**3.1 Cardiac magnetic resonance**

370 Myocarditis

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

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

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

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

channel proteins), myocardial inflammation and inherited arrhythmic syndromes.

**3. The diagnosis of myocarditis in patients with ventricular arrhythmias** 

Myocardial inflammation represents a potent pro-arrhythmic substrate, myocarditis should always be taken into account when facing with ventricular arrhythmias. Furthermore the detection of myocarditis as the pathological substrate underlying ventricular arrhythmias may be crucial as the identification of myocarditis as the etiology of the arrhythmias is actually important for targeting therapies and may have implications even for patients' relatives as discussed below in the chapter. In the last decades the development of new imaging techniques, in particular CMR, led to an increased recognition of myocarditis as a

necrosis or rather a superimposed autoimmune or viral process.

cause of ventricular arrhythmias.

et al., 2009).

arrhythmias.

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 hyperemia) (Figure 1).

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 (nonischemic 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

Myocarditis Presenting with Ventricular Arrhythmias:

(Class of recommendation IIb, Level of evidence C).

implications of diagnosis are certain.

implications of diagnosis are uncertain.

has scientific but no clinical implications.

graded clinical indications according to the following scheme:

Grade 3: there are alternative tools to obtain a definite diagnosis.

ischemic heart disease or overt valvular or myocardial disease.

immunohistochemistry and virology studies are not available.

further in this chapter.

Role of Electroanatomical Mapping-Guided Endomyocardial Biopsy in Differential Diagnosis 373

characterization of the myocardial inflammatory process, the assessment of myocyte

A recent statement from AHA/ACC/ESC (Cooper et al., 2007) aimed to define the role of endomyocardial biopsy in the management of cardiovascular disease, identified 14 clinical scenarios in which the incremental diagnostic, prognostic and therapeutic value of endomyocardial biopsy could be estimated and compared with the procedural risks. According to this statement, in the absence of randomized clinical trials or multicenter studies, endomyocardial biopsy may be considered in the setting of unexplained ventricular arrhythmias (Clinical scenario 13) only in exceptional cases in which the perceived likelihood of meaningful prognostic and therapeutic benefit outweighs the procedural risks

Nevertheless there is growing evidence that endomyocardial biopsy may be crucial to clarify the pathological substrate and therefore the cause of otherwise unexplained ventricular arrhythmias, with a possible impact on both treatment and prognosis as detailed

Accordingly a recent document from the Italian federation of Cardiology (Leone et al., 2009) suggested indications to endomyocardial biopsy different from the above-mentioned statement, in particular with regard to patients with ventricular arrhythmias. The authors

Grade 1: there are no alternative tools to obtain a definite diagnosis and the clinical

Grade 2A: there are no alternative tools to obtain a definite diagnosis and the clinical

Grade 2B: there are no alternative tools to obtain a definite diagnosis but the diagnosis

According to this grading, taking into account the potential diagnostic usefulness of endomyocardial biopsy in different myocardial disorders, the authors identified several clinical scenarios. In the presence of sustained and/or life-threatening ventricular arrhythmias, when a myocarditis is suspected or is a possible diagnosis, the grade of recommendation to perform endomyocardial biopsy is 1. Similarly in the presence of AV blocks associated with a clinical context consistent with a diagnosis of myocarditis, recommendations are Grade 2A and 2B in the presence or in the absence of left ventricular dysfunction respectively. Therefore the Italian Federation of Cardiology document seems to more adequately address the diagnostic and therapeutic issues that are frequently faced by cardiologists in everyday clinical practice when dealing with patients with severe ventricular arrhythmias or atrioventricular conduction disturbances and no evidence of

Both documents do also indicate how many samples are needed in different clinical conditions, how to handle and process myocardial samples, and which studies are necessary to obtain the desired diagnostic information. In the case of clinically suspected myocarditis 5 to 10 samples must be obtained to perform histology and immunohistochemistry studies and molecular bioloy studies to detect the presence of viral genomes. Samples for molecular biology must be flash-frozen in liquid nitrogen and stored at -80°C. Endomyocardial biopsy should better not be performed in patients with clinically suspected myocarditis, if

necrosis and fibrosis as well as the possible detection of viral genomes.

setting of myocarditis presenting with either arrhythmia or heart failure reported a sensitivity and specificity of more then up to 90% (Mahrholdt et al., 2004). Moreover, CMR was able to differentiate active from healing inflammation in patients presenting with chronic myocarditis.

In particular, De Cobelli and colleagues studied patients presenting with chronic myocarditis assessed with EMB and CMR; they found areas of high signal intensity in T2 weighted images in 36% of patients with histological evidence of active myocarditis, but not in patients with borderline myocarditis. They also found areas of late gadolinium enhancement in 84% and 44% of patients with active and borderline myocarditis, respectively. A midwall pattern of late enhancement was a frequent finding in patients with both active myocarditis and borderline myocarditis, whereas a subepicardial pattern was only observed in patients with histological evidence of active myocarditis (De Cobelli et al., 2004). Taken together, these data support the need to include sequences for the detection of myocardial inflammation when CMR is performed in the non-invasive diagnostic work-up of patients presenting with ventricular arrhythmias (Figure 2). In addition CMR represents an important noninvasive tool in the follow-up of patients with a diagnosis of myocarditis.

Fig. 2. CMR findings in a patient with chronic myocarditis presenting with ventricular arrhythmias. ECG shows repetitive polymorphic ventricular ectopic beats (A). CMR shows sub-epicardial late enhancement in the posterior and postero-lateral walls (B) and transmural edema in the same location (C). Histology shows the presence of active myocarditis (D).
