Accepted Manuscript

Arrhythmias in Myocarditis: State of the Art

Giovanni Peretto, MD, Simone Sala, MD, Stefania Rizzo, MD, Giacomo De Luca,
MD, Corrado Campochiaro, MD, Silvia Sartorelli, MD, Giulia Bendetti, MD, Anna
Palmisano, MD, Antonio Esposito, MD, Moreno Tresoldi, MD, Gaetano Thiene, MD,
Cristina Basso, MD, Paolo Della Bella, MD

PII: S1547-5271(18)31169-X
DOI: https://doi.org/10.1016/j.hrthm.2018.11.024
Reference: HRTHM 7826

To appear in: Heart Rhythm

Received Date: 30 September 2018

Please cite this article as: Peretto G, Sala S, Rizzo S, De Luca G, Campochiaro C, Sartorelli S, Bendetti
G, Palmisano A, Esposito A, Tresoldi M, Thiene G, Basso C, Della Bella P, Arrhythmias in Myocarditis:
State of the Art, Heart Rhythm (2018), doi: https://doi.org/10.1016/j.hrthm.2018.11.024.

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 ACCEPTED MANUSCRIPT

Arrhythmias in Myocarditis:
State of the Art

SHORT/RUNNING TITLE
A challenging hot topic in inflammatory heart disease

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AUTHORS
Giovanni Peretto1,2,MD, Simone Sala1, MD, Stefania Rizzo3, MD, Giacomo De Luca4, MD, Corrado
Campochiaro2,4, MD, Silvia Sartorelli2,4, MD, Giulia Bendetti2,5, MD, Anna Palmisano5, MD, Antonio

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Esposito5, MD, Moreno Tresoldi4, MD, Gaetano Thiene3, MD, Cristina Basso3, MD, Paolo Della
Bella1, MD

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Affiliations
1. Department of Cardiac Electrophysiology and Arrhythmology, IRCCS San Raffaele Hospital,
Milan, Italy

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2. Vita-Salute San Raffaele University, Milan, Italy
3. Cardiovascular Pathology Unit, Department of Cardiac, Thoracic and Vascular Sciences,
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University and Hospital of Padua, Padua, Italy
4. Department of Immunology, Rheumatology, Allergology and Rare Diseases (UnIRAR), IRCCS
San Raffaele Hospital, Milan, Italy
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5. Cardiac Magnetic Resonance Unit, Department of Radiology and Cardiovascular Imaging, IRCCS
San Raffaele Hospital, Milan, Italy
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1,2,3,4,5 - All of the Authors take responsibility for all aspects of the reliability and freedom from
bias of the data presented and their discussed interpretation.
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Corresponding Author
Giovanni Peretto, MD
Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital
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Via Olgettina 60, 20132 Milan, Italy

Tel./Fax. +39 02 2643 7484/7326
E-mail: peretto.giovanni@gmail.com
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Funding sources / grant support

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This research did not receive any specific grant from funding agencies in the public,
commercial, or not-for-profit sectors

Disclosures / conflicts of interest

None

Keywords
Arrhythmias – Myocarditis – Ventricular tachycardia – Inflammation – Endomyocardial biopsy – Imaging

Word count
5983

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1 ABSTRACT

3 Many kinds of arrhythmias may occur in patients with myocarditis at any stage of the disease.

4 However, as compared to the other clinical presentations, arrhythmic myocarditis has been poorly

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5 described so far in the literature. In fact, arrhythmias occurring in either ongoing or previous

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6 myocardial inflammation are complex and heterogeneous, and the disease itself is often

underdiagnosed, thus limiting data collection and interpretation. However, differently from the

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7

8 other clinical presenations, arrhythmic myocarditis require specific diagnostic, prognostic and

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9 therapeutic considerations. The aim of the current paper is to critically summarize the state of the
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10 art on myocarditis presenting with arrhythmias in terms of epidemiology, aetiology, diagnosis,

11 prognosis and treatment.

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12
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13
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14 INTRODUCTION AND CLINICAL CLASSIFICATION

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16 Myocarditis is a complex inflammatory disease of the myocardium, usually secondary to viral

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17 infections or immune dysregulating phenomena, with extremely heterogeneous clinical

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18 manifestations.1 Among them, different kinds of potentially life-threatening brady- and tachy-

19 arrhythmias may present at any stage of the disease, as an expression of myocardial electrical

20 instability.2 However, no independent characterization of myocarditis presenting with arrhythmias

21 as the first clinical manifestation is reported in international referral documents, like the 2013

22 position paper of the European Society of Cardiology on myocarditis.3 In this review, arrhythmias

23 in myocarditis will be presented in detail in terms of epidemiology, pathophysiology, diagnosis,

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24 prognosis and therapy, at the best of updated clinical evidence. In particular, based on current

25 classification,4 arrhythmias will be described according to different evolutive stages of myocarditis

26 (Figure 1): a) acute (or hot) inflammatory stage; b) chronic (or cold) postinflammatory stage.

27 Figures 2-4 show exemplificative cases of arrhythmias in patients with acute (Figure 2), chronic

28 (Figure 3), or special forms (Figure 4) of myocarditis. Additional references can be found in online

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29 supplements.

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30

PART 1 - HOT-PHASE ARRHYTHMIAS: ACUTE AND FULMINANT MYOCARDITIS

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31

32

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33 Epidemiology
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34 Although considered uncommon in inflammatory disease of the myocardium,3 arrhythmias may

35 present in both acute and fulminant myocarditis, leading to sudden cardiac death (SCD), especially
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36 in young males.5 Overall, the prevalence of undiagnosed myocarditis in post-mortem series ranges
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37 from 9 to 44%,4 in particular involving 2% of infants, 5% of children, and 4-8 % of athletes younger
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38 than 40 years old.4,6 Ventricular arrhythmias (VA) are reported secondary to lymphocytic

39 myocarditis.5 However, they are more commonly associated with GCM and CS, with prevalence of
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40 29% and 55%,8 respectively. Of note, in the presence of minimal myocardial inflammation or
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41 isolated pericardits, arrhythmias are significantly less common (overall prevalence < 10%) and
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42 more frequently of supraventricular origin.9 In particular, the prevalence of atrial fibrillation is

43 widely ranging from 2.5% of patients with myopericarditis9 to 2/3 of those with isolated atrial

44 GCM.10 Also bradyarrhythmias are infrequent in acute and fulminant myocarditis,11 except for

45 some special aetiologies including CS, GCM, Chagas disease or some systemic autoimmune

46 diseases involving myocardium.12 In particular, atrioventricular blocks (AVB) of any degree have

47 been reported with a variable prevalence in both patients with GCMand CS.13

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48

49 Aetiology

50 Although specific data about arrhythmic patients are lacking,4 viruses are supposed to be the most

51 common cause of isolated myocarditis in economically developed countries.14 Documented

52 arrhythmias have been reported more commoly in HIV myocarditis 15 than in other more common

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53 infections like adenovirus, parvovirus B19, human herpes virus 6 and enterovirus.14 Among

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54 bacteria, Chlamydial genome has been found in myocarditis causing SCD in young elite athletes.16

Other agents, like Borrelia burgdorferi in Lyme’s disease and Corynebacterium diphtheriae, can

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55

56 cause both VA and acute-phase advanced AVB in developed and developing countries,

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57 respectively.4 In Latin America the same arrhythmic manifestations are more commonly due to the
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58 parasite Trypanosoma Cruzi, the aetiologic agent of Chagas disease.17 Finally, a number of

59 autoimmune or idiopathic inflammatory diseases like CS and GCM 18 have been associated with a
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60 very high risk of SCD from brady or tachyarrhythmias. By converse, VA have rarely been described
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61 in systemic lupus erythematous and other systemic autoimmune diseases potentially associated
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62 with myocarditis.12

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64 Pathophysiology
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65 Several hypotheses have been postulated to explain arrhythmogenicity during the acute phase of
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66 viral myocarditis (Figure 5 and Supplementary References): 1) a direct cytopathic effect, leading to

67 electrical instability from myocytes membrane lysis; 2) ischaemia from coronary macrovascular or

68 microvascular disease, as shown in viruses with endothelial tropism like parvovirus B19 as a result

69 of P-antigen mediated endothelial dysfunction; 3) gap junction dysfunction from impaired

70 myocardial expression of connexins, as documented during coxsackievirus B3-induced myocarditis

71 in animal models; 4) abnormal calcium handling and ion channel impairment, in particular in

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72 myocarditis overlapping with arrhythmogenic cardiomyopathy or channelopathies. On the other

73 hand, pathogenesis in non-infective forms of myocarditis is less clear. In particular, as a possible

74 result of T cell-mediated autoimmunity, myocardial infiltration by giant cells or noncaseating

75 granulomas can lead to both conduction disease and VA in GCM and CS, respectively.

76 Furthermore, mechanical pressure of non-caseating lesions on the conduction system (mass

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77 effect) can explain some cases of AVB in GCM and CS. Pathophysiology of heart blocks in

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78 lymphocytic myocarditis has been explained in a restricted number of cases, like in neonatal

cardiac lupus. However, clinical-pathological studies have shown a selective involvement of the

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79

80 conduction system in some myocarditis presenting with bradyarrhythmias.

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81
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82 Diagnosis

83 In the acute phase, patients with arrhythmic myocarditis may present with a spectrum of
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84 symptoms ranging from palpitation to syncope or cardiocirculatory arrest.1 12-leads ECG is the
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85 cornerstone of diagnosis at presentation. However, given their paroxysmal nature, many

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86 arrhythmias may have completely resolved at the time of clinical evaluation. Unfortunately,

87 baseline ECG findings in acute myocarditis can be extremely various and generally nonspecific,
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88 including ST-T alterations and new-onset arrhythmias like any-degree AVB, bundle branch blocks,

or tachyarrhythmias.2,3 Echocardiogram has limited usefulness and lacks specificity. In patients

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89
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90 with cardiogenic shock precipitated by arrhythmias, severe systolic dysfunction is a common

91 finding. Left ventricular wall may appear thickened because of oedema.19 Regional wall motion

92 abnormalities and pericardial effusion are inconstantly found.3 Elevation in myocardial specific

93 biomarkers, i.e. troponin I/T and natriuretic peptides, is not predictive of cardiac arrhythmias

94 secondary to myocarditis.4,20 However, the diagnosis of myocarditis should not be dismissed

95 because of undetectable or normal myocardial specific biomarkers.20 Especially in the presence of

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96 ventricular tachyarrhythmias, coronary angiography is needed to rule-out epicardial coronary

97 artery disease.3,4 In hemodinamically stable patients, Cardiac magnetic resonance (CMR) is

98 becoming a sensitive, non-invasive routine test for confirmation of acute myocarditis.4,21 Diagnosis

99 is suggested by the presence or at least two of the Lake Louise criteria, including early

100 enhancement (hyperaemia as an equivalent of vasodilation), oedema on T2-weighted/STIR

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101 sequences, and late gadolinium enhancement (LGE) in a nonischemic pattern.21 Notably, both

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102 oedema and LGE may significantly reduce or even disappear a few weeks after the initial illness,6,22

thus decreasing CMR sensitivity. In this context, modern T1 and T2 mapping can increase

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103

104 sensitivity and reduce artifacts, respectively.23 However, in the presence of irregular heart rhythm

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105 or tachycardia, significant artifacts may impair accuracy. Furthermore, in arrhythmic patients with
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106 myocarditis, CMR sensitivity has been reported to be lower, as compared to the other clinical

107 presentations.24 As for nuclear imaging, although its routine use is not recommended in
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108 myocarditis,3 Fluorodeoxyglucose positron emission tomography (FDG-PET) scan has been
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109 proposed in CS for both diagnosis and treatment response monitoring.8 Nowadays, although
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110 invasive, endomyocardial biopsy (EMB) is reported as the gold standard for the definite diagnosis

111 of myocarditis.3,25 In haemodynamically ustable patients because of malignant arrhythmias

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112 (particularly Mobitz type 2 second-degree or higher heart block and sustained or symptomatic
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113 VA), EMB should be performed as soon as possible, being the only way to diagnose specific
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114 histotypes like GCM, CS and eosinophilic myocarditis.18 Even in stable patients undergone CMR,

115 EMB allows for aetiologic identification to choose specific theapy, but also to avoid unnecessary

116 treatment like early device implantation.3,4 However, potential limitations (typically sampling

117 errors in patients with focal myocarditis) and complications (generally rare, but including

118 ventricular rupture and cardiac tamponade in the most severe cases) should be always taken into

119 account when evaluating EMB indication. Furthermore, controversies exist about the optimal

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120 target site (right, left or both ventricles) and the incremental diagnostic yield of substrate-guided

121 biopsies. For all of these reasons, an integrated multimodal diagnostic evaluation is always

122 recommended in patients with acute myocarditis.

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124 Prognosis

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125 In patients with fulminant myocarditis, refractory life-threatening VA may lead to adverse short-

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126 term prognosis,26 Fatal arrhythmia is also a common mechanism of cardiac death in GCM.7

However, when promptly managed, acute-phase arrhythmias tend to be self-limiting and do not

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127

128 bear a significant long-term prognostic value.4 Of note, the risk of SCD in myocarditis does not

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129 correlate with the severity of myocardial inflammation, and myocardial healing is not necessarily
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130 associated to the disapperaence of arrhythmias, especially in young patients.6 Physical exertion is

131 associated with an increased risk of SCD in the acute phase,5 while the presence of LGE in biopsy-
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132 proved viral myocarditis might predict subsequent risk of VA.27 Also high-degree AVB in
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133 myocarditis have been associated with mortality and morbidity in follow-up.28 Among the other
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134 predictors of arrhythmic risk, sinus bradycardia, prolonged QRS duration, wall motion

135 abnormalities and systolic dysfunction, persistent or fluctuating cardiac troponin levels, LGE at
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136 CMR and frequent non-sustained VA have been proposed, alone or in combination,29,30 although

not validated by large prospective trials.4 In the acute phase of myocarditis, acute kidney injury
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137
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138 and hyperglycaemia is associated with a poor outcome.31,32 By converse, in the presence of

139 pericardial involvement, dome-shaped ST-segment elevation (localized, < 5 mm, with reciprocal

140 changes), early T-wave inversion and PQ depression suggest a more benign pericarditis-like

141 course.9 However, assuming normalization of LV function, asymptomatic arrhythmias in FU can be

142 largely underdiagnosed, since exercise ECG and Holter monitoing are clearly indicated only in

143 athletes before readmission to competitive sports participation.6 A more extensive use of long-

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144 term monitoring strategies, including implanable loop recorders in selected cases, may allow for

145 early detection of arrhythmias in follow-up.

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147 Treatment

148 Management of acute life-threatening arrhythmias is generally supportive, often including acute

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149 heart falilure treatment with mechanical support in centers capable of advanced arrhythmia

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150 management.4,29 DC-shocks and antiarrhythmic therapy may be used in the acute phase to

interrupt significant VA. There is a lack of evidence to support the use of specific antiarrhythmic

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151

152 agents beyond the conventional strategies indicated in updated guidelines.4,18 In the presence of

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153 refractory electrical storms despite the use of aggressive anti-arrhythmic drug therapy, GCM
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154 should be suspected.7 Evidence of aetiology-based treatment in acute arrhythmic myocarditis is

155 extremely poor. In general, immunosuppression should not be used unless virus-negative EMB-
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156 proved myocarditis is diagnosed (Supplementary Figure 1).3,18 Updated clinical evidence suggests a
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157 preference for steroid-sparing strategies, like azathioprine.3,12 By converse, immunosuppressive

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158 therapy is particularly indicated in cases of GCM, CS, or eosinophilic myocarditis,18,19 including

159 calcineurin inhibitors and corticosteroids regimen in GCM.33 In patients with CS and frequent
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160 symptomatic VA immunosuppression in combination with antiarrhythmic medication therapy can

be useful to reduce VA burden, followed by radiofrequency catheter ablation if needed.18 As

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161
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162 suggested by guidelines, in the absence of long-term longitudinal data on the mortality or

163 morbidity of the patients with history of myocarditis, it is reasonable to defer device implantation
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164 after the resolution of any potentially reversible episode of acute myocarditis. Severe AVB

165 should be managed via temporary pacemakers.4 In patients with acute-phase malignant VA,

166 wearable life vests have been presented as a possible therapeutic option,34 but their effects on

167 mortality are still to be proved. Of note, the presence of malignant VA or heart block in GCM or CS

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168 might warrant earlier consideration of an implantable cardioverter defibrillator (ICD) due to the

169 known high risk of arrhythmic death or refractory heart failure.35,36 As for lyfestyle, competitive

170 sport participation should be avoided for 3 to 6 months after the diagnosis of myocarditis,

171 requiring careful clinical evaluation and functional testing before competitive sport participation is

172 resumed.6

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173

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174

PART 2 - COLD-PHASE ARRHYTHMIAS: CHRONIC AND PREVIOUS MYOCARDITIS

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175

176

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177 Epidemiology
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178 Long-term evolution of inflammatory cardiomyopathy with left ventricular (LV) dilatation and

179 dysfunction may result from unhealed myocarditis.37 Nowadays 10% of non-ischaemic dilated
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180 cardiomyopathies (DCM) are due to myocarditis, and 2/3 of patients with LV dysfunction of
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181 unknown origin show a viral genome in the myocardium.4,38 In these patients the risk of SCD is
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182 long-term and may be similar to that for other NIDCMs.19 In fact, even after inflammation

183 recovery, scar-related VA can occur any time during follow-up.39 Furthermore, undiagnosed
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184 previous or chronic myocarditis is a possible cause of otherwise unexplained premature

ventricular complexes (PVC) in adults, children and athletes.6,37

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185
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186

187 Aetiology

188 In the chronic stage of myocarditis, persisitent viral infections are a possible but infrequent cause

189 of inflammatory DCM and associated arrhythmias.5,19 By converse, more than 1/3 of patients with

190 Chagas disease develop late myocardial damage with progressive conduction defects and VA.40

191 Among the more common virus-negative variants, arrhythmias have been reported in either

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192 organ-specific or systemic autoimmune diseases with a chronic or recurrent course, like

193 spondyloarthritis, systemic sclerosis or inflammatory myopathies.12 Of note, up to 5% of VA from

194 myocardial scarring are caused by late-stage CS.4,8 It should be considered, however, that a

195 significant proportion of chronic virus-negative DCM with inflammatory infiltrates may have a

196 genetic base, as found in left-dominant or biventricular arrhythmogenic cardiomyopathy and in

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197 the early stage of familial DCMs.19,41 Finally, chronic inflammatory cardiomyopathies presenting

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198 with arrhythmias may also result from cocaine or other toxic fagents.18,42

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199

200 Pathophysiology

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201 Arrhythmias in late-stage myocarditis may result from either persistent inflammation or
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202 postinflammatory myocardial scar (Supplementary References). In chronic active myocarditis,

203 recovery from initial inflammatory phase is not observed, and persistent disease activity is thought
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204 to be due to viral genome persistence or more probably to immune dysregulating phenomenon.
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205 Although genome wide association studies support the hypothesis of viral persistence, an
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206 inappropriate autoimmune adaptive response to viral and myocardial proteins seems to be the

207 predominant driver of inflammatory disease persistence, thus maintaining the arrhythmogenic
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208 substrate described in the acute phase. In such a complex context, physical activity may be a
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209 negative modifier of the disease, as shown in both viral and autoimmune models. On the other
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210 hand, in the postinflammatory phase, fibrosis resulting from healed myocardium may lead to scar-

211 related arrhythmogenesis. Furthermore, athough LV size and ejection fraction usually remain

212 normal during acute inflammatory stage, LV dilatation can be observed in late-stage myocarditis,

213 even in the absence of documented persistence of inflammation. However, with the possible

214 exception of patients with midwall LGE at CMR, more recent data suggest that evolution to DCM is

215 not as frequent as reported in the past. Nevertheless, the formation of reentry circuits due to the

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216 regional slowing of action potentials due to electric remodeling of the heart has been shown in

217 postinflammatory heart disease as a consequence of myocardial fibrosis and evolution to DCM

218 phenotype. Consistently, monomorphic VA may occur as scar-related phenomenon, as already

219 shown in patients with nonischemic LV scar or DCM. Of note, in patients with VA and fibrofatty

220 replacement, differential diagnosis or overlapping phenotype with left-dominant arrhythmogenic

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221 cardiomyopathy should be carefully considered.

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222

Diagnosis

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223

224 Overall, many of the diagnostic techniques illustrated in acute myocarditis apply also to the

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225 chronic stage of the disease.4,19 In particular, many of the criteria to identify active or recurrent
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226 myocarditis come from noninvasive diagnostic techniques including ECG, Holter monitoring and

227 exercise stress test, since almost any new-onset electrical abnormality may indicate myocarditis
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228 persistence or recurrence, as more commonly found in CS or GCM.18 Furthermore, baseline ECG
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229 may show the signs of associated DCM, including reduced R wave amplitude, left bundle branch
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230 block or intraventricular conduction delay, abnormal Q waves, low voltages, and repolarization

231 abnormalities.3 Also scar-related VA, particularly of left side origin, can be found in previous
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232 myocarditis,43 even in the presence of preserved ejection fraction.44 This is particularly challenging
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233 in young people presenting with normal echocardiogram and clinically-relevant monomorphic
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234 PVC, which might be misclassified as idiopathic. In this context, as a second line imaging

235 technique, CMR is a useful diagnostic modality in identifying previous or active myocarditis in

236 patients with unexplained VA,43 as well as in those with DCM of undetermined cause.19 In detail,

237 post-myocarditis replacement fibrosis can be identified by subepicardial or intramural LGE, while

238 hyperintensity in T2/STIR sequence could be suggestive of a persistent inflammation.21 Of note, in

239 the presence of poor or minimal inflammatory activity modern T1 and T2 mapping techniques may

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240 increase CMR accuracy.23 Among substrate evaluation techniqes, three-dimensional

241 electroanatomical mapping (EAM) is particularly useful in patients presenting with VA, allowing for

242 identification of low voltage areas as the electrical equivalent of myocardial scarring sites, like in

243 arrhythmogenic cardiomyopathy.45 EAM may be helpful also in indentifying early signs of

244 myocardial disease when diagnosis is unclear.46 Since an epicardial substrate is more commonly

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245 identified in patients with myocarditis, segment per segment correspondence with LGE at CMR

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246 was 66% for epicardial unipolar vs. 40% epicardial bipolar vs. 24% endocardial unipolar vs. 1%

endocardial bipolar EAM.47 The presence of widespread and confluent RV epicardial scarring with

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247

248 involvement of the basal septum, anterior LV wall and perivalvular regions is suggestive of CS.4,8 To

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249 identify occult inflammation in idiopathic DCMs and arrhythmias, FDG-PET scan has been also
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250 proposed, correlating with abnormal EAM in up to 79% of patients,19 but with too poor data

251 consistency to support its widespread use beyond CS treatment response monitoring. Finally, even
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252 in the chronic stage of myocarditis, EMB remains the gold standard diagnostic technique,3,25
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253 providing information about myocarditis aetiology and inflammatory activity.48 Furthermore, EMB
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254 allows for clarification of differential diagnosis in the setting of unexplained VA or DCM, even at

255 early stages.41,43 However, the focal nature of the diseases and the rare involvement of the
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256 interventricular septum have significantly limited the sensitivity of EMB, which however can be

improved by CMR or EAM guidance to reduce sampling error.49,50 The main clinical findings and
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257
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258 diagnostic indications in hot-phase vs. cold-phase myocarditis are reported in Supplementary

259 Tables 1 and 2, respectively.

260

261 Prognosis

262 Arrhythmic risk in late stage myocarditis is significantly related to evolution to DCM, which occurs

263 in up to 21% of patients after acute event, representing a significant issue for device implantation

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264 in primary prevention.4,5 In CS outcome may be particularly adverse, because of the high

265 frequency of ICD shock in patients initially presenting with either VA, advanced AVB, or systolic

266 dysfunction.8,51 Persistence of viral infection, or probably just of inflammatory infiltrates in the

267 myocardium have been proposed as factors associated with DCM evolution.41,52 Among early

268 electrical predictors of adverse outcome, intraventricular conduction abnormalities with a QRS

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269 width of >120 ms should be mentioned.4 Late potentials and other signal-averaged ECG

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270 abnormalities have been inconstantly reported in both acute and chronic stages of myocarditis,

with no definite associations with negative prognosis (Supplementary References). The presence

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271

2,37
272 of LGE at CMR has been described as a risk factor for VA in EMB-proved viral myocarditis as

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273 well as in CS.53 Furthermore, LGE has been associated with long-term arrhythmias in athletes even
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274 when acute inflammation has resolved.27 Midwall LGE pattern in particular has a negative

275 prognostic value, being associated with morbidity and mortality even after cardiac
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276 resynchronization therapy.41 Although LGE extent has been exceptionally reported as a predictor
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277 of long-term adverse outcome in post-myocarditic patients,27 a threshold effect has been
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278 described in CS, with extensive LV and RV involvement being particularly high-risk feature, even

279 when LV ejection fraction (LVEF) is > 50%.53,54 In the absence of ad hoc studies, nowadays invasive
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280 electrophysiological study (EPS) has no role in risk stratification of asymptomatic patients with

history of myocarditis.4,18 However, programmed ventricular stimulation may be useful in patients

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281
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282 with documented VT.19 In particular, inducibility of the clinical monomorphic VT was found in

283 almost 60% of patients with previous myocarditis.47 In contrast, EPS has been proposed as a

284 potential tool for risk stratification for SCD in patients with CS,55 particularly for those with neither

285 documented arrhythmias nor meeting standard criteria for ICD implantation in primary

286 prevention.18

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288 Treatment

289 According to international guidelines, arrhythmia management outside the acute phase should be

290 in line with current guidelines on arrhythmia and device implantation.4,18 Antiarrhythmic

291 medications, amiodarone in particular, may be effective in treating new-onset arrhythmias, but

292 their efficacy in chronic myocarditis is limited.18 In CS beta-blockers, sotalol and amiodarone are

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293 the most commonly used drugs.12 Corticosteroids may improve AV node recovery, but long term

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294 efficacy has not been demonstrated, so that artifical pacing is often required.8 Based on the results

of randomized clinical trials on myocarditis, although none of them addressed arrhythmias

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296 specifically, immunosuppression may be useful in achieving LV reverse remodeling and improve

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297 heart failure symptoms (Supplementary Figure 1). In particular, while waiting for the advent of
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298 biological targeted therapy, steroid-sparing strategies are currently of choice.3,12 In general, the

299 indications for device implantation in inflammatory cardiomyopathy are the same as for non-
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300 ischaemic DCM.4,41 In particular, ICD implantation in secondary prevention is indicated in patients
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301 with myocarditis after cardiac arrest due to ventricular fibrillation or after symptomatic ventricular
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302 tachycardia, especially if arrhythmias persist after the acute phase despite pharmacotherapy.4,18

303 However, device selection should reflect the presence, extent and potential reversibility of LV
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304 dysfunction in order to appropriately choose a pacemaker or ICD with or without cardiac

resynchronization capability.19 Of note, since inflammation may resolve, indications of device

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305
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306 implantation are particularly challenging in primary prevention during the active inflammatory

307 phase.4 Thus, for patients with new-onset DCM and LVEF <30% caused by clinically suspected or

308 confirmed myocarditis, a watchful waiting strategy is preferred.19 A significant exception is

309 represented by patients with CS and Chagas disease, in which ICD implantation should be

310 considered when LVEF is < 35% and < 40%, respectively.4,18 However, ICD is reasonable also in

311 cases of CS with LVEF > 35% with history of syncope and/or evidence of scar at CMR or FDG-PET

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312 and/or positive EPS.18 Of note, in patients with CS and indication for permanent pacing,

313 implantation of an ICD should be preferred.18 Patients with left bundle branch block and a stable

314 postinflammatory DCM non responsive to conventional therapy, should instead undergo cardiac

315 resynchronization therapy.4,19 Radiofrequency transcatheter ablation (TCA) has been successfully

316 used to control arrhythmias in some patients with previous myocarditis, in particular in case of

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317 drug-refractory VA.18,19 Although TCA of arrhythmia using endocardial approach could achieve

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318 acute termination of clinical arrhythmia,4 there is emerging evidence supportive of simultaneous

endo-epicardial approach trying to eliminate the arrhythmogenic foci in patients with history of

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320 myocarditis.4,56 The effectiveness of TCA in patients with chronic active myocarditis is yet be

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321 proven. In patients with CS, TCA of VA is usually considered after an ICD implantation or failure of
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322 antiarrhythmic drug therapy,57 but recurrences are common because of intrinsically relapsing

323 nature of the disease.4,8 An overview on updated therapeutic indications in different stages of
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324 myocarditis, is reported in Supplementary Table 2.

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1. Cooper LT Jr. Myocarditis. N Engl J Med 2009;360:1526-1538.

2. Baksi AJ, Kanaganayagam GS, Prasad SK. Arrhythmias in viral myocarditis and pericarditis. Card

Electrophysiol Clin 2015;7:269-281.

3. Caforio ALP, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis,

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FIGURE LEGENDS
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FIGURE 1 - Pathophysiology of inflammatory heart disease.

Natural history of myocarditis is shown. A pathogenic noxa (infective or noninfective) is

responsible for acute myocarditis, in either its classical (lymphocytic) or special (other histotypes)

forms. Myocarditis may heal completely (on the left) with or without replacement fibrosis and

subsequent arrhythmic risk. In other cases, in part depending on modulating factors (on the right),

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myocarditis becomes chronic, with variable degrees of myocardial scar, and possible evolution to

inflammatory DCM with an increased risk of heart failure. Histological, imaging and prognostic

features for each evolutive phase are shown.

AM = acute myocarditis; CM = chronic myocarditis; CMR = cardiac magnetic resonance; EMB =

endomyocardial biopsy; FDG = fluorodeoxyglucose; HF = heart failure; IDCM = inflammatory

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dilated cardiomyopathy; LGE = late gadolinium enhancement; LV = left ventricular; VA = ventricular

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arrhythmias.

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FIGURE 2 - Arrhythmic myocarditis: acute (hot) phase.

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Example of acute arrhythmic myocarditis. Arrhythmia at presentation is ventricular fibrillation (A).
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Acute-phase CMR shows abnormal signal -orange arrows- at T2-weighted/STIR sequences,

consistent with oedema (B). EMB with hematoxylin eosin (HE) stain and immunohistochemistry
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(IHC) shows inflammatory infiltrates with CD43+ lymphocytes -green arrows-, oedema and
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necrosis of cardiomyocytes (C), with molecular findings suggesting acute viral lymphocytic
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myocarditis from HHV6 virus.

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FIGURE 3 - Arrhythmic myocarditis: chronic (cold) phase.

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Example of a chronic myocarditis. Arrhythmia at presentation is a monomorphic ventricular

tachycardia (A). CMR shows DCM with no oedema but only LGE, in a non-ischaemic pattern -

orange arrows-, consistent with previous myocarditis (B). Endocardial EAM shows abnormal low-

voltage areas consistent with scar (C); of note, sensitivity of unipolar EAM is superior as compared

to bipolar EAM, suggesting a deep intramyocardial or subepicardial substrate. EMB with trichrome

(TC) stain and immunohistochemistry (IHC) shows replacement fibrosis -blue arrows- and

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hypertrophy of cardiomyocytes, together with oedema and inflammatory infiltrates with CD43+

lymphocytes -green arrows- (D); final diagnosis is autoimmune chronic inflammatory DCM.

FIGURE 4 - Arrhythmic myocarditis: special aetiologies.

Example of special aetiology in a patient presenting with recurrent drug-refractory ventricular

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arrhythmias. Baseline ECG shows complete AVB (A). FDG-PET scan shows increased glucose uptake

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in myocardium suggesting sarcoidosis (B). EMB shows inflammatory infiltrates with CD68+

macrophages and noncaseating granulomas -green arrows- confirming the diagnosis of CS (C).

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FIGURE 5 - Arrhythmogenesis in myocarditis.
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Pathophisiological mechanisms responsible for arrhythmias in the different stages of myocarditis

are shown. Red headlines indicate mechanisms more commonly associated with acute
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inflammation, while the blue ones represent those more typically found in the postinflammatory
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stage.
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AC = arrhythmogenic cardiomyopathy; DCM = dilated cardiolyopathy; PVB19 = parvovirus B19.

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Pathogenic noxa
Classical • Infective (usually viral) Special
forms • Noninfective (usually autoimmune) forms

AM
Phase 1

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Oedema, CD3+ FDG uptake, giant
T-lymphocytes cells, granulomas

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Modulating factors

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Oedema, necrosis, inflammatory infiltrate • Genetic background
• Pathogen persistence
Healing Evolution • Molecular mimicry

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Phase 2

Relapse • Immune dysregulation

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Scar – Scar + CM IDCM

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EMB

Restitutio ad integrum TE
Replacement fibrosis Replacement fibrosis
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Persistent iflammation Hypertrophy, inflammation, fibrosis
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LV dilatation
CMR

Nonischaemic LV systolic dysfunction

Normal Nonischaemic
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LGE Wall thinning

LGE
Oedema Nonischaemic LGE
Incostant oedema

VA – + + +
Risk

HF – – + + +
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A

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A C

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B

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Ion channel dysfunction

Overlapping phenotypes
Cell lysis (i.e. channellopathies, AC)
Cytopathic viruses

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Cardiomyocytes dysfunction

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Massive oedema (fulminant myocarditis)
Postinflammatory DCM

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Chronic inflammation
Pericardial inflammation

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Viruses

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Supraventricular
tachyarrhythmias Mass effect

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Granulomas
Giant cells
Microvascular ischaemia

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Endotehliotropic viruses

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(i.e. PVB19) Bradyarrhythmias
Nonischaemic scar
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Postinflammatory replacement fibrosis
Fatty replacement Chronic inflammation
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Overlapping phenotypes (AC) Ventricular

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tachyarrhythmias

Conduction system disease Gap junction dysfunction

Nonviral infections (i.e. Chagas, Lyme disease, diphtheria) Viruses (i.e. Coxsackie B3)
Selective immune dysregulation (i.e. neonatal lupus) Overlapping phenotypes (i.e. AC)
Mechanical compression (i.e. granulomas, giant cells)