GEAM Study Aims At Assessing the Role of Genetic Testing in Patients with Arrhythmic Myocarditis.

Official title

GEAM: Yield of GEnetic Testing in Arrhythmic Myocarditis

Overview

This study aims to answer multiple unsolved questions in the field of arrhythmic myocarditis. * Improving the diagnostic work-up. While endomyocardial biopsy (EMB) and cardiac magnetic resonance (CMR) constitute the gold standard diagnostic techniques for myocarditis, the role of genetic testing is still unclear. Identifying the subset of patients with CGVs, will contribute to justifying the application of genetic testing in myocarditis. * Generating models for risk prediction. Outcomes and arrhythmic risk stratification remain uncertain for myocarditis. Based on an advanced multimodal work-up, multiparametric risk scores may be created and subsequently validated, in order to predict the arrhythmic risk of specific myocarditis, especially in the case of CGVs. * Identifying disease-specific and genotype-specific signatures. Genotype-phenotype associations are expected to benefit from a multimodal and multiparametric approach, in order to allow etiology-specific features in arrhythmic myocarditis. Most of the current signatures are limited to combined EMB-CMR studies. Signatures would likely benefit from implementing additional parameters, including arrhythmia features and myocardial inflammatory status. * Tailoring treatment strategies. Transcriptional analysis will identify overexpressed genes associated with myocarditis and arrhythmias, representing a possible therapeutic target. A multimodal and multidisciplinary model will integrate phenotype, genotype, and transcriptional profile for a personalized treatment.

Detailed description

Arrhythmic myocarditis is responsible for a significant proportion of out-of-hospital cardiac arrest and death in the young population. Although considered an uncommon feature, arrhythmias may present in myocarditis in both acute and chronic phase, leading to sudden cardiac death (SCD), especially in young males. Overall, the prevalence of undiagnosed myocarditis in post-mortem series ranges from 9% to 44%, involving 2% of infants, 5% of children, and 4-8% of athletes \<40-year-old. Ventricular arrhythmias (VAs) are reported secondary to lymphocytic myocarditis. However, they are more commonly associated with giant cell myocarditis (GCM) and cardiac sarcoidosis (CS), with prevalence of 29% and 55%, respectively In addition, genetically-determined susceptibility might underlie arrhythmic myocarditis.

First, recent reports suggest that pathogenic variants in genes associated with nonischemic cardiomyopathies (NICM), hereby defined as cardiomyopathic gene variants (CGVs) are frequently found in patients with myocarditis proven by CMR and/or EMB, complicated by ventricular arrhythmias (VA). NICM constitute a heterogeneous group of diseases characterized by distinct structural and functional myocardial abnormalities in the absence of obstructive epicardial coronary artery disease. The main NICM overlapping with myocarditis are dilated (DCM) and arrhythmogenic cardiomyopathy (ACM).

Second, myocardial inflammation (M-Infl) has also been recently described in NICM complicated by arrhythmias. Preclinical data support a relevant role of M-Infl in the pathophysiology of AINICM, and its association with adverse outcomes.

Furthermore, there is a growing interest in transcriptomics in the setting of inflammatory and genetic cardiomyopathies. Cardiac transcriptome revealed specific subgroups of patients with early and overt DCM. In animal models of experimental autoimmune myocarditis, transcriptomics, transcriptomics allowed to depict the single-cell landscape of the cardiac immune cells in different phases of the disease. The addition of the cardiac transcriptome to the genotype and phenotype of patients increases the possibility for individualized medicine.

Primary outcome measures

• To provide baseline characterization of VA in the study cohort. [Time frame: Baseline]
• To provide baseline characterization of VA in the study cohort. [Time frame: baseline]
• To provide baseline characterization of VA in the study cohort. [Time frame: baseline]
• To provide follow-up characterization of VA in study cohort. [Time frame: 12 months]
• To provide follow-up characterization of VA in study cohort. [Time frame: 12 months]
• To screen for CGVs in study groups [Time frame: 6 months]
• To screen for CGVs in study groups vs healthy controls [Time frame: 6 months]
• To investigate the pathophysiological basis of arrhythmic myocarditis in study group (exploratory endpoint) [Time frame: during the procedure]

Secondary outcome measures (8)

• To provide baseline characterization of VA according to sex [Time frame: Baseline]
• To provide baseline characterization of VA according to sex [Time frame: baseline]
• To provide baseline characterization of VA according to sex [Time frame: baseline]
• To provide follow-up characterization of VA according to sex [Time frame: 12 months]
• To provide follow-up characterization of VA according to sex [Time frame: 12 months]
• To screen for CGVs in study groups [Time frame: 6 months]
• To screen for CGVs in study groups vs healthy controls [Time frame: 6 months]
• To investigate the pathophysiological basis of arrhythmic myocarditis according to sex (exploratory endpoint) [Time frame: during the procedure]

Eligibility criteria

Inclusion criteria

Patients with ventricular arrhythmias (VA+) and without (VA-)

• Diagnosis of myocarditis proven by EMB (ESC criteria) and/or CMR (updated Lake Louise criteria)
• Age ≥ 10 years
• Baseline ECG telemonitoring
• Written informed consent Healthy controls
• Provided a negative known history of myocarditis
• The sample must have been biobanked as part of the study IMMUNORADAR

Exclusion criteria

Patients with ventricular arrhythmias (VA+) and without (VA-)

• Obstructive coronary artery disease, or lack of coronary angiography/computed tomography (CT) scan in patients >40 years.
• Absent informed consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

Italy · 1 center

• Scientific Institute San Raffaele — Milan

Publications

• Tedesco M, Giannese F, Lazarevic D, Giansanti V, Rosano D, Monzani S, Catalano I, Grassi E, Zanella ER, Botrugno OA, Morelli L, Panina Bordignon P, Caravagna G, Bertotti A, Martino G, Aldrighetti L, Pasqualato S, Trusolino L, Cittaro D, Tonon G. Chromatin Velocity reveals epigenetic dynamics by single-cell profiling of heterochromatin and euchromatin. Nat Biotechnol. 2022 Feb;40(2):235-244. doi: 1 PMID 34635836
• Tiron C, Campuzano O, Fernandez-Falgueras A, Alcalde M, Loma-Osorio P, Zamora E, Caballero A, Sarquella-Brugada G, Cesar S, Garcia-Cuenllas L, Garcia-Alvarez A, Jorda P, Arbelo E, Tomas-Querol C, Pineda V, Martinez D, Brugada R. Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Myocarditis. Circ Genom Precis Med. 2022 Jun;15(3):e003408. doi: 10.1161/CIRCGEN.121.003408. Epub 2 PMID 35522179
• Peretto G, Casella M, Merlo M, Benedetti S, Rizzo S, Cappelletto C, Di Resta C, Compagnucci P, De Gaspari M, Dello Russo A, Casari G, Basso C, Sala S, Sinagra G, Della Bella P, Cooper LT Jr. Inflammation on Endomyocardial Biopsy Predicts Risk of MACE in Undefined Left Ventricular Arrhythmogenic Cardiomyopathy. JACC Clin Electrophysiol. 2023 Jul;9(7 Pt 1):951-961. doi: 10.1016/j.jacep.2022.10.032. PMID 36752457
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):4 PMID 25741868
• Peretto G, De Luca G, Villatore A, Di Resta C, Sala S, Palmisano A, Vignale D, Campochiaro C, Lazzeroni D, De Gaspari M, Rizzo S, Busnardo E, Ferro P, Gianolli L, Basso C, Dagna L, Esposito A, Benedetti S, Della Bella P. Multimodal Detection and Targeting of Biopsy-Proven Myocardial Inflammation in Genetic Cardiomyopathies: A Pilot Report. JACC Basic Transl Sci. 2023 Jul 5;8(7):755-765. doi: 10.10 PMID 37547072
• Peretto G, Sala S, Basso C, Rizzo S, Radinovic A, Frontera A, Limite LR, Paglino G, Bisceglia C, De Luca G, Campochiaro C, Sartorelli S, Palmisano A, Esposito A, Busnardo E, Villatore A, Baratto F, Cireddu M, Marzi A, D'Angelo G, Gulletta S, Vergara P, De Cobelli F, Dagna L, Mazzone P, Della Bella P. Inflammation as a Predictor of Recurrent Ventricular Tachycardia After Ablation in Patients With M PMID 33004129
• Peretto G, Sala S, De Luca G, Marcolongo R, Campochiaro C, Sartorelli S, Tresoldi M, Foppoli L, Palmisano A, Esposito A, De Cobelli F, Rizzo S, Thiene G, Basso C, Dagna L, Caforio ALP, Della Bella P. Immunosuppressive Therapy and Risk Stratification of Patients With Myocarditis Presenting With Ventricular Arrhythmias. JACC Clin Electrophysiol. 2020 Oct;6(10):1221-1234. doi: 10.1016/j.jacep.2020.05 PMID 33092747
• Peretto G, Sala S, Rizzo S, Palmisano A, Esposito A, De Cobelli F, Campochiaro C, De Luca G, Foppoli L, Dagna L, Thiene G, Basso C, Della Bella P. Ventricular Arrhythmias in Myocarditis: Characterization and Relationships With Myocardial Inflammation. J Am Coll Cardiol. 2020 Mar 10;75(9):1046-1057. doi: 10.1016/j.jacc.2020.01.036. PMID 32138965

Identifiers

NCT: NCT06889662 · GEAM

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗