**2. Myocarditis and ventricular arrhythmias**

Endomyocardial biopsy and autopsy findings have clearly demonstrated that myocarditis represents a frequent cause of life-threatening ventricular arrhythmias and sudden death. Post-mortem studies suggest that myocarditis is a major cause of sudden, unexpected death in adults less than 40 years of age (accounting for approximately 20% of cases - Fabre & Sheppard, 2006; Doolan et al., 2004). Indeed myocarditis may frequently cause ventricular arrhythmias associated with systolic dysfunction of left or right ventricle or both. In both its acute and chronic phase myocarditis may be associated with severe arrhythmias that can significantly affect the natural course of the disease, as they can further contribute to the deterioration of cardiac systolic and diastolic function and can be the ultimate cause of death in these patients (Magnani et al. 2006; Zeppenfeld et al. 2007; Graner et al, 2007). Mechanisms of arrhythmogenesis in the context of myocarditis include myocyte necrosis, replacement fibrosis (favoring re-entry mechanism), proarrhythmic effects of cytokines and inflammatory mediators possibly through a modulation of ion channel function.

In patients with chronic active myocarditis, the perpetuation of inflammation is often related to viral persistence or to autoimmune self-maintaining mechanisms, and replacement fibrosis seems to represent a major arrhythmogenic substrate in this case, together with the permanence of an inflammatory milieu surrounding myocardiocytes. Moreover it has been demonstrated that enteroviral persistence perpetrates myocardial damage even in the absence of overt myocardial inflammation, through the release of proteases capable of cleaving dystrophin (Andreoletti et al., 2007). This in turns causes cytoskeleletal anomalies that can affect myocyte mechanical and even electric properties and finally lead to myocyte death, possibly contributing to arrhythmogenesis.

Myocarditis may be the cause of ventricular arrhythmias even in subjects with no previous symptoms or presenting with an apparently normal heart or minimal electrocardiographic

identification of myocarditis as the substrate of arrhythmias is actually important for

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

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

Endomyocardial biopsy and autopsy findings have clearly demonstrated that myocarditis represents a frequent cause of life-threatening ventricular arrhythmias and sudden death. Post-mortem studies suggest that myocarditis is a major cause of sudden, unexpected death in adults less than 40 years of age (accounting for approximately 20% of cases - Fabre & Sheppard, 2006; Doolan et al., 2004). Indeed myocarditis may frequently cause ventricular arrhythmias associated with systolic dysfunction of left or right ventricle or both. In both its acute and chronic phase myocarditis may be associated with severe arrhythmias that can significantly affect the natural course of the disease, as they can further contribute to the deterioration of cardiac systolic and diastolic function and can be the ultimate cause of death in these patients (Magnani et al. 2006; Zeppenfeld et al. 2007; Graner et al, 2007). Mechanisms of arrhythmogenesis in the context of myocarditis include myocyte necrosis, replacement fibrosis (favoring re-entry mechanism), proarrhythmic effects of cytokines and

inflammatory mediators possibly through a modulation of ion channel function.

finally lead to myocyte death, possibly contributing to arrhythmogenesis.

In patients with chronic active myocarditis, the perpetuation of inflammation is often related to viral persistence or to autoimmune self-maintaining mechanisms, and replacement fibrosis seems to represent a major arrhythmogenic substrate in this case, together with the permanence of an inflammatory milieu surrounding myocardiocytes. Moreover it has been demonstrated that enteroviral persistence perpetrates myocardial damage even in the absence of overt myocardial inflammation, through the release of proteases capable of cleaving dystrophin (Andreoletti et al., 2007). This in turns causes cytoskeleletal anomalies that can affect myocyte mechanical and even electric properties and

Myocarditis may be the cause of ventricular arrhythmias even in subjects with no previous symptoms or presenting with an apparently normal heart or minimal electrocardiographic

patients with electrocardiographic diagnosis of Brugada syndrome.

**2. Myocarditis and ventricular arrhythmias** 

targeting therapies.

arrhythmias.

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

Myocarditis Presenting with Ventricular Arrhythmias:

subclinical disorders that may cause sudden death (UCARE, 1997).

of an active myocarditis may represent a further arrhythmic trigger.

cardiomyopathy.

**2.1.1 Myocarditis and genetically determined arrhythmic syndromes** 

It should be also emphasized that myocarditis is a cause of sudden arrhythmic death even in competitive athletes, more frequently exposed to viral infections of upper airways. With this regard it has been claimed but never conclusively demonstrated that exercise in the context

In the last decades several studies suggested a role for myocardial inflammation in the pathogenesis of different genetically determined arrhythmic syndromes and cardiomyopathies. In the presence of gene mutations leading to abnormal structure and/or function of structural and functional proteins, myocardial inflammation may act as a mechanism of myocardial damage, amplificating the dysfunction related to the genetic abnormalities, or rather as trigger of specific clinical manifestations, such as arrhythmias, occurring later in the natural history of the disease. Myocardial inflammation has been observed in necropsy and endomyocardial biopsy studies in genetically determined myocardial disorders, including ARVC, Brugada syndrome and hypertrophic

In ARVC myocardial inflammation may be seen in up to 75% of hearts at autopsy, and probably it plays a role in triggering ventricular tachyarrhythmias (Thiene et al., 2001). Nobody knows whether inflammation is a reactive phenomenon to cell death, or whether it

Role of Electroanatomical Mapping-Guided Endomyocardial Biopsy in Differential Diagnosis 369

In a study performed in our Institution in 1994 seventeen young patients (10 males and 7 females, aged 14 to 38 years, mean 26.4) without overt organic heart disease, who had been resuscitated from sudden cardiac arrest were submitted to noninvasive (electrocardiography, 2D-echocardiography, and magnetic resonance imaging) and invasive (coronary angiography with ergonovine testing, electrophysiologic study and biventricular angiography and endomyocardial biopsy) cardiac studies. Six to 8 biopsy fragments per patient were processed for histology and electron microscopy and read by a pathologist blinded to clinical data. Two groups of patients were distinguished by invasive and noninvasive examinations: Group 1 consisted of 9 patients with entirely normal parameters; Group 2 consisted of 8 patients with structural, nonspecific cardiac abnormalities. In this latter group, mild to moderate dilatation and hypokinesia of the left ventricle were documented in 4 patients, concentric left ventricular hypertrophy was seen in three patients, and RV dysfunction was noted in 1 patient. Histologic examination was abnormal in all patients and revealed specific lesions in 65% of them; in particular an active myocarditis was diagnosed in 6 out of 9 patients in the Group 1. In these 6 patients immunosuppressive therapy (steroids plus azathioprine) administered on top of conventional antiarrhthmic treatment led to dispappearance of ventricular arrhythmias and healing of myocardial inflammation at follow-up endomyocardial biopsies (Frustaci et al., 1994) Similarly in a study from the Padua group in a series of 273 sudden cardiac deaths victims, 76 cases (28%) presented a macroscopically normal heart: of these 60 (79%) had abnormal histology with a 36% of cases of active myocarditis (Corrado et al., 2001). These data suggest that myocarditis represents an important, frequently unrecognized and underestimated, cause of sudden arrhythmic death. Moreover these studies dramatically demonstrate that sudden arrhythmic death may represent the very first clinical manifestation of myocarditis. Accordingly the consensus document based on the two main registries on sudden arrhythmic death (the UCARE, Unexplained Cardiac Arrest Registry of Europe and the IVF-US, Idiopathic Ventricular Fibrillation Registry of United States) includes myocarditis among the

Brugada-like phenotype, myocarditis of the right ventricle is one of the most frequently found when patients with Brugada syndrome are submitted to an extensive invasive and non-invasive evaluation (Frustaci et al., 2005; Okubo et al., 2010). In facts, a study on 18 patients with Brugada Syndrome (diagnosed according to the consensus criteria) presenting with sustained ventricular arrhythmias or syncope, revealed the presence of biopsy-proven myocarditis in most patients (Frustaci el al., 2005). The complex links between myocarditis and genetically determined arrhythmic disorders is further discussed below in this chapter. Various studies on experimental animal models contributed to demonstrate that both autoimmune and viral myocarditis may cause major ventricular arrhythmia. Studies on murine models of myocarditis demonstrated that persistence of inflammation after the acute phase is associated with electrical abnormalities associated with ventricular arrhythmias; interestingly, a close correlation between the location of inflammatory burden (associated with myocyte necrosis), the reported electric abnormalities and the site of origin of arrhythmias was found (Kishimoto et al., 1983; Hoshino et al., 1982;). The major mechanisms involved in the genesis of arrhythmias seems to be the formation of micro-reentry circuits, favored by myocyte injury and replacement fibrosis, and triggered activity mainly due to the pro-arrhythmic effects of cytokines. Moreover it was reported that the environment surrounding myocytes could influence the electrophysiological properties of the myocardium, this phenomenon is known as electrical remodeling. As previously pointed out the inflammatory process of the myocardium may itself be arrhythmogenic, nonetheless the change in the electrophysiological properties of the myocardiocytes seems also play a role in causing the arrhythmias. Changes in expression of surface ion channels, as assessed by quantitative determination of mRNA expression, have been demonstrated in animal experimental models of both viral and autoimmune myocarditis; these changes, affecting mainly potassium and calcium channels, causes modification of the ventricular effective refractory period, which appear to be longer in myocarditis, an increase in monofasic action potential duration of the ventricular myocardium and an augment of ventricular vulnerability that ultimately favors the genesis of ventricular arrhythmias (Saito et al., 2006). Interestingly, some data suggests that these changes may be transient and can reverse after the healing of the inflammatory process. Altogether, these data further support the hypothesis that active inflammation represents a major substrate of ventricular arrhythmias and suggests that pro-arrhythmic changes of myocardial electrical properties caused by the inflammation might be, completely or partially, reversed after the healing of the inflammatory process.

#### **2.1 Myocarditis and sudden arrhythmic death**

In the last decades myocarditis has emerged as an important cause of sudden arrhythmic death also in patients with a structurally and functionally normal heart. The most striking evidence that myocarditis may be the substrate of sudden arrhythmic death is represented by a study on Air Force recruits victims of cardiac sudden death in which myocarditis was recognized as the cause of death in 40% of cases (Phillips et al., 1986)

Although no data on cardiac function before death were available in the study, the percentage of cases in which myocarditis was observed at necropsy studies indicates the high arrhythmic risk related to myocarditis. In more recent studies the percentage of myocarditis detected at necropsy in subjects with sudden arrhythmic death and an apparently normal heart ranged from 5 to 12% (Doolan et al., 2004; Thelemann et al., 2001).

Brugada-like phenotype, myocarditis of the right ventricle is one of the most frequently found when patients with Brugada syndrome are submitted to an extensive invasive and non-invasive evaluation (Frustaci et al., 2005; Okubo et al., 2010). In facts, a study on 18 patients with Brugada Syndrome (diagnosed according to the consensus criteria) presenting with sustained ventricular arrhythmias or syncope, revealed the presence of biopsy-proven myocarditis in most patients (Frustaci el al., 2005). The complex links between myocarditis and genetically determined arrhythmic disorders is further discussed below in this chapter. Various studies on experimental animal models contributed to demonstrate that both autoimmune and viral myocarditis may cause major ventricular arrhythmia. Studies on murine models of myocarditis demonstrated that persistence of inflammation after the acute phase is associated with electrical abnormalities associated with ventricular arrhythmias; interestingly, a close correlation between the location of inflammatory burden (associated with myocyte necrosis), the reported electric abnormalities and the site of origin of arrhythmias was found (Kishimoto et al., 1983; Hoshino et al., 1982;). The major mechanisms involved in the genesis of arrhythmias seems to be the formation of micro-reentry circuits, favored by myocyte injury and replacement fibrosis, and triggered activity mainly due to the pro-arrhythmic effects of cytokines. Moreover it was reported that the environment surrounding myocytes could influence the electrophysiological properties of the myocardium, this phenomenon is known as electrical remodeling. As previously pointed out the inflammatory process of the myocardium may itself be arrhythmogenic, nonetheless the change in the electrophysiological properties of the myocardiocytes seems also play a role in causing the arrhythmias. Changes in expression of surface ion channels, as assessed by quantitative determination of mRNA expression, have been demonstrated in animal experimental models of both viral and autoimmune myocarditis; these changes, affecting mainly potassium and calcium channels, causes modification of the ventricular effective refractory period, which appear to be longer in myocarditis, an increase in monofasic action potential duration of the ventricular myocardium and an augment of ventricular vulnerability that ultimately favors the genesis of ventricular arrhythmias (Saito et al., 2006). Interestingly, some data suggests that these changes may be transient and can reverse after the healing of the inflammatory process. Altogether, these data further support the hypothesis that active inflammation represents a major substrate of ventricular arrhythmias and suggests that pro-arrhythmic changes of myocardial electrical properties caused by the inflammation might be, completely or partially, reversed after the healing of the

In the last decades myocarditis has emerged as an important cause of sudden arrhythmic death also in patients with a structurally and functionally normal heart. The most striking evidence that myocarditis may be the substrate of sudden arrhythmic death is represented by a study on Air Force recruits victims of cardiac sudden death in which myocarditis was

Although no data on cardiac function before death were available in the study, the percentage of cases in which myocarditis was observed at necropsy studies indicates the high arrhythmic risk related to myocarditis. In more recent studies the percentage of myocarditis detected at necropsy in subjects with sudden arrhythmic death and an apparently normal heart ranged from 5 to 12% (Doolan et al., 2004; Thelemann et al., 2001).

inflammatory process.

**2.1 Myocarditis and sudden arrhythmic death** 

recognized as the cause of death in 40% of cases (Phillips et al., 1986)

In a study performed in our Institution in 1994 seventeen young patients (10 males and 7 females, aged 14 to 38 years, mean 26.4) without overt organic heart disease, who had been resuscitated from sudden cardiac arrest were submitted to noninvasive (electrocardiography, 2D-echocardiography, and magnetic resonance imaging) and invasive (coronary angiography with ergonovine testing, electrophysiologic study and biventricular angiography and endomyocardial biopsy) cardiac studies. Six to 8 biopsy fragments per patient were processed for histology and electron microscopy and read by a pathologist blinded to clinical data. Two groups of patients were distinguished by invasive and noninvasive examinations: Group 1 consisted of 9 patients with entirely normal parameters; Group 2 consisted of 8 patients with structural, nonspecific cardiac abnormalities. In this latter group, mild to moderate dilatation and hypokinesia of the left ventricle were documented in 4 patients, concentric left ventricular hypertrophy was seen in three patients, and RV dysfunction was noted in 1 patient. Histologic examination was abnormal in all patients and revealed specific lesions in 65% of them; in particular an active myocarditis was diagnosed in 6 out of 9 patients in the Group 1. In these 6 patients immunosuppressive therapy (steroids plus azathioprine) administered on top of conventional antiarrhthmic treatment led to dispappearance of ventricular arrhythmias and healing of myocardial inflammation at follow-up endomyocardial biopsies (Frustaci et al., 1994) Similarly in a study from the Padua group in a series of 273 sudden cardiac deaths victims, 76 cases (28%) presented a macroscopically normal heart: of these 60 (79%) had abnormal histology with a 36% of cases of active myocarditis (Corrado et al., 2001). These data suggest that myocarditis represents an important, frequently unrecognized and underestimated, cause of sudden arrhythmic death. Moreover these studies dramatically demonstrate that sudden arrhythmic death may represent the very first clinical manifestation of myocarditis. Accordingly the consensus document based on the two main registries on sudden arrhythmic death (the UCARE, Unexplained Cardiac Arrest Registry of Europe and the IVF-US, Idiopathic Ventricular Fibrillation Registry of United States) includes myocarditis among the subclinical disorders that may cause sudden death (UCARE, 1997).

It should be also emphasized that myocarditis is a cause of sudden arrhythmic death even in competitive athletes, more frequently exposed to viral infections of upper airways. With this regard it has been claimed but never conclusively demonstrated that exercise in the context of an active myocarditis may represent a further arrhythmic trigger.

## **2.1.1 Myocarditis and genetically determined arrhythmic syndromes**

In the last decades several studies suggested a role for myocardial inflammation in the pathogenesis of different genetically determined arrhythmic syndromes and cardiomyopathies. In the presence of gene mutations leading to abnormal structure and/or function of structural and functional proteins, myocardial inflammation may act as a mechanism of myocardial damage, amplificating the dysfunction related to the genetic abnormalities, or rather as trigger of specific clinical manifestations, such as arrhythmias, occurring later in the natural history of the disease. Myocardial inflammation has been observed in necropsy and endomyocardial biopsy studies in genetically determined myocardial disorders, including ARVC, Brugada syndrome and hypertrophic cardiomyopathy.

In ARVC myocardial inflammation may be seen in up to 75% of hearts at autopsy, and probably it plays a role in triggering ventricular tachyarrhythmias (Thiene et al., 2001). Nobody knows whether inflammation is a reactive phenomenon to cell death, or whether it

Myocarditis Presenting with Ventricular Arrhythmias:

**3.1 Cardiac magnetic resonance** 

hyperemia) (Figure 1).

Role of Electroanatomical Mapping-Guided Endomyocardial Biopsy in Differential Diagnosis 371

Cardiac Magnetic resonance offers a combination of clarity of anatomical visualization, interobserver consistency and quantitative accuracy, even when evaluating the right ventricle, which enables to overcome the major pitfalls of echocardiography. Furthermore it is characterized by the unique feature of providing some degree of tissue characterization, thus allowing to obtain non-invasively information about the presence of necrosis, fibrosis and edema. Nonetheless CMR has some limitations due to the technical difficulty in obtaining good images in patients with arrhythmias that cause high variability of cardiac cycle length and also due to safety issues related to the presence of cardiac rhythm devices. Recently a panel of international experts on CMR has published a white paper in which imaging protocols and diagnostic criteria are defined that should be used in the setting of myocarditis. According to this consensus (Friedrich et al., 2009), a diagnosis of myocarditis can be set when at least two of the following features are present: one area of non-ischemic (i.e. sparing of sub-endocardial layers of the myocardium and/or distribution of areas not consistent with coronary perfusion territories) late gadolinium enhancement (consistent with myocyte injury and scarring), global or regional signal increase in T2-weighted images (indicative of tissue oedema) and global early gadolinium enhancement (consistent with

Fig. 1. Diagnosis of myocarditis through CMR in a patient with sustained ventricular arrhythmias. Evidence of spotty areas of sub-epicardial and midwall late enhancement (non-

ischemic pattern) in the lateral wall (A), associated with areas of edema (high signal intensity on T2-weighted images) in the same location (B). The presence of both late enhancement and edema fulfils the criteria proposed by the consensus document.

In many studies CMR has demonstrated to be useful for the assessment of the presence of pathological substrates underlying ventricular arrhythmias. Its use allowed to detect the presence of structural cardiomyopathies including myocarditis (Ordovas et al. 2008) in up to 30% of patients. Clinical studies specifically addressing the diagnostic yield of CMR in the

is the consequence of an infection or immune mechanism. Viruses have been detected in the myocardium of some ARVC patients and have been claimed to support an infective etiology of the disease (Bowles et al., 2002). Others say that the viruses are innocent bystanders or that spontaneous cell degeneration may serve as a milieu favoring viral settlement in the myocardium (Calabrese et al., 2006). In addition we and others demonstrated that myocarditis may present with clinical and arrhythmic features and structural right ventricular abnormalities resemblig those observed in ARVC. (Chimenti et al., 2004; Pieroni et al., 2009).

With regard to Brugada syndrome we studied 18 consecutive patients with clinical phenotype of Brugada syndrome and normal cardiac structure and function on noninvasive examinations. Clinical presentation was ventricular fibrillation in 7 patients, sustained polymorphic ventricular tachycardia in 7, and syncope in 4. All patients underwent cardiac catheterization, coronary and ventricular angiography, biventricular endomyocardial biopsy, and DNA screening of the *SCN5A* gene. Biopsy samples were processed for histology, electron microscopy, and molecular screening for viral genomes. In 14 patients histology showed a prevalent or localized right ventricular myocarditis, arrhythmogenic right ventricular cardiomyopathy in 1 patient and cardiomyopathic changes in 3. In the latter 4 patients genetic studies identified *SCN5A* gene mutations causing in vitro abnormal function of mutant proteins. In these patients, myocyte cytoplasm degeneration and a significant increase of apoptotic myocytes in right and left ventricle versus normal controls were observed (Frustaci et al., 2005). This study highlighted the complexities between the clinical manifestations of Brugada syndrome, the presence of *SCN5A* mutations, and the presence of structural heart disease and provided striking new evidence implicating myocarditis in the transient development of Brugada-like ECG abnormalities and arrhythmias.

However it still remains unclear whether myocardial inflammation may be part of the structural changes following an abnormal ion channel function, or rather right ventricular myocarditis may mimic ECG and arrhythmic features of Brugada syndrome. Further studies combining genetic analysis and accurate pathology studies are needed to clarify the complex menage a trois between abnormal gene function (whether affecting desmosomal or ion channel proteins), myocardial inflammation and inherited arrhythmic syndromes.

Myocarditis has been also observed in patients with hypertrophic cardiomyopathy and severe arrhythimic manifestations, suggesting that inflammation may act as a trigger for life-threatening ventricular arrhythmias when affecting a myocardium already prone to electrical instability (Frustaci et al., 2007). Even in this context it is not clear whether myocardial inflammation was the result of a reactive process related to ischemic myocyte necrosis or rather a superimposed autoimmune or viral process.
