; Nunes, M.P.; Teixeira, M.M.; Rocha, M.O.C. Diagnosis and management of Chagas disease and cardiomyopathy. Nat. Rev. Cardiol. 2012, 9, 576–589.
  64. World Health Organization. Chagas Disease (Also Known as American Trypanosomiasis). Available online: (accessed on 12 October 2022).
  65. Nunes, M.C.P.; Beaton, A.; Acquatella, H.; Bern, C.; Bolger, A.F.; Echeverría, L.E.; Dutra, W.O.; Gascon, J.; Morillo, C.A.; Oliveira-Filho, J.; et al. Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association. Circulation 2018, 138, e169–e209.
  66. Bonney, K.M.; Luthringer, D.J.; Kim, S.A.; Garg, N.J.; Engman, D.M. Pathology and Pathogenesis of Chagas Heart Disease. Annu. Rev. Pathol. 2019, 14, 421–447.
  67. Fernandes, M.C.; Andrews, N.W. Host cell invasion by Trypanosoma cruzi: A unique strategy that promotes persistence. FEMS Microbiol. Rev. 2012, 36, 734–747.
  68. Bestetti, R.B.; Otaviano, A.P.; Fantini, J.P.; Cardinalli-Neto, A.; Nakazone, M.A.; Nogueira, P.R. Prognosis of patients with chronic systolic heart failure: Chagas disease versus systemic arterial hypertension. Int. J. Cardiol. 2013, 168, 2990–2991.
  69. Vilas Boas, L.G.; Bestetti, R.B.; Otaviano, A.P.; Cardinalli-Neto, A.; Nogueira, P.R. Outcome of Chagas cardiomyopathy in comparison to ischemic cardiomyopathy. Int. J. Cardiol. 2013, 167, 486–490.
  70. Pereira Nunes Mdo, C.; Barbosa, M.M.; Ribeiro, A.L.; Amorim Fenelon, L.M.; Rocha, M.O. Predictors of mortality in patients with dilated cardiomyopathy: Relevance of chagas disease as an etiological factor. Rev. Esp. Cardiol. 2010, 63, 788–797.
  71. Morillo, C.A.; Marin-Neto, J.A.; Avezum, A.; Sosa-Estani, S.; Rassi, A.; Rosas, F.; Villena, E.; Quiroz, R.; Bonilla, R.; Britto, C.; et al. Randomized Trial of Benznidazole for Chronic Chagas’ Cardiomyopathy. N. Engl. J. Med. 2015, 373, 1295–1306.
  72. Heidenreich, P.A.; Bozkurt, B.; Aguilar, D.; Allen, L.A.; Byun, J.J.; Colvin, M.M.; Deswal, A.; Drazner, M.H.; Dunlay, S.M.; Evers, L.R.; et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022, 145, e895–e1032.
  73. Blum, J.A.; Zellweger, M.J.; Burri, C.; Hatz, C. Cardiac involvement in African and American trypanosomiasis. Lancet Infect. Dis. 2008, 8, 631–641.
  74. Koten, J.W.; De Raadt, P. Myocarditis in Trypanosoma rhodesiense infections. Trans. R. Soc. Trop. Med. Hyg. 1969, 63, 485–489.
  75. Adams, J.H.; Haller, L.; Boa, F.Y.; Doua, F.; Dago, A.; Konian, K. Human African trypanosomiasis (T.b. gambiense): A study of 16 fatal cases of sleeping sickness with some observations on acute reactive arsenical encephalopathy. Neuropathol. Appl. Neurobiol. 1986, 12, 81–94.
  76. Blum, J.A.; Burri, C.; Hatz, C.; Kazumba, L.; Mangoni, P.; Zellweger, M.J. Sleeping hearts: The role of the heart in sleeping sickness (human African trypanosomiasis). Trop. Med. Int. Health 2007, 12, 1422–1432.
  77. Ferrero, P.; Piazza, I.; Lorini, L.F.; Senni, M. Epidemiologic and clinical profiles of bacterial myocarditis. Report of two cases and data from a pooled analysis. Indian Heart J. 2020, 72, 82–92.
  78. Canter, C.E.; Simpson, K.E. Diagnosis and Treatment of Myocarditis in Children in the Current Era. Circulation 2014, 129, 115–128.
  79. Yeung, C.; Baranchuk, A. Diagnosis and Treatment of Lyme Carditis: JACC Review Topic of the Week. J. Am. Coll. Cardiol. 2019, 73, 717–726.
  80. Caforio, A.L.P.; Adler, Y.; Agostini, C.; Allanore, Y.; Anastasakis, A.; Arad, M.; Böhm, M.; Charron, P.; Elliott, P.M.; Eriksson, U.; et al. Diagnosis and management of myocardial involvement in systemic immune-mediated diseases: A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Disease. Eur. Heart J. 2017, 38, 2649–2662.
  81. Bruestle, K.; Hackner, K.; Kreye, G.; Heidecker, B. Autoimmunity in Acute Myocarditis: How Immunopathogenesis Steers New Directions for Diagnosis and Treatment. Curr. Cardiol. Rep. 2020, 22, 28.
  82. Chen, P.; Baldeviano, G.C.; Ligons, D.L.; Talor, M.V.; Barin, J.G.; Rose, N.R.; Cihakova, D. Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4(+) T cells. Clin. Exp. Immunol. 2012, 169, 79–88.
  83. Bracamonte-Baran, W.; Čiháková, D. Cardiac Autoimmunity: Myocarditis. Adv. Exp. Med. Biol. 2017, 1003, 187–221.
  84. Baldeviano, G.C.; Barin, J.G.; Talor, M.V.; Srinivasan, S.; Bedja, D.; Zheng, D.; Gabrielson, K.; Iwakura, Y.; Rose, N.R.; Cihakova, D. Interleukin-17A Is Dispensable for Myocarditis but Essential for the Progression to Dilated Cardiomyopathy. Circ. Res. 2010, 106, 1646–1655.
  85. Thuny, F.; Naidoo, J.; Neilan, T.G. Cardiovascular complications of immune checkpoint inhibitors for cancer. Eur. Heart J. 2022, 43, 4458–4468.
  86. Tan, S.; Day, D.; Nicholls, S.J.; Segelov, E. Immune Checkpoint Inhibitor Therapy in Oncology: Current Uses and Future Directions: JACC: CardioOncology State-of-the-Art Review. JACC Cardio Oncol. 2022, 4, 579–597.
  87. Wei, S.C.; Meijers, W.C.; Axelrod, M.L.; Anang, N.A.S.; Screever, E.M.; Wescott, E.C.; Johnson, D.B.; Whitley, E.; Lehmann, L.; Courand, P.Y.; et al. A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention. Cancer Discov. 2021, 11, 614–625.
  88. Moslehi, J.; Salem, J.E. Immune Checkpoint Inhibitor Myocarditis Treatment Strategies and Future Directions. JACC Cardio Oncol. 2022, 4, 704–707.
  89. Ameratunga, R.; Woon, S.T.; Sheppard, M.N.; Garland, J.; Ondruschka, B.; Wong, C.X.; Stewart, R.A.H.; Tatley, M.; Stables, S.R.; Tse, R.D. First Identified Case of Fatal Fulminant Necrotizing Eosinophilic Myocarditis Following the Initial Dose of the Pfizer-BioNTech mRNA COVID-19 Vaccine (BNT162b2, Comirnaty): An Extremely Rare Idiosyncratic Hypersensitivity Reaction. J. Clin. Immunol. 2022, 42, 441–447.
  90. Ilonze, O.J.; Guglin, M.E. Myocarditis following COVID-19 vaccination in adolescents and adults: A cumulative experience of 2021. Heart Fail. Rev. 2022, 27, 2033–2043.
  91. Sung, K.; McCain, J.; King, K.R.; Hong, K.; Aisagbonhi, O.; Adler, E.D.; Urey, M.A. Biopsy-Proven Giant Cell Myocarditis Following the COVID-19 Vaccine. Circ. Heart Fail. 2022, 15, e009321.
  92. Patone, M.; Mei, X.W.; Handunnetthi, L.; Dixon, S.; Zaccardi, F.; Shankar-Hari, M.; Watkinson, P.; Khunti, K.; Harnden, A.; Coupland, C.A.C.; et al. Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex. Circulation 2022, 146, 743–754.
  93. Heymans, S.; Cooper, L.T. Myocarditis after COVID-19 mRNA vaccination: Clinical observations and potential mechanisms. Nat. Rev. Cardiol. 2022, 19, 75–77.
  94. Yonker, L.M.; Swank, Z.; Bartsch, Y.C.; Burns, M.D.; Kane, A.; Boribong, B.P.; Davis, J.P.; Loiselle, M.; Novak, T.; Senussi, Y.; et al. Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis. Circulation 2023, 147, 867–876.
  95. Marrama, D.; Mahita, J.; Sette, A.; Peters, B. Lack of evidence of significant homology of SARS-CoV-2 spike sequences to myocarditis-associated antigens. EBioMedicine 2022, 75, 103807.
  96. Barmada, A.; Klein, J.; Ramaswamy, A.; Brodsky, N.N.; Jaycox, J.R.; Sheikha, H.; Jones, K.M.; Habet, V.; Campbell, M.; Sumida, T.S.; et al. Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis. Sci. Immunol. 2023, 8, eadh3455.
  97. Ammirati, E.; Veronese, G.; Bottiroli, M.; Wang, D.W.; Cipriani, M.; Garascia, A.; Pedrotti, P.; Adler, E.D.; Frigerio, M. Update on acute myocarditis. Trends Cardiovasc. Med. 2021, 31, 370–379.
  98. Brambatti, M.; Matassini, M.V.; Adler, E.D.; Klingel, K.; Camici, P.G.; Ammirati, E. Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes. J. Am. Coll. Cardiol. 2017, 70, 2363–2375.
  99. Bang, V.; Ganatra, S.; Shah Sachin, P.; Dani Sourbha, S.; Neilan Tomas, G.; Thavendiranathan, P.; Resnic Frederic, S.; Piemonte Thomas, C.; Barac, A.; Patel, R.; et al. Management of Patients With Giant Cell Myocarditis. J. Am. Coll. Cardiol. 2021, 77, 1122–1134.
  100. Wojnicz, R.; Nowalany-Kozielska, E.; Wojciechowska, C.; Glanowska, G.; Wilczewski, P.; Niklewski, T.; Zembala, M.; Poloński, L.; Rozek, M.M.; Wodniecki, J. Randomized, Placebo-Controlled Study for Immunosuppressive Treatment of Inflammatory Dilated Cardiomyopathy. Circulation 2001, 104, 39–45.
  101. Frustaci, A.; Chimenti, C.; Calabrese, F.; Pieroni, M.; Thiene, G.; Maseri, A. Immunosuppressive Therapy for Active Lymphocytic Myocarditis. Circulation 2003, 107, 857–863.
  102. Frustaci, A.; Russo, M.A.; Chimenti, C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: The TIMIC study. Eur. Heart J. 2009, 30, 1995–2002.
  103. Chimenti, C.; Russo, M.A.; Frustaci, A. Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC trial. Eur. Heart J. 2022, 43, 3463–3473.
  104. Cheng, C.Y.; Cheng, G.Y.; Shan, Z.G.; Baritussio, A.; Lorenzoni, G.; Tyminska, A.; Ozieranski, K.; Iliceto, S.; Marcolongo, R.; Gregori, D.; et al. Efficacy of immunosuppressive therapy in myocarditis: A 30-year systematic review and meta analysis. Autoimmun. Rev. 2021, 20, 102710.
  105. Ozierański, K.; Tymińska, A.; Marchel, M.; Januszkiewicz, Ł.; Maciejewski, C.; Główczyńska, R.; Marcolongo, R.; Caforio, A.L.; Wojnicz, R.; Mizia-Stec, K.; et al. A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of immunosuppression in biopsy-proven virus-negative myocarditis or inflammatory cardiomyopathy (IMPROVE-MC). Cardiol. J. 2022, 29, 329–341.
  106. Cooper, L.T.J.; Berry, G.J.; Shabetai, R. Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N. Engl. J. Med. 1997, 336, 1860–1866.
  107. Ekström, K.; Lehtonen, J.; Kandolin, R.; Räisänen-Sokolowski, A.; Salmenkivi, K.; Kupari, M. Incidence, Risk Factors, and Outcome of Life-Threatening Ventricular Arrhythmias in Giant Cell Myocarditis. Circ. Arrhythm. Electrophysiol. 2016, 9, e004559.
  108. Cooper, L.T.J.; Hare, J.M.; Tazelaar, H.D.; Edwards, W.D.; Starling, R.C.; Deng, M.C.; Menon, S.; Mullen, G.M.; Jaski, B.; Bailey, K.R.; et al. Usefulness of immunosuppression for giant cell myocarditis. Am. J. Cardiol. 2008, 102, 1535–1539.
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