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Inherited Cardiomyopathies Revealed by Clinically Suspected Myocarditis

2020; Wolters Kluwer; Volume: 13; Issue: 4 Linguagem: Inglês

10.1161/circgen.119.002744

2574-8300

Flavie Ader, Elodie Surget, Philippe Charron, Alban Redheuil, Amir Zouaghi, Alice Maltret, Éloi Marijon, Isabelle Denjoy, Alexis Hermida, Véronique Fressart, Estelle Gandjbakhch,

Cardiovascular Effects of Exercise

HomeCirculation: Genomic and Precision MedicineVol. 13, No. 4Inherited Cardiomyopathies Revealed by Clinically Suspected Myocarditis Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBInherited Cardiomyopathies Revealed by Clinically Suspected MyocarditisHighlights From Genetic Testing Flavie Ader, MD, Elodie Surget, MD, Philippe Charron, MD, PhD, Alban Redheuil, MD, PhD, Amir Zouaghi, MD, Alice Maltret, MD, Eloi Marijon, MD, PhD, Isabelle Denjoy, MD, Alexis Hermida, MD, Véronique Fressart, MD and Estelle Gandjbakhch, MD, PhD Flavie AderFlavie Ader Sorbonne Universités, APHP, UF Cargiogénétique et Myogénétique, Service de Biochimie Métabolique, Hôpital Universitaire Pitié-Salpêtrière (F.A., V.F.). , Elodie SurgetElodie Surget https://orcid.org/0000-0003-0362-6351 Sorbonne Universités, APHP, Institut de Cardiologie, ICAN, Hôpital universitaire Pitié-Salpêtrière (E.S., A.R., A.Z., E.G.). , Philippe CharronPhilippe Charron Centre de Références des Maladies Cardiaques Héréditaires, Paris, France (F.A., P.C., A.M., E.M., I.D., V.F., E.G.). Sorbonne Universités, APHP, Département de Génétique, Hôpital Universitaire Pitié-Salpêtrière (P.C.). , Alban RedheuilAlban Redheuil Sorbonne Universités, APHP, Institut de Cardiologie, ICAN, Hôpital universitaire Pitié-Salpêtrière (E.S., A.R., A.Z., E.G.). , Amir ZouaghiAmir Zouaghi Sorbonne Universités, APHP, Institut de Cardiologie, ICAN, Hôpital universitaire Pitié-Salpêtrière (E.S., A.R., A.Z., E.G.). , Alice MaltretAlice Maltret Centre de Références des Maladies Cardiaques Héréditaires, Paris, France (F.A., P.C., A.M., E.M., I.D., V.F., E.G.). , Eloi MarijonEloi Marijon https://orcid.org/0000-0001-7227-3428 Centre de Références des Maladies Cardiaques Héréditaires, Paris, France (F.A., P.C., A.M., E.M., I.D., V.F., E.G.). , Isabelle DenjoyIsabelle Denjoy APHP, Département de Cardiologie, Hôpital Universitaire Bichat, Paris (I.D.). , Alexis HermidaAlexis Hermida Département de Cardiologie, Hôpital Universitaire, Amiens, France (A.H.). , Véronique FressartVéronique Fressart Sorbonne Universités, APHP, UF Cargiogénétique et Myogénétique, Service de Biochimie Métabolique, Hôpital Universitaire Pitié-Salpêtrière (F.A., V.F.). Centre de Références des Maladies Cardiaques Héréditaires, Paris, France (F.A., P.C., A.M., E.M., I.D., V.F., E.G.). and Estelle GandjbakhchEstelle Gandjbakhch Correspondence to: Estelle Gandjbakhch, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75013 Paris, France. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4846-5021 Sorbonne Universités, APHP, Institut de Cardiologie, ICAN, Hôpital universitaire Pitié-Salpêtrière (E.S., A.R., A.Z., E.G.). Centre de Références des Maladies Cardiaques Héréditaires, Paris, France (F.A., P.C., A.M., E.M., I.D., V.F., E.G.). Originally published10 Jun 2020https://doi.org/10.1161/CIRCGEN.119.002744Circulation: Genomic and Precision Medicine. 2020;13:e002744Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 11, 2020: Ahead of Print Myocarditis has been associated with inherited cardiomyopathies, such as arrhythmogenic right ventricular (RV) cardiomyopathy/dysplasia (ARVC/D), hypertrophic cardiomyopathy, or dilated cardiomyopathy, but the links between the entities and the frequency of the association remain unclear.1-3In this study, we aimed to assess the genetic basis of myocarditis in selected patients in which clinically suspected myocarditis associated with sustained ventricular arrhythmias (VAs) and/or RV abnormalities was the first clinical manifestation of the disease.Between 2014 and 2018, 16 consecutive patients referred to the University Hospital of Paris with clinically suspected acute myocarditis according to current criteria4 associated with sustained VAs or RV abnormalities underwent genotyping. None of these patients had history of cardiomyopathy before myocarditis. Patients with significant RV abnormalities were screened first for a panel of 12 ARVC/D-associated genes (n=10). Others (n=6) were screened for a panel of 51 cardiomyopathy-associated genes including the major ARVC/D genes. All patients gave their informed consent for genetic testing and clinical data collection. Data were anonymized, and no authorization approval from ethic or institutional review committee was required for this study according to French ethic and regulatory law.The median age at myocarditis was 30 years (range, 11–75), and 7 patients were women. Only 2 patients had a history of cardiac disease before myocarditis diagnosis (premature ventricular contractions in one and paroxysmal atrial fibrillation in the other) but no diagnosis of cardiomyopathy. Two patients presented with recurrent episodes (defined as increase troponin level associated with chest pain and T1 and T2 hypersignals at cardiac magnetic resonance imaging). Two required temporary external hemodynamic support: one (patient no. 6) for severe left ventricular dysfunction after ventricular fibrillation and one for fulminant myocarditis with severe left ventricular dysfunction. Thirteen patients presented sustained VAs, including 8 during the active phase of myocarditis. All patients showed left ventricular involvement with mostly subepicardial late-gadolinium enhancement areas and 12 had RV morphological abnormalities; 8 fulfilled a probable or definite ARVC/D diagnosis. Clinical characteristics of patients are detailed within the Table and in the Table I in the Data Supplement.Table. Clinical Characteristics of Mutations CarriersPt#GeneMutationMAF (GnomAD Database)Prediction Softwares GVGD/SIFT/CADDGradeClinical Presentation at Myocarditis DiagnosisMyocarditis CriteriaFamily History at Time of MyocarditisBaseline ECG After Myocarditis ResolutionArrhythmiasRV AbnormalitiesLV AbnormalitiesARVC TFC (Genetic Excluded)2PKP2 (Hg19 NM_004572.3)*c.2026T>C4.10-5C65/PD/264Recurrent acute myocarditis (4 episodes) at 17yoElevated troponin (19xunl), increased T2 + subepicardial LGE at MRI (LLC+)NoneTWI V1-4, microvoltageRVOT VT at 18yoRV dilatation (109 mL/m2); anteroapical akinesia; epicardial LGE (RVOT, inferior wall)Subepicardial LGE in septum and lateral wall with edema2M/1 mp.Ser688Pro‡3DES (Hg19, NM_001927.3)†c.322G>A0C55/PD/335Acute myocarditis at 22 yo with VFElevated troponin (33xunl), increased T2 + subepicardial LGE at MRI (LLC+),NAMicrovoltageLV latero-basal VTNoneDiffuse subepicardial LGE with edema0p.Glu108Lys‡6DSP (Hg19, NM_004415.2)†c.448C>T0NA4Fulminant myocarditis at 31 yo with VT/VFDiffuse increased T1/T2 + subepicardial LGE at MRI (LLC+)NoneMicrovoltageVT/VF, electrical storm, bifocal PVC from RVNoneLVEF 50%, multifocal subepicardial and intramyocardial LGE with edema of lateral and septoapical wall.1 mp.Arg150Ter8PKP2 (Hg19 NM_004572.3)*c.2146-1G>C3.10-5NA5Acute myocarditis at 13 yo with VTChest pain, elevated troponin (36xunl), fever, increased T2 + subepicardial LGE at MRI (LLC+)Myocarditis (mother)TWI V1-6VT during active myocarditis (LBBB morphology with left axis)LGE anterolateral wall, dilated RVOTSubepicardial LGE of anteroapico-lateral and inferior walls with edema2M/1 m10RYR2 (Hg19 NM_001035.2)+ DTNA (Hg19 NM_001390.4)†c.2972C>T p.Ser991Leu (RYR2)/0/1.10-5C0/PD/334/4Acute myocarditis revealed by syncopal VT at 30 yoIncreased T1/T2 + subepicardial LGE at MRI (LLC+)SCD (uncle 42 yo, grand-father 60 yo)Microvoltage, TWI V3-6, and DIIDIIVFpolymorphic syncopal VTNoneEdema and LGE of infero-latero basal and anterolateral walls, LVEF 51%0c.176T>CC65/PD/26p.Ile59Thr (DTNA)11PKP2 (Hg19 NM_004572.3)*c.1378+1G>A4.10-6NA5Acute myocarditis revealed by VF at 17 yoElevated troponin (10xunl), increased T1/T2 + subepicardial LGE at MRI (LLC+)NoneMicrovoltageFV, PVC with LBBB and RBBB morphologyInferior akinesia, lateral hypokinesia moderate RV dilatation, RVEF 44%Transmural edema of lateral wall, subepicardial LGE of inferior and lateral walls, LVEF 55%2 m13PKP2 (Hg19 NM_004572.3)*p.Ser837Valfs*94‡0NA5Acute myocarditis at 75 yo with electrical stormFever, inflammatory syndrome, increased T2 + subepicardial LGE at MRI (LLC+), pericardial effusionNoneiRBBB, TWI V1-3AF, electrical storm (VT with RBBB morphology)Lateral wall dyskinesia, moderate RV dilatation, and dysfunctionSupepicardial LGE of latero-basal wall and septum with edema, LVEF 62%.1M/1 m15DSG2 (Hg19 NM_001943.4)*c.367C>T0C0/PD/254Recurrent acute myocarditis (4 episodes) at 37 yoElevated troponin (39×unl), chest pain, increased T1/T2 + subepicardial LGE at MRI (LLC+)NoneTWI V1-4, LPHBAFRV dilatation (108 mL/m2); inferior hypokinesia; lateral dyskinesiaSubepicardial LGE+ edema of latero-inferior wall1M/1 mp.Pro123Ser16PKP2 (Hg19 NM_004572.3)*p.Arg79Ter‡4.10-6NA5Acute myocarditis with VT at 52 yoIncreased T1/T2 + subepicardial LGE at MRI (LLC+), pericardial effusionAF (father)TWI V1-V4VT with LBBB morphology and superior axisInferior akinesia and RV dilatationInfero-lateral subepicardial LGE with edema, LVEF 60%2M, 1 mInterpretation of GVGD score from C0 (probably benign) to C65 (damaging), SIFT is interpreted from Tolerated (To) to Deleterious (D), CADD score is considered as probably damaging over 25. AF indicates atrial fibrillation; ARVC/D, arrhythmogenic right ventricular cardiomyopathy/dysplasia; CADD, combined annotation dependent depletion; D, deleterious; GVGD, Grantham Variation and Grantham Deviation score; iRBBB:incomplete right bundle branch block; LBBB, left bundle branch block; LGE, late-gadolinium enhancement; LLC, 2018 Lake Louise Criteria; LPFB, left posterior fascicular block; LV, left ventricular; LVEF, left ventricular ejection fraction; M, major ARVC/D diagnosis criteria; m, minor ARVC/D diagnosis criteria; MAF, minor allele frequency; MRI, magnetic resonance imaging; NA, nonavailable; PD, probably damaging; PVC, premature ventricular contractions; RBBB, right bundle branch block; RV, right ventricular; RVEF, right ventricular ejection fraction; RVOT, right ventricular outflow tract; SCD, sudden cardiac death; SIFT, sorting intolerant from tolerant; TFC, task force criteria; TWI, T-wave inversion; unl, upper normal limit; VF, ventricular fibrillation; VT, ventricular tachycardia; and yo, years-old.* Panel of 12 ARVC/D associated genes: CTNNA3, DES, DSG2, DSP, JUP, LMNA, PKP2, PLN, RYR2, SCN5A, TGFB3, TMEM43.† Panel of 51 genes: ABCC9, ACTC1, ACTN2, ALPK3, ANKRD1, BAG3, CRYAB, CSRP3, DES, DSG2, DSP, DTNA, EMD, FHL1, FLNC, GATA4, GLA, HCN4, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, PDLIM3, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN5A, TAZ, TCAP, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL.‡ Already reported.On genetic testing, 9 (56%) patients carried a definite (grade 5) or probable (grade 4) pathogenic variant (American College of Medical Genetics and Genomics criteria), predominantly in ARVC/D-associated genes, corresponding to 10 variants. The most prevalent gene was PKP2 (5 mutations), followed by DSP, DGS2, DES, RYR2, and DTNA, with one pathogenic variant each. One patient carried a heterozygous missense RYR2 associated with a DTNA pathogenic variant. Five (50%) patients with a probable or definite ARVC/D diagnosis carried a pathogenic desmosomal variant. Among the 6 patients carrying a pathogenic desmosomal variant, 2 did not fulfill a probable/definite ARVC/D diagnosis. Two patients carrying a desmosomal gene mutation (PKP2 or DSG2) had recurrent episodes of acute myocarditis. In patient no. 8 (PKP2 mutation), end-stage heart failure led to heart transplantation at age 16, three years after the myocarditis episode. Analysis of explanted heart showed extensive biventricular fibro-fatty infiltration and mild lymphocyte infiltrates. His mother (PKP2 mutation) also had a clinically suspected acute myocarditis at age 32 and was diagnosed with ARVC/D at age 38 of years. There were no significant differences in the clinical presentation between the mutation and the nonmutation carriers (Table II in the Data Supplement).In this case-series, we report a high proportion of definite or probable pathogenic variants in selected patients with a clinically suspected myocarditis and either RV involvement or sustained VAs. Most pathogenic variants were identified in ARVC/D-associated genes but also in DES, RYR2, and DTNA. Our results demonstrate that acute clinically suspected myocarditis can be the first clinical expression of inherited cardiomyopathy, especially arrhythmogenic cardiomyopathy, and that these diagnoses are not exclusive of each other.The mechanism (exogenous or endogenous) underlying myocarditis in inherited cardiomyopathies is not clear. Whether clinical signs of myocarditis such as chest pain, elevated troponin level, and myocardial edema seen on magnetic resonance imaging reflect associated viral myocarditis or a nonviral acute phase of the disease remains unresolved. Recently, an autoimmune mechanism in ARVC/D was suggested after the identification of anti-DSG2 antibodies in serum of ARVC/D patients.5 Moreover, this result questions the interpretation of subepicardial left ventricular late-gadolinium enhancement areas seen on magnetic resonance imaging that are often mistaken for myocarditis sequelae. However, this finding is not specific to myocarditis and can be part of the phenotype of arrhythmogenic cardiomyopathy-associated genes.3,4Our results suggest (1) careful examination of the right ventricle and a check for family history for all patients with acute clinically suspected myocarditis and (2) family screening and genetic testing proposed to patients with acute clinically suspected myocarditis and RV involvement or sustained VAs. Although the diagnostic value of genetic testing seems high in selected patients with clinically suspected myocarditis, the frequency of an inherited cardiomyopathy background in unselected patients with acute myocarditis is probably much lower. Further studies including systematic genetic study of unselected patients with acute myocarditis are necessary to assess the frequency and clinical features of underlying inherited cardiomyopathy.As not all patients were screened for the large panel of 51 genes, the mutation rate may have been underestimated. No additional investigations, like positron emission tomography–computed tomography or endomyocardial biopsy, were performed to investigate the origin of myocarditis in most patients.Nonstandard Abbreviations and AcronymsARVC/DArrhythmogenic right ventricular cardiomyopathy/dysplasiaRVright ventricularVAsventricular arrhythmiasSources of FundingNone.DisclosuresNone.FootnotesThe Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCGEN.119.002744.For Sources of Funding and Disclosures, see page 346.Correspondence to: Estelle Gandjbakhch, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75013 Paris, France. 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An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis.Eur Heart J. 2018; 39:3932–3944. doi: 10.1093/eurheartj/ehy567CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByLota A, Hazebroek M, Theotokis P, Wassall R, Salmi S, Halliday B, Tayal U, Verdonschot J, Meena D, Owen R, de Marvao A, Iacob A, Yazdani M, Hammersley D, Jones R, Wage R, Buchan R, Vivian F, Hafouda Y, Noseda M, Gregson J, Mittal T, Wong J, Robertus J, Baksi A, Vassiliou V, Tzoulaki I, Pantazis A, Cleland J, Barton P, Cook S, Pennell D, Garcia-Pavia P, Cooper L, Heymans S, Ware J and Prasad S (2022) Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy, Circulation, 146:15, (1123-1134), Online publication date: 11-Oct-2022.Monda 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. 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Kontorovich A, Patel N, Moscati A, Richter F, Peter I, Purevjav E, Selejan S, Kindermann I, Towbin J, Bohm M, Klingel K and Gelb B (2021) Myopathic Cardiac Genotypes Increase Risk for Myocarditis, JACC: Basic to Translational Science, 10.1016/j.jacbts.2021.06.001, 6:7, (584-592), Online publication date: 1-Jul-2021. August 2020Vol 13, Issue 4 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.119.002744PMID: 32522011 Originally publishedJune 10, 2020 Keywordscardiac arrhythmiagenetic testinggeneticsmyocarditiscardiomyopathyPDF download Advertisement SubjectsPrecision Medicine