Arrhythmogenic right ventricular cardiomyopathy/dysplasia on the basis of the revised diagnostic criteria in affected families with desmosomal mutations

Protonotarios, Nikos; Anastasakis, Aris; Antoniades, Loizos; Chlouverakis, Gregory; Syrris, Petros; Basso, Cristina; Asimaki, Angeliki; Theopistou, Artemisia; Stefanadis, Christodoulos; Thiene, Gaetano; McKenna, William J.; Tsatsopoulou, Adalena

doi:10.1093/eurheartj/ehr043

Cited by 73 publications

(47 citation statements)

References 17 publications

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“…Genetic studies have identified mutations in several genes associated with ARVC, including 5 desmosomal and 4 nondesmosomal genes. [5][6][7][8][9][10][11][12] Previous studies have shown that genetic identification is related to different clinical characteristics of ARVC. [13][14][15][16] However, the correlation between genotype and VA features remains unclear.…”

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confidence: 99%

Correlation of Ventricular Arrhythmias With Genotype in Arrhythmogenic Right Ventricular Cardiomyopathy

Bao

Wang

Yao

et al. 2013

Circ Cardiovasc Genet

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A total of 90 unrelated Chinese subjects with definite (n=69), borderline (n=15), or possible (n=6) diagnosis of ARVC and 300 age-, sex-, and ethnicity-matched healthy control subjects were recruited for gene analysis at our center. ARVC was diagnosed in all patients according to the revised diagnostic Task Force Criteria. 17 None of the control subjects had a history of cardiovascular or other systemic diseases.This study was performed in accordance with the principles of the Declaration of Helsinki and approved by the Ethics Committees of our hospital. The informed consent for the electrophysiological (EP) study and genetic testing was provided by all participants. EP study was not performed on the control subjects. Clinical EvaluationClinical evaluation including 12-lead ECG and transthoracic echocardiography was performed in all cases. Cardiovascular magnetic resonance and 24-hour Holter monitoring were performed. The EP characteristics of ARVC were assessed by EP study, and the results were correlated with genetic testing of 9 genes that have previously been reported to be related to ARVC, including plakophilin-2 (PKP2), desmocollin-2 (DSC2), desmoglein-2 (DSG2), desmoplakin (DSP), plakoglobin (JUP), transforming growth factor-β3 (TGFβ3), transmembrane protein 43 (TMEM43), desmin (DES), and Lamin A/C (LMNA).All clinical data were reviewed independently by 3 cardiologists with resolution of differences by consensus.Background-Although mutations of several genes are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), the exact correlation between genotype and ventricular arrhythmia features remains unclear. This study was aimed to examine the possible association of the 9 known genes of ARVC with clinical and electrophysiological characteristics. Methods and Results-Ninety subjects diagnosed with ARVC who underwent electrophysiological study were recruited for screening the 9 known ARVC-causing genes. A total of 53 mutations were identified in 57 (63%) subjects. Mutation carriers had more frequent clinical ventricular tachycardia (VT; 89% versus 55%; P<0.001) and negative T waves in V 1 to V 3 (61% versus 33%; P=0.016). Subjects with plakophilin-2 (PKP2) mutations also had more frequent VT than those without mutations in PKP2. Comparison between subjects with multiple and single mutations showed that syncope occurred more often in the former group (58% versus 24%; P=0.018). VT was significantly more often induced in mutation carriers compared with noncarriers (75% versus 39%; P=0.001), as well as in PKP2 mutation carriers compared with subjects without PKP2 mutations (80% versus 48%; P=0.002). Induced VT with a rate ≥200 bpm was more often documented in mutation carriers (88% versus 54%; P=0.013), as well as in PKP2 mutation carriers (91% versus 67%; P=0.041). Conclusions-Pathogenic

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confidence: 99%

Correlation of Ventricular Arrhythmias With Genotype in Arrhythmogenic Right Ventricular Cardiomyopathy

Bao

Wang

Yao

et al. 2013

Circ Cardiovasc Genet

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“…Mutations in genes encoding desmosomal proteins have been identified as the causative molecular defect in more than 50% of probands. Recently, the identification of a pathogenic mutation has been incorporated into the revised diagnostic criteria for ARVC [6] , leading to a significant increase in diagnostic yield for the disease [2,9] . A pathogenic mutation is defined as a DNA alteration associated with the disease that alters or is expected to alter the encoded protein, is not observed or is rare in a large healthy control population and either alters the structure or function of the protein or has demonstrated linkage to the disease phenotype [6] .…”

Section: Discussionmentioning

confidence: 99%

“…Approximately half of all cases of ARVC are familial. The most common genetic causes of ARVC are mutations in genes encoding desmosomal proteins which lead to cell adhesion defect [2,3] . However, reduced penetrance, variable expressivity and the fact that genetic test results should be viewed as probabilistic make ARVC diagnosis a challenge for clinicians [4,5] .…”

Section: Introductionmentioning

confidence: 99%

Arrhythmogenic Right Ventricular Cardiomyopathy: The Challenge of Genetic Interpretation in Clinically Suspected Cases

Anastasakis¹,

Vouliotis²,

Protonotarios³

et al. 2012

Cardiology

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This is the case of a 43-year-old Caucasian man with frequent episodes of paroxysmal atrial fibrillation (AF) and normal resting electrocardiogram (ECG), who fulfilled two minor diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC): late potentials by signal-averaged ECG and regional right ventricular outflow tract (RVOT) dyskinesia with mildly dilated RVOT end-diastolic diameter. Genetic test results revealed a disease-associated missense mutation in DSC2 (p.E102K), adding a major diagnostic criterion according to recently published modified Task Force Criteria. However, 2 years after successful ablative therapy for AF, the patient remains completely asymptomatic, without any clinical signs of ARVC. Both ventricular and supraventricular arrhythmias had vanished after AF ablation. Our patient mainly suffered AF without significant ventricular arrhythmias, a very uncommon clinical presentation of ARVC.

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“…This is quite evident in the recessive cardiocutaneous syndromes, which are characterized by an earlier clinical onset of cardiac involvement with a higher penetrance of complications than the autosomal-dominant form. 33 In the clinical setting, candidates for genetic test include both ARVC index cases and family members of those gene-positive. There is not yet a well-defined role for routine genetic screening to confirm a clinical diagnosis in index cases.…”

Section: Genetic Backgroundmentioning

confidence: 99%