"Let the physician define the nature of the disease, its underlying cause and its method of cure and treat it faithfully according to the medical rule" - Thiruvalluvar  (ThiruKural:  948)

 

 

Ventricular arrhythmias (VA) due to myocar- ditis can range from asymptomatic prema- ture  ventricular contractions to  refractory electrical storm and sudden cardiac death  (2). Lack of reliable diagnostic tests, a variable natural history, and  paucity of signs and symptoms make it an under- diagnosed and undertreated entity. Early identifica- tion of underlying myocarditis is of paramount importance in the prevention of arrhythmias and long-term sequelae. Initiation of immunosuppression (IST) can not only reduce the arrhythmic burden, but also limit the progression of myocardial fibrosis. Furthermore, catheter ablation has been associated with high recurrence when performed in the inflam- matory phase.

 

Myocarditis is generally suspected in the context of cardiovascular manifestations following respiratory  or gastrointestinal illness and is usually self-limited. However, increasingly, it  has been diagnosed either  as an isolated immune mediated disease (virus negative) or as a part of systemic autoimmune dis- eases (3). So, how do we suspect underlying myocardial inflammation? Pleomorphism and cycle length irregularity during VA are more often seen in the inflammatory phase of the disease (4). It is important to make the distinction between pleomor- phic (>1 morphologically different QRS complex during the same episode) and polymorphic VA (continuously changing QRS configuration from beat to beat) (5). Careful examination of the resting sinus rhythm electrocardiogram, can also help us to suspect underlying inflammation (6). Cardiac magnetic reso- nance (CMR), using the Lake Louise criteria, has an accuracy of 78% in diagnosing myocarditis (7). 18Flurodeoxyglucose positron emission tomography– computed tomography (18FDG-PET CT) can  also  be an useful tool in the acute phase and in the follow-up of inflammatory cardiomyopathies, including cardiac sarcoidosis (8).

 

In this issue of JACC: Clinical Electrophysiology, Peretto et al. (9) have reported the role of IST in reducing VA in patients with CMR and endomyo- cardial biopsy–proven virus-negative myocarditis (VNM). The study population comprised 255 patients with VA and  immune-mediated myocarditis either as a part of systemic immune disease (16.1%) or as an isolated entity (83.9%). The IST-positive cohort (45.8%) was treated with antiarrhythmic drugs  (AADs) and a 2-drug immunosuppression regimen (prednisolone for 6 months and a steroid sparing agent for 12 months),  whereas  the  remainder  (54.2%) were treated with conventional AADs. Before therapy, indirect immunofluorescence assays detec- ted the presence of anti-heart and anti-intercalated disc (AIDA) antibodies in 93 (36.5%) and 28 (11.0%) patients, respectively. During the initial follow-up of 24 months, the occurrence of major VA was similar in IST-positive (10.3%) and IST-negative (17.2%) groups. However, IST was independently associated with protection from major VA (22.7% vs. 50.7%) when the follow-up was extended to 38 T 21 months. Addi- tionally, IST was associated with a significant improvement in cardiac biomarkers as well as echo- cardiographic evidence of left ventricular (LV) reverse remodeling. The investigators also reported a trend of worsening cardiac function and progressive LV dila- tation following the cessation of IST. This indicates the possibility of chronic persistent inflammation and hence a role for long-term IST in select patients. Presentation with major VA and presence of AIDA were found to be independent predictors of major VA during follow-up.

 

A heightened humoral immune response in myocarditis may be due to molecular mimicry by cross-reacting antibodies to viral antigens or a result of autoantibodies generated against self-antigens following myocardial injury (10). Binding of AIDA to intercalated discs has been implicated in arrhythmo- genesis and may serve as a more specific diagnostic and prognostic marker of VA. Previous studies have identified these same autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy and, more importantly, their relatives as well (11). It would have been interesting if the investigators had analyzed the effect of IST in reducing VA in the sub- group of patients with AIDA. Longitudinal studies are needed to assess the specificity and diagnostic utility of these antibodies. The generation of these autoan- tibodies is secondary to an adaptive cellular response mediated by macrophages and T cells. It is important to realize that the development of antibodies is a downstream effect in the immunological cascade during myocarditis. Immunohistochemistry to iden- tify mediators of cellular immunity (macrophages, T helper cells) may help to diagnose this entity in an earlier stage. In this regard, dendritic cells have been found to be a surrogate marker of granulomatous inflammation and may help in the evaluation sus- pected myocarditis (12). Additionally, individual im- mune responses may differ, depending on the degree of genetic susceptibility to myocarditis as a result of polymorphisms in the major histocompatibility com- plex genes (13).

Recent methods of incorporating immunohisto- chemistry and viral genome analysis has  increased the diagnostic yield of endomyocardial biopsy in myocarditis. Autoimmune myocarditis (including gi- ant cell myocarditis, sarcoidosis, and eosinophilic myocarditis) in particular, is characterized by a good therapeutic response to IST. Multiple small studies in virus-negative patients suggest that IST may improve LV function (14), laying the foundation for the current work by Peretto et al. (9). The long duration of IST with meticulous monitoring of arrhythmic and echo- cardiographic parameters, as well as prolonged follow-up, makes this study unique. The investigators need to be complimented for managing these patients in a holistic fashion with the effective integration of multiple specialties. The inputs of immunologists in the team and rigorous monitoring for toxicity un- doubtedly contributed to the absence of major IST- related adverse effects in this study.

This study attempts to clarify the role of IST in patients with VNM, but there are a few limitations. Several factors are considered by the physician before initiating long-term IST, such as probability of spon- taneous remission, age, frailty, diabetes mellitus, and previous infections. More than one-half of the study cohort (53.7%) did not receive IST, due to contrain- dications or patient refusal for long-term steroid therapy. Although, the investigators used 1:1 match- ing, lack of randomization and the heterogenous na- ture of the study population affect the interpretation  of the results. Initial presentation with major VA was associated with a higher risk of arrhythmic events during follow-up. This observation suggests that we need to rethink the potential benefits of early implantable cardioverter-defibrillator implantation in the acute stage of myocarditis (15). Additional outcome studies with longer follow-up are needed to address the validity of this contention.

 

In a certain subset of patients, VA or LV dysfunc- tion did not improve following IST. This may be attributed to several causes: inadequate dose or duration of IST, steroid resistance, and fibrosis,  as well as residual inflammation. The distinction regarding the phase of the disease (active inflamma- tion vs. fibrosis) is critical to successful management of arrhythmias in these patients (16). In patients with increased fibrosis, catheter ablation remains an useful adjunct to AADs and implantable cardioverter- defibrillator therapy, whereas those patients with predominant inflammation are better managed with immunosuppression. In this regard, we  have observed that 18FDG-PET CT is a useful investigation to characterize the inflammatory activity, monitor response to IST, and detect steroid resistance (17). In addition, 18FDG-PET CT may be a more useful tool than CMR to monitor the myocardial inflammatory burden in patients with cardiac implantable elec- tronic devices. Early identification of  patients  who are clinical nonresponders to IST can help individu- alize treatment strategies. These patients may benefit from escalation of steroid therapy or corticosteroid- sparing treatment, including biological agents. Of note, the presence of inflammasome, a macromole- cule in a cell that responds to stress by releasing proinflammatory IL-1-beta, can be a target  of therapy (18). Several ongoing randomized studies investigating the role of target-specific anti-inflam- matory treatment, such as rituximab, in VNM might open new avenues of management. Spontaneous re- missions and relapses are known to occur in immune- mediated myocarditis, and IST needs to be tailored accordingly.

 

The present study supports a recommendation that IST is safe and feasible in patients with VNM. It reduced the arrhythmic burden and promoted reverse remodeling of the LV during follow-up.  Future studies need to focus on simplifying the diagnostic workflow, assessing the contribution of autoimmunity to clinical phenotype of VNM, identi- fying markers of disease activity, and determining the optimal duration of IST. Understanding the immu- nopathology of this disease will help in earlier diag- nosis and more effective treatment strategies. Like all good studies, this one has raised several interesting questions and future areas worthy of exploration.

 

ADDRESS FOR CORRESPONDENCE: Dr. C. Narasimhan, Department of Electrophysiology, AIG Hos- pitals, Mindspace Road, Hyderabad, India. E-mail: calambur1@gmail.com.

 

REFERENCE S

 

1.  Tiruvalluvar, Cuttananta Prr. Thirukkural cou- plets, with clear prose rendering in English. 1st ed. Madras,: South India Saiva Siddhanta Works Pub. Society, Tinnevelly, 1971.

 

2.  Peretto G, Sala S, Rizzo S, et al. Arrhythmias in myocarditis: state of the art. Heart Rhythm 2019; 16:793–801.

 

3.  Bracamonte-Baran W, Cihakova D. Cardiac autoimmunity: myocarditis. Adv Exp Med Biol 2017;1003:187–221.

 

4.   Panda S, Kaur D, Lalukota K, Sundar G, Pavri BB, Narasimhan C. Pleomorphism during ventricular tachycardia: a distinguishing feature between cardiac sarcoidosis and idiopathic VT. Pacing Clin Electrophysiol 2015;38:694–9.

 

5.  Aliot EM, Stevenson WG, Almendral- Garrote JM, et al. EHRA/HRS expert consensus on catheter ablation of ventricular arrhythmias: developed in a partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Car- diology (ACC) and the American Heart Association (AHA). Europace 2009;11:771–817.

 

6.   Bera D, Saggu D, Yalagudri S, et al. Outflow- tract ventricular tachycardia: can 12 lead ECG during sinus rhythm identify underlying cardiac sarcoidosis? Indian Pacing Electrophysiol J 2020; 20:83–90.

 

7.  Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol 2009;53:1475–87.

 

8.   Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and man- agement of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm 2014;11:1305–23.

 

9.   Peretto G, Sala S, De Luca G, et al. Immunosup- pressive therapy and risk stratification of patients with myocarditis presenting with ventricular arrhythmias. J Am Coll Cardiol EP 2020;6:1221–34.

 

10.     Tschope C, Cooper LT, Torre-Amione G, Van Linthout S. Management of myocarditis-related cardiomyopathy in adults. Circ Res 2019;124: 1568–83.

 

11.   Caforio ALP, Re F, Avella A, et al. Evidence from family studies for autoimmunity in arrhythmogenic right ventricular cardiomyopathy: associations of circulating anti-heart and anti-intercalated disk autoantibodies with disease severity and family history. Circulation 2020;141:1238–48.

 

12.    Honda Y, Nagai T, Ikeda Y, et al. Myocardial immunocompetent cells and macrophage pheno- types as histopathological surrogates for diagnosis of cardiac sarcoidosis in Japanese. J Am Heart Assoc 2016;5:e004019.

 

13.    Li HS, Ligons DL, Rose NR. Genetic complexity of autoimmune myocarditis. Autoimmun Rev 2008;7:168–73.

 

14.  Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflamma- tory cardiomyopathy: the TIMIC study. Eur Heart J 2009;30:1995–2002.

 

15. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for manage- ment of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018;72: 1677–749.

 

16.  Yalagudri S, Zin Thu N, Devidutta S, et al. Tailored approach for management of ventricular tachycardia in cardiac sarcoidosis. J Cardiovasc Electrophysiol 2017;28:893–902.

 

17. Shelke AB, Aurangabadkar HU, Bradfield JS, Ali Z, Kumar KS, Narasimhan C. Serial FDG-PET scans help to identify steroid resistance in cardiac sarcoidosis. Int J Cardiol 2017;228: 717–22.

 

18.  Kron J, Mauro AG, Bonaventura A, et al. Inflammasome formation in granulomas in cardiac sarcoidosis. Circ Arrhythm Electrophysiol 2019;12: e007582.

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