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Left-Dominant Arrhythmogenic Cardiomyopathy With Heterozygous Mutations in DSP and MYBPC3

2019; Lippincott Williams & Wilkins; Volume: 12; Issue: 6 Linguagem: Inglês

10.1161/circimaging.119.008913

1942-0080

Naka Sakamoto, Shunsuke Natori, Shohei Hosoguchi, Akiho Minoshima, Tadanori Noro, Kazumi Akasaka, Nobuyuki Sato, Seiko Ohno, Yoshihiko Ikeda, Hatsue Ishibashi‐Ueda, Minoru Horie, Naoyuki Hasebe,

Cardiac Arrhythmias and Treatments

HomeCirculation: Cardiovascular ImagingVol. 12, No. 6Left-Dominant Arrhythmogenic Cardiomyopathy With Heterozygous Mutations in DSP and MYBPC3 Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessCase ReportPDF/EPUBLeft-Dominant Arrhythmogenic Cardiomyopathy With Heterozygous Mutations in DSP and MYBPC3 Naka Sakamoto, MD, PhD, Shunsuke Natori, MD, PhD, Shohei Hosoguchi, MD, Akiho Minoshima, MD, PhD, Tadanori Noro, MD, Kazumi Akasaka, MD, PhD, Nobuyuki Sato, MD, PhD, Seiko Ohno, MD, PhD, Yoshihiko Ikeda, MD, PhD, Hatsue Ishibashi-Ueda, MD, PhD, Minoru Horie, MD, PhD and Naoyuki Hasebe, MD, PhD Naka SakamotoNaka Sakamoto Naka Sakamoto, MD, PhD, Department of Cardiology, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa 078, Japan. Email E-mail Address: [email protected] Department of Cardiology, Asahikawa Medical University (N. Sakamoto, S.H., A.M., K.A., N. Sato, N.H.). , Shunsuke NatoriShunsuke Natori Department of Cardiology, Hokkaido Social Work Association Furano Hospital (S.N., T.N.). , Shohei HosoguchiShohei Hosoguchi Department of Cardiology, Asahikawa Medical University (N. Sakamoto, S.H., A.M., K.A., N. Sato, N.H.). , Akiho MinoshimaAkiho Minoshima Department of Cardiology, Asahikawa Medical University (N. Sakamoto, S.H., A.M., K.A., N. Sato, N.H.). , Tadanori NoroTadanori Noro Department of Cardiology, Hokkaido Social Work Association Furano Hospital (S.N., T.N.). , Kazumi AkasakaKazumi Akasaka Department of Cardiology, Asahikawa Medical University (N. Sakamoto, S.H., A.M., K.A., N. Sato, N.H.). , Nobuyuki SatoNobuyuki Sato Department of Cardiology, Asahikawa Medical University (N. Sakamoto, S.H., A.M., K.A., N. Sato, N.H.). , Seiko OhnoSeiko Ohno Department of Cardiovascular Medicine (S.O., M.H.), Shiga University of Medical Science, Otsu. Center for Epidemiologic Research in Asia (S.O., M.H.), Shiga University of Medical Science, Otsu. Department of Bioscience and Genetics (S.O.), National Cerebral and Cardiovascular Center, Suita. , Yoshihiko IkedaYoshihiko Ikeda Department of Pathology (Y.I., H.I.-U.), National Cerebral and Cardiovascular Center, Suita. , Hatsue Ishibashi-UedaHatsue Ishibashi-Ueda Department of Pathology (Y.I., H.I.-U.), National Cerebral and Cardiovascular Center, Suita. , Minoru HorieMinoru Horie Department of Cardiovascular Medicine (S.O., M.H.), Shiga University of Medical Science, Otsu. Center for Epidemiologic Research in Asia (S.O., M.H.), Shiga University of Medical Science, Otsu. and Naoyuki HasebeNaoyuki Hasebe Department of Cardiology, Asahikawa Medical University (N. Sakamoto, S.H., A.M., K.A., N. Sato, N.H.). Originally published30 May 2019https://doi.org/10.1161/CIRCIMAGING.119.008913Circulation: Cardiovascular Imaging. 2019;12:e008913A 47-year-old woman, admitted with heart failure to a local hospital, was referred to a university hospital for further evaluation and treatment. Her chief complaint of dyspnea on exertion improved after treatment with diuretics. The 12-lead ECG showed T-wave inversion in V3 to V6 and the inferior leads and premature ventricular complexes with right bundle branch block morphology (Figure 1). Holter monitoring recorded 984 premature ventricular complexes with triplets. The premature ventricular complexes were of left ventricular (LV) origin, based on their right bundle branch block morphology. There were late potentials on the signal-averaged ECG with a 40-Hz filter. Echocardiography showed mild LV dilatation with global and regional systolic dysfunction (ejection fraction, 42%) and preserved right ventricular volume and contraction (Movies I through III in the Data Supplement). Cardiac computed tomography was performed not only to exclude coronary artery disease but also to evaluate the myocardium; no evidence of coronary stenosis was found, but the scans showed extensive low-attenuation areas representing intramyocardial fat mainly in the LV wall (Figure 2A and 2D). Cine cardiac magnetic resonance imaging revealed mild LV dilatation with global and regional systolic dysfunction (ejection fraction, 38%) and preserved right ventricular volume and contraction (Figure 2B; Movies IV and V in the Data Supplement). Cardiac magnetic resonance imaging showed late gadolinium enhancement in the mid-myocardial septum and subepicardial anterolateral LV myocardium (Figure 2C and 2E). Endomyocardial biopsy from the right side of the interventricular septum revealed moderate fibrofatty replacement, mild hypertrophy, and moderate disarrangement of the myocytes (Figure 3A through 3C). Transmission electron microscopy of a segment of the intercalated discs showed disarrangement of the filaments and widening of the fascia adherens gap (Figure 3D and 3E). Left-dominant arrhythmogenic cardiomyopathy was diagnosed based on the findings of T-wave inversion in the LV leads, arrhythmia of LV origin, LV systolic dysfunction, the presence of intramyocardial fat on computed tomography, late gadolinium enhancement in the LV, and histological evidence of fibrofatty replacement.1Download figureDownload PowerPointFigure 1. ECG showing T-wave inversion in the left-sided leads and a premature ventricular complex of left ventricular origin.Download figureDownload PowerPointFigure 2. Cardiac computed tomography (CT) showing low-attenuation areas and magnetic resonance imaging (MRI) showing late gadolinium enhancement (LGE) areas in the mid-wall and subepicardial left ventricular (LV) myocardium, consistent with fibrofatty infiltration. Images are in the short axis view (A, postcontrast CT images; B, balanced steady-state free precession Cine MRI images; and C, LGE MRI images), axial view (D, late-enhancement CT image), and 4-chamber view (E, LGE MRI image). The black arrows indicate low-attenuation areas and the white arrows LGE areas, consistent with fibrofatty infiltration.Download figureDownload PowerPointFigure 3. Histological findings from endomyocardial biopsy. Moderate fibrofatty replacement, mild hypertrophy, and moderate disarrangement of the myocytes with hematoxylin and eosin staining (A and B), and mild fibrosis with Masson trichrome staining (C). Transmission electron microscopy of a segment of the intercalated discs (arrowheads) showing disarrangement of the filaments and widening of the fascia adherens gap (arrows) (D and E).Genetic analysis revealed heterozygous pathogenic mutations in desmoplakin gene (DSP) (c.4650delTG, p.V1551E fs74X) and the myosin-binding protein C gene (MYBPC3) (c.2459G>A, p.R820Q)2 (Figure I in the Data Supplement). The former (ie, the DSP mutation) has not been previously described in any publication or in public databases. Mutations in DSP, the desmosomal gene associated with arrhythmogenic cardiomyopathy, and MYBPC3, the sarcomere gene, cause hypertrophic cardiomyopathy. Recently, the variable clinical expression of both arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy was reported in members of an Italian family who carried heterozygous mutations in DSP and MYBPC3.3 In our case, the histological findings suggest that the fibrofatty replacement and intercalated disc remodeling are associated with DSP mutation.4 They also suggest that the hypertrophy and disarrangement of the myocytes are associated with MYBPC3 mutation. The combined effects of the 2 gene mutations possibly represent a novel pathophysiological mechanism for left-dominant arrhythmogenic cardiomyopathy.To our knowledge, this is the first report of the very rare co-occurrence of DSP and MYBPC3 mutations to be accompanied by the results of imaging and histological investigations.DisclosuresNone.Footnotes*Drs Sakamoto and Natori contributed equally to this work.The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.119.008913.Naka Sakamoto, MD, PhD, Department of Cardiology, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa 078, Japan. Email [email protected]ac.jpReferences1. Sen-Chowdhry S, Syrris P, Prasad SK, Hughes SE, Merrifield R, Ward D, Pennell DJ, McKenna WJ. Left-dominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity.J Am Coll Cardiol. 2008; 52:2175–2187. doi: 10.1016/j.jacc.2008.09.019CrossrefMedlineGoogle Scholar2. Konno T, Shimizu M, Ino H, Matsuyama T, Yamaguchi M, Terai H, Hayashi K, Mabuchi T, Kiyama M, Sakata K, Hayashi T, Inoue M, Kaneda T, Mabuchi H. A novel missense mutation in the myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients.J Am Coll Cardiol. 2003; 41:781–786. CrossrefMedlineGoogle Scholar3. De Bortoli M, Calore C, Lorenzon A, Calore M, Poloni G, Mazzotti E, Rigato I, Marra MP, Melacini P, Iliceto S, Thiene G, Basso C, Daliento L, Corrado D, Rampazzo A, Bauce B. Co-inheritance of mutations associated with arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy.Eur J Hum Genet. 2017; 25:1165–1169. doi: 10.1038/ejhg.2017.109CrossrefMedlineGoogle Scholar4. Basso C, Czarnowska E, Della Barbera M, Bauce B, Beffagna G, Wlodarska EK, Pilichou K, Ramondo A, Lorenzon A, Wozniek O, Corrado D, Daliento L, Danieli GA, Valente M, Nava A, Thiene G, Rampazzo A. Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies.Eur Heart J. 2006; 27:1847–1854. doi: 10.1093/eurheartj/ehl095CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByPérez-Riera A, Barbosa-Barros R and Belhassen B (2019) Letter by Pérez-Riera et al Regarding Article, "Left-Dominant Arrhythmogenic Cardiomyopathy With Heterozygous Mutations in DSP and MYBPC3", Circulation: Cardiovascular Imaging, 12:9, Online publication date: 1-Sep-2019.Sakamoto N, Natori S, Hosoguchi S, Minoshima A, Noro T, Akasaka K, Sato N, Ohno S, Ikeda Y, Ishibashi-Ueda H, Horie M and Hasebe N (2019) Response by Sakamoto et al to Letter Regarding Article, "Left-Dominant Arrhythmogenic Cardiomyopathy With Heterozygous Mutations in DSP and MYBPC3", Circulation: Cardiovascular Imaging, 12:9, Online publication date: 1-Sep-2019. Bueno Marinas M, Celeghin R, Cason M, Thiene G, Basso C and Pilichou K (2020) The Role of MicroRNAs in Arrhythmogenic Cardiomyopathy: Biomarkers or Innocent Bystanders of Disease Progression?, International Journal of Molecular Sciences, 10.3390/ijms21176434, 21:17, (6434) June 2019Vol 12, Issue 6 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCIMAGING.119.008913PMID: 31142139 Originally publishedMay 30, 2019 Keywordsbiopsycomputed tomographymutationcardiomyopathiesmagnetic resonance imagingPDF download Advertisement SubjectsArrhythmiasCardiomyopathyComputerized Tomography (CT)GeneticsMagnetic Resonance Imaging (MRI)