Myocarditis and Dilated Cardiomyopathy

C H A P T E R

64 Myocarditis and Dilated Cardiomyopathy Ziya Kaya1,2, Patricia Raczek1,2 and Noel R. Rose3 1

Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany 2Germany Centre for Cardiovascular Research, DZHK, Heidelberg, Germany 3Department of Pathology, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, United States

O U T L I N E Historical Background

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Myocarditis—Clinical, Pathologic, and Epidemiologic Features

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Treatment

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Dilated Cardiomyopathy—Clinical, Pathologic, and Epidemiologic Features

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Treatment

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Autoimmune Features

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Genetic Features

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Animal Models

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Perspectives

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Acknowledgments

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References

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Further Reading

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HISTORICAL BACKGROUND The role of autoimmunity in cardiovascular disease has long been a topic of investigation in the clinic and the laboratory. Years of research effort were devoted to establishing a link between streptococcal infection and rheumatic heart disease based on an autoimmune response (see Chapter 63). Chagas disease is still believed to be based on a cross-reaction of antibodies to Trypanosoma cruzi with myocardial or cardiac conductive tissue (Coura and Borges-Pereira, 2012). Finally, postpericardiotomy syndrome and postmyocardial infarction syndrome are sometimes cited as instances of an autoimmune response instigated by damaged or necrotic tissue (Maisch et al., 1979). This chapter reviews the evidence linking autoimmunity with two important forms of heart disease, myocarditis and dilated cardiomyopathy (DCM). It must be stated, ab initio, that immunologic testing has so far not been effective in allowing a clear distinction between autoimmune and other etiologies of these diseases. The classic description of myocarditis was given by Corvisart in 1812 (referenced in Gravanis and Sternby, 1991), but for many years, progress in studying the disease was impeded by the uncertainties of clinical diagnosis. Definitive diagnosis was dependent upon autopsy examination. Interest in the disease increased in recent years because of the introduction of antemortem diagnostic tools, especially the endomyocardial biopsy (EBM), greater understanding of the role of cardiotropic viruses, and the availability of new modalities of therapy.

The Autoimmune Diseases, 6th. DOI: https://doi.org/10.1016/B978-0-12-812102-3.00064-6

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Copyright © 2020 Elsevier Inc. All rights reserved.

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MYOCARDITIS—CLINICAL, PATHOLOGIC, AND EPIDEMIOLOGIC FEATURES Myocarditis is inflammation of the heart muscle leading to impaired function of the myocardium. The several types of myocarditis can be classified by etiology, histology, immunohistochemistry, clinical pathology, or clinical criteria. Clinical findings can span asymptomatic cases to severe disease with associated arrhythmia and heart failure. Even in the same patient, symptoms vary as the disease progresses. The most serious manifestation of myocarditis is heart failure due to dysfunction of the left ventricle (LV) (Hufnagel et al., 2000). This dysfunction might develop gradually with mild symptoms or rapidly, leading to cardiogenic shock. Supraventricular and/or ventricular arrhythmias are other symptoms linked to myocarditis. Patients might present with palpitations, dizziness, or syncope. Conduction disturbances or serious ventricular arrhythmia suggest giant cell myocarditis, cardiac sarcoidosis, or Borrelia burgdorferi associated myocarditis. Sudden cardiac death in previously healthy young adults can be caused by heart failure or severe arrhythmia. Another major symptom is anginalike chest pain. In these cases, acute coronary syndrome should be ruled out by catheterization. After further exclusion of other pathologies (such as aortic dissection, atrial or ventricular tachycardia, ulcer diseases, or severe anemia), myocarditis should be considered (Baccouche et al., 2009). After initial systolic dysfunction, about half of the cases improve spontaneously or after standard heart failure treatment. Therefore it is recommended to postpone invasive therapeutic interventions, such as the implantation of a cardioverter or defibrillator, for about 3 6 months after onset of the disease or start of treatment. Cases presenting predominantly with heart failure tend to have a worse prognosis than those presenting with arrhythmia or chest pain (Caforio et al., 2007). The most common cause of myocarditis is viral infection. Patients may recall a recent viral illness with symptoms of malaise, chills and fever, upper respiratory or gastrointestinal symptoms, myalgia, and chest pain. Most cases, however, cannot be traced back to an obvious preceding illness. Adenovirus and enterovirus have mostly been associated with cardiomyocyte infection, and parvovirus B19 attacks cardiac endothelial cells. Today, human herpes virus 6 and HIV are the major pathogens causing myocarditis (Breinholt et al., 2010). Other causes are diverse and include bacteria, protozoa, alcohol, drugs, and toxins. In South and Central America, Chagas disease is a major cause of heart muscle inflammation. The hemoflagellate T. cruzi is transmitted to humans via the bite of the reduviid bug triatomine. Most patients initially have only mild, influenza-like symptoms, but 10% 30% of the infected individuals develop fulminant myocarditis. For a long time, conclusive diagnosis of myocarditis was difficult because suitable diagnostic methods were lacking. The diagnosis was supported by the exclusion of other diseases that could explain the symptoms. Today, even though our diagnostic possibilities have expanded and improved, there is still room for further modifications and more specific criteria to diagnose myocarditis. The first indication is clinical symptoms such as chest pain, heart failure, and arrhythmia. Electrocardiogram (ECG) and echocardiography are the basic diagnostic tools for the heart, but they do not provide specific signs for myocarditis. Their value lies more in excluding other causes and in assessing heart function. Even normal findings in a patient do not exclude myocarditis. Echocardiography can help to record disease progression because temporal changes in systolic function, chamber size and thickness can be evaluated regularly (Caforio et al., 2013). The most important noninvasive method to date is magnetic resonance imaging (MRI). It is helpful in the evaluation of numerous morphological and functional aspects of myocardial impairment and allows a thorough tissue characterization (Friedrich et al., 2009; Olimulder et al., 2009; Bruder et al., 2013; Lurz et al., 2012). Tissue pathologies, such as myocardial edema and hyperemia, capillary leak, necrosis, and fibrosis as well as contraction abnormalities and pericardial effusion can be detected (Kuchynka et al., 2015). The Lake Louise criteria have been proposed to standardize the evaluation of findings in MRI and improve diagnostic accuracy (Friedrich et al., 2009). They combine three different cardiac magnetic resonance techniques and are based on myocardial edema as a sign of acute inflammation, early gadolinium enhancement linked to hyperemia and late gadolinium enhancement linked to increased myocardial necrosis or fibrosis. Late gadolinium enhancement is also an important prognostic factor as well as a significant predictor of cardiovascular mortality (Gru¨n et al., 2012). MRI is, in general, better suited for acute cases with inflammation than chronic cases with less inflammatory activity. Even though MRI diagnosis has improved, EBM still constitutes the gold standard in the diagnosis of myocarditis, since it is the only method for a definitive diagnosis in vivo. It dates to the 1980s, when the Dallas criteria were used as a standardized method to evaluate samples (Aretz et al., 1987). Today, the application of the Dallas criteria has been limited due to low sensitivity and high interobserver variability. Even though endomyocardial biopsy (EMB) is invasive and sampling errors may occur, it offers important information for diagnosis, prognosis, and therapy (Hufnagel et al., 2000; Caforio et al., 2015; Lassner et al., 2014). By immunohistochemistry,

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FIGURE 64.1 Lymphocytic myocarditis. There is a heavy infiltrate of large activated lymphocytes throughout the myocardium. Myocyte necrosis is noted in the middle of this image. Fibrosis is present on the right side of the image. (H&E 4003).

FIGURE 64.2 Borderline myocarditis. (A) A single cluster of perivascular lymphocytes is present. No myocardial damage is identified. (H&E4003). (B) A CD8 immunohistochemical stain highlights the infiltrating T lymphocytes. (H&E 4003).

inflammatory cell infiltrates as well as activated immunological processes can be identified and characterized (Maisch and Pankuweit, 2012; Malik et al., 2015; Palecek et al., 2010). EMB allows classification of the types of myocarditis, pathogens can be detected by polymerase chain reaction, and a quantitative assessment of viral load is possible. Perforin-positive cells and human leukocyte antigen (HLA) expression can be evaluated (Figs. 64.1 64.4). Myocarditis typically has a three-phased progression (Cooper, 2009; Kindermann et al., 2012; Dennert et al., 2008). In the first, or acute phase, viral pathogens enter cardiomyocytes via the coxsackie adenoviral receptor under participation of the coreceptors (Noutsias et al., 2003). This phase lasts several days to weeks as the virus replicates, and a reaction of nonspecific immunity takes place. Viral and inflammatory mediators lead to myocardial impairment. Patients in this phase are often asymptomatic. The second phase begins 2 4 weeks after onset of the disease and is characterized by a specific immune reaction with cellular and antibody-mediated response. In this phase the start of an autoimmune reaction is possible. In this reaction, antibodies against heart-specific structures such as myosin or troponin are produced, which cause additional damage to the cardiac tissue. The onset of the third phase after several weeks or months is marked either by an improvement of cardiac function or a deterioration into chronic cardiomyopathy. In between 50% and 70% of the cases the inflammation retreats and LV function increases. If improvement does not occur in this phase, a persistent dysfunction and development of postinflammatory DCM is usually the long-term consequence. Many factors, such as the degree of initial damage, intensity and duration of inflammation, and persistence of viral pathogens influence the course of the disease (Schultheiss et al., 2011; D’Ambrosio et al., 2001).

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FIGURE 64.3 Fulminant myocarditis. The myocardium is replaced by a marked polymorphous inflammatory infiltrate composed predominantly of lymphocytes and macrophages with rarer eosinophils and neutrophils. Global myocyte injury and loss is noted. No giant cells are present. (H&E 1003).

FIGURE 64.4 Giant cell myocarditis. The myocardium is infiltrated by a patchy and diffuse inflammatory infiltrate composed primarily of lymphocytes and macrophages. Multiple collections of giant cells are seen within the infiltrate along with eosinophils. There is significant injury and loss of myocytes in areas of inflammation, while adjacent myocardium is relatively uninvolved. (H&E 503).

The extent of myocardial damage in the acute phase is one of the most important factors determining the recovery of LV function in later periods (Baccouche et al., 2009; Maisch and Pankuweit, 2012; Cooper and Myocarditis, 2009; Kindermann et al., 2012; Dennert et al., 2008). Most people do not develop continuing myocarditis after exposure to viruses, which suggests a genetic susceptibility. A higher prevalence in patients with a family history of myocarditis has also been observed, which would seem to support this theory (Hufnagel et al., 2000; Dennert et al., 2008).

TREATMENT With the diagnosis of myocarditis, physical activity should be limited for 6 months or until the regression of inflammation and restitution of LV function (Hufnagel et al., 2000). Standard heart failure treatment seems to have a potential positive influence on inflammatory changes and outcome of myocarditis patients and is widely recommended (Bahk et al., 2008; Saegusa et al., 2007; Yuan et al., 2004; Pauschinger et al., 2005). This includes angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers, beta blockers, and aldosterone antagonists (McMurray et al., 2012; Yancy et al., 2013a,b). However, nonsteroidal anti-inflammatory drugs

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(NSAIDs) and digoxin have not been recommended. In critical cases mechanical circulatory support can aid as a temporary solution until the decision between treatment and transplantation is made. Heart transplantation is the last option in severe cases of heart failure. Devices for treating arrhythmia should be postponed since a significant improvement of LV function and retreat of arrhythmia can often be seen after a few weeks with the regression of myocardial inflammation. The optimal treatment depends on the type of myocarditis present. This is one reason why it is important to have a classification by EMB. For giant cell myocarditis, eosinophilic myocarditis, and cardiac sarcoidosis, immunosuppressive therapy is indicated, but the dose and duration of treatment have not yet been standardized. Lu et al. (2016) have stated that immunosuppressive therapy does not affect mortality or the need for heart transplantation but has a favorable effect on the improvement of LV systolic function. The results of smaller studies still should be verified in larger, multicenter studies. Another approach is treatment with intravenous immunoglobulins and immunoadsorption, but the effect is still disputed. In the first phase of myocarditis, antiviral treatment is used to stop viral replication and contain damage to cardiomyocytes. Interferon beta treatment seems to be beneficial in the cases of adenovirus and enterovirus infection but not necessarily in other types (Ku¨hl et al., 2003). Specifically for enterovirus, interferon beta therapy may be associated with long-term prognostic benefit (Ku¨hl et al., 2012).

DILATED CARDIOMYOPATHY—CLINICAL, PATHOLOGIC, AND EPIDEMIOLOGIC FEATURES DCM is characterized by left ventricular dilation and contractile dysfunction with the absence of abnormal loading conditions and severe coronary artery disease. It is one of the most common causes of heart failure and the most common indication for heart transplant worldwide (Maron et al., 2006). The prevalence is estimated to be around 40 cases per 100,000 individuals with an annual incidence of 7 cases per 100,000 (Maron et al., 2006; Manolio et al., 1992; Taylor et al., 2006). Racial differences have been detected, whereas sex does not seem to make a difference in susceptibility (Manolio et al., 1992; Yancy et al., 2013a,b). About 60% of all childhood cardiomyopathies are the cases of DCM (Liupshultz et al., 2003; Nugent et al., 2003) and infants younger than 12 months have the highest incidence (Nugent et al., 2003; Towbin et al., 2006). The overall mortality is higher in children than in adults; therefore, age is an important risk factor for the deaths of DCM. Symptoms usually include congestive heart failure with excessive sweating, ankle edema, orthopnea, fatigue after mild exertion, palpitations, and syncope. Circulatory collapse, arrhythmia, and thromboembolic events are also possible. There is a risk of sudden death, particularly in infants (Nugent et al., 2003), caused by electromechanical dissociation or ventricular arrhythmia. There are varying causes for DCM. Genetic mutations in genes for cytoskeletal, sarcomere, nuclear envelope proteins, transcriptional pathways, and mitochondrial proteins make up about 35% of the cases (Grunig et al., 1998; Michels et al., 1992). The inheritance is mostly an autosomal dominant trait (Michels et al., 1992; McNally et al., 2013). Hereditary DCM can be classified in predominantly cardiac types, mutations associated with neuromuscular diseases such as Duchenne and Becker muscular dystrophy or DCM as part of a syndrome. The most common mutations for predominant cardiac phenotypes are in titin and lamin A/C genes (Gerull et al., 2002; Fatkin et al., 1999; Parks et al., 2008). Acquired causes include myocarditis, alcohol, drugs, and toxins. About 20% of the myocarditis patients develop a chronic DCM while the disease progresses (D’Ambrosio et al., 2001). Alcohol, cocaine, and methamphetamine abuse have a cardiotoxic effect and can lead to DCM. The same applies to anthracycline, a cytostatic used in therapy for cancer, whose cardiotoxicity can occur during treatment or many years afterward. In addition, certain metabolic and endocrine disturbances have been linked to DCM. A special case is peripartum cardiomyopathy. It can occur in the last month of pregnancy or within 5 months of delivery; however, the exact pathologic mechanisms and cause are still unknown (Pearson et al., 2000). In DCM patients the LV assumes a spherical shape. Hypertrophy and fibrosis restrict the heart function, and ventricular relaxation and filling are reduced. There is a significant decrease in stroke volume and cardiac output. Preload and afterload as well as end-diastolic pressure are increased, resulting in elevated wall stress. Compensatory changes in the vascular system such as an increase in systemic vascular resistance, a decrease in arterial compliance, and an increase in venous pressure will usually occur. These exacerbating circumstances cause secondary neurohormonal changes, for example, an increase in sympathetic adrenergic activity and a

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reduction in vagal activity further add to the wall stress and elevate myocardial oxygen demand. Myocytes incur damage, leading to a further reduction in myocardial performance. Because of its heritability, genetic testing and screening at-risk family members is important in affected families. In patients with DCM, ECG can show nonspecific repolarization abnormalities, left ventricular hypertrophy, pathological Q waves, poor R wave progression, prolongation in the PR interval, AV block, left bundle branch block, or left anterior hemiblock. In cardiac radiography, cardiomegaly and pulmonary venous redistribution may be visible. Like ECG and radiography, echocardiography can detect abnormalities of the heart but none specific for DCM. Global LV hypokinesis is common, sometimes regional wall motion abnormalities, intracardiac thrombi, and functional mitral regurgitation due to annular dilation can occur. Doppler parameters can assist in quantifying the severity of diastolic dysfunction (Nishimura and Tajik, 1997). MRI is a noninvasive option for examining ventricular volume, wall thickness, contractile function, and tissue characterization. Histologically, irregular myocyte hypertrophy with or without the areas of fibrosis and myocyte damage can be detected. Lymphocytic infiltrates are the regular markers of inflammation. Furthermore, specific disorders may be identified which can be helpful in choosing the correct treatment. Polymerase chain reaction is a possible method for identifying viral genome in affected patients. Biomarkers such as B-type natriuretic peptide (BNP) and N-terminal BNP play an important prognostic role as their elevation is proportional to the severity of heart failure (Maisel et al., 2002).

TREATMENT The most important goals in the treatment of DCM are the improvement of survival and reduction of hospital admissions. Heart failure guidelines should be applied. Standard first-line drugs are ACE inhibitors and beta blockers. Mineralocorticoid antagonists and the If-channel inhibitor ivabradine provide additional survival benefits when combined with ACE inhibitors and beta blockers (Pitt et al., 1999; Zannad et al., 2011; Swedberg et al., 2010). Studies have shown that sacubitril valsartan therapy has better outcomes than treatment with enalapril. Digoxin is useful for patients with sustained atrial fibrillation or refractory heart failure symptoms. To control symptoms loop diuretics are recommended, as well as salt and fluid restriction. Other vasodilatory, natriuretic, and inotropic drugs were tested in clinical trials, but they do not seem to have a positive influence on the outcome (Chen et al., 2013). New drugs are being tested in ongoing trials. A specific genetic diagnosis might indicate additional or alternative drug therapy. Device therapy can be used for patients with arrhythmia and to prevent sudden death. Implantation of implantable cardioverter defibrillators are recommended for patients at highest risk. Patients with combined DCM and symptomatic bradycardia are eligible for biventricular pacing. Heart transplantation or implantation of long-term mechanical circulatory support such as an extracorporeal membrane oxygenation are to be seen as last measures only. For all patients with DCM an enrollment in a multidisciplinary heart failure service is advised. Its primary function is in educating patients about their disease and giving advice for living with DCM, as well as offering support and monitoring at-risk patients.

AUTOIMMUNE FEATURES In recent years, autoimmunity has been accepted as a significant contributing factor in the pathology of inflammatory cardiovascular diseases. Patients suffering from classic autoimmune diseases have a higher risk for developing cardiovascular diseases (Jastrze˛bska et al., 2013), which emphasizes the connection between autoimmunity and cardiovascular diseases. Cardiac autoantibodies have many different points of origin; they can be directed against contractile elements, stress (“heat shock”) proteins, mitochondrial and extracellular matrix antigens, and cardiac receptors. At present, antibodies against cardiac myosin, troponin, the β1-receptor and muscarinic 2-receptor (M2-receptor) are thought to have the greatest impact in the development of cardiomyopathies (Satta and Vuilleumier, 2015; Bornholz et al., 2017; Mu¨ller et al., 2016b; Caforio et al., 2008a,b; Lappe´ et al., 2008; Nussinovitch and Shoenfeld, 2010, 2012, 2013a,b; Kaya et al., 2010). They can be divided into two types of autoantibodies. The first ones are classic autoantibodies, which signal an immune response that injuries the target tissue. Relevant antibodies are directed against cardiac myosin and cardiac troponin. The second class is “functional autoantibodies.” They are directed against G-protein-coupled receptors (GPCR) and influence receptor-mediated signal cascades by binding to the receptor

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and acting as ligands. They thus have an impact on physiological functions similar to the physiologically specific receptor ligand but usually without appropriate controlling feedback mechanisms. In cardiomyopathy patients, GPCR-autoantibodies (GPCR-AABs) are associated primarily with electrical cardiac abnormalities, arrhythmia, ventricular tachycardia, sudden death, and myocarditis (Caforio et al., 2008a; Root-Bernstein and Fairweather, 2015; Wallukat et al., 1992; Chiale et al., 1995; Brisinda et al., 2012; Iwata et al., 2001). Mainly β1-adrenergic and M2-receptor autoantibodies seem to play an important role in cardiomyopathy. β 1-Autoantibody effects (β1-AABs) cause the activation of the adenylate cyclase (cAMP increase) (Dandel et al., 2012), activation of protein kinase A (Krause et al., 1996), elongation of the action potential, increase of the L-type calcium ion current (Christ et al., 2001), change of mitochondrial structure and membrane potential (Wang et al., 2013), induction of apoptosis and cell death (Staudt et al., 2003; Jane-wit et al., 2007; Haberland et al., 2011), and maturation and degranulation of cardiac mast cells (Okruhlikova et al., 2007). β1-AABs also activate the mitogenactivated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) pathway. They may contribute to cardiac hypertrophy (Tutor et al., 2007). Changes in T-cell proliferation and secretion have also been observed (Du et al., 2012). M2-Autoantibody effects (M2-AABs) are associated with a negative chronotropic effect and the blocking of cardiac parasympathetic innervation (Wallukat et al., 1999; Goin et al., 1997) by inhibiting the L-type calcium ion channels. This could explain electric abnormalities often observed in the heart in the presence of these antibodies (Lazzerini et al., 2008; Hong et al., 2009; Dobrev et al., 2004). M2-AABs also seem to influence the regulation of COX-2 and iNOS mRNA, hereby possibly contributing to proinflammatory conditions (Ganzinelli et al., 2009). The first autoantibodies in DCM patients were identified in 1992, with the detection of IgG class antibodies directed against alpha- and beta-myosin heavy chains (Caforio et al., 1992). Similiar antibodies were found in some patients with Chagas cardiomyopathy (Ballinas-Vedugo et al., 2003) and women with peripartum cardiomyopathy (Haghikia et al., 2015). Myosin is a motor protein in the contractile apparatus of the cardiomyocyte. It consists of two heavy chains and four light chains. For the heavy chain two isoforms exist, the alpha-myosin heavy chain and beta-myosin heavy chain. The beta-myosin heavy chain is not heart specific; it appears in the heart muscle as well as in the skeletal muscle, whereas alpha-myosin heavy chain can, to our knowledge, only be found in the myocardium. Therefore anti-alpha-myosin autoantibodies are heart specific (Becker et al., 2017). In 2007 anticardiac troponin I autoantibodies were detected in patients with DCM, in the following years also in patients with Chagas cardiomyopathy and peripartum myopathy. In animal models, those antibodies were generated and administered to mice resulting in dilatation and dysfunction of the heart (Okazaki et al., 2003). Treatment strategies against functional autoantibodies show promising results in early clinical trials. Patients with β1-AABs showed benefits from immunoadsorption for antibody removal (Dandel et al., 2012). To detect and measure GPCR-AABs, two groups of assays have been applied (Bornholz et al., 2017). The first group (bioassay) uses changes of a second messenger signal in (living) cells that occur after the binding of GPCR-ABBs to the receptor. The second method, enzyme-linked immunosorbent assay (ELISA), is used to directly detect GPCR-AABs after binding to epitope mimics. ELISA provides information about the type or amount of antibodies in a sample but cannot measure their functionality. For both assays data about sensitivity and specificity are often unclear and validation and standardization deficient. Therefore numbers for the prevalence of autoantibodies in cardiomyopathy patients and healthy subjects vary from study to study. Antimyosin antibodies were found in up to 5% of healthy individuals (Caforio et al., 2008a; Nussinovitch and Shoenfeld, 2013a,b), whereas DCM patients had a prevalence of 50% 66%. In comparison, patients with ischemic or valvular cardiomyopathy showed the same prevalence of anti-c myosin-AABs as healthy individuals (Caforio et al., 1992; Konstadoulakis et al., 1993). For β1-AABs and M2-AABs a prevalence of around 10% in healthy individuals is estimated, increasing with age. A coexistence of both antibodies was detected in 65% of healthy subjects (Liu et al., 1999). Different studies delivered a wide range for the presence of β1-AABs in DCM patients between 26% and 95% (Sto¨rk et al., 2006), again with a high coexistence of M2-AABs (Hoebeke et al., 1994). Myocarditis patients even had a prevalence of up to 96%. In contrast, ischemic cardiomyopathy patients had a prevalence of β1-AABs lower than 15% (Nussinovitch and Shoenfeld, 2013a,b; Sto¨rk et al., 2006; Nikolaev et al., 2007). Levels of β1-AABs were correlated with a negative prognosis, higher mortality and increased risk for electric abnormalities and sudden death in some studies (Caforio et al., 2008b; Nussinovitch and Shoenfeld, 2013a,b). However, other studies could not prove this connection. It is unclear if antibody titers can give information about the severity of the disease progression. For the detection of functional β1-AABs a new screening technology is currently being tested in the Etiology, Titre-Course, and Survival (ETiCS) study on patients with EMB-proven new-onset myocarditis. This assay is called functional fluorescence energy transfer and uses novel cAMP sensors (Nikolaev et al., 2007; Deubner et al., 2010; Beavo and

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Brunton, 2002; Staudt et al., 2004). M2-AABs were found in 15% 50% of DCM patients (Nussinovitch and Shoenfeld, 2012). The occurrence of M2-AABs in DCM patients is associated with electric abnormalities (Lazzerini et al., 2008; Lee et al., 2011). The data are based on bioassay and ELISA measurements. About half of the patients with Chagas cardiomyopathy were tested positive for anti-c myosin and anti-c troponin T autoantibodies, but about the same amount of Chagas patients presenting without cardiac symptoms were also positive for these antibodies β1- and M2-AABs are frequently found in Chagas heart patients (Talvani et al., 2006). A correlation between levels of autoantibodies and severity of the disease was not found. Because of the high prevalence of autoantibodies in DCM patients, treatment options which target pathogenic autoantibodies are promising. Autoantibodies can be removed from the patients’ circulation or attacked and destroyed in vivo. Unselected plasmapheresis (therapeutic plasma exchange, TPE) and apheresis technologies (immunoadsorption) have been proposed. During TPE the patients’ blood is transferred to a device that separates plasma and blood cells. The cells are returned to the patients’ circulation, and the plasma, which contains the autoantibodies, is replaced by donor plasma or a plasma surrogate. TPE is a common technique in the treatment of autoimmune disorders [Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee]. In DCM patients TPE was so far only used in case studies. These did, however, show good results. Immunoadsorption also begins with connecting the patients’ circulation to a machine that separates plasma and blood cells. The plasma is passed through a column containing ligands that enable the binding of immunoglobulins, specific IgG subclasses, or specific antibodies. The targeted molecules are left behind while the cleared plasma joins the blood cells and is transferred back into the patients’ circulation. With this method, specific antibodies can be filtered from the plasma. Immunoadsorption was first applied to DCM patients in 1996 (Wallukat et al., 1996). Of the 8 patients 7 showed benefits and shifted to lower NYHA classes. Follow-up studies demonstrated an increase in LV ejection fraction, cardiac index, and stroke volume index immediately after immunoadsorption (Felix et al., 2000, 2002; Mobini et al., 2003). In addition, lasting positive effects such as increased cardiac function, decreased diastolic diameter, improved echocardiographic and cardiopulmonary exercise parameters, and improved endothelial function for months or even years following treatment were documented (Reinthaler et al., 2015; Mu¨ller et al., 2000; Cooper et al., 2007; Knebel et al., 2004; Staudt et al., 2006a,b; Herda et al., 2010; Bulut et al., 2010, 2011, 2013; Doesch et al., 2009, 2010; Trimpert et al., 2010). For patients who benefited from immunoadsorption a significant increase in regulatory T-cells was observed, which was associated with long-term patient health improvement (Bulut et al., 2010, 2011, 2013). The studies mentioned above focused primarily on β1-AABs. Subgroup analysis revealed that mostly patients with high levels of autoantibodies benefit from immunoadsorption therapy (Dandel et al., 2012). Therefore it is important in clinical practice to differentiate between cardiomyopathy patients who tested positive or negative for cardiac autoantibodies to make adequate therapy decisions. Immunoadsorption is a relatively expensive procedure, but worth the gain in patient benefits and survival rate. New therapeutic possibilities that directly attack and neutralize autoantibodies in vivo are being tested. Methods such as intravenous IgG treatment, B-cell depletion and aptamer-based neutralization of GPCRs might offer more therapy options for DCM patients in the future.

GENETIC FEATURES Because of the possible autoimmune origin of myocarditis and DCM in humans, and the well-documented association of experimental myocarditis with the major histocompatibility complex (MHC) in mice (Rose et al., 1988), a number of studies to determine the relationship with the human MHC (HLA) have been carried out. Anderson et al. (1984) reported that DCM patients had an increased frequency of HLA-DR4 and a decreased frequency of HLA-DR6. These findings were corroborated by Limas et al. (1990), who also demonstrated an increased frequency of HLA-DR4 in DCM patients. A genetic predisposition toward cardiac autoimmunity was demonstrated, in that 72% of HLA-DR4 1 patients had anti-ßl adrenergic receptor antibodies compared with 21% of HLA-DR4 2 patients. In the largest study to date, Carlquist et al. (1991) reconfirmed these findings and also found that the DR4-DQw4 haplotype conferred heightened risk of disease. In a metaanalysis of five studies, they confirmed that the DR4 association with myocarditis was sustained among different patient populations. No differences in disease phenotypes have been reported. The availability of EBMs has allowed genetic studies of CVB3 infection in viral myocarditis in humans. Tschopp et al. (2017) reported that non-obese diabetic 2 (NOD2) , a nucleotide-binding domain, mediates viral uptake and inflammation in the heart.

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ANIMAL MODELS Since enteroviruses are often implicated in human myocarditis and DCM, these agents have been widely used to investigate the pathogenic mechanisms. Although infections by CVB3 are relatively common, the development of clinically significant, ongoing myocardial disease in humans is relatively uncommon, suggesting that differences in host response play a critical role in disease susceptibility. These differences are likely to be genetically determined and may relate to the expression of virus-specific receptor on heart tissue or to the immune response of the host. Because it is difficult to examine the role that genetic polymorphisms play in humans, investigators have developed models of coxsackievirus-induced myocarditis in mice, for which many genetically different, inbred strains are available. A model of the time course of viral myocarditis is illustrated in Fig. 64.5. All strains of mice tested developed acute myocarditis starting 2 or 3 days after CVB3 infection. Viral disease reached its peak on day 7 and gradually resolved so that by day 21 the heart was histologically normal. No infectious virus was found after day 9. In a few strains of mice, however, the myocarditis persisted (Rose et al., 1987; Cihakova and Rose, 2008), but the histologic picture shifted. The first phase was characterized by the focal necrosis of myocytes and accompanying a focal acute inflammatory response with a mixed cell infiltrate consisting of polymorphonuclear and mononuclear cells. In those mice that developed the second phase of disease, the inflammatory process was diffuse rather than focal and consisted mainly of mononuclear interstitial infiltrates, including both T- and B-lymphocytes and little or no myocyte necrosis. In the mice that developed the second phase of disease, heart-reactive autoantibodies were present and shown to be specific for the cardiac isoform of myosin (Neu et al., 1987a). This finding suggested that the second phase represented an autoimmune response initiated by the viral infection. Direct evidence to support this hypothesis was produced by immunizing the susceptible strains of mice with purified cardiac myosin and showing that they developed a very similar histologic picture of myocarditis (Neu et al., 1987b). No heart disease was found in animals immunized in a similar manner with skeletal myosin, and none appeared in the strains of mice that were not genetically susceptible to the second phase of virus-induced myocarditis. Further evidence that the disease was due to an immune response to cardiac myosin was assembled by inducing specific tolerance to cardiac myosin (Wang et al., 2000; Fousteri et al., 2011). The finding first suggested that the second phase represents an autoimmune response initiated by molecular mimicry between viral and heart antigens (Cunningham et al., 2004). Other evidence showed that the autoimmune response depends upon virus-induced damage to the heart. (Horwitz et al., 2000) found that transgenic mice expressing interferon gamma (IFN-γ) in their pancreatic cells failed to produce CVB3-induced myocarditis, even though the virus proliferated greatly in other sites. The virus infection may serve as an adjuvant for cardiac antigens that have been expressed or liberated during the viral infection of the heart (Rose, 2000). Other viruses unrelated to coxsackieviruses such as cytomegalovirus produce a similar autoimmune myocarditis following infection. The experiments showing that myocarditis can be produced by immunization with cardiac myosin in animals with no viral infection establish that the disease does not depend upon persisting virus even though it is possible to demonstrate traces of viral RNA. FIGURE 64.5 Schematic of the pathogenesis of viral myocarditis.

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Unless subjected to exercise stress, most mice survived autoimmune myocarditis whether induced by virus infection or by immunization with cardiac myosin. Gradually the disease waned in severity (Cihakova and Rose, 2008; Rose and Hill, 1996). In some mice, however, the histologic picture changed to produce a mainly fibrotic disease. As the process continued, there was a thinning of the ventricular cell walls and a large increase in size of the left ventricle. By day 35, after infection or immunization, there were definite signs of cardiac insufficiency and by day 60, most of the animals died of heart failure. This form of the disease, whether induced by viral infection or myosin autoimmunity, replicated the major characteristics of DCM, suggesting that DCM can represent an end stage of autoimmune myocarditis. A striking finding in the investigations described above was that strains of mice highly susceptible to the autoimmune myocarditis following viral infection were susceptible to the myosin-induced disease. Other strains were resistant to both forms of myocarditis. These observations indicated that the susceptibility to autoimmune myocarditis was under a large measure of genetic control. As in most autoimmune diseases, genes of the MHC have an important influence on the development and course of autoimmune disease (Li et al., 2008a). In both the viral and myosin-induced models the H-2s, H-2a, and H-2b alleles were associated with increased morbidity of autoimmune myocarditis, whereas other H-2 alleles were associated with low susceptibility. The genetic findings in the mouse can be related to human myocarditis through experiments by Hayward et al. (2006) and Taneja and David (2009), who demonstrated a spontaneous myocarditis model in NOD mice carrying the transgenically introduced human HLA-DQ8 allele associated with greater susceptibility to human DCM. Like most autoimmune diseases, non-MHC genes play a determining role in susceptibility to myocarditis. Genome-wide linkage analysis revealed at least two prominent loci that had significant effects on susceptibility to autoimmune myocarditis. A putative susceptibility gene, eam1, was located on the proximal end of chromosome 1 and eam2 on the distal region of chromosome 6 (Guler et al., 2005; Li et al., 2008b). Both chromosomal segments bore genes determining susceptibility to a number of other autoimmune diseases such as autoimmune encephalomyelitis and autoimmune arthritis as well as spontaneous diabetes. In addition to lending themselves to genetic studies the experimental models of autoimmune myocarditis provide the opportunity of following the inflammatory process from the beginning to the end (Rose, 2011). The first major question to be considered was the basis of the susceptibility to autoimmune myocarditis following the virus infection. Studies show that two critical cytokines, IL-1β and TNF-α, were both necessary and sufficient for the progression from viral myocarditis to autoimmune myocarditis (Lane 1992). Blocking either one of these two cytokines prevented the transition from viral to autoimmune myocarditis. Even more significant was the demonstration that providing either of these two cytokines in recombinant form to genetically resistant mice caused them to develop the autoimmune myocarditis. Early signs of susceptibility to autoimmune myocarditis become evident early in the course of viral infection. Significantly, the elevations of IL-1β were found as early as 8 hours after viral infection (Fairweather et al., 2004a; Fairweather et al., 2004b). The innate immune response to the virus determined later susceptibility to autoimmune disease. Adoptive transfer experiments using myosin or myosin peptide induced disease have shown that the induction of autoimmune myocarditis depends upon myosinspecific CD4 T-cells (Smith and Allen, 1991; Chen et al., 2012; Li et al., 2008b). The course of the inflammation during autoimmune myocarditis can be traced to the relative proportions of certain key cytokines emanating from different CD4 T-cell families. Differing forms of autoimmune myocarditis are associated with greater production of IL-12p35 P40 (a Th1 signal), IL-4 (a Th2 signal), and IL-23p19p40 (a signal of the Th17 response) (Rose, 2011). For example, IFN-γ, a signature of Th1 responses, retards the development of myocarditis, and its deficiency produces a particularly severe form lymphocytic disease. A rapidly developing, fatal form of eosinophilic myocarditis occurs in the absence of both IFN-γ and IL-17A (Barin et al.,2013). These findings are striking examples of the cytokine “interactome”; they further suggest that a balance of cytokines affects not only the severity but the profile of inflammation. IL-4 promotes a particularly severe form of giant-cell myocarditis in mice, and eosinophil-derived IL-4 drives progression of myocarditis to DCM (Diny et al., 2017). IL-17A, a cytokine associated with neutrophilic inflammation, has little impact on the severity of overall inflammation in the myosin-induced autoimmune disease. It is, however, critical for the later progression to DCM; animals deprived of IL-17A fail to develop postmyocarditis cardiac remodeling and the subsequent fibrotic disease (Baldeviano et al., 2010). The disease can be prevented by administering antibody to IL-17A earlier during inflammation. This key role of IL-17 may be related to its established ability to increase granulocyte proliferation as well as to activate macrophages. Wu et al. (2014) found that IL-17A stimulates cardiac fibroblasts to produce GM-CSF, which, in turns, stimulates both leukocytes and Ly6Chigh-bearing monocytes/macrophages. Similar studies in humans supported the rationale for targeting Th-17-related cytokines for the treatment of DCM (Myers et al., 2016). An issue critical to understanding the pathogenesis of autoimmune myocarditis is the dynamic

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balance of mediators tending to favor inflammation and cardiomyocyte injury with mediators that reduce or retard inflammation. As mentioned previously, other cardiac-specific antigens can induce autoimmune myocarditis. Goser et al. (2006) demonstrated the provocation of an autoimmune response to cardiac troponin I, which induces severe inflammation in the myocardium of mice followed by fibrosis and heart failure, with marked mortality. These investigators identified two sequence motifs of cardiac troponin I that induced inflammation and fibrosis in the myocardium (Kaya et al., 2008). Interestingly, these same animals eventually developed immunity to cardiac myosin following at least 90 days of inflammation. Thus autoimmune myocarditis, like most autoimmune diseases, is characterized by the production of multiple organ specific autoantibodies.

PERSPECTIVES When the first edition of “The Autoimmune Diseases” was published in 1985, research on the inflammatory cardiopathologies was taking on new life. Cardiac transplantation and EBM focused greater attention on the details of histopathology of the heart muscle and years of study of cardiotropic coxsackievirus melded into an opportunity to appraise a recurrent question in the investigations of many autoimmune diseases: how could a viral infection trigger an autoimmune disorder? Myocarditis has proven to be an accessible model for studying the question. The disease can be reasonably replicated in the mouse with the candidate virus, and viral peptides were defined that tracked the course of virus-induced myocarditis. The door was opened to trace the inflammatory process with respect to both cellular composition and mediator balance from imitation of the immune response to heart failure. Together, these studies are leading to promise of earlier diagnosis and more specific therapies. The lessons learned may well be applied to other immune-mediated disorders.

Acknowledgments The figures were prepared by Dr. Marc Halushka and Dr. Jobert Barin, Department of Pathology, Johns Hopkins University.

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Further Reading Ciha´kova´, D., Sharma, R.B., Fairweather, D., Afanasyeva, M., Rose, N.R., 2004. Animal models for autoimmune myocarditis and autoimmune thyroiditis. Methods Mol. Med. 102, 175 193. Do¨rffel, W.V., Wallukat, G., Do¨rffel, Y., Felix, S.B., Baumann, G., 2004. Immunoadsorption in idiopathic dilated cardiomyopathy, a 3-year follow-up. Int. J. Cardiol. 97, 529 534. Fu, M.L., Hoebeke, J., Matsui, S., Matoba, M., Magnusson, Y., Hedner, T., et al., 1994. Autoantibodies against cardiac G-protein-coupled receptors define different populations with cardiomyopathies but not with hypertension. Clin. Immunol. Immunopathol. 72, 15 20. Krejci, J., Mlejnek, D., Sochorova, D., Nemec, P., 2016. Inflammatory cardiomyopathy: a current view on the pathophysiology, diagnosis, and treatment. BioMed. Res. Int. Available from: https://doi.org/10.1155/2016/4087632Article ID 4087632, 11 pages, 2016. Lipshultz, S., Sleeper, L., Towbin, J., et al., 2003. The incidence of pediatric cardiomyopathy in two regions of the United States. N. Engl. J. Med. 348, 1647. Matsumoto, Y., Park, I.K., Kohyama, K., 2007. B-cell epitope spreading is a critical step for the switch from C-protein-induced myocarditis to dilated cardiomyopathy. Am. J. Pathol. 170, 43 51. Mu¨ller, A.M., Bockstahler, M., Hristov, G., Weiß, C., Fischer, A., Korkmaz-Ico¨z, S., et al., 2016a. Identification of novel antigens contributing to autoimmunity in cardiovascular diseases. Clin. Immunol. 173, 64 75. Xiao, J., Shimada, M., Liu, W., Hu, D., Matsumori, A., 2009. Anti-inflammatory effects of eplerenone on viral myocarditis. Eur. J. Heart Fail. 11 (4), 349 353.

VII. ORGAN SPECIFIC AUTOIMMUNE DISEASES