Introduction
Myocarditis refers to an inflammatory process in the heart that can be initiated by various factors. The most common cause of myocarditis is viral infection [
1]. However, other factors such as systemic autoimmune disease, toxins, or hypersensitivity to medications may induce myocarditis through an autoimmune reaction by various mechanisms. Even in viral myocarditis, an autoimmune reaction such as antigen mimicry may be induced. A novel cause of myocarditis is immune checkpoint inhibitor (ICI)-induced myocarditis, a rare but severe complication in this evolving field of therapy in oncology.
In this review, we will describe the pathophysiology of autoimmunity in myocarditis. A specific focus will be on ICI-induced myocarditis. This review will not discuss diagnostic approaches or prognostic features but focus on pathogenesis of autoimmune processes and link them to therapeutic strategies. A thorough understanding of the pathophysiology of ICI-induced myocarditis and other subtypes of myocarditis will be necessary to develop effective therapies.
Definition, Etiology, and Epidemiology
Acute myocarditis is defined as an acute inflammatory disease of the myocardium, caused by a variety of infectious (e.g., viral, bacterial) and noninfectious conditions (including cardiotoxins, hypersensitivity reactions, systemic disorders, and radiation). The list of possible causal agents is constantly expanding and recently immune checkpoint inhibitors (ICI), a new class of paradigm-shifting immune-oncologic therapies was found to have potential cardiotoxic properties by triggering myocarditis [
2]. The ESC working group on myocardial and pericardial diseases recommends distinguishing between viral myocarditis, autoimmune myocarditis, and viral and immune myocarditis [
3]. Acute myocarditis is defined as a new-onset of symptoms (days up to 3 months) or worsening of symptoms, whereas subacute and chronic myocarditis is defined as having symptoms for more than 3 months [
3].
Due to the absence of a sensitive noninvasive diagnostic test, no comprehensive population–based epidemiological data exist about the prevalence, or presenting symptoms of various etiologies as of today. However, early studies suggest that cardiac involvement may occur in 3.5 to 5% of patients during outbreaks of coxsackievirus [
4]. Also, cardiac magnetic resonance imaging studies (CMR) have shown that myocarditis continues to be underdiagnosed and that broader CMR screening may be necessary to identify patients with less aggressive forms of myocarditis [
5]. PVB19 is the most frequent virus detected by PCR analysis. However, similar percentages of PVB19-positive analysis have been demonstrated in patients with non-inflammatory cardiomyopathy undergoing cardiac surgery questioning the role of PVB19 persistence as pathogenic agent and suggesting it may be an innocent bystander [
6]. Due to PCR amplification of viral genomes, other viruses (such as adenovirus, Epstein-Barr, and influenza virus) have been identified, but the pathophysiological and prognostic significance is still uncertain [
7,
8]. Other infectious causes of myocarditis include
Trypanosoma cruzi—a protozoan parasite causing Chagas disease, and bacteria such as group A streptococcus. An often overlooked cause for myocarditis is hypersensitivity to medications (such as dobutamine or phenytoin [
9]) or drugs (such as methamphetamine or cocaine [
10]). Myocarditis may also be found on endomyocardial biopsies (EMBs) amongst patients with stress-induced or Takotsubo cardiomyopathy [
11]. The most aggressive forms of non-infectious myocarditis are giant cell myocarditis and eosinophilic necrotizing myocarditis, which are frequently lethal despite maximal medical treatment. A new entity is ICI-induced myocarditis, which is a result of an “unleashed” immune system with high mortality [
2].
In general, many cases of myocarditis are likely underdiagnosed due to subclinical or nonspecific symptoms [
5,
12]. On the other hand, subtle cardiac symptoms may be overshadowed by systemic manifestations of severe underlying infections. An analysis of national inpatient sample data from 2005 to 2014 in the USA concluded a gradual increase of reported cases of myocarditis from 95 per 1 million in 2005 to 144 per 1 million in 2014 [
13]. Overall in-hospital mortality was reported to be 4.43% with a significant increase of cardiogenic shock from 6.95% in 2005 to 11.99% in 2014 [
13]. Another study included data from the USA on 27,129 hospitalizations with discharge diagnosis myocarditis from 2007 to 2014. Cardiogenic shock and ventricular fibrillation/cardiac arrest occurred in 6.5% and 2.5%, respectively, with females being more affected than males [
14]. The global incidence of myocarditis in 2017 as reported by the Global Burden of Disease project was 3,071,000 cases [
15]. The incidence of ICI myocarditis may be up to 1–2% with significant mortality (30%) [
16•]. Combination of ICI treatment increases the risk of myocarditis as compared with single drug therapy. Given the early success of ICI in advanced cancer [
17], we expect to see an increase of autoimmune diseases related to this novel drug class in the future [
18].
Current Therapy and Future Directions
Treatment of myocarditis includes general nonspecific measures to treat the sequelae of heart disease, including heart failure (HF) therapy and treatment of arrhythmias according to current guidelines and scientific statements [
3]. Mechanical circulatory support and transplantation may remain a potential last resort for patients with refractory heart failure despite optimum medical therapy.
Furthermore, therapy for viral myocarditis has been focusing on specific antiviral treatment, while non-viral autoimmune myocarditis has been treated with broad band immunosuppressive agents and some immune modulating drugs [
3]. Immunosuppression appears mandatory in specific noninfectious settings of acute myocarditis such as giant cell myocarditis, necrotizing eosinophilic myocarditis, and cardiac sarcoidosis.
However, the shared end pathway of inflammation, tissue remodeling, fibrosis and progression to DCM, and cardiac failure make both immune suppression and immune modulation valid therapeutic options for a wide array of myocarditis subtypes.
Immunosuppression targets general inflammation and is achieved classically with corticosteroids, cyclosporine A, azathioprine, or a combination of the aforementioned. Most data of immunosuppressive therapy have been obtained using corticosteroids alone, or in combination with azathioprine or cyclosporine A. Several randomized controlled trials provide results for prednisone and azathioprine at 3 months [
80], 6 months [
81], and 1 year [
82], for prednisone alone at 3 months [
83], and for combined prednisone, cyclosporine A, or azathioprine at 6 months [
84]. However, differences in patient selection and study design, as well as focus on LVEF as primary endpoint on relative short follow-up durations, have led to contradicting results. A recent retrospective analysis by Merken and colleagues revealed a potential beneficial effect of immunosuppression in patients with myocarditis [
85]. A prospective multicenter trial using azathioprine and prednisone is currently ongoing (NCT01877746). In giant cell myocarditis, immunosuppression including corticosteroids, cyclosporine, and the possible addition of azathioprine is the main treatment strategy. Sudden interruption of immunosuppression in these cases within the first 2 years has been associated with fatal relapse of the disease [
86].
In the event of immunotherapy-induced myocarditis (e.g., by checkpoint inhibitors), the assumption of an immune antigen reaction similar to an allograft rejection or rheumatic disease, vindicates the use of immunosuppression with corticosteroids. However, until now only case reports and case series have been published to guide this conclusion [
87]. Additional immunosuppressive therapy with mycophenolate mofetil or calcineurin inhibitors may be beneficial. Successful treatment with equine antithymocyte globulin in ICI-related and corticosteroid-resistant myocarditis has been reported [
88].
To further affect myocarditis via immune modulation, uncontrolled studies on intravenous immunoglobulin therapy showed promising results for improved recovery of LVEF [
89,
90]. However, a randomized investigation (IMAC trial) showed no effective outcome, but only 15% of patients had biopsy-proven myocarditis of non-specified cause in this study [
91]. Immunoadsorption and plasmapheresis aims to lower cardiotoxic antibodies and immune complexes in the plasma, and reported effects of small randomized studies are promising [
92,
93].
Immune modulating agents allow for a more targeted approach with reduced side effects. An anti-CD3 monoclonal antibody (muronumab) suppresses lymphocyte activation and proliferation. IL-6 antibody blocks the Il-6 receptor and has been shown to be beneficial in viral myocarditis [
94]. The involvement of T cell to B cell crosstalk and the emergence of specific anti-cardiac antibodies related to severe cases of myocarditis give room for more targeted therapies than the simple elimination of antibodies via plasmapheresis or immunoadsorption. Costimulatory blockade, the inhibition of CD28 and B7 T cell receptors has been shown to reduce T cell proliferation, B cell activation, and sensitization via circulating antibodies [
95]. The concept of costimulatory blockade has been applied to tolerance induction models in non-human primates and has shown prolonged graft survival with decreased CD4+ T cell activity [
95]. Similar approaches target the CD28 receptor itself with belatacept, a humanized antibody that has proven to be beneficial in renal transplant recipients [
95].
These single agents target specific cells and/or a specific cytokine milieu. A broader, more conceptual approach has been adopted from the field of transplantation: the induction of tolerance aims to restore a stable balance between effector and regulatory forces, suppress autoreactivity, keep overabundant T cell activity in check and enhance myocardial tissue repair [
38,
96].
Studies of the T cell repertoire were able to show an association of specific clonal deletion of T cells in tolerant patients after bone marrow transplantation [
97]. Transgenic murine models of myocarditis that had myosin laden antigen presented on mTECS in the thymus were able to clonally delete autoreactive T cells and were protected from myocarditis induction [
40]. Further studies and the following of T cell clones are needed in order to harness clonal deletion for myocarditis therapy.
Regulatory failure leads to imbalance of effector and regulatory T cells. The idea of restoring the said balance has been attempted by increasing the peripheral Treg pool. Studies on tolerance induction in solid organ transplants in non-human primates have harnessed the adoptive transfer of ex vivo expanded, autologous Treg infusions to alter T effector vs T regulatory balance in favor of a less inflammatory setting [
98,
99]. Ongoing trials on tolerance induction in kidney graft recipients with the help of Treg infusions in humans underline the feasibility and potential of ex vivo expanded, recipient targeted adoptive cell transfer [
100‐
102]. Understanding the underlying mechanism of innate and adaptive immune players at different stages of autoimmune myocarditis is crucial to further develop targeted therapies.
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