Long-term Efficacy, Genotypic Risk Stratification And Pathogenic Mechanism Of Transcatheter Radiofrequency Ablation For Arrhythmogenic Cardiomyopathy

PART Ⅰ Catheter ablation of arrhythmogenic cardiomyopathy ventricular tachycardia:18-year experience in 284 patientsBackground and Objective:The study aims to describe the long-term outcome of radiofrequency catheter ablation for ventricular tachycardia（VT）in a large cohort arrhythmogenic cardiomyopathy（ACM）patients.Methods and Results:Radiofrequency catheter ablation was performed in 284 ACM patients due to VT between July 2000 and January 2019.An endocardial approach was used initially,with epicardial ablation procedures reserved for those patients who failed an endocardial ablation.Activation,entrainment,pace and substrate mapping strategies were used with regional ablation applied.A total of 393 ablation procedures were performed including endocardial approach only（n=377）and endo and epicardial combined（n=16）.Right ventricular basal free wall was accounted as the primary substrate of VT in 258（65.6%）patients.There were 81 patients underwent redo ablation procedure（second time=81;≥3 times=28）.New targets were observed in 68.8%of redo procedures.There were 171 VT recurrences and 19 deaths occurred during the follow-up.Ventricular tachycardia-free survival rate of the first,second,and last ablation procedure was 56.7%,73.2%,and 78.1%,respectively.Multivariate analysis showed>₃ induced VTs in the procedure was correlated with rehospitalized VT recurrence[hazard ratio（HR）1.467,95%confidence interval（CI）1.052-2.046;P=0.024].For all-cause mortality,rehospitalized VT and≥3 induced VTs were the independent risk factors（HR 2.954,95%CI 1.8068.038;P=0.034;HR 3.189,95%CI 1.073-9.482;P=0.037）.Conclusion:Endocardial ablation is effective to ARVC VT though it may require repeated procedures.Induced multiple VTs was correlated with worse outcomes.PART Ⅱ Impact of Genotype on Recurrence of Life-Threatening Ventricular Arrhythmia Post Ablation in Patients with Arrhythmogenic CardiomyopathyBackground and Objective:The effect of genetic variants on recurrence of life-threatening ventricular tachycardia（VT）in arrhythmogenic cardiomyopathy（ACM）patients after radiofrequency catheter ablation（RFCA）remains poorly understood.Methods:We retrospectively recruited ACM patients with life-threatening VT that had undergone RFCA and screened for ACM causing genes.Life-threatening VT was defined as sustained VT,cardiac arrest,or appropriate shock therapy from ICD.Results:Ninety-two patients,aged 39.6 ± 13.1 years,89.1%male,60.9%having pathogenic variants with a definite diagnosis,and had undergone RFCA duo to life-threatening VT were included.Overall,our analysis shows that risk of VT recurrence after RFCA was higher in those with pathogenic variants in the known ACM genes（HR,2.49;95%CI,1.19-5.23;P=0.016）,PKP2（HR,2.52;95%CI,1.17-5.47;P=0.019）,or multiple genes（HR,5.88;95%CI,1.74-19.91;P=0.004）,independent of demographic and clinical factors.PKP2 mutation carriers had the worse arrhythmic outcome（P=0.023）than other desmosome genes carriers.Similarly,multiple-genes carriers had worse outcome than single-gene carriers（P=0.002）.However,there was no association between the genotype and the VT recurrence in those who underwent multiple RFCA.Conclusion:Patients with ACM who carry pathogenic variants in known ACM genes,particularly in PKP2 gene or multiple genes,are at increased risk of VT recurrence post RFCA,often requiring repeated ablation.The findings suggest the need for additional medical therapy in ACM patients with specific mutations.PART Ⅲ The EP300/TP53 Pathway,a Suppressor of the Hippo and Canonical WNT Pathways,is Activated in Human Hearts with Arrhythmogenic Cardiomyopathy in the Absence of Overt Heart FailureBackground and Objective:Arrhythmogenic cardiomyopathy（ACM）is a primary myocardial disease that typically manifests with cardiac arrhythmias,progressive heart failure and sudden cardiac death（SCD）.ACM is mainly caused by mutations in genes encoding desmosome proteins.Desmosomes are cell-cell adhesion structures and hubs for mechanosensing and mechanotransduction.The objective was to identify the dysregulated molecular and biological pathways in human ACM in the absence of overt heart failure.Methods and Results:Transcriptomes in the right ventricular endomyocardial biopsy samples from three independent individuals carrying truncating mutations in the DSP gene and 5 control samples were analyzed by RNA-Seq（discovery group）.These cases presented with cardiac arrhythmias and had a normal right ventricular function.The RNA-Seq analysis identified-5,000 differentially expressed genes（DEGs）,which predicted suppression of the Hippo and canonical WNT pathways,among others.Dysregulated gene expression pathways,identified by RNA-Seq,were tested for validation in the right and left ventricular tissues from 5 independent autopsy-confirmed ACM cases with defined mutations,who were victims of SCD and had no history of heart failure.Protein levels and nuclear localization of the cWNT and Hippo pathway transcriptional regulators were reduced in the right and left ventricular validation samples.In contrast,levels of acetyltransferase EP300,known to suppress the Hippo and canonical WNT pathways,were increased and its bona fide target TP53 was acetylated.RNA-Seq data identified apical junction,reflective of cell-cell attachment,as the most disrupted biological pathway,which was corroborated by disrupted desmosomes and intermediary filament structures.The changes were associated with increased apoptosis and fibro-adipogenesis in the ACM hearts.Conclusion:Altered apical junction structures is associated with activation of the EP300-TP53 and suppression of the Hippo/cWNT pathways in human ACM caused by defined mutations in the absence of an overt heart failure.The findings implicate altered mechano-transduction in the pathogenesis of ACM.