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      The Electrocardiographic Manifestations of Arrhythmogenic Right Ventricular Dysplasia

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          Abstract

          The ECG is abnormal in most patients with arrhythmogenic right ventricular dysplasia (ARVD). Right ventricular parietal block, reduced QRS amplitude, epsilon wave, T wave inversion in V1-3 and ventricular tachycardia in the morphology of left bundle branch block are the characteristic changes that reflect the underlying genetic predetermined pathology and pathoelectrophysiology. Recognizing the characteristic ECG changes in ARVD will be of help in making a correct diagnosis of this rare disease.

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          Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs

          Changsung Kim, Johnson Wong, Jianyan Wen … (2013)
          Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in-vitro modelling of human genetic disorders for pathogenic investigations and therapeutic screens 1–7 . However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging due to the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease characterized by pathological fatty infiltration and cardiomyocyte loss predominantly in the right ventricle (RV) 8 , which is associated with life-threatening ventricular arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly in PKP2 encoding plakophilin-2 9 . The median age at presentation of ARVD/C is 26 years 8 . We used Yamanaka’s methods 1,10 to generate iPSC lines from fibroblasts of two patients with ARVD/C and PKP2 mutations 11,12 . Mutant PKP2 iPSC-CMs demonstrate abnormal plakoglobin nuclear translocation and decreased β-catenin activity 13 in cardiogenic conditions; yet these abnormal features are insufficient to reproduce the pathological phenotypes of ARVD/C in standard cardiogenic conditions. Here we show that induction of adult-like metabolic energetics from an embryonic/glycolytic state and abnormal peroxisome proliferator-activated receptor-gamma (PPARγ) activation underlie the pathogenesis of ARVD/C. By coactivating normal PPAR-alpha (PPARα)-dependent metabolism and abnormal PPARγ pathway in beating embryoid bodies (EBs) with defined media, we established an efficient ARVD/C in-vitro model within two months. This model manifests exaggerated lipogenesis and apoptosis in mutant PKP2 iPSC-CMs. iPSC-CMs with a homozygous PKP2 mutation also displayed calcium-handling deficits. Our study is the first to demonstrate that induction of adult-like metabolism plays a critical role in establishing an adult-onset disease model using patient-specific iPSCs. Using this model, we revealed crucial pathogenic insights that metabolic derangement in adult-like metabolic milieu underlies ARVD/C pathologies, enabling us to propose novel disease-modifying therapeutic strategies.
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            Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy.

            Eduardo Garcia-Gras, Raffaella Lombardi, Michael J Giocondo … (2006)
            Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC. We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state. Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC. These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.
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              Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology.

              W. J. McKenna, G. Thiene, A. Nava … (1994)
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                Author and article information

                Journal
                Journal ID (nlm-ta): Curr Cardiol Rev
                Journal ID (iso-abbrev): Curr Cardiol Rev
                Journal ID (publisher-id): CCR
                Title: Current Cardiology Reviews
                Publisher: Bentham Science Publishers
                ISSN (Print): 1573-403X
                ISSN (Electronic): 1875-6557
                Publication date (Print): August 2014
                Publication date (Electronic): August 2014
                Volume: 10
                Issue: 3
                Pages: 237-245
                Affiliations
                [1 ]Lankenau Medical Center, Lankenau Institute for Medical Research, Jefferson Medical College, Philadelphia, Pennsylvania, USA
                [2 ]Xijing Hospital, Forth Military Medical University, Xi’an, Shaanxi, China
                [3 ]Hôpital de la Salpétriêre, Paris, France
                Author notes
                [* ]Address correspondence to this author at the Lankenau Medical Center & Lankenau Institute for Medical Research, 558 MOB East, 100 Lancaster Avenue, Wynnewood, PA 19096, USA; E-mail: ldlzhang@ 123456gmail.com
                Article
                Publisher ID: CCR-10-237
                DOI: 10.2174/1573403X10666140514102928
                PMC ID: 4040875
                PubMed ID: 24827798
                SO-VID: d7d4d6f7-fde2-476e-a5b3-98b6836f9f06
                Copyright © © 2014 Bentham Science Publishers
                License:

                This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                Date received : 10 June 2013
                Date revision received : 10 June 2013
                Date accepted : 28 January 2014
                Categories
                Subject: Article

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: ecg,arvd,desmosomal genes,ventricular tachyarrhythmia,scd.
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: ecg, arvd, desmosomal genes, ventricular tachyarrhythmia, scd.

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