Ignite Creation Date:
2024-10-26 @ 3:40 PM
Last Modification Date:
2024-10-26 @ 3:40 PM
Study NCT ID:
NCT06591260
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-09-07
Brief Title:
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
Sponsor:
None
Organization:
None
Study Overview
Official Title:
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
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MYOPED
Brief Summary:
Myocarditis is a complex inflammatory disease usually occurring secondary to viral infections autoimmune processes or toxic agents Clinical presentations are multiple including chest-pain heart failure and a broad spectrum of arrhythmias In turn outcome is largely unpredictable ranging from mild self-limiting disease to chronic stage and progressive evolution towards dilated cardiomyopathy to rapid adverse outcome in fulminant forms Subsequently myocarditis is often underdiagnosed and undertreated and optimal diagnostic and therapeutic strategies are still to be defined This study both retrospective and prospective originally single-center and subsequently upgraded to multicenter aims at answering multiple questions about myocarditis with special attention to its arrhythmic manifestations
Optimal diagnostic workflow is still to be defined In fact although endomyocardial biopsy EMB is still the diagnostic gold standard especially for aetiology identification it is an invasive technique Furthermore it may lack sensitivity because of sampling errors By converse modern imaging techniques - cardiac magnetic resonance CMR in particular - have been proposed as alternative or complementary diagnostic tool in inflammatory heart disease Other noninvasive diagnostic techniques like delayed-enhanced CT DECT scan or position emission tomography PET scan are under investigation
Biomarkers to identify myocarditis aetiology predisposition prognosis and response to treatment are still to be defined
Arrhythmic myocarditis is largely underdiagnosed and uninvestigated Importantly myocarditis presenting with arrhythmias requires specific diagnostic prognostic and therapeutic considerations At the group leader hospital which is an international referral center for ventricular arrhythmias management and ablation a relevant number of patients with unexplained arrhythmias had myocarditis as underlying aetiology The experience of a dedicated third-level center is going to be shared with other centers to considerably improve knowledge and management of arrhythmic myocarditis
The role of CMR as well as alternative noninvasive imaging techniques in defining myocarditis healing is a relevant issue In particular optimal timing for follow-up diagnostic reassessment is still to be defined in patients with myocarditis at different inflammatory stages either with or without aetiology-dependent treatment
Uniformly-designed studies are lacking to compare myocarditis among different patient subgroups differing by variables like clinical presentations myocarditis stage associated cardiac or extra-cardiac diseases aetiology-based treatment associated arrhythmic manifestations diagnostic workup and devices or ablation treatment
Optimal diagnostic workflow is still to be defined In fact although endomyocardial biopsy EMB is still the diagnostic gold standard especially for aetiology identification it is an invasive technique Furthermore it may lack sensitivity because of sampling errors By converse modern imaging techniques - cardiac magnetic resonance CMR in particular - have been proposed as alternative or complementary diagnostic tool in inflammatory heart disease Other noninvasive diagnostic techniques like delayed-enhanced CT DECT scan or position emission tomography PET scan are under investigation
Biomarkers to identify myocarditis aetiology predisposition prognosis and response to treatment are still to be defined
Arrhythmic myocarditis is largely underdiagnosed and uninvestigated Importantly myocarditis presenting with arrhythmias requires specific diagnostic prognostic and therapeutic considerations At the group leader hospital which is an international referral center for ventricular arrhythmias management and ablation a relevant number of patients with unexplained arrhythmias had myocarditis as underlying aetiology The experience of a dedicated third-level center is going to be shared with other centers to considerably improve knowledge and management of arrhythmic myocarditis
The role of CMR as well as alternative noninvasive imaging techniques in defining myocarditis healing is a relevant issue In particular optimal timing for follow-up diagnostic reassessment is still to be defined in patients with myocarditis at different inflammatory stages either with or without aetiology-dependent treatment
Uniformly-designed studies are lacking to compare myocarditis among different patient subgroups differing by variables like clinical presentations myocarditis stage associated cardiac or extra-cardiac diseases aetiology-based treatment associated arrhythmic manifestations diagnostic workup and devices or ablation treatment
Detailed Description:
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 ie fulminant acute coronary syndrome-like pericarditis-like heart failure non-ischaemic dilatedhypokinetic 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-myocarditismyo-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 ANA 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 ANA 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 andor DECT PET or multiplefusion 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 viralinfective myocarditis immunologists in non-infectiveautoimmune 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 patients39 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 34standard FU34 see below Patients with active myocarditis will undergo 34intensive FU34 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 andor 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-ICDWCD 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-ICDWCD 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 ie 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 N1000
Primary
Diagnostic concordance
Secondary
Inflammatory activity presence type quantification Fibrosis presence type quantification Coronary microvascular disease Comparison between EMB sampling site and abnormal substrate localization at imaging including substrate-guided EMB or alternative biopsy techniques Role of EMB guided by electroanatomical map Diagnostic performance of DECT andor PET especially when CMR is contraindicated Comparison between CMRDECT findings and PET scan including fusion imaging or advanced imaging techniques including strain analysis at echocardiogram Comparison between substrate abnormalities localizations as assessed by second level imaging techniques and arrhythmias type characteristics and origin site Comparison among different diagnostic techniques EMB CMRDECT PET in terms of safety and diagnostic accuracy Evaluation of differential diagnosis with other cardias diseases and particularly with arrhythmogenic cardiomyopathy of any localization left right biventricular to identify updated diagnostic criteria Comparison between information provided by all the techniques above and data from electroanatomical mapping EAM Other analyses
Aim 2 Evaluation of blood exams and biomarkers N1000
Primary
Identification of diagnostic biomarkers Identification of aetiology biomarkers
Secondary
Cardiac and inflammatory biomarkers evaluation in different myocarditis subtypes Identification of biomarkers of inflammatory stage acute vs chronic active vs previous Comparison between local and systemicperipheral inflammation Correlations with EMB and second-level imaging CMR DECT PET findings Identification of genetic factors with any role in predisposition prognosis response to treatment or any other correlation either in the presence or in the absence of underlying cardiomyopathy or autoimmuneinflammatory disease Identification of prognostic biomarkers Identification of biomarkers associated with treatment response Evaluation of any tissueorgan damage or associated comorbidities Study of cardiac autoantibodies Study of any cell tissue genetic or circulating biomarker Correlations with clinical presentations Other analyses
Aim 3 Validation of optimal management of arrhythmic myocarditis N1000
Primary
Evaluation of effects on major endpoints
Secondary
Evaluation of effects on minor endpoints Role of electrophysiological study in risk stratification Role of loop recorders in arrhythmia monitoring Role of transcatheter ablation any technique on arrhythmic outcomes Identification of optimal timing for any electrophysiologicaldevice procedure Role of pharmacological antiarrhythmic treatment Role of aetiology-specific treatment on arrhythmic outcomes Identification of criteria for device implants PM ICD S-ICD CRT-D in myocarditis patients Validation of therapeutic strategies and their optimal timing in patients with supraventricular arrhythmias bradyarrhythmias or ventricular arrhythmias Correlation between arrhythmia typefeatures with any other diagnostic exam performed at baseline or during FU mainly EMB CMRDECTPET echocardiogram stress tests blood exams geneticbloodtissuecell biomarkers Indications and timing for device ICD CRT-D implant in primary prevention based on multiparametric risk assessment and in relation to different general and aetiology-dependent treatments Other analyses
Aim 4 Evaluation of healing timing in myocarditis N500 Primary Any degree of recovery by 3 6 9 12 and 12 months Secondary Comparison of healing times in treated vs untreated patients Correlations between healing times and clinical presentation types Correlations between healing times and any biomarker Correlations between healing times and any outcomes Validation of exercise stress test role after myocarditis healing Evaluation of PET scan or other diagnostic techniques as alternatives to CMR in special populations Other analyses
Aim 5 Subgroup analyses N500 hugely variable in each subanalysis A vs NA groups A myocarditis subgroups NA myocarditis subgroups including fulminant Infective vs autoimmune vs toxic forms Treated by aetiology-driven therapy vs standard cardiological treatment Different myocarditis stages and differential diagnoses Isolated vs in the context o a systemic disease or genetic disease Myocarditis vs perimyocarditis myopericarditis Primary Differences in major outcomes Secondary Differences in minor outcomes Differences in any biomarker Differences in any diagnostic exam Differences in aetiology Differences in predisposition Differences in inflammatory activity Differences in pericardial involvement Differences in systemic involvement Differences in arrhythmias types and features Differences in clinical presentation Differences in treatment response including novel treatments Validation of local aetiologypathophysiology-dependent treatments Validation of biomarkers and imaging techniques in monitoring response to treatment Identification of optimal follow-up timeline Other analyses
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 ie fulminant acute coronary syndrome-like pericarditis-like heart failure non-ischaemic dilatedhypokinetic 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-myocarditismyo-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 ANA 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 ANA 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 andor DECT PET or multiplefusion 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 viralinfective myocarditis immunologists in non-infectiveautoimmune 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 patients39 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 34standard FU34 see below Patients with active myocarditis will undergo 34intensive FU34 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 andor 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-ICDWCD 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-ICDWCD 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 ie 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 N1000
Primary
Diagnostic concordance
Secondary
Inflammatory activity presence type quantification Fibrosis presence type quantification Coronary microvascular disease Comparison between EMB sampling site and abnormal substrate localization at imaging including substrate-guided EMB or alternative biopsy techniques Role of EMB guided by electroanatomical map Diagnostic performance of DECT andor PET especially when CMR is contraindicated Comparison between CMRDECT findings and PET scan including fusion imaging or advanced imaging techniques including strain analysis at echocardiogram Comparison between substrate abnormalities localizations as assessed by second level imaging techniques and arrhythmias type characteristics and origin site Comparison among different diagnostic techniques EMB CMRDECT PET in terms of safety and diagnostic accuracy Evaluation of differential diagnosis with other cardias diseases and particularly with arrhythmogenic cardiomyopathy of any localization left right biventricular to identify updated diagnostic criteria Comparison between information provided by all the techniques above and data from electroanatomical mapping EAM Other analyses
Aim 2 Evaluation of blood exams and biomarkers N1000
Primary
Identification of diagnostic biomarkers Identification of aetiology biomarkers
Secondary
Cardiac and inflammatory biomarkers evaluation in different myocarditis subtypes Identification of biomarkers of inflammatory stage acute vs chronic active vs previous Comparison between local and systemicperipheral inflammation Correlations with EMB and second-level imaging CMR DECT PET findings Identification of genetic factors with any role in predisposition prognosis response to treatment or any other correlation either in the presence or in the absence of underlying cardiomyopathy or autoimmuneinflammatory disease Identification of prognostic biomarkers Identification of biomarkers associated with treatment response Evaluation of any tissueorgan damage or associated comorbidities Study of cardiac autoantibodies Study of any cell tissue genetic or circulating biomarker Correlations with clinical presentations Other analyses
Aim 3 Validation of optimal management of arrhythmic myocarditis N1000
Primary
Evaluation of effects on major endpoints
Secondary
Evaluation of effects on minor endpoints Role of electrophysiological study in risk stratification Role of loop recorders in arrhythmia monitoring Role of transcatheter ablation any technique on arrhythmic outcomes Identification of optimal timing for any electrophysiologicaldevice procedure Role of pharmacological antiarrhythmic treatment Role of aetiology-specific treatment on arrhythmic outcomes Identification of criteria for device implants PM ICD S-ICD CRT-D in myocarditis patients Validation of therapeutic strategies and their optimal timing in patients with supraventricular arrhythmias bradyarrhythmias or ventricular arrhythmias Correlation between arrhythmia typefeatures with any other diagnostic exam performed at baseline or during FU mainly EMB CMRDECTPET echocardiogram stress tests blood exams geneticbloodtissuecell biomarkers Indications and timing for device ICD CRT-D implant in primary prevention based on multiparametric risk assessment and in relation to different general and aetiology-dependent treatments Other analyses
Aim 4 Evaluation of healing timing in myocarditis N500 Primary Any degree of recovery by 3 6 9 12 and 12 months Secondary Comparison of healing times in treated vs untreated patients Correlations between healing times and clinical presentation types Correlations between healing times and any biomarker Correlations between healing times and any outcomes Validation of exercise stress test role after myocarditis healing Evaluation of PET scan or other diagnostic techniques as alternatives to CMR in special populations Other analyses
Aim 5 Subgroup analyses N500 hugely variable in each subanalysis A vs NA groups A myocarditis subgroups NA myocarditis subgroups including fulminant Infective vs autoimmune vs toxic forms Treated by aetiology-driven therapy vs standard cardiological treatment Different myocarditis stages and differential diagnoses Isolated vs in the context o a systemic disease or genetic disease Myocarditis vs perimyocarditis myopericarditis Primary Differences in major outcomes Secondary Differences in minor outcomes Differences in any biomarker Differences in any diagnostic exam Differences in aetiology Differences in predisposition Differences in inflammatory activity Differences in pericardial involvement Differences in systemic involvement Differences in arrhythmias types and features Differences in clinical presentation Differences in treatment response including novel treatments Validation of local aetiologypathophysiology-dependent treatments Validation of biomarkers and imaging techniques in monitoring response to treatment Identification of optimal follow-up timeline Other analyses
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None