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
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Occurrence of major cardiac events
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Other
入排标准
- 年龄范围
- 0 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Written informed consent.
- •Age < 18 years.
- •Clinically suspected myocarditis.
- •Enrollment performed by one of the participating Centers.
排除标准
- •Absence of written informed consent.
- •Age > 18 years (adults)
结局指标
主要结局
Occurrence of major cardiac events
时间窗: By 10-year follow-up
death; cardiac death; malignant ventricular arrhythmias ( = VT, VF, appropriate ICD therapy); heart transplantation; end-stage heart failure
Assessment of diagnostic accuracy (in terms of true/false positive/negative rates) between EMB and second level imaging findings - Primary
时间窗: By 10-year follow-up
Diagnostic concordance in terms of sensitivity, specificity, positive predictive value, negative predictive value
Comparison of troponin values in patients with different aetiologies
时间窗: At baseline assessment
Measurement of troponin blood concentration (ng/l) and comparison of values found in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Description of troponin values changes during follow-up
时间窗: By 10-year follow-up
Measurement of troponin blood concentration (ng/l) during follow-up, and description of its relative variation compared to baseline assessment.
Comparison of creatine-phosphokinase values in patients with different aetiologies
时间窗: At baseline assessment
Measurement of creatine-phosphokinase (U/l) and comparison of values found in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Description of creatine-phosphokinase values changes during follow-up
时间窗: By 10-year follow-up
Measurement of creatine-phosphokinase (U/l) during follow-up, and description of its relative variation compared to baseline assessment.
Comparison of natriuretic peptides values in patients with different aetiologies
时间窗: At baseline assessment
Measurement of natriuretic peptides (pg/ml) and comparison of values found in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Description of natriuretic peptides values changes during follow-up
时间窗: By 10-year follow-up
Measurement of natriuretic peptides (pg/ml) during follow-up, and description of its relative variation compared to baseline assessment.
Comparison of C-reactive protein values in patients with different aetiologies
时间窗: At baseline assessment
Measurement of C-reactive protein (mg/l) and comparison of values found in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Description of C-reactive protein values changes during follow-up
时间窗: By 10-year follow-up
Measurement of C-reactive protein (mg/l) during follow-up, and description of its relative variation compared to baseline assessment.
Comparison of erythrocyte sedimentation rate values in patients with different aetiologies
时间窗: At baseline assessment
Measurement of erythrocyte sedimentation rate (mm/h) and comparison of values found in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Description of erythrocyte sedimentation rate values changes during follow-up
时间窗: By 10-year follow-up
Measurement of erythrocyte sedimentation rate (mm/h) during follow-up, and description of its relative variation compared to baseline assessment.
Comparison of procalcitonin values in patients with different aetiologies
时间窗: By 10-year follow-up
Measurement of procalcitonin (mcg/ml) and comparison of values found in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Comparison of serum uric acid values in patients with different aetiologies
时间窗: By 10-year follow-up
Measurement of serum uric acid (mg/dl) and comparison of values found in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Comparison of leukocyte values in patients with different aetiologies
时间窗: By 10-year follow-up
Measurement of leukocytes (U/ml) in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Comparison of hemoglobin values in patients with different aetiologies
时间窗: By 10-year follow-up
Measurement of hemoglobin (g/dl) in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Comparison of platelet values in patients with different aetiologies
时间窗: By 10-year follow-up
Measurement of platelets (U/ml) in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Comparison of thyroid function in patients with different aetiologies
时间窗: By 10-year follow-up
Measurement of thyroid stimulating hormone (mU/ml; total and fractions) in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Comparison of organ damage in patients with different aetiologies
时间窗: By 10-year follow-up
Measurement of organ damage by application of the Sequential Organ Failure Assessment (SOFA) score in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Reporting the results of autoimmunity screening
时间窗: By 10-year follow-up
Measurement of circulating autoantibodies (U/ml) in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Reporting the results of infectious screening
时间窗: By 10-year follow-up
Measurement of viral antibodies (U/ml) in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Reporting the results of toxicology screening
时间窗: By 10-year follow-up
Measurement of toxic urynalisis (U/ml) in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Reporting the results of genetic test screening
时间窗: By 10-year follow-up
Reporting the results of next generation sequencing analysis (mutation type) in patients with different aetiologies (viral; autoimmune; toxic; non-myocarditis).
Validation of optimal management of arrhythmic myocarditis by comparing the occurrence of major cardiac events in patients undergoing different therapeutic strategies - Primary
时间窗: By 10-year follow-up
Evaluation of the occurrence of major cardiac events (death; cardiac death; malignant ventricular arrhythmias= VT, VF, appropriate ICD therapy; heart transplantation; end-stage heart failure) in patient groups differing for: 1-General cardiac treatment. 2-Specific aetiology-driven treatment. 3-Cardiac device implant. 4-Arrhythmia ablation.
Evaluation of healing timing in myocarditis - Primary
时间窗: By 10-year follow-up
Any degree of recovery through analysis of CMR, other second level imaging, echocardiogram, cardiac and inflammatory biomarkers, symptoms, arrhythmia burden, and exercise tolerance.
Comparison of the incidence of major cardiac events in different patient
时间窗: At baseline assessment
Evaluation of the occurrence of major cardiac events (death; cardiac death; malignant ventricular arrhythmias= VT, VF, appropriate ICD therapy; heart transplantation; end-stage heart failure) in different patient groups: A. Arrhythmic myocarditis subgroups (1-4). B. Non-arrhythmic myocarditis subgroups (i.e.: fulminant, acute coronary syndrome-like, pericarditis-like, heart failure, nonischaemic dilated /hypokinetic cardiomyopathies of unknown aetiology...). C.Infectious vs. autoimmune vs. toxic myocarditis. D.Myocarditis treated by aetiology-based treatment vs. isolated cardiac medical treatment. E.Myocarditis at different disease stages: acute, hyperacute, fulminant, chronic active, post-inflammatory, or active vs. previous vs. non-myocarditis. F. Myocarditis presenting as organ-specific diseases vs. in the context of a genetic disorder or systemic disease. G.Myocarditis vs. peri-myocarditis/myo-pericarditis. H.Other subgroups.
Comparison of the incidence of major cardiac events in different patient subgroups - Primary
时间窗: By 10-year follow-up
Evaluation of the occurrence of major cardiac events (death; cardiac death; malignant ventricular arrhythmias= VT, VF, appropriate ICD therapy; heart transplantation; end-stage heart failure) in different patient groups: A. Arrhythmic myocarditis subgroups (1-4). B. Non-arrhythmic myocarditis subgroups (i.e.: fulminant, acute coronary syndrome-like, pericarditis-like, heart failure, nonischaemic dilated /hypokinetic cardiomyopathies of unknown aetiology...). C.Infectious vs. autoimmune vs. toxic myocarditis. D.Myocarditis treated by aetiology-based treatment vs. isolated cardiac medical treatment. E.Myocarditis at different disease stages: acute, hyperacute, fulminant, chronic active, post-inflammatory, or active vs. previous vs. non-myocarditis. F. Myocarditis presenting as organ-specific diseases vs. in the context of a genetic disorder or systemic disease. G.Myocarditis vs. peri-myocarditis/myo-pericarditis. H.Other subgroups.
次要结局
- Occurrence of minor arrhythmic events(At baseline assessment and through study completion (up to 10 years))
- Any modification in imaging parameters(At baseline assessment and through study completion (up to 10 years))
- Any modification in clinical parameters(By 10-year follow-up)
- Any modification in New York Heart Association class(By 10-year follow-up)
- Any modification in exercise peak heart rate(By 10-year follow-up)
- Any modification in exercise peak systolic blood pressure(By 10-year follow-up)
- Any modification in exercise walking distance(By 10-year follow-up)
- Any modification in exercise oxygen consumption(By 10-year follow-up)
- Any modification in exercise-induced arrhythmias(By 10-year follow-up)
- Identification of the prevalence of associated diseases(By 10-year follow-up)
- Any modification in arrhythmia burden(By 10-year follow-up)
- Any modification in arrhythmia morphology(By 10-year follow-up)
- Any modification in arrhythmia regularity(By 10-year follow-up)
- Any modification in arrhythmia tolerance(By 10-year follow-up)
- Prevalence of coronary circulation abnormalities(By 10-year follow-up)
- Prevalence of electrophysiological study(By 10-year follow-up)
- Results of electrophysiological study(By 10-year follow-up)
- Prevalence of ventricular arrhythmia ablation(By 10-year follow-up)
- Results of ventricular arrhythmia ablation(By 10-year follow-up)
- Prevalence of supraventricular arrhythmia ablation(By 10-year follow-up)
- Results of supraventricular arrhythmia ablation(By 10-year follow-up)
- Prevalence of cardiac device implants(By 10-year follow-up)
- Comparison of arrhythmia detection by continuous vs. non-continuous monitoring(By 10-year follow-up)
- Assessment of the withdrawal timing of non-permanent cardiac devices(By 10-year follow-up)
- Prevalence of CT scan(By 10-year follow-up)
- Results of CT scan(By 10-year follow-up)
- Prevalence of PET scan(By 10-year follow-up)
- Results of PET scan(By 10-year follow-up)
- Results of electroanatomical mapping(By 10-year follow-up)
- Prevalence of electroanatomical mapping(By 10-year follow-up)
- Prevalence of stress tests(By 10-year follow-up)
- Results of stress tests - ECG(By 10-year follow-up)
- Results of stress tests - wall motion abnormalities(By 10-year follow-up)
- Results of stress tests - coronary flow reserve(By 10-year follow-up)
- Myocarditis recurrences(At baseline assessment (including past medical history) and through study completion (up to 10 years))
- Response to treatment - systolic function(At baseline assessment and through study completion (up to 10 years))
- Response to treatment - malignant ventricular arrhythmias(At baseline assessment and through study completion (up to 10 years))
- Prognostic risk stratification - malignant ventricular arrhythmias(Through study completion (up to 10 years))
- Prognostic risk stratification - heart failure(Through study completion (up to 10 years))
- Prognostic risk stratification - cardiac death(Through study completion (up to 10 years))
- Description of multidisciplinary workup models(At baseline assessment and through study completion (up to 10 years))
- Prognostic impact of multidisciplinary workup models(At baseline assessment and through study completion (up to 10 years))
- Comparison between EMB and second level imaging findings in detecting myocardial inflammation(At baseline assessment and through study completion (up to 10 years))
- Comparison between EMB and second level imaging findings in detecting myocardial fibrosis(At baseline assessment and through study completion (up to 10 years))
- Comparison between EMB and second level imaging findings in detecting coronary microvascular disease(At baseline assessment and through study completion (up to 10 years))
- Comparison between EMB sampling site and abnormal substrate localization at imaging(At baseline assessment and through study completion (up to 10 years))
- Comparison between substrate-guided vs. standard EMB sampling. Substrate defined by any second level imaging technique (CMR, PET, DECT, electroanatomical mapping). EMB sampling performed at any cardiac site.(At baseline assessment and through study completion (up to 10 years))
- Comparison between different second level imaging findings(At baseline assessment and through study completion (up to 10 years))
- Associations between arrhythmia morphology and substrate localization(At baseline assessment and through study completion (up to 10 years))
- Associations between arrhythmia morphology and inflammatory stage(At baseline assessment and through study completion (up to 10 years))
- Associations between arrhythmia regularity and inflammatory stage(At baseline assessment and through study completion (up to 10 years))
- Prevalence of adverse effects associated with EMB(At baseline assessment and through study completion (up to 10 years))
- Prevalence of adverse effects associated with immunosuppressive therapy(At baseline assessment and through study completion (up to 10 years))
- Prevalence of overlap syndromes and differential diagnoses(At baseline assessment and through study completion (up to 10 years))
- Comparison between histology abnormalities and arrhythmias(At baseline assessment and through study completion (up to 10 years))
- Comparison between genetic test results and myocarditis features(At baseline assessment and through study completion (up to 10 years))
- Corrrelation between troponin abnormalities and follow-up occurrence of malignant ventricular arrhythmias(At baseline assessment and through study completion (up to 10 years))
- Corrrelation between troponin abnormalities and follow-up occurrence of heart failure(At baseline assessment and through study completion (up to 10 years))
- Corrrelation between NTproBNP abnormalities and follow-up occurrence of malignant ventricular arrhythmias(At baseline assessment and through study completion (up to 10 years))
- Corrrelation between NTproBNP abnormalities and follow-up occurrence of heart failure(At baseline assessment and through study completion (up to 10 years))
- Corrrelation between C-reactive protein abnormalities and follow-up occurrence of malignant ventricular arrhythmias(At baseline assessment and through study completion (up to 10 years))
- Corrrelation between C-reactive protein abnormalities and follow-up occurrence of heart failure(At baseline assessment and through study completion (up to 10 years))
- Corrrelation between histological abnormalities and follow-up occurrence of malignant ventricular arrhythmias(At baseline assessment and through study completion (up to 10 years))
- Corrrelation between histological abnormalities and follow-up occurrence of heart failure(At baseline assessment and through study completion (up to 10 years))
- Comparison of minor arrhythmic events in patients undergoing different(At baseline assessment and through study completion (up to 10 years))
- Comparison of left ventricular end-diastolic volume in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of right ventricular end-diastolic volume in patients undergoing(At baseline assessment and through study completion (up to 10 years))
- Comparison of left ventricular ejection fraction in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of right ventricular ejection fraction in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of biventricular global longitudinal strain in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of left atrial volume in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of left ventricular diastolic dysfunction in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of pericardial abnormalities in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of valvular abnormalities in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of CMR abnormalities in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of DECT abnormalities in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of PET abnormalities in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of electroanatomical mapping abnormalities in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of symptoms in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of exercise tolerance in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of troponin in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of NTproBNP in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of C-reactive protein in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of arrhythmia burden in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of arrhythmia morphology in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of arrhythmia regularity in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of arrhythmia tolerance in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Evaluation of myocarditis healing time in patients undergoing different therapeutic strategies(At baseline assessment and through study completion (up to 10 years))
- Comparison of the incidence of minor arrhythmic events in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of left ventricular ejection fraction in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of CMR abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of DECT abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of PET abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of electroanatomical abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of troponin abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of NTproBNP abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of C-reactive protein abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of autoantibodies abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of genetic test abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of histological abnormalities in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of exercise tolerance in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of arrhythmia burden in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of arrhythmia morphology in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of arrhythmia regularity in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
- Comparison of myocarditis healing time in different patient subgroups(At baseline assessment and through study completion (up to 10 years))
研究者
Giovanni Peretto
MD, Principal Investigator
Scientific Institute San Raffaele