**1. Introduction**

364 Myocarditis

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S, Sadoshima J, Beuve A, Simmons WJ, Li H. Thioredoxin 1-Mediated Post-Translational Modifications: Reduction, Transnitrosylation, Denitrosylation and Myocarditis is defined as a disease characterized by myocardial inflammation associated with myocyte necrosis. It can be caused by infections, autoimmune response primarily affecting the myocardium or by systemic autoimmune or inflammatory disorders (Aretz et al., 1986). Viral infections are the most frequent cause and account for the vast majority of cases in North America and Europe (Cooper, 2009).

Cardiac symptoms that develop during myocarditis may follow after a delay of days to weeks from the beginning of the pathological process; they are quite unspecific and include fatigue, dyspnoea, palpitations, malaise and atypical chest discomfort. Even the clinical cardiac signs may be vague in many patients and generally include cardiac murmurs, gallop rhythms and other signs of heart failure and sometimes pericardial rubs when the pericardium is also involved in the inflammatory process. Myocarditis is often associated with various types of ECG abnormalities (including bundle branch blocks, Q waves resembling those related to myocardial infarction, repolarization abnormalities and QRS prolongation) and rhythm disturbance such as atrio-ventricular blocks, supraventricular tachycardias and ventricular ectopies and tachycardias. Echocardiography may reveal overt systolic dysfunction or a reduction of peak systolic velocities at TDI; moreover, regional wall motion abnormalities and diastolic dysfunction may be found (Cooper, 2009; Feldman et al. 2000). Therefore, this disease should always be considered in patients who present with rapidly progressive cardiomyopathy, chest pain with ECG anomalies that mimic an acute coronary syndrome but with normal coronary arteries or idiopathic ventricular arrhythmias. Furthermore, in young people myocarditis may be frequently responsible for sudden cardiac death, particularly after strenuous physical exertion (Doolan et al., 2004; Corrado D et al. 2001). With this regard it should be highlighted that the recognition of myocarditis in patients presenting with aborted sudden death or major ventricular arrhythmias is actually challenging in everyday clinical practice, as the diagnosis may be difficult and may require the use of invasive procedures. Nevertheless, the detection of myocarditis in patients presenting with ventricular arrhythmias may have a pivotal importance, because the

Myocarditis Presenting with Ventricular Arrhythmias:

Role of Electroanatomical Mapping-Guided Endomyocardial Biopsy in Differential Diagnosis 367

and cardiac structural abnormalities (Theleman et al., 2001; Friedman et al., 1994). Subtle abnormalities not detectable by first-line examinations such as echocardiography may be present in patients with myocarditis presenting with ventricular arrhythmias. Other imaging modalities such as cardiac magnetic resonance (CMR) and even ventricular angiography are generally needed to detect these abnormalities. In a study published in 2001 we found small aneurysms at ventricular angiography in patients with apparently idiopathic major ventricular arrhythmias; it should be underlined that all the patients enrolled in this study were also submitted to CMR that failed to detect microaneurysms in most patients (It is possible that currently used cine-sequences for functional analysis of both ventricles may enhance the diagnostic performance of CMR even in this setting). Histological examination of myocardial samples drawn from areas surrounding the aneurysms revealed the presence of active lymphocytic myocarditis with intense myocytolisis. Notably, no patient suffered from cardiac sudden death or malignant ventricular arrhythmias during a 1-year follow-up and sequential Holter recording showed progressive reduction of the arrhythmic burden. Furthermore neither heart failure episodes nor decrease of LV function were reported in the study population (Chimenti et al., 2001). Under this respect it should be noticed that inflammatory microaneurysms were also found in experimental animal models of myocarditis, namely in hamster and mice which survived to acute viral myocarditis, and they seem to cause electroanatomical abnormalities that are associated with development of severe ventricular arrhythmias; interestingly, in the inoculated animals the prognosis associated with the development of microaneurysms in the setting of experimental viral myocarditis was good with a survival similar to normal

animals who had no aneurysms (Hoschino et al., 1984; Matsumori et al 1983).

Myocarditis may selectively affect the right ventricle causing structural abnormalities, including microaneurysms, and arrhythmic manifestations typical of arrhythmogenic right ventricular cardiomyopathy. In fact myocardial inflammatory infiltrates associated with myocyte necrosis and replacement fibrosis, may lead to functional and structural changes of right ventricular myocardium resembling those produced by fibrofatty replacement, and representing the substrate of abnormal voltage map and ventricular arrhythmias (Hoffmann et al, 1993; Pieroni et al., 2009). Namely, our group demonstrated that biopsy-proven myocarditis is present in up to 50% of patients fulfilling current diagnostic criteria of arrhythmogenic right ventricular cardiomyopathy at non-invasive evaluation (including cardiac magnetic resonance), moreover myocarditis was associated to the presence of lowvoltage areas, as detected by 3D electro-anatomic mapping (Pieroni et al., 2009). Consistently it has been recently reported that also right ventricular sarcoidosis may mimic electroanatomic mapping features and arrhythmic presentation of arrhythmogenic right ventricular cardiomyopathy (Ott et al., 2003; Koplan et al. 2006; Vaisawala et al., 2009). Myocarditis represents a frequent cause of ventricular arrhythmias also in competitive athletes and its recognition and differential diagnosis with other cardiomyopathies with different prognosis may have important implications for sport eligibility (Basso C et al., 2007). In fact, a recent study by our group demonstrated the presence of myocarditis, diagnosed by endomyocardial biopsy, in most elite athletes presenting with major arrhythmias and apparently normal heart. Moreover it should be emphasized that according to current diagnostic recommendations (the 2nd consensus document on Brugada Syndrome underlined the need to exclude other pathological conditions), the presence of a myocarditis should be always excluded in patients with electrocardiographic features leading to the diagnosis of Brugada syndrome. Among the pathologic conditions that can lead to a

identification of myocarditis as the substrate of arrhythmias is actually important for targeting therapies.

In the last decades the development of new diagnostic techniques, in particular cardiac magnetic resonance, has led to an increased recognition of myocarditis as a cause of ventricular arrhythmias. However endomyocardial biopsy still represents the gold standard for the diagnosis of myocarditis. The main criticism against a wider use of endomyocardial biopsy in the diagnostic approach to patients with ventricular arrhythmias is represented by the possible sampling error in the presence of a focal myocarditis. We recently demonstrated that three dimensional electroanatomical mapping (3D-EAM) may guide endomyocardial biopsy identifying the segments of ventricular wall presenting an abnormal voltage, thus reducing sampling error and increasing sensitivity of biopsy. The systematic association of endomyocardial biopsy with electroanatomical mapping represents a significant improvement of the diagnostic tools available to identify the substrate of ventricular arrhythmias.

In this chapter we describe the role of electroanatomical mapping-guided endomyocardial biopsy in the differential diagnosis of myocardial pathological substrates in patients with ventricular arrhythmias. We report the results of our group and other groups adopting this technique in different categories of patients, including subjects with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC), competitive athletes and patients with electrocardiographic diagnosis of Brugada syndrome.
