Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Myocarditis
2022; Wolters Kluwer; Volume: 15; Issue: 3 Linguagem: Inglês
10.1161/circgen.121.003408
ISSN2574-8300
AutoresColoma Tirón, Óscar Campuzano, Anna Fernàndez-Falgueras, Mireia Alcalde, Pablo Loma-Osorio, Elisabet Zamora, A. Caballero, Geòrgia Sarquella-Brugada, Sergi César, Luisa Álvarez, Ana García‐Álvarez, Paloma Jordà, Elena Arbelo, Carlos Tomás-Querol, Víctor Pineda, Daniel Martı́nez, Ramón Brugada,
Tópico(s)Cardiac Structural Anomalies and Repair
ResumoHomeCirculation: Genomic and Precision MedicineVol. 15, No. 3Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Myocarditis Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBPrevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Myocarditis Coloma Tiron, MD, Oscar Campuzano, PhD, Anna Fernández-Falgueras, MSc, Mireia Alcalde, PhD, Pablo Loma-Osorio, MD, PhD, Elisabet Zamora, MD, PhD, Angel Caballero, MD, Georgia Sarquella-Brugada, MD, PhD, Sergi Cesar, MD, Luisa Garcia-Cuenllas, MD, Ana García-Álvarez, MD, Paloma Jordà, MD, Elena Arbelo, MD, PhD, Carlos Tomás-Querol, MD, Victor Pineda, MD, PhD, Daniel Martínez, MD, PhD and Ramon Brugada, MD, PhD Coloma TironColoma Tiron https://orcid.org/0000-0002-8424-5907 Inherited Cardiac Diseases Unit, Department of Cardiology (C.T., A.F.-F., R.B.), Hospital Universitari Dr Josep Trueta, Girona, Spain. Medical Science Department, School of Medicine (C.T., O.C., P.L.-O., G.S.-B., R.B.) Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain (C.T., O.C., E.Z., A.G., E.A., R.B.). , Oscar CampuzanoOscar Campuzano https://orcid.org/0000-0001-5298-5276 Medical Science Department, School of Medicine (C.T., O.C., P.L.-O., G.S.-B., R.B.) Cardiovascular Genetics Center, Institut d'Investigacions Biomèdiques de Girona (O.C., A.F.-F., M.A., R.B.), University of Girona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain (C.T., O.C., E.Z., A.G., E.A., R.B.). Biochemistry and Molecular Genetics Department, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (O.C.), University of Barcelona, Spain. , Anna Fernández-FalguerasAnna Fernández-Falgueras Inherited Cardiac Diseases Unit, Department of Cardiology (C.T., A.F.-F., R.B.), Hospital Universitari Dr Josep Trueta, Girona, Spain. Cardiovascular Genetics Center, Institut d'Investigacions Biomèdiques de Girona (O.C., A.F.-F., M.A., R.B.), University of Girona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain (C.T., O.C., E.Z., A.G., E.A., R.B.). , Mireia AlcaldeMireia Alcalde Cardiovascular Genetics Center, Institut d'Investigacions Biomèdiques de Girona (O.C., A.F.-F., M.A., R.B.), University of Girona, Spain. , Pablo Loma-OsorioPablo Loma-Osorio https://orcid.org/0000-0002-3839-539X Intensive Cardiac Care Unit, Department of Cardiology (P.L.-O.), Hospital Universitari Dr Josep Trueta, Girona, Spain. Medical Science Department, School of Medicine (C.T., O.C., P.L.-O., G.S.-B., R.B.) , Elisabet ZamoraElisabet Zamora Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain (C.T., O.C., E.Z., A.G., E.A., R.B.). Cardiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (E.Z., A.C.). Medical Science Department, School of Medicine, Universitat Autònoma de Barcelona, Spain (E.Z.). , Angel CaballeroAngel Caballero Cardiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (E.Z., A.C.). , Georgia Sarquella-BrugadaGeorgia Sarquella-Brugada https://orcid.org/0000-0002-6857-8904 Medical Science Department, School of Medicine (C.T., O.C., P.L.-O., G.S.-B., R.B.) Arrhythmias Unit, Hospital Sant Joan de Déu (G.S.-B., S.C., L.G.-C.), University of Barcelona, Spain. , Sergi CesarSergi Cesar https://orcid.org/0000-0002-2798-1756 Arrhythmias Unit, Hospital Sant Joan de Déu (G.S.-B., S.C., L.G.-C.), University of Barcelona, Spain. , Luisa Garcia-CuenllasLuisa Garcia-Cuenllas https://orcid.org/0000-0001-8614-7406 Arrhythmias Unit, Hospital Sant Joan de Déu (G.S.-B., S.C., L.G.-C.), University of Barcelona, Spain. , Ana García-ÁlvarezAna García-Álvarez https://orcid.org/0000-0002-1718-2424 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain (C.T., O.C., E.Z., A.G., E.A., R.B.). Medical Science Department, School of Medicine, Universitat Autònoma de Barcelona, Spain (E.Z.). Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain (A.G., P.J., E.A.). , Paloma JordàPaloma Jordà https://orcid.org/0000-0002-9236-1713 Institut Clínic Cardiovascular, Hospital Clínic (A.G., P.J., E.A.), Universitat de Barcelona, Spain. Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain (A.G., P.J., E.A.). , Elena ArbeloElena Arbelo https://orcid.org/0000-0003-0424-6393 Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain (C.T., O.C., E.Z., A.G., E.A., R.B.). Institut Clínic Cardiovascular, Hospital Clínic (A.G., P.J., E.A.), Universitat de Barcelona, Spain. , Carlos Tomás-QuerolCarlos Tomás-Querol Department of Cardiology, Hospital Universitario Arnau de Vilanova, Lleida, Spain (C.T.-Q.). Institut de Recerca Biomèdica de Lleida, Spain (C.T.-Q.). , Victor PinedaVictor Pineda https://orcid.org/0000-0002-2227-0867 Radiology Department (V.P.), Hospital Universitari Dr Josep Trueta, Girona, Spain. , Daniel MartínezDaniel Martínez https://orcid.org/0000-0001-7492-5311 Pathology Department, Hospital Clínic (D.M.), Universitat de Barcelona, Spain. and Ramon BrugadaRamon Brugada Correspondence to: Ramon Brugada, MD, PhD, Servei de Cardiologia, Hospital Josep Trueta, Avinguda França s/n, Girona 17007, Spain. Email E-mail Address: [email protected] https://orcid.org/0000-0001-6607-3032 Inherited Cardiac Diseases Unit, Department of Cardiology (C.T., A.F.-F., R.B.), Hospital Universitari Dr Josep Trueta, Girona, Spain. Medical Science Department, School of Medicine (C.T., O.C., P.L.-O., G.S.-B., R.B.) Cardiovascular Genetics Center, Institut d'Investigacions Biomèdiques de Girona (O.C., A.F.-F., M.A., R.B.), University of Girona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain (C.T., O.C., E.Z., A.G., E.A., R.B.). Originally published6 May 2022https://doi.org/10.1161/CIRCGEN.121.003408Circulation: Genomic and Precision Medicine. 2022;15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 6, 2022: Ahead of Print The relationship between myocarditis and genetic cardiomyopathies has been described previously,1–3 but genetic testing in patients with myocarditis is not yet currently advocated. With the aim to clarify its value, we have genetically analyzed a retrospective cohort of 28 patients with myocarditis admitted in a 10-year period to further deepen the understanding of this association.Myocarditis was diagnosed following the European Society of Cardiology criteria,4 taking into account clinical presentation, ECG, myocardial cytolysis markers, echocardiography, and tissue characterization by cardiac magnetic resonance imaging or endomyocardial biopsy. Patients were classified into 2 groups depending on clinical severity. Severe myocarditis was defined as severe ventricular dysfunction (left ventricular ejection fraction, <30%), cardiogenic shock, or sustained ventricular arrhythmias. The rest of cases were classified as nonsevere myocarditis. Family history was obtained by clinical interview.A genetic test including 71 cardiomyopathy-associated genes was performed. Pathogenicity of variants was defined according to the current American College of Medical Genetics and Genomics guidelines. The genetic study was considered positive when a pathogenic variant (PV) or a likely PV (P/LPV) was detected.The data supporting the findings of this study are available from the corresponding author upon request. The study conforms to the principles of the Helsinki II Declaration. The study was approved by the institutional review board.The cohort with severe myocarditis (n=12) was composed of 7 men (mean age, 41 years; range, 25–74) and 5 women (mean age, 30 years; range, 15–54). A total of 4 genetic rare P/LPVs were identified: a novel frameshift deletion in FLNC (p.Pro1555Leufs*52) in a 25-year-old man presenting with sustained ventricular arrhythmias, a novel gross deletion from exons 2 (partial) to 5 in RBM20 (c.1104_1585+467del) in a 37-year-old woman presenting with cardiogenic shock (Figure [A–C]), and a previously reported nonsense variant in BAG3 (p.(Gln88*)) identified in 2 unrelated patients, both presenting with cardiogenic shock and requiring heart transplantation: a 30-year-old man (Figure [D–F]) without family history of cardiomyopathies and a 15-year-old woman with family history of dilated cardiomyopathy.Download figureDownload PowerPointFigure. Cardiac magnetic resonance images (MRIs) of the patient with a likely pathogenic variant in RBM20. A, End diastolic frame from short-axis cine MRI shows severe left ventricular dilatation with mild pericardial effusion. B, Short-axis T2-weighted STIR image shows subepicardial increased signal (arrow) indicating focal edema in the anterior wall of the left ventricle, and (C) short-axis delayed-enhancement image shows an area of subepicardial enhancement in the anterior wall with nonischemic distribution suggesting acute myocarditis.Endomyocardial biopsy images of the patient with a pathogenic variant in BAG3.D, Endomyocardial biopsy shows a focus of necrotic cardiomyocytes with few lymphocytes, ×400. E, C9 stain highlights the necrotic myocardial cells, ×400. F, CD3 stain shows mild lymphocytic infiltrate at the periphery of a necrotic area.Among remaining patients with severe myocarditis (n=8), either the genetic study was negative or a variant of unknown significance was detected. None of them had a family history of cardiomyopathies.The cohort with nonsevere myocarditis (n=16) was composed of 15 men (mean age, 35 years; range, 18–68) and one 20-year-old woman. One nonsense PV was identified in DSP (p.(Gln113*)) in the woman. She presented with chest pain, elevated cardiac enzymes, pericardial effusion, and normal left ventricular ejection fraction and had a family history of arrhythmogenic cardiomyopathy.In remaining patients with nonsevere myocarditis (n=15), either the genetic study was negative or variants of unknown significance were detected. None of them had a family history of cardiomyopathies.Several recent studies have demonstrated the existence of rare PV in cardiomyopathy-associated genes in patients with myocardial diseases that had been so far exclusively attributed to environmental factors. Therefore, it has been seen that up to 12% of patients with alcoholic and chemotherapy-induced cardiomyopathy5 are carriers of novel rare P/LPV in cardiomyopathy-associated genes.To date, myocarditis has also been considered mainly an environmental disease, but it has been seen that sudden cardiac death cases attributed to myocarditis after autopsy carry rare PV-causing cardiomyopathies in their relatives,2 and a high proportion of rare PV has been found in selected patients with myocarditis and right ventricular involvement or sustained ventricular arrhythmias.In the present work, 5 of 28 patients (17.9% [95% CI, 7.9–35.6]; 3 women and 2 men) experiencing myocarditis carried a P/LPV in cardiomyopathy-associated genes. Regarding pathogenicity classification, 4 of them were novel, suggesting a deleterious role, and one has been previously described as definitively disease causing.According to predefined clinical groups, 4 of 12 patients with severe myocarditis (33.3% [95% CI, 13.8–60.9]) carried a P/LPV. Among patients with nonsevere myocarditis, only 1 of 16 (6.3% [95% CI, 1.1–28.3]) carried a PV. This difference in P/LPV frequency between severe and nonsevere myocarditis has not been described before. The data suggest that genetics could not only influence myocardium vulnerability to inflammation but also severity of presentation.In this series, 2 of 2 (100%) patients with a family history of cardiomyopathy carried a P/LPV. Thus, a detailed family history in a patient presenting with myocarditis is of paramount importance.1,2In summary, our data confirm the role of genetic testing in cardiomyopathy-associated genes in severe forms of myocarditis patients and in those with a family history of cardiomyopathy for early identification of relatives at risk.This study was performed in a limited number of patients. Further studies in larger cohorts and family screening should be performed to confirm our results. It should be noted that being a retrospective study, patients who died have not been included. Though, our previous results, in autopsy patients, also confirmed this genetic hypothesis.2Article InformationSources of FundingThis work was supported by Obra Social La Caixa Foundation (LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), Fondo Investigacion Sanitaria (FIS PI16/01203 and FIS PI17/01690) from Instituto Salud Carlos III (ISCIII), and Fundacio Privada Daniel Bravo Andreu. Centro de Investigación en Red en Enfermedades Cardiovasculares is an initiative of the ISCIII, Spanish Ministry of Economy.Disclosures Dr Brugada is a consultant for Genincode. The other authors report no conflicts.FootnotesFor Sources of Funding and Disclosures, see page 256.Correspondence to: Ramon Brugada, MD, PhD, Servei de Cardiologia, Hospital Josep Trueta, Avinguda França s/n, Girona 17007, Spain. Email [email protected]orgReferences1. Ader F, Surget E, Charron P, Redheuil A, Zouaghi A, Maltret A, Marijon E, Denjoy I, Hermida A, Fressart V, et al. Inherited cardiomyopathies revealed by clinically suspected myocarditis: highlights from genetic testing.Circ Genom Precis Med. 2020; 13:e002744. doi: 10.1161/CIRCGEN.119.002744LinkGoogle Scholar2. Campuzano O, Fernández-Falgueras A, Sarquella-Brugada G, Sanchez O, Cesar S, Mademont I, Allegue C, Mates J, Pérez-Serra A, Coll M, et al. A genetically vulnerable myocardium may predispose to myocarditis.J Am Coll Cardiol. 2015; 66:2913–2914. doi: 10.1016/j.jacc.2015.10.049CrossrefMedlineGoogle Scholar3. Leone O, Pieroni M, Rapezzi C, Olivotto I. The spectrum of myocarditis: from pathology to the clinics.Virchows Arch. 2019; 475:279–301. doi: 10.1007/s00428-019-02615-8CrossrefMedlineGoogle Scholar4. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, Fu M, Heliö T, Heymans S, Jahns R, et al; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.Eur Heart J. 2013; 34:2636–48, 2648a. doi: 10.1093/eurheartj/eht210CrossrefMedlineGoogle Scholar5. Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, Smith AM, Toepfer CN, Getz K, Gorham J, Patel P, et al. Genetic variants associated with cancer therapy-induced cardiomyopathy.Circulation. 2019; 140:31–41. doi: 10.1161/CIRCULATIONAHA.118.037934LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByMonda E and Limongelli G (2022) Is There a Role for Genetic Testing in Patients With Myocarditis?, Circulation: Genomic and Precision Medicine, 15:5, (e003824), Online publication date: 1-Oct-2022.Qu H, Feldman A and Hakonarson H Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies, Journal of the American Heart Association, June 2022Vol 15, Issue 3 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.121.003408PMID: 35522179 Originally publishedMay 6, 2022 KeywordscardiomyopathiesmyocarditisgeneticsPDF download Advertisement SubjectsCardiomyopathyGeneticsInflammatory Heart Disease
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