Role of Endomyocardial Biopsy and Aetiology-based Treatment in Pediatric Patients with Inflammatory Heart Disease in Arrhythmic and Non-arrhythmic Clinical Presentations: an Integrated Approach for the Optimal Diagnostic and Therapeutic Management (MYOPED)

This study, previously designed as a single-center experience, is multicenter, observational and both retrospective and prospective.

Retrospective phase includes all clinical data occurring before the index event (hospitalization or clinically suspected myocarditis) and myocarditis diagnosis. Prospective phase includes all data following index event and myocarditis diagnosis.

This study has multiple aims.

To compare EMB with noninvasive diagnostic techniques (CMR, DECT, PET scan, either alone or in association).

To assess the role of blood biomarkers for identification of aetiology, predisposition, prognosis, response to treatment, inflammatory activity, clinical presentation.

To describe myocarditis presenting with arrhythmias, with special focus on ventricular arrhythmias at different myocarditis stages and in different clinical contexts. To validate and generalize the leader hospital model for optimal diagnostic and therapeutical management of arrhythmias in myocarditis patients (given the role of the leader hospital as an international referral center for arrhythmias ablation and management).

To evaluate the timing needed for myocarditis healing in different patients subgroups, as assessed by noninvasive imaging techniques (CMR, DECT, PET scan), either alone or in association.

To compare patients subgroups of myocarditis, in terms of epidemiology, aetiology, prognosis, and diagnostic-therapeutical strategies. Among the others, the main study subgroups will be:

A. Arrhythmic vs. non-arrhythmic myocarditis. B. Arrhythmic myocarditis subgroups. C. Non-arrhythmic myocarditis subgroups (i.e.: fulminant, acute coronary syndrome-like, pericarditis-like, heart failure, non-ischaemic dilated/hypokinetic cardiomyopathies of unknown aetiology…).

D. Infectious vs. autoimmune vs. toxic myocarditis. E. Myocarditis treated by aetiology-based treatment vs. isolated cardiac medical treatment.

F. Myocarditis at different disease stages: acute, hyperacute, fulminant, chronic active, post-inflammatory, or active vs. previous vs. non-myocarditis.

G. Myocarditis presenting as organ-specific diseases vs. in the context of a genetic disorder or systemic disease.

H. Myocarditis vs. peri-myocarditis/myo-pericarditis. I. Other analyses.

Any adult patient with clinically suspected myocarditis, of any clinical presentation and any degree of severity, will be considered as suitable for study enrollment.

Patients will undergo diagnostic and therapeutical strategies considered as clinically indicated in a patient-tailored manner, as suggested by international guidelines recommendations and best local clinical practice. Patients will be free of either accepting or refusing any diagnostic or therapeutical proposal. Whenever accepted, data will be simply collected and analyzed.

Based on clinical presentation, patients will be divided into two groups, arrhythmic (group A) and non-arrhythmic (group NA, including any other clinical presentation).

Independently of A/NA groups, all patients will undergo optimal diagnostic and therapeutic strategies, as summarized in panel A. In parallel, special diagnostic and therapeutical strategies will be performed in patients with arrhythmic presentation or evidence of arrhythmias, as shown in panel B. Proposed flowcharts (Panels A and B) represent only an approximate algorithm. Exceptions can be made in single cases, based on clinical indications.

Panel A - Diagnostic and therapeutical workup in all patients. Independently of groups (A/NA), all patients will undergo optimal diagnostic and therapeutical workup, guided by updated scientific evidence merged with the clinical experience of the center.

Baseline diagnostic workup will include: complete blood exams, 12-leads ECG, continuous telemetric monitoring, transthoracic doppler echocardiogram, coronary artery imaging (coronary angiography or CT scan). Any other clinically relevant diagnostic test will be collected.

In life-threatening presentations (cardiogenic shock or malignant arrhythmias), support treatment by optimal medical therapy, inotropic or mechanical circulatory support, and acute-phase arrhythmia management (including cardioversion, defibrillation, or temporary pacing) will be performed, as indicated, before completing diagnostic workup.

Final diagnosis of myocarditis will include, whenever applicable:

A. For stable patients: 1) a second-level imaging technique (CMR as first choice; and/or DECT, PET, or multiple/fusion imaging techniques, based on clinical indications); followed by: 2) EMB, whenever clinically indicated. Blood exams for aetiology screening will be personalized upon clinical indications.

B. For unstable patients: EMB only, as recommended. Blood exams for aetiology screening will be personalized upon clinical indications.

Diagnostic criteria for myocarditis, as assessed by any diagnostic technique, will be defined based on international scientific evidence and will be constantly updated. Similar considerations apply to myocarditis staging and aetiology definition. Whenever not available at local institutions, diagnostic exams can be performed and analyzed at external centers.

All patients with myocarditis (or any alternative final diagnosis), will undergo standard cardiological optimal medical treatment (COMT), as indicated. By converse, aetiology-dependent treatment will be performed only in patients with a final diagnosis of any active (acute, fulminant, chronic active) myocarditis of defined aetiology (EMB-proved). Multidisciplinary assessment, including infective disease specialists (in viral/infective myocarditis), immunologists (in non-infective/autoimmune myocarditis) or any other specialist as needed, will be used to identify indications to treatment, drug choice (either approved or with a justified unapproved indication), treatment duration and safety profile, aiming at the best patients\' interest. Toxic myocarditis will be treated accordingly, by evaluating the opportunity of withdrawing pathogenic noxa.

This protocol will not interfere with local best clinical practice. Patients with non-active myocarditis (previous or healed) or with non-myocarditis, will undergo \"standard FU\"; (see below). Patients with active myocarditis will undergo \"intensive FU\"; (see below).

Independently of FU modalities, diagnostic reassessment will be considered in the presence of at least one of the following instability criteria: a) new unexplained cardiac symptoms (dyspnoea, chest pain, syncope, palpitation); b) new unexplained increase in troponin or natriuretic peptides; c) new imaging abnormal signs; d) new unexplained clinically relevant arrhythmias. Diagnostic reassessment will include second-level imaging and/or EMB, as shown above. Subsequent therapeutical workup will be in line with the above explanations. In stable patients or undergone myocarditis healing, exercise stress test will be obtained, whenever possible.

Panel B - Diagnostic and therapeutical workup of patients with arrhythmias In parallel with (and independently of) Panel A content, patients with arrhythmias (group A) will undergo specific diagnostic and therapeutical management for arrhythmias, as a result of the integration between international guidelines recommendations and the experience of an international referral center for arrhythmia management and ablation.

To oversimplify, 4 groups of patients will be considered.

Group 1: major ventricular arrhythmias, including haemodynamically unstable VT (hu-VT) and ventricular fibrillation (VF).

After electrical stabilization and support treatment (panel A), indication to secondary prevention ICD implant will be multiparametric and patient-tailored. In patients with active myocarditis, subcutaneous ICD (S-ICD) or wearable CD (WCD) will be considered. Antiarrhythmic drugs will be considered in all Group 1 patients. In addition, all Group 1 patients will undergo COMT and aetiology-dependent treatment whenever applicable (panel A). Ablation of ventricular arrhythmias will be considered in patients with severe arrhythmic presentation, or symptomatic, or refractory to optimal medical treatment. Electrophysiological study (EPS) may be used in selected cases. A cardiac resynchronization therapy with defibrillator function (CRT-D) will replace ICD whenever indicated.

Group 2: other ventricular arrhythmias, including high-burden (hb) premature ventricular complexes (PVC); nonsustained VT (NSVT); haemodynamically stable VT (hs-VT).

Whenever clinically indicated, Group 2 patients will undergo invasive EPS (or in alternative noninvasive programmed ventricular stimulation in ICD carriers) to stratify arrhythmic risk. Patients with positive EPS will undergo ICD (or S-ICD/WCD) as in Group 1. Patients with negative EPS, as well as Group 2 cases not undergoing EPS, will undergo watchful waiting strategy (always with an intensive FU) with or without loop recorder implant: in these cases, ICD (or S-ICD/WCD) will be implanted only following documentation of relevant VA in FU. In addition, all Group 2 patients will undergo antiarrhythmic treatment, COMT and aetiology-dependent treatment whenever applicable (panel A). In symptomatic or drug-refractory cases, ablation of ventricular arrhythmias will be considered. A CRT-D will replace ICD whenever indicated.

Group 3: bradyarrhythmias, including advanced (2nd type II or 3rd degree) atrioventricular block (AVB); critical sinus pauses from sinus node disease (SND).

After electrical stabilization and support treatment (panel A), including the use of temporary pacemaker as a bridge-to-decision, patients will undergo watchful waiting strategy or definitive device implant. Instead of a pacemaker (PM), ICD will be considered in the presence of high-risk criteria for ventricular tachyarrhythmias, including: a) overlap with Group 1 presentation; b) overlap with Group 2 presentation, especially in the presence of positive EPS; c) other indications for primary prevention ICD implant (severe systolic dysfunction); d) signs of increased tachyarrhythmic risk (scar signs); e) patients with special aetiologies leading to an increased tachyarrhythmic risk (i.e: cardiac sarcoid, giant cell myocarditis, Chagas disease, overlapping genetic syndromes). In addition, all Group 3 patients will undergo COMT and aetiology-dependent treatment whenever applicable (panel A). A CRT-D or a CRT-P will replace ICD or PM, respectively, whenever indicated.

Group 4: supraventricular arrhythmias, including atrial fibrillation (AF); atrial flutter (AFlu); atrial tachycardia (AT).

Following acute-phase rate control (RaC), stable rhythm control (RyC) strategy will be considered as the therapeutical target, together with appropriate anticoagulation, as needed. Normal sinus rhythm will be obtained through either electrical or pharmacological cardioversion. In patients with unsuccessful attempts of sinus rhythm conversion, optimal treatment of active myocarditis will be considered as a primary target. Following myocarditis healing, in the presence of persistent arrhythmias, patients will be considered for RyC via electrical or pharmacological cardioversion. Transcatheter ablation will be an option for patients with drug-symptomatic, recurrent or refractory arrhythmias. Permanent RaC strategy will be considered only in non responders. Widespread use of implantable loop recorders will apply, as clinically indicated. In addition, all Group 4 patients will undergo COMT and aetiology-dependent treatment whenever applicable (panel A).

Aims in detail. Aim 1 Comparison between EMB and second level imaging findings (N=1000)

Primary:

Diagnostic concordance

• Occurrence of minor arrhythmic events [Срок оценки: At baseline assessment and through study completion (up to 10 years)]
• Any modification in imaging parameters [Срок оценки: At baseline assessment and through study completion (up to 10 years)]
• Any modification in clinical parameters [Срок оценки: By 10-year follow-up]
• Any modification in New York Heart Association class [Срок оценки: By 10-year follow-up]
• Any modification in exercise peak heart rate [Срок оценки: By 10-year follow-up]
• Any modification in exercise peak systolic blood pressure [Срок оценки: By 10-year follow-up]
• Any modification in exercise walking distance [Срок оценки: By 10-year follow-up]
• Any modification in exercise oxygen consumption [Срок оценки: By 10-year follow-up]
• Any modification in exercise-induced arrhythmias [Срок оценки: By 10-year follow-up]
• Identification of the prevalence of associated diseases [Срок оценки: By 10-year follow-up]
• Any modification in arrhythmia burden [Срок оценки: By 10-year follow-up]
• Any modification in arrhythmia morphology [Срок оценки: By 10-year follow-up]