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Background: Patients with a type 2 or 3 Brugada syndrome (BS) pattern and a negative sodium channel blocker challenge (SCBC) are not considered as affected. Their arrhythmic prognosis is generally considered good, but it has never been specifically evaluated. Objective: The purpose of this study was to evaluate the arrhythmic prognosis in patients with a type 2 or 3 electrocardiogram (ECG) not converted to type 1 ECG during an SCBC. Methods: Clinical data, 12-lead ECG, results of the SCBC and electrophysiological study (EPS), and follow-up were collected. Results: Among the 500 patients who underwent an SCBC in our institution, 158 displayed a type 2 or 3 ECG. After the SCBC, 93 (59%) had a type 1 ECG (positive group [PG]), whereas 65 (41%) remained negative (negative group [NG]). An EPS was performed in 31 (33%) PG patients and 15 (23%) NG patients. Ventricular fibrillation was induced in 21 PG patients (67%), whereas no patient in the NG was inducible (P <.001). During a follow-up of 37 ± 17 months, no sudden death occurred. Three syncopes were observed in the NG versus one syncope, two ventricular tachycardias, and one appropriate shock in the PG. Conclusion: This study demonstrates that the presence or absence of coved type ST-segment elevation during the SCBC denotes a profound electrophysiological difference as demonstrated by the absence of inducibility during EPS in the NG that may be responsible for the good prognosis of patients with a type 2 or 3 ECG pattern not converted to type 1. [Copyright &y& Elsevier]

Mitral Valve Prolapse (MVP) affects 3% of the population and is characterized by a heterogeneous mitral leaflet remodeling. The pathophysiological mechanisms involved in MVP development are not fully understood, the only therapeutic option remains the surgical valve replacement. The first mutation causing MVP has been recently identified on the FLNA gene. The generation of a unique knock-in (KI) rat model for the FLNA-P637Q mutation paves the road to study the molecular mechanisms involved in MVP development. The aim of our study was to characterize the functional, morphological and molecular expression of the valvular disease in our unique KI rat model. 5 wild-type (WT) and 10 KI rats were evaluated at 3, 6 and 26 weeks. Comprehensive 2D echocardiography was performed to determine valve function and morphology. 3D quantitative analysis of the mitral valve (MV) remodelling was done using micro-tomodensitometry (microCT). MV tissue composition was analysed based on histological and immunohistochemistry. Based on the qualitative echocardiographic assessment of the valve, a high genotype-phenotype concordance was observed (100%, 93% and 100% for each time points). The anterior leaflet was longer in KI comparatively to WT rats (+ 12 to + 14% increase at all time points P < 0.01). Using microCT analysis, we confirmed the larger 3D MV volume in KI compared to WT (+ 20 to + 58%; all time points P < 0.05). Histological and immunohistological analyses pointed out towards a myxomatous valve disease (leaflet's thickening, hypercellularity, proteoglycans accumulation without calcification). Our results attest for the presence of a myxomatous MV dystrophy in the KI rat model comparable to the one described in MVP patients. These findings confirm this unique model is pertinent for the study of pathophysiological molecular mechanisms associated with MVP development and offers a new opportunity to identify potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Ventricular arrhythmic events are responsible for 50% of death in heart failure but no reliable predictive marker is known to discriminate patients at risk of fatal arrhythmia. Interestingly, familial predisposition has been reported suggesting a role of genetic factors. Identify genetic markers increasing the arrhythmic risk in heart failure population. We prospectively included heart failure patients with left ventricular ejection fraction (LVEF) under 35% and a cardioverter defibrillator in primary prevention in 22 French centres between 2009 and 2017. Patients were followed for 72 months and divided into two groups: cases with an arrhythmic event during follow-up and controls. A Genome Wide Association Study (GWAS) was done. Single Nucleotide Polymorphisms (SNPs) genotyping was performed on Affymetrix Axiom Precision Medicine Research Array plates. 332 cases and 567 controls were included (86% men, mean age at implantation 52 ± 11 years). 78% of patients had ischaemic cardiopathy, 20% had dilated cardiomyopathy. Mean LVEF was 27 ± 5%. No statistical difference was found between cases and controls on clinical parameters or electrocardiographic measures. No locus shows genome-wide significant association (P < 5.10 − 8) on the GWAS analysis. However, 16 signals with a p-value between 5.10 − 8 and 5.10 − 5 were investigated. eQTL and chromatin conformation point to 35 genes with cardiac expression previously associated with heart failure, cardiomyopathies, arrhythmias and inflammation. Variants identified point to regulatory regions of the genome and may then propose a molecular mechanism predisposing patients to arrhythmias (Fig. 1). No locus raises genome-wide significance, but several signals with a nominal p-value point to relevant genes and pathways. Replication of the GWAS is ongoing on a cohort of 156 new patients with a less severe cardiopathy implanted with a cardioverter defibrillator in secondary prevention. [ABSTRACT FROM AUTHOR]

Hereditary sinus node dysfunction (SND) with atrioventricular block (AVB) is a rare disease characterized by permanent heart rate decrease associated with paroxysmal dizziness and syncope. Pacemaker implantation remains the main therapy. To date, only few genes are known associated with this disease. Most of the cases remain genetically unsolved. The aim of the study is to identify a new gene responsible for familial sinus node and atrioventricular conduction dysfunction (SND +AVB). A genome-wide linkage analysis is performed to map the SND + AVB locus and is completed by performing Whole Genome Sequencing (WGS). Candidate variants (Single Nucleotide Variants (SNV) and Copy Number Variations (CNV) will be kept if rare and shared by affected members. We investigated a 4 generations pedigree with 25 family members, 13 of them were affected or probably affected by an autosomal dominant SND + AVB. The mean age of cardiac pacemaker implantation was 42 years old, the youngest of them had at 25 years old. Among the family WGS was performed in two first cousins. We exclude the presence of rare variants among the gene previously associated with SND or AVB. Our results suggest the presence of the mutation in a new gene. Thanks to the linkage analysis we may isolate a region associated with the phenotype and then identify candidate rare variant shared by the 2 affected members whole genome sequenced. Such candidate variants will be tested in other affected family members, prioritized according tissue expression and pathogenicity prediction. [ABSTRACT FROM AUTHOR]

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease, affecting preferentially people under 40 years old with ventricular arrhythmia to sudden death. To date, the rate of successful genotyping is about 50%. Desmosomal genes (PKP2, DSC2, DSG2, DSP, JUP) are the most frequently mutated, the implication of the other genes associated with other cardiomyopathies is still debated. The pathogenicity of variants among these genes should be assessed not only based on the rarity because of the presence of rare variants in individuals in the general population. Assess the pathogenicity of variants and the relevance of genes involved in ACM. DNA from 179 patients with ACM were sequenced on a panel of 71 heart disease genes including 11 genes most often described in ACM. The pathogenicity of variants is assessed according to international guidelines (ACMG score) with 2 bioinformatic tools. We performed burden (CAST) and dispersion tests (SKAT, SKAT-O) on the 71 genes between patients and a control population. Among the 179 patients, 34.6% have a pathogenic variant with PKP2 in 42 patients. Furthermore, 17.3% of patients have uncertain significance variants in genes involved in ACM. Burden tests showed a significant enrichment in pathogenic variants in PKP2, DSP, DSC2 and DSG2 (P < 0.001) and in uncertain significance variants in the PKP2, DSG2 and DSC2 genes (P < 0.01). No enrichment was observed among other genes. Patients with a variant in genes involved in ACM are diagnosed earlier than patients without variant (P < 0.05). Only desmosomal genes count a significate proportion of pathogenic variants in patients with ACM compared to control population. Uncertain significance variants in PKP2, DSC2, DSG2 genes seem to contribute to ACM and should be investigated. The age of symptom onset is correlated with the presence of pathogenic variant, thus justifying early family screening for better clinical management. [ABSTRACT FROM AUTHOR]

Familial genetic and genome wide studies associated FLNA, DCHS1, DZIP1 and TNS1 genes with mitral valve prolapse (MVP). These genes point to the cellular mechanical stress response as a unifying common pathway in MVP. The myofibroblastic differentiation of the valve interstitial cells (VICs) has been described as one of the main mechanisms associated with MVP. We recently developed a unique knock-in (KI) rat model expressing the Filamin A FlnA-P637Q mutation identified MVP patients. To determine the primary cell culture conditions of the mitral VICs to limit myofibroblastic differentiation with the objective to analyze in vitro the impact of the FlnA-P637Q mutation on VICs responses to mechanical stress. Mitral valves were dissected from 3 week-old WT and KI rats, then grown on collagen coated dishes in either 4.5 g/l or 1 g/l glucose DMEM supplemented with 10 or 2% Fetal Calf Serum (FCS). Growth rate and myofibroblastic differentiation of the cells were analyzed by immunofluorescence, western blot and qPCR experiments. Our preliminary results show that WT and KI cells grow with similar growth rates (t1/2= 24 h) in 4.5 g/l glucose/10% FCS DMEM. In addition, immunofluorescence and qPCR experiments show that both cell types exhibit significant smooth muscle actin (SMA-ACTA2) expression as soon as they are grown in culture ("Passage" P0). SMA expression further increases (× 1.5) when cells are trypsinized and amplified once (P1) or twice (P2). On the other hand, growing the cells in 1 g/l glucose/2% FCS resulted in a 45% decrease of SMA expression at P0 and P1. SMA expression finally reaches, at P2, the level of high glucose culture condition. Our preliminary studies enabled us to establish culture conditions that limit myofibroblastic differentiation of WT and FlnA-P637Q mitral VICs at early "passages". The response of these "quiescent" cells to mechanical stress and the impact of FlnA-P637Q mutation are now under study. [ABSTRACT FROM AUTHOR]

Filamin-A mitral valve prolapse/dystrophy (FLNA-MVP) phenotype associates moderate MVP and a paradoxical restricted motion in diastole. We aim to assess the association of MVP with restricted motion in diastole in MVP patients (restricted MVP). We prospectively enrolled 475 MVP probands (64 ± 13 years). Patients underwent a clinical examination and a comprehensive echocardiographic analysis of mitral valve apparatus. Among the 475 probands, 48 (101%, 95% CI 7.7–13.3) had both a MVP and a doming aspect in diastole. Patients with restricted MVP exhibited shorter chordae tendinaes, and a shorter distance between papillary muscle tip and mitral annulus. Compared with controls, mitral valve leaflets were lengthened, thickened and mitral valve annulus was enlarged. The prevalence of polyvalvular disease and bicuspid aortic valve was not increased in restricted MVP patients compared with conventional MVP. Familial form of restricted MVP was identified even in the absence of Filamin-A mutation. Restricted MVP is a quite frequent finding in MVP patients and is associated with unique features of the MV apparatus. Restricted MVP can be regarded as a third type of MVP beside myxomatous Barlow disease and fibro-elastic deficiency MVP. [ABSTRACT FROM AUTHOR]

Introduction The Brugada syndrome (BrS) is an inherited cardiac disorder predisposing to ventricular arrhythmias and sudden death. In the present day, only 30% of BrS cases have known genetic causes. Using whole-exome sequencing in a large pedigree with affected members, we identified a rare variant (p.R211H) in RRAD, the gene encoding Rad GTPase. Objective The aim of this work was to elucidate the mechanisms by which the RRAD p.R211H variant leads to BrS. Methods The study was performed in two cell models, i.e., cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) reprogrammed from the proband carrying the familial mutation and his healthy brother (non-carrier) and neonatal mouse cardiomyocytes (NMC) infected with adenoviruses encoding wildtype human RAD (ad_WT-RAD) or GFP (ad_GFP), and knock-in mouse mo del carrying the equivalent p.R210H Rad mutation (KI mice). Results iPSC-CMs from the proband displayed a severe decrease of INa and a moderate decrease of ICaL. Overexpression of WT-RAD in NMC triggered similar impact on both currents. The iPSC-CMs carrying the variant exhibited reduced action potential upstroke velocity, prolonged action potentials and increased incidence of early afterdepolarizations. Combined with the electrical phenotype, these cells showed cortical distribution of actin, cell rounding and reduced focal adhesion count. In mice, Rad was predominantly expressed in the right ventricle outflow tract compared to the other cardiac compartments. This pattern of expression was not altered by the variant. KI mice displayed ventricular conduction disorders under ajmaline challenge and histological anomalies, including fibrosis development, in the right ventricular wall. Conclusion Mutation in the RAD GTPase recapitulate the typical electrophysiological signature of Brugada syndrome coupled with cytoskeleton disturbances in cardiomyocytes derived from the patient. KI mice showed both cardiac electrical and structural disturbances. [ABSTRACT FROM AUTHOR]