Familial Arrhythmogenic Right Ventricular Cardiomyopathy Research Articles

Bioinformatic analysis of a plakophilin-2-dependent transcription network: implications for the mechanisms of arrhythmogenic right ventricular cardiomyopathy in humans and in boxer dogs.

Previous studies in murine hearts and in cell systems have shown that modifications in the expression or sequence integrity of the desmosomal molecule plakophilin-2 (PKP2) can alter the downstream expression of transcripts necessary for the electrical and mechanical function of the heart. These findings have provided support to mechanistic hypotheses that seek to explain arrhythmogenic right ventricular cardiomyopathy (ARVC) in humans. However, the relation between PKP2 expression and the transcriptome of the human heart remains poorly explored. Furthermore, while a number of studies have documented the clinical similarity between familial ARVC in humans and inheritable ARVC in boxer dogs, there is a puzzling lack of convergence as to the possible genetic causes of disease in one species vs. the other. We implemented bioinformatics analysis tools to explore the relation between the PKP2-dependent murine and human transcriptomes. Our data suggest that genes involved in intracellular calcium regulation, and others involved in intercellular adhesion, form part of a co-ordinated gene network. We further identify PROX1 and PPARA (coding for the proteins Prox1 and PPAR-alpha, respectively) as transcription factors within the same network. On the basis our analysis, we hypothesize that the molecular cascades initiated by the seemingly unrelated genetic mutations in humans and in boxers actually converge downstream into a common pathway. This can explain the similarities in the clinical manifestation of ARVC in humans and in the boxer dogs.

Whole-Exome Sequencing Identified a Novel Desmoglein-2 Gene Mutation Associated with Familial Arrhythmogenic Right Ventricular Cardiomyopathy

OBJECTIVE: To evaluate novel variations in a Chinese family of Han ethnicity, with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) by the powerful technology of Whole-Exome Sequencing (WES). METHODS: Genomic DNA from representative family members was extracted and processed for WES via standardized methods. The exome sequence data was analyzed by Genome Analysis Toolkit software. Sanger sequencing was performed on DNA from the proband for genotype confirmation and from the other family members for familial co-segregation analysis. RESULTS: A rare single nucleotide variant c.1592T>G (p.Phe531Cys) in exon 10 of DSG2 was identi ed by WES in the affected individuals but not in the healthy control, which was con rmed by Sanger sequencing, suggesting the mutation probably was a causal mutation for the familial disorder of ARVC. CONCLUSION: We identi ed a rare disease-causing mutation of the DSG2 gene associated with familial ARVC. The results might contribute to the early genetic analysis in inherited cardiomyopathies.

0247 : Detection and prevalence of large PKP2 deletion in arrhythmogenic right ventricular cardiomyopathy using exome sequencing, qPCR and multiplex ligation-dependent probe amplification (MLPA®)

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited heart muscle disease mainly caused by desmosomal gene mutations. PKP2 is the major ARVC causing-gene and presents frequent truncating mutations leading to haploinsufficiency. Large deletions of PKP2 , which are not detected with standard Sanger sequencing, have been reported in few ARVC patients. This study aimed to compare different screening methods for detection of large PKP2 deletions and to determine their prevalence in the ARVC population. We included 19 patients and 1 family of 4 members with a diagnosis of familial ARVC, which were screened negative by Sanger sequencing. A whole exome capture was performed with the Agilent SureSelect ® all Exon V5 50Mb kit and sequenced with a HiSeq2000 ® . The depth of coverage distribution of each PKP2 exon was analysed and compared to the mean coverage distribution of the cohort. Heterozygous PKP2 deletion was suspected in presence of coverage < –2 standard deviation (SD). All suspected large deletions were confirmed with qPCR. MLPA ® was performed in 50 supplementary unrelated ARVC probands and in our cohort to compare the accuracy of this method with exome sequencing. The analysis of coverage depth identified one patient with a heterozygous deletion of the whole PKP2 gene and in the family, a heterozygous deletion of PKP2 exon 4 which cosegregrated(Figure). qPCR and MLPA ® analysis confirmed this result. The prevalence of large deletions of PKP2 in gene negative familial ARVC was 10,5%. MLPA ® identified large PKP2 deletions in two additional unrelated probands. Our study shows that large PKP2 deletions are not infrequent in ARVC and should therefore be screened in patients with unidentified mutations. This study demonstrates that whole exome sequencing is an accurate technique to detect such mutations. However, MLPA ® appears as an efficient and costless technique in this purpose. Figure: Heterozygous PKP2 exon 4 deletion in the family

Can intensive exercise harm the heart? You can get too much of a good thing.

Can intensive exercise harm the heart? You can get too much of a good thing.

“Repaired” Tetralogy of Fallot Mimicking Arrhythmogenic Right Ventricular Cardiomyopathy (Another Phenocopy)

Described is a 41-year-old man who at age 6 had partial resection of an obstructed right ventricular outflow tract with insertion of a patch and closure of a ventricular septal defect (tetralogy of Fallot). At age 41, cardiac transplantation was performed because of right ventricular outflow patch aneurysm, numerous episodes of ventricular tachycardia, and chronic heart failure, all features of the familial form of arrhythmogenic right ventricular cardiomyopathy (ARVC). Additionally, the patient had bundle branch block and epsilon waves on electrocardiogram, other features of ARVC. The case is described to introduce the concept of acquired ARVC, because the patient had many of the clinically recognized features of familial ARVC.

Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin

ObjectiveTo determine the prevalence of desmosomal gene mutations in athletes with complex arrhythmias (VA) of right ventricular (RV) origin and structural RV abnormalities to evaluate whether there is sufficient genetic...

Lower than Expected Desmosomal Gene Mutation Prevalence in Endurance Athletes with Complex Ventricular Arrhythmias of Right Ventricular Origin

Objective To determine the prevalence of desmosomal gene mutations in athletes with complex arrhythmias (VA) of right ventricular (RV) origin and structural RV abnormalities to evaluate whether there is sufficient genetic overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC) to consider them the same or different entities. Design Observational cohort Setting Tertiary hospital referrals Patients Forty-seven consecutive athletes (age 42 (11) years) with complex VA of RV morphology (excluding idiopathic right ventricular outflow tract ventricular tachycardia), who performed 14 (9) h/week of moderate to intense sport practise for 19 (9) years. Interventions Clinical evaluation (detailed sports history, multi-modality imaging, electrophysiological study) and sequencing of five candidate desmosomal genes. Results A clinical diagnosis of definite or suspected ARVC by task force criteria (TFC) was met in 24 (51%) and 17 (36%), respectively. ARVC classification was not related to the rate of major arrhythmic events (p=0.28). Pathogenic mutations (four novel) were identified in six athletes (12.8%), which is below published rates for familial ARVC (27–52%). Moreover, only two athletes had a suggestive family history. Severe RV dysfunction was more frequent in mutation carriers (33% vs 2%, p=0.04), but otherwise TFC features were similar to those without mutations. No mutations were found in the 20 athletes performing more than average weekly exercise, yet all met the criteria for definite or suspected ARVC. Conclusions In this athletic cohort, we found lower than expected rates of desmosomal gene mutations, particularly among those performing the most exercise. This adds further weight to the hypothesis that an ARVC-like phenotype may be acquired through intense exercise without an identifiable genetic predisposition.

Abstract 2935: Clinical-Instrumental Characteristics and Prognosis in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy: 30 Years of Experience in a Referral Center

There are few studies regarding the clinical and instrumental presentation of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC); all available data derive from few specialized centers. We sought to describe clinical characteristics, instrumental findings and prognosis in a large cohort of patients (pts) with an ARVC diagnosis. From 1976 to 2006 all pts matching ARVC diagnostic criteria were enrolled in the Heart Muscle Disease Registry of Trieste and underwent a structured diagnostic protocol and follow-up. 104 pts were studied, 66% males, mean age 33±13 years; 84% were symptomatic at enrolment (mean duration 44±67 months); 75% had symptomatic arrhythmias (43% with previous sustained ventricular tachycardia or ventricular fibrillation (SVT/VF)), 36% syncope, 20% heart failure (12% in NYHA class III-IV). Familial ARVC were present in 46% of pts. ECG was abnormal in 72% (right bundle branch block 25%; epsilon potentials 15%; anterior negative T waves 51%; QRS dispersion &gt;40ms 11%). At signal averaged ECG late potentials were present in 58% of pts. At 2D echo, mean right ventricle (RV) end-diastolic area was 30± 8 cm2 and RV fractional area contraction (FAC) 30±13%; RV aneurysms were present in 67%. RV systolic dysfunction (defined as FAC&lt;40%) was present in 78%, characterized severe (FAC &lt;30%) in 48%. Left ventricular systolic dysfunction was present in 27% of pts. Stress test was interrupted in 11% of cases for ventricular arrhythmias (55% SVT/VF). RV fibrofatty tissue was present in 52% of Nuclear Magnetic Resonance and in 59% of RV endomyocardial biopsy (performed respectively in 24 and 27% of pts). During a mean follow-up of 132±89 months, 3 pts were lost; 20 out of the remaining 101 pts (20%) experienced death/heart transplantation, 6 (3%) died for refractory HF; 4 pts (2%) underwent heart transplantation (HT); 6 pts (3%) died suddenly; one (0.5%) for extracardiac disease and 3 (1.6%) for unknown reason. Ten-year cumulative survival free from HT was 57%. In our population ARVC presentation was characterized by symptomatic, frequently sustained ventricular arrhythmias. Notably, LV involvement was present in approximately one third of pts at enrolment. In the long term, the overall prognosis was severe.

Cardiovascular Magnetic Resonance in Arrhythmogenic Right Ventricular Cardiomyopathy Revisited: Comparison With Task Force Criteria and Genotype

We sought to assess the utility of cardiovascular magnetic resonance (CMR) in the evaluation of arrhythmogenic right ventricular cardiomyopathy (ARVC) in relation to diagnostic criteria and genotype. Timely diagnosis of ARVC is difficult as clinical findings may be subtle and nonspecific in early disease. The role of CMR is controversial owing to the absence of a standardized protocol, insufficient experience with the modality, and inherent difficulties in imaging the right ventricle. Comprehensive CMR examination was performed in 232 patients undergoing evaluation for suspected ARVC. CMR outcomes were compared with: 1) prospective clinical diagnosis using Task Force guidelines, with and without the proposed modifications for familial ARVC; and 2) gene-carrier status in 35 individuals from genotyped families. CMR studies were positive in all 64 patients who prospectively fulfilled Task Force criteria, resulting in 100% sensitivity. Specificity in relation to Task Force criteria was low (29%). Of the 119 apparent false positives detected by CMR, however, 63 fulfilled modified diagnostic criteria for familial ARVC and 7 were obligate gene carriers, suggesting that CMR frequently identifies individuals with early disease, in whom Task Force criteria are relatively insensitive. This was borne out by evaluation of genotyped individuals (26 gene-positive and 9 gene-negative), in whom CMR had a sensitivity of 96% and a specificity of 78%. CMR is a valuable component of the diagnostic workup for ARVC when performed with a dedicated protocol by specialists with experience in analysis of volumes, right ventricular wall motion, and delayed-enhancement imaging.

Arrhythmogenic right ventricular cardiomyopathy due to a novel plakophilin 2 mutation: Wide spectrum of disease in mutation carriers within a family

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial disease, with male preponderance, characterized by progressive fibrofatty replacement of the right ventricle and ventricular arrhythmias. Mutations in plakophilin-2 (PKP2), a desmosomal protein, have been reported to underlie familial ARVC. We report a novel ARVC PKP2 mutation and present the clinical findings in three female mutation carriers. We sequenced PKP2 from genomic DNA isolated from peripheral blood lymphocytes in a female proband who presented with cardiac arrest and in her four first-degree relatives. Clinical testing and diagnosis of ARVC was based on International Task Force criteria. The proband was diagnosed with ARVC due to right ventricular enlargement and regional hypokinesis, along with repolarization abnormalities and frequent ventricular ectopy. A novel 28 bp insertion in exon 11 of the PKP2 gene was found which causes a frameshift in the coding region. This results in a change in the amino acid sequence of the protein with a premature stop codon at position 740. Of the four relatives, only the mother and younger sister were identified as mutation carriers. The mother was phenotypically normal, while the younger sister has repolarization abnormalities and frequent ventricular ectopy. We report a novel PKP2 mutation that causes familial ARVC. All mutation carriers in this kindred group were women, and the family showed incomplete penetrance and variable expression of ARVC. Premature truncation of the plakophilin-2 protein appears to be the predominant mechanism whereby PKP2 mutations elicit the ARVC phenotype.