**5. Clinical implications of myocarditis diagnosis in patients with ventricular arrhythmias**

Despite the improvement of diagnostic techniques in defining the characteristics and the etiology of the inflammatory process and the more specific comprehension of the mechanisms leading to myocardial damage, a specific standardized treatment of myocarditis is not yet available. However in the last decades several studies and trials have clearly demonstrated that an etiologic definition of myocarditis based on the immunohistological evaluation of inflammation and proof of viral infection by PCR on biopsies is essential for targeting appropriate treatment strategies indicating that myocarditis patients may benefit from immunosuppression, provided that viral persistence is excluded, while patients with viral persistence fail to respond favourably or deteriorate by immunosuppression.

Several studies have demonstrated the negative prognostic role of viral persistence. In a recent study Kuhl and colleagues analyzed 172 patients with dilated cardiomyopathy and biopsy-proven viral infection in endomyocardial biopsies. The authors reported a high prevalence of enteroviral and parvovirus B19 infection (32.6% and 36.6%, respectively) and found that viral persistence was associated with a progressive impairment of left ventricular ejection fraction, whereas spontaneous viral elimination was associated with a significant improvement in left ventricular function (Kuhl et al., 2005).

Autoimmunity, on the other hand, may play an outstanding role in the progression of myocardial damage and persistence of symptoms, including ventricular arrhythmias. Notably, both acute viral infection and chronic viral persistence can induce autoimmunity by mechanisms not fully elucidated. Molecular mimicry has been suggested as one mechanism to explain chronic myocarditis (Caforio et al., 2002; Rose et al., 2006) and several cellular antigens have been identified to cross-react with viral antigens, thus providing possible targets in virus-induced myocarditis. Autoantibody production also may be caused by the initial myocyte damage by viral infection, releasing increased amounts of selfantigens into the circulation. Autoantibodies against adrenergic and acetylcholine receptors contractile structures, extracellular matrix proteins, proteins involved in energy metabolism, calcium receptors and homeostasis and antistress proteins have all been detected in patients with myocarditis (Neumann et al., 1994; Pankuweit et al., 1997). Furthermore, autoimmunity is considered the main pathogenetic mechanism underlying eosinophilic, giant-cell and granulomatous myocarditis (Cihakova et al., 2008), as well as myocarditis associated with connective tissue diseases, peripartum cardiomyopathy (Ansari et al., 2002) or heart transplant, in which immunosuppression has been proven effective.

considered as a possible therapeutic strategy. In fact there is growing evidence that in patients with ARVC, RFCA is effective in abolishing ventricular tachycardias, but the rate or recurrence of arrhthmias with the same or a different morphology may be very high even when an epicardial approach is adopted (Dalal et al., 2007). On the contrary several reports have demonstrated that RFCA may be effective in eliminating ventricular arrhythmias in myocardial inflammatory disorders, including Chagas cardiomyopathy and sarcoidosis (Sosa et al., 1999; Sarabanda et al., 2005; Jefic et al., 2009; Henz et al., 2009). Recent reports and also our experience suggest that endocardial ablation cannot be sufficient in some patients and a combined endo-epicardial approach is required for definitive results. (See

**5. Clinical implications of myocarditis diagnosis in patients with ventricular** 

Despite the improvement of diagnostic techniques in defining the characteristics and the etiology of the inflammatory process and the more specific comprehension of the mechanisms leading to myocardial damage, a specific standardized treatment of myocarditis is not yet available. However in the last decades several studies and trials have clearly demonstrated that an etiologic definition of myocarditis based on the immunohistological evaluation of inflammation and proof of viral infection by PCR on biopsies is essential for targeting appropriate treatment strategies indicating that myocarditis patients may benefit from immunosuppression, provided that viral persistence is excluded, while patients with viral persistence fail to respond favourably or deteriorate by

Several studies have demonstrated the negative prognostic role of viral persistence. In a recent study Kuhl and colleagues analyzed 172 patients with dilated cardiomyopathy and biopsy-proven viral infection in endomyocardial biopsies. The authors reported a high prevalence of enteroviral and parvovirus B19 infection (32.6% and 36.6%, respectively) and found that viral persistence was associated with a progressive impairment of left ventricular ejection fraction, whereas spontaneous viral elimination was associated with a significant

Autoimmunity, on the other hand, may play an outstanding role in the progression of myocardial damage and persistence of symptoms, including ventricular arrhythmias. Notably, both acute viral infection and chronic viral persistence can induce autoimmunity by mechanisms not fully elucidated. Molecular mimicry has been suggested as one mechanism to explain chronic myocarditis (Caforio et al., 2002; Rose et al., 2006) and several cellular antigens have been identified to cross-react with viral antigens, thus providing possible targets in virus-induced myocarditis. Autoantibody production also may be caused by the initial myocyte damage by viral infection, releasing increased amounts of selfantigens into the circulation. Autoantibodies against adrenergic and acetylcholine receptors contractile structures, extracellular matrix proteins, proteins involved in energy metabolism, calcium receptors and homeostasis and antistress proteins have all been detected in patients with myocarditis (Neumann et al., 1994; Pankuweit et al., 1997). Furthermore, autoimmunity is considered the main pathogenetic mechanism underlying eosinophilic, giant-cell and granulomatous myocarditis (Cihakova et al., 2008), as well as myocarditis associated with connective tissue diseases, peripartum cardiomyopathy (Ansari et al., 2002) or heart

below, Clinical implications of myocarditis diagnosis)

improvement in left ventricular function (Kuhl et al., 2005).

transplant, in which immunosuppression has been proven effective.

**arrhythmias** 

immunosuppression.

Immunosuppression is clearly recommended essentially for the treatment of eosinophilic, granulomatous, giant-cell myocarditis and lymphocytic myocarditis associated with connective tissue diseases or with the rejection of a transplanted heart. With regard to idiopathic lymphocytic myocarditis, beyond acute phase where a spontaneous resolution has been reported in up to 40% of the cases, many patients with idiopathic myocarditis and chronic heart failure are likely to benefit from immunosuppression. An up-regulation of HLA antigens in the myocardial tissue of patients with lymphocytic myocarditis has been proposed as a marker of susceptibility to beneficial effects of immunosuppression (Wojnicz et al., 2001). Recently the data from a randomized double-blind, placebo-controlled study designed to evaluate the efficacy of immunosuppression in virus-negative inflammatory cardiomyopathy have been reported (Frustaci et al., 2009). Eighty-five patients with myocarditis and chronic (>6 months) heart failure unresponsive to conventional therapy and no evidence of myocardial viral genomes were randomized to receive either prednisone and azathioprine (43 patients, Group 1) or placebo (42 patients, Group 2) in addition to conventional therapy for heart failure. Primary outcome was the 6 months improvement in left-ventricular function. Group 1 showed a significant improvement of left-ventricular ejection fraction and a significant decrease in left-ventricular dimensions and volumes compared with baseline. None of Group 2 patients showed improvement of ejection fraction, that significantly worsened compared with baseline. No major adverse reaction was registered as a result of immunosuppression. These data confirmed the efficacy of immunosuppression in virus-negative inflammatory cardiomyopathy. Lack of response in 12% of cases suggested the presence of not screened viruses or mechanisms of damage and inflammation not susceptible to immunosuppression. Antiviral therapy is a logical strategy advocated for the treatment of myocarditis in patients with evidence of viral presence in myocardial tissue. In a small phase II study 22 patients with myocarditis and biopsy-proven viral persistence (15 enteroviral and 7 adenoviral) were treated with interferon-beta 18x106 IU/week for 24 weeks. Interferon-b treatment resulted in complete elimination of both enteroviral and adenoviral genomes and hemodynamic improvement, as shown by improvement of EF and amelioration of heart failure symptoms. Importantly, treatment with interferon-beta was safe and well-tolerated, with no adverse cardiac effects, and flulike side effects could be efficiently eliminated by non-steroidal anti-inflammatory drugs (Kuhl et al., 2003). After these encouraging results, a prospective placebo-controlled randomized multicenter study, the Betaferon® in Chronic Viral Cardiomyopathy (BICC) trial, was initiated in 2002 and presented at the 2008 American Heart Association scientific sessions. The primary endpoint was virus elimination or reduction of virus load. At 24-week follow-up, compared to placebo, virus elimination and/or viral load reduction were significantly higher in the interferon group. Moreover, interferon-beta showed a good safety profile and was associated with beneficial effects on clinical secondary endpoints, such as NYHA functional class and quality of life, as assessed by Minnesota questionnaire, although echocardiographic and hemodynamic parameters were not statistically significantly different. This interesting phase II study showed proof of concept for targeted therapy based on molecular diagnosis in inflammatory cardiomyopathy. Future directions in the field of antiviral therapy include preventing direct viral damage and inhibition of viral proliferation

by preventing the interaction of viruses with their cellular receptor and their consequent signalling amplification systems, such as the tyrosine kinase p56lck, phosphatase CD45 and downstream ERK1/2 (Liu et al., 2000). Therefore, additional research is required to further understand the mechanisms of viral heart disease and consequently identify new potential targets for therapy.

Myocarditis Presenting with Ventricular Arrhythmias:

Clin. 2007;25:423-9.

2006;15:11–17.

Heart Fail 2002; 4: 411-417.

Electrophysiol 2008;19:1219.

Immunol 2008; 99: 95-114.

Med J Aust 2004;180:110-112.

tachyarrhythmias. Circulation 2001;104:168-73.

J Am Coll Cardiol 2004; 43: 2305 - 2313.

Cooper LT. Myocarditis. N Engl J Med. 2009;360:1526–38.

normal heart. Cardiovasc Res 2001;50:399-408.

recurrent arrhythmias. J Am Coll Cardiol 2006;47:1649-54.

classification. Am J Cardiovasc Pathol 1987;1:3-14.

Role of Electroanatomical Mapping-Guided Endomyocardial Biopsy in Differential Diagnosis 383

Ansari AA, Fett JD, Carraway RE, et al. Autoimmune mechanisms as the basis for human peripartum cardiomyopathy. Clin Rev Allergy Immunol 2002; 23: 301-324. Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis. A histopathologic definition and

Avella A, d'Amati G, Pappalardo A, et al. Diagnostic value of endomyocardial biopsy

cardiomyopathy/dysplasia. J Cardiovasc Electrophysiol. 2008;19:1127-34. Basso C, Carturan E, Corrado D, Thiene G. Myocarditis and dilated cardiomyopathy in

Bowles NE, Ni J, Marcus F, Towbin JA. The detection of cardiotropic viruses in the

Caforio AL, Mahon NJ, Tona F,McKenna WJ. Circulating cardiac autoantibodies in dilated

Calabrese F, Basso C, Carturan E, Valente M, Thiene G. Arrhythmogenic right ventricular

Casella M, Dello Russo A. (2008). *An atlas of radioscopic catheter placement for the electrophysiologist.* Springer-Verlag. ISBN:978-1-84800-226-5, London. Chauhan VS, Hameedullah I, Nanthakumar K, Downar E. Epicardial catheter ablation of

Chimenti C, Calabrese F, Thiene G, Pieroni M, Maseri A, Frustaci A. Inflammatory left

Chimenti C, Pieroni M, Maseri A, Frustaci A. Histologic findings in patients with clinical

Cihakova D; Rose NR. Pathogenesis of myocarditis and dilated cardiomyopathy. Adv

Cooper LT, Baughman KL, Feldman AM et al. American Heart Association; American

Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with apparently

Dalal D, Jain R, Tandri H, Dong J, Eid SM, Prakasa K, et al. Long-term efficacy of catheter

ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol 2007;50:432-40. De Cobelli F, Pieroni M, Esposito A, et al. Delayed gadolinium-enhanced cardiac magnetic

Doolan A, Langlois N, Semsarian C. Causes of sudden cardiac death in young Australians.

dysplasia/cardiomyopathy. J Am Coll Cardiol. 2002;39:892–895.

guided by electroanatomic voltage mapping in arrhythmogenic right ventricular

athletes: diagnosis, management, and recommendations for sport activity. Cardiol

myocardium of patients with arrhythmogenic right ventricular

cardiomyopathy and myocarditis: pathogenetic and clinical significance. Eur J

cardiomyopathy/dysplasia: is there a role for viruses? Cardiovasc Pathol.

incessant ventricular tachycardia in giant cell myocarditis. J Cardiovasc

ventricular microaneurysms as a cause of apparently idiopathic ventricular

and instrumental diagnosis of sporadic arrhythmogenic right ventricular dysplasia.

College of Cardiology; European Society of Cardiology. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2007;116:2216-33.

ablation of ventricular tachycardia in patients with arrhythmogenic right

resonance in patients with chronic myocarditis presenting with heart failure or

No specific trial or data from single-center studies on the treatment of myocarditis presenting with ventricular arrhythmias are currently available in literature. In patients with acute myocarditis, therapy for arrhythmias is essentially supportive, since arrhythmias usually resolve after the acute phase of the disease, which can last several weeks, together with the resoluton of the inflammatory process. Even in chronic myocarditis, management of ventricular arrhythmias is currently confined to antiarrhythmic drug therapy, with limited efficacy, and to implantable cardioverter-defibrillator for higher-risk patients, including those with hemodynamically unstable ventricular tachycardias (Zipes et al., 2006) and those with aborted sudden death. Radiofrequency catheter ablation has been demonstrated to be effective in reducing ventricular tachycardia occurrence in patients with Chagas cardiomyopathy and sarcoidosis. Regarding ventricular arrhythmias in patients with lymphocytic myocarditis, isolated reports suggest that RFCA may be effective, (Chauhan et al., 2008; Hama et al. 2009; Kettering et al., 2009; Zeppenfeld et al., 2007) but its safety and long-term efficacy in this setting is unclear. In our Institution we documented the safety and efficacy of RFCA in a series of consecutive patients with chronic active myocarditis presenting with drug-refractory ventricular tachycardias. We enrolled 20 pts with biopsy-proven myocarditis and drug-refractory ventricular tachycardia including 5 pts presenting with electrical storm. All patients underwent endocardial RFCA with an irrigation catheter, using contact electroanatomical mapping. Recurrence of sustained ventricular tachycardia after endocardial RFCA was treated with additional epicardial RFCA. Endocardial RFCA was acutely successful in 14 pts (70%), while in the remaining 6 pts (30%) clinical ventricular tachycardia was successfully ablated by epicardial RFCA thus demonstrating that in patients with myocarditis, RFCA of drug-refractory ventricular tachycardia is feasible, safe and effective and that epicardial RFCA should be considered as an important therapeutic option to increase success rate (Pieroni and colleagues in press).
