RESUMO
The demographical history of France remains largely understudied despite its central role toward understanding modern population structure across Western Europe. Here, by exploring publicly available Europe-wide genotype datasets together with the genomes of 3234 present-day and six newly sequenced medieval individuals from Northern France, we found extensive fine-scale population structure across Brittany and the downstream Loire basin and increased population differentiation between the northern and southern sides of the river Loire, associated with higher proportions of steppe vs. Neolithic-related ancestry. We also found increased allele sharing between individuals from Western Brittany and those associated with the Bell Beaker complex. Our results emphasise the need for investigating local populations to better understand the distribution of rare (putatively deleterious) variants across space and the importance of common genetic legacy in understanding the sharing of disease-related alleles between Brittany and people from western Britain and Ireland.
Assuntos
Genética Populacional , Humanos , França , Genoma Humano/genética , Demografia , Variação Genética , Alelos , Genótipo , História Medieval , Europa (Continente)RESUMO
While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.
Assuntos
Células-Tronco Pluripotentes Induzidas , Humanos , Animais , Camundongos , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Cromatina/genética , Proteínas de Ligação a DNA/metabolismo , GenomaRESUMO
OBJECTIVE: Variants in the FLNA gene have been associated with mitral valve dystrophy (MVD), and even polyvalvular disease has been reported. This study aimed to analyse the aortic valve and root involvement in FLNA-MVD families and its impact on outcomes. METHODS: 262 subjects (37 (18-53) years, 140 male, 79 carriers: FLNA+) from 4 FLNA-MVD families were included. Echocardiography was performed in 185 patients and histological analysis in 3 explanted aortic valves. The outcomes were defined as aortic valve surgery or all-cause mortality. RESULTS: Aortic valve alterations were found in 58% of FLNA+ compared with 6% of FLNA- (p<0.001). 9 (13.4%) FLNA+ had bicuspid aortic valve compared with 4 (3.4%) FLNA- (p=0.03). Overall, the transvalvular mean gradient was slightly increased in FLNA+ (4.8 (4.1-6.1) vs 4.0 (2.9-4.9) mm Hg, p=0.02). The sinuses of Valsalva and sinotubular junction diameters were enlarged in FLNA+ subjects (all p<0.05). 8 FLNA+ patients underwent aortic valve surgery (0 in relatives; p<0.001). Myxomatous remodelling with an infiltration of immune cells was observed. Overall survival was similar between FLNA+ versus FLNA- subjects (86±5% vs 85±6%, p=0.36). There was no statistical evidence for an interaction between genetic status and sex (p=0.15), but the survival tended to be impaired in FLNA+ men (p=0.06) whereas not in women (p=0.71). CONCLUSION: The patients with FLNA variants present frequent aortic valve disease and worse outcomes. Bicuspid aortic valve is more frequent in patients carrying the FLNA-MVD variants. These unique features should be factored into the management of patients with dystrophic and/or bicuspid aortic valve.
Assuntos
Doença da Válvula Aórtica Bicúspide , Doenças das Valvas Cardíacas , Cardiopatia Reumática , Feminino , Humanos , Masculino , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Valva Aórtica/patologia , Filaminas/genética , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/cirurgiaRESUMO
AIMS: Degenerative mitral valve dystrophy (MVD) leading to mitral valve prolapse is the most frequent form of MV disease, and there is currently no pharmacological treatment available. The limited understanding of the pathophysiological mechanisms leading to MVD limits our ability to identify therapeutic targets. This study aimed to reveal the main pathophysiological pathways involved in MVD via the multimodality imaging and transcriptomic analysis of the new and unique knock-in (KI) rat model for the FilaminA-P637Q (FlnA-P637Q) mutation associated-MVD. METHODS AND RESULTS: Wild-type (WT) and KI rats were evaluated morphologically, functionally, and histologically between 3-week-old and 3-to-6-month-old based on Doppler echocardiography, 3D micro-computed tomography (microCT), and standard histology. RNA-sequencing and Assay for Transposase-Accessible Chromatin (ATAC-seq) were performed on 3-week-old WT and KI mitral valves and valvular cells, respectively, to highlight the main signalling pathways associated with MVD. Echocardiographic exploration confirmed MV elongation (2.0 ± 0.1 mm vs. 1.8 ± 0.1, P = 0.001), as well as MV thickening and prolapse in KI animals compared to WT at 3 weeks. 3D MV volume quantified by microCT was significantly increased in KI animals (+58% vs. WT, P = 0.02). Histological analyses revealed a myxomatous remodelling in KI MV characterized by proteoglycans accumulation. A persistent phenotype was observed in adult KI rats. Signalling pathways related to extracellular matrix homeostasis, response to molecular stress, epithelial cell migration, endothelial to mesenchymal transition, chemotaxis and immune cell migration, were identified based on RNA-seq analysis. ATAC-seq analysis points to the critical role of transforming growth factor-ß and inflammation in the disease. CONCLUSION: The KI FlnA-P637Q rat model mimics human myxomatous MVD, offering a unique opportunity to decipher pathophysiological mechanisms related to this disease. Extracellular matrix organization, epithelial cell migration, response to mechanical stress, and a central contribution of immune cells are highlighted as the main signalling pathways leading to myxomatous MVD. Our findings pave the road to decipher underlying molecular mechanisms and the specific role of distinct cell populations in this context.
Assuntos
Prolapso da Valva Mitral , Valva Mitral , Adulto , Humanos , Ratos , Animais , Lactente , Valva Mitral/metabolismo , Filaminas/genética , Filaminas/metabolismo , Transcriptoma , Microtomografia por Raio-X , Prolapso da Valva Mitral/patologia , FenótipoRESUMO
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an exercise and emotional stress-induced life-threatening inherited heart rhythm disorder, characterized by an abnormal cellular calcium homeostasis. Most reported cases have been linked to mutations in the gene encoding the type 2 ryanodine receptor gene, RYR2. We generated induced pluripotent stem cells (hiPSCs) from peripheral blood mononuclear cells (PBMC) from three CPVT-affected patients, two of them carrying p.R4959Q mutation and one carrying p.Y2476D mutation. These generated hiPSC lines are a useful model to study pathophysiological consequences of RYR2 dysfunction in humans and the molecular basis of CPVT.
Assuntos
Células-Tronco Pluripotentes Induzidas , Cálcio/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Mutação/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia VentricularRESUMO
Down-regulation of Connexin43 (Cx43) has often been associated with the development of cardiac fibrosis. We showed previously that Scn5a heterozygous knockout mice (Scn5a+/-), which mimic familial progressive cardiac conduction defect, exhibit an age-dependent decrease of Cx43 expression and phosphorylation concomitantly with activation of TGF-ß pathway and fibrosis development in the myocardium between 45 and 60 weeks of age. The aim of this study was to investigate whether Gap-134 prevents Cx43 down-regulation with age and fibrosis development in Scn5a+/- mice. We observed in 60-week-old Scn5a+/- mouse heart a Cx43 expression and localization remodeling correlated with fibrosis. Chronic administration of a potent and selective gap junction modifier, Gap-134 (danegaptide), between 45 and 60 weeks, increased Cx43 expression and phosphorylation on serine 368 and prevented Cx43 delocalization. Furthermore, we found that Gap-134 prevented fibrosis despite the persistence of the conduction defects and the TGF-ß canonical pathway activation. In conclusion, the present study demonstrates that the age-dependent decrease of Cx43 expression is involved in the ventricular fibrotic process occurring in Scn5a+/- mice. Finally, our study suggests that gap junction modifier, such as Gap-134, could be an effective anti-fibrotic agent in the context of age-dependent fibrosis in progressive cardiac conduction disease.
Assuntos
Benzamidas/farmacologia , Cardiomiopatias/prevenção & controle , Conexina 43/metabolismo , Fibroblastos/efeitos dos fármacos , Miocárdio/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/deficiência , Prolina/análogos & derivados , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Camundongos da Linhagem 129 , Camundongos Knockout , Miocárdio/patologia , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Fosforilação , Prolina/farmacologia , Pirazóis/farmacologia , Transdução de Sinais , Regulação para Cima , Remodelação Ventricular/efeitos dos fármacosRESUMO
Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. Conclusion: In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.
Assuntos
Doença do Sistema de Condução Cardíaco/genética , Estudos de Associação Genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Fatores Etários , Doenças Assintomáticas , Síndrome de Brugada/genética , Criança , Pré-Escolar , Eletrocardiografia , Feminino , Seguimentos , Mutação com Ganho de Função , Humanos , Lactente , Recém-Nascido , Síndrome do QT Longo/genética , Mutação com Perda de Função , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
Aims: QT prolongation during mental stress test (MST) has been associated with familial idiopathic ventricular fibrillation. In long QT syndrome (LQTS), up to 30% of mutation carriers have normal QT duration. Our aim was to assess the QT response during MST, and its accuracy in the diagnosis of concealed LQTS. Methods and results: All patients who are carrier of a KCNQ1 or KCNH2 mutations without QT prolongation were enrolled. A control group was constituted of patients with negative exercise and epinephrine tests. Electrocardiogram were recorded at rest and at the maximum heart rate during MST and reviewed by two physicians. Among the 70 patients enrolled (median age 41±2.1 years, 46% male), 36 were mutation carrier for LQTS (20 KCNQ1 and 16 KCNH2), and 34 were controls. KCNQ1 and KCNH2 mutation carriers presented a longer QT interval at baseline [405(389; 416) and 421 (394; 434) ms, respectively] compared with the controls [361(338; 375)ms; P < 0.0001]. QT duration during MST varied by 9 (4; 18) ms in KCNQ1, 3 (-6; 16) ms in KCNH2, and by -22 (-29; -17) ms in controls (P < 0.0001). These QT variations were independent of heart rate (P < 0.3751). Receiver operating characteristic curve analysis identified a cut-off value of QT variation superior to -11 ms as best predictor of LQTS. It provided 97% sensitivity and 97% specificity of QT prolongation in the diagnosis of LQTS. Conclusion: We identified a paradoxical response of the QT interval during MST in LQTS. Easy to assess, MST may be efficient to unmask concealed LQTS in patients at risk of this pathology.
Assuntos
Eletrocardiografia , Frequência Cardíaca/genética , Canal de Potássio KCNQ1/genética , Canal de Potássio KCNQ2/genética , Síndrome do QT Longo/diagnóstico , Mutação , Estresse Psicológico/fisiopatologia , Fibrilação Ventricular/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Síndrome do QT Longo/genética , Síndrome do QT Longo/fisiopatologia , Masculino , Conceitos Matemáticos , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Risco , Estresse Psicológico/diagnóstico , Estresse Psicológico/psicologia , Fibrilação Ventricular/genética , Fibrilação Ventricular/fisiopatologia , Adulto JovemRESUMO
Mitral valve prolapse (MVP) is a common condition that affects 2%-3% of the general population. MVP is thought to include syndromic forms such as Marfan syndrome and non-syndromic MVP, which is the most frequent form. Myxomatous degeneration and fibroelastic deficiency (FED) are regarded as two different forms of non-syndromic MVP. While FED is still considered a degenerative disease associated with ageing, frequent familial clustering has been demonstrated for myxomatous MVP. Familial and genetic studies led to the recognition of reduced penetrance and large phenotypic variability, and to the identification of prodromal or atypical forms as a part of the complex spectrum of the disease. Whereas autosomal dominant mode is the common inheritance pattern, an X linked form of non-syndromic MVP was recognised initially, related to Filamin-A gene, encoding for a cytoskeleton protein involved in mechanotransduction. This identification allowed a comprehensive description of a new subtype of MVP with a unique association of leaflet prolapse and paradoxical restricted motion in diastole. In autosomal dominant forms, three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31-32. Although deciphering the underlying genetic defects is still a work in progress, DCHS1 mutations have been identified (11p15.4) in typical myxomatous disease, highlighting new molecular pathways and pathophysiological mechanisms leading to the development of MVP. Finally, a large international genome-wide association study demonstrated the implication of frequent variants in MVP development and opened new directions for future research. Hence, this review focuses on phenotypic, genetic and pathophysiological aspects of MVP.
Assuntos
Prolapso da Valva Mitral/genética , Valva Mitral/fisiopatologia , Mutação , Animais , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Valva Mitral/diagnóstico por imagem , Prolapso da Valva Mitral/diagnóstico por imagem , Prolapso da Valva Mitral/epidemiologia , Prolapso da Valva Mitral/fisiopatologia , Fenótipo , Prognóstico , Fatores de Risco , SíndromeRESUMO
Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)-which encodes a circulating pro-angiogenic factor mainly secreted from the liver-shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA.
Assuntos
Proteínas Semelhantes a Angiopoietina/genética , Predisposição Genética para Doença , Aneurisma Intracraniano/genética , Mutação/genética , Fases de Leitura Aberta/genética , Proteína 6 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina/sangue , Células Cultivadas , Códon sem Sentido/genética , Família , Feminino , Células HEK293 , Humanos , Aneurisma Intracraniano/sangue , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores de RiscoRESUMO
Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis. Methods and results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations. Phenotype was characterized by a comprehensive echocardiography focusing on mitral valve apparatus in comparison with control relatives. In this X-linked disease valves lesions were severe in men and moderate in women. Most men had classical features of mitral valve prolapse (MVP), but without chordal rupture. By contrast to regular MVP, mitral leaflet motion was clearly restricted in diastole and papillary muscles position was closer to mitral annulus. Valvular abnormalities were similar in the four families, in adults and young patients from early childhood suggestive of a developmental disease. In addition, mitral valve lesions worsened over time as encountered in degenerative conditions. Polyvalvular involvement was frequent in males and non-diagnostic forms frequent in females. Overall survival was moderately impaired in men (P = 0.011). Cardiac surgery rate (mainly valvular) was increased (33.3 ± 9.8 vs. 5.0 ± 4.9%, P < 0.0001; hazard ratio 10.5 [95% confidence interval: 2.9-37.9]) owing mainly to a lifetime increased risk in men (76.8 ± 14.1 vs. 9.1 ± 8.7%, P < 0.0001). Conclusion: FLNA-MVD is a developmental and degenerative disease with complex phenotypic expression which can influence patient management. FLNA-MVD has unique features with both MVP and paradoxical restricted motion in diastole, sub-valvular mitral apparatus impairment and polyvalvular lesions in males. FLNA-MVD conveys a substantial lifetime risk of valve surgery in men.
Assuntos
Filaminas/genética , Prolapso da Valva Mitral/genética , Prolapso da Valva Mitral/patologia , Valva Mitral/patologia , Adolescente , Adulto , Ecocardiografia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/diagnóstico por imagem , Mutação/genética , Fenótipo , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Inherited cardiac conduction disease is a rare bradyarrhythmia associated with mutations in various genes that affect action potential propagation. It is often characterized by isolated conduction disturbance of the His-Purkinje system, but it is rarely described as a syndromic form. OBJECTIVES: The authors sought to identify the genetic defect in families with a novel bradyarrhythmia syndrome associated with bone malformation. METHODS: The authors genetically screened 15 European cases with genotype-negative de novo atrioventricular (AV) block and their parents by trio whole-exome sequencing, plus 31 Japanese cases with genotype-negative familial AV block or sick sinus syndrome by targeted exon sequencing of 457 susceptibility genes. Functional consequences of the mutation were evaluated using an in vitro cell expression system and in vivo knockout mice. RESULTS: The authors identified a connexin-45 (Cx45) mutation (p.R75H) in 2 unrelated families (a de novo French case and a 3-generation Japanese family) who presented with progressive AV block, which resulted in atrial standstill without ventricular conduction abnormalities. Affected individuals shared a common extracardiac phenotype: a brachyfacial pattern, finger deformity, and dental dysplasia. Mutant Cx45 expressed in Neuro-2a cells showed normal hemichannel assembly and plaque formation. However, Lucifer yellow dye transfer and gap junction conductance between cell pairs were severely impaired, which suggested that mutant Cx45 impedes gap junction communication in a dominant-negative manner. Tamoxifen-induced, cardiac-specific Cx45 knockout mice showed sinus node dysfunction and atrial arrhythmia, recapitulating the intra-atrial disturbance. CONCLUSIONS: Altogether, the authors showed that Cx45 mutant p.R75H is responsible for a novel disease entity of progressive atrial conduction system defects associated with craniofacial and dentodigital malformation.
Assuntos
Bloqueio Atrioventricular/etiologia , Conexinas/genética , DNA/genética , Deformidades Dentofaciais/complicações , Mutação , Adolescente , Adulto , Animais , Bloqueio Atrioventricular/genética , Bloqueio Atrioventricular/fisiopatologia , Criança , Pré-Escolar , Conexinas/metabolismo , Análise Mutacional de DNA , Deformidades Dentofaciais/genética , Deformidades Dentofaciais/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Eletrocardiografia , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto JovemRESUMO
BACKGROUND: Sodium-channel blocker challenge (SCBC) is frequently performed to unmask Brugada syndrome. OBJECTIVE: We aim to identify predictors of positivity and complications of SCBC in the setting of familial screening of Brugada syndrome. METHODS: All consecutive patients from 2000 to 2014 who benefit from a sodium-channel blocker and belong to a family with at least 2 subjects affected by the syndrome were enrolled and followed prospectively. Data were reviewed by 2 physicians blinded to the clinical and genetic status. RESULTS: Of the 672 SCBCs performed in 137 families, 337 (50%) were positive. Multivariate analysis identified ajmaline (odds ratio [OR] 2.98; 95% CI 1.65-4.91) and a significant S wave in lead DII (OR 3.11; 95% CI 2.12-4.58), DIII (OR 2.75; 95% CI 1.78-4.25), or V5 (OR 3.71; 95% CI 2.54-5.44) as predictors of a positive SCBC (P < .0001). Eleven patients (1.6%) presented complications (10 ventricular arrhythmias and 1 atrial flutter), but no deaths occurred. Familial history of complications (OR 41; lower quartile, upper quartile 10, 203; P < .0001), young age (P = .04), and decreased electrocardiographic conduction parameters at baseline (P = .04) were predictors of complications. QRS enlargement during SCBC was not associated with complications. During a median follow-up of 106 months (lower quartile, upper quartile 54, 143 months), 11 life-threatening arrhythmias occurred. CONCLUSION: SCBC in the screening of familial Brugada syndrome is safe. The risk of complication is considerably increased in the case of familial history of complicated SCBC, in young patients, and in the presence of decreased electrocardiographic conduction parameters. However, QRS enlargement during the test is not directly related to complications and should not be used to prematurely stop the test unless leading to false-negative results.
Assuntos
Ajmalina/farmacologia , Síndrome de Brugada/diagnóstico , Eletrocardiografia/efeitos dos fármacos , Flecainida/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Adulto , Ajmalina/administração & dosagem , Síndrome de Brugada/tratamento farmacológico , Síndrome de Brugada/fisiopatologia , Relação Dose-Resposta a Droga , Reações Falso-Positivas , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Prognóstico , Estudos Retrospectivos , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagemRESUMO
BACKGROUND: Although the implantable cardioverter-defibrillator (ICD) remains the main therapy for Brugada syndrome (BrS), it does not reduce life-threatening ventricular arrhythmia. Based on pathophysiologic mechanisms, hydroquinidine (HQ) has been suggested for effective prevention of arrhythmia. OBJECTIVE: The purpose of this study was to provide evidence-based data supporting HQ use to prevent life-threatening ventricular arrhythmia in high-risk patients with BrS. METHODS: We performed a prospective multicenter randomized (HQ vs placebo) double-blind study with two 18-month crossover phases in patients with BrS and implanted with an ICD. RESULTS: Among the 50 patients enrolled (mean age 47.0 ± 11.4 years, 42 [84%] male), 26 (52%) fully completed both phases. Thirty-four (68%) presented HQ-related side effects, mainly gastrointestinal, which led to discontinuation of the therapy in 13 (26%). HQ lengthened the QTc interval (409 ± 32 ms vs 433 ± 37 ms; P = .027) and increased repolarization dispersion as evaluated by Tpe max in precordial leads (89 ± 15 ms vs 108 ± 27 ms; P <.0001) with no significant changes in J-point elevation. During the 36-month follow-up, 1 appropriate ICD shock (0.97% event per year), 1 self-terminating ventricular fibrillation, and 1 inappropriate ICD shock occurred under placebo therapy. No arrhythmic events were reported under HQ therapy. CONCLUSION: Although HQ seems to be effective in preventing life-threatening ventricular arrhythmia, it could not be an alternative for ICD implantation. Its frequent side effects greatly reduce its probable compliance and therefore do not reveal a significant effect. HQ increases repolarization dispersal with no changes in BrS pattern, which could indicate a more complex action of HQ than its Ito blocking effect alone.
Assuntos
Síndrome de Brugada/terapia , Desfibriladores Implantáveis , Eletrocardiografia , Quinidina/análogos & derivados , Fibrilação Ventricular/prevenção & controle , Adulto , Antiarrítmicos/uso terapêutico , Síndrome de Brugada/complicações , Síndrome de Brugada/fisiopatologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Quinidina/uso terapêutico , Fatores de Risco , Fatores de Tempo , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/fisiopatologiaAssuntos
Catecolaminas/sangue , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Síndrome do QT Longo/complicações , Estresse Psicológico/sangue , Adolescente , Feminino , Humanos , Síndrome do QT Longo/sangue , Síndrome do QT Longo/fisiopatologia , Masculino , Estresse Psicológico/complicaçõesRESUMO
Brugada syndrome is a rare inherited arrhythmia syndrome leading to an increased risk of sudden cardiac death, despite a structurally normal heart. Diagnosis is based on a specific electrocardiogram pattern, observed either spontaneously or during a sodium channel blocker test. Among affected patients, risk stratification remains a challenge, despite recent insights from large population cohorts. As implantable cardiac defibrillators - the main therapy in Brugada syndrome - are associated with a high rate of complications in this population, the main challenge is risk stratification of patients with Brugada syndrome. Aside from the two main predictors of arrhythmia (symptoms and spontaneous electrocardiogram pattern), many risk factors have been recently suggested for stratifying risk of sudden cardiac death in Brugada syndrome. We have reviewed these data and discuss current guidelines in light of recent progress in this complex field.
Assuntos
Síndrome de Brugada/terapia , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Cardioversão Elétrica/instrumentação , Síndrome de Brugada/complicações , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/mortalidade , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis/normas , Cardioversão Elétrica/efeitos adversos , Cardioversão Elétrica/normas , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Humanos , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Population-based studies suggest that genetic factors contribute to sudden cardiac death (SCD). METHODS AND RESULTS: In the first part of the present study (Diagnostic Data Influence on Disease Management and Relation of Genetic Polymorphisms to Ventricular Tachy-arrhythmia in ICD Patients [DISCOVERY] trial) Cox regression was done to determine if 7 single-nucleotide polymorphisms (SNPs) in 3 genes coding G-protein subunits (GNB3, GNAQ, GNAS) were associated with ventricular tachyarrhythmia (VT) in 1145 patients receiving an implantable cardioverter-defibrillator (ICD). In the second part of the study, SNPs significantly associated with VT were further investigated in 1335 subjects from the Oregon SUDS, a community-based study analyzing causes of SCD. In the DISCOVERY trial, genotypes of 2 SNPs in the GNAS gene were nominally significant in the prospective screening and significantly associated with VT when viewed as recessive traits in post hoc analyses (TT vs CC/CT in c.393C>T: HR 1.42 [CI 1.11-1.80], P=0.005; TT vs CC/CT in c.2273C>T: HR 1.57 [CI 1.18-2.09], P=0.002). TT genotype in either SNP was associated with a HR of 1.58 (CI 1.26-1.99) (P=0.0001). In the Oregon SUDS cohort significant evidence for association with SCD was observed for GNAS c.393C>T under the additive (P=0.039, OR=1.21 [CI 1.05-1.45]) and recessive (P=0.01, OR=1.52 [CI 1.10-2.13]) genetic models. CONCLUSIONS: GNAS harbors 2 SNPs that were associated with an increased risk for VT in ICD patients, of which 1 was successfully replicated in a community-based population of SCD cases. To the best of our knowledge, this is the first example of a gene variant identified by ICD VT monitoring as a surrogate parameter for SCD and also confirmed in the general population. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00478933.
Assuntos
Cromograninas/genética , Morte Súbita Cardíaca/etiologia , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Insuficiência Cardíaca/fisiopatologia , Taquicardia Ventricular/genética , Fibrilação Ventricular/genética , Idoso , Estudos de Coortes , Desfibriladores Implantáveis , Feminino , Insuficiência Cardíaca/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/terapia , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/terapiaRESUMO
BACKGROUND: The Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in SCN5A, the molecular mechanisms underlying this condition are still largely unknown. METHODS AND RESULTS: We combined whole-exome sequencing and linkage analysis to identify the genetic variant likely causing Brugada syndrome in a pedigree for which SCN5A mutations had been excluded. This approach identified 6 genetic variants cosegregating with the Brugada electrocardiographic pattern within the pedigree. In silico gene prioritization pointed to 1 variant residing in KCNAB2, which encodes the voltage-gated K(+) channel ß2-subunit (Kvß2-R12Q). Kvß2 is widely expressed in the human heart and has been shown to interact with the fast transient outward K(+) channel subunit Kv4.3, increasing its current density. By targeted sequencing of the KCNAB2 gene in 167 unrelated patients with Brugada syndrome, we found 2 additional rare missense variants (L13F and V114I). We then investigated the physiological effects of the 3 KCNAB2 variants by using cellular electrophysiology and biochemistry. Patch-clamp experiments performed in COS-7 cells expressing both Kv4.3 and Kvß2 revealed a significant increase in the current density in presence of the R12Q and L13F Kvß2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kvß2-R12Q were significantly increased in comparison with wild-type Kvß2. CONCLUSIONS: Altogether, our results indicate that Kvß2 dysfunction can contribute to the Brugada electrocardiographic pattern.
Assuntos
Síndrome de Brugada/genética , Mutação com Ganho de Função/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Eletrocardiografia , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Superfamília Shaker de Canais de Potássio , Canais de Potássio Shal/genética , Sequenciamento do ExomaRESUMO
For the last 10 years, applying new sequencing technologies to thousands of whole exomes has revealed the high variability of the human genome. Extreme caution should thus be taken to avoid misinterpretation when associating rare genetic variants to disease susceptibility. The Brugada syndrome (BrS) is a rare inherited arrhythmia disease associated with high risk of sudden cardiac death in the young adult. Familial inheritance has long been described as Mendelian, with autosomal dominant mode of transmission and incomplete penetrance. However, all except 1 of the 23 genes previously associated with the disease have been identified through a candidate gene approach. To date, only rare coding variants in the SCN5A gene have been significantly associated with the syndrome. However, the genotype/phenotype studies conducted in families with SCN5A mutations illustrate the complex mode of inheritance of BrS. This genetic complexity has recently been confirmed by the identification of common polymorphic alleles strongly associated with disease risk. The implication of both rare and common variants in BrS susceptibility implies that one should first define a proper genetic model for BrS predisposition prior to applying molecular diagnosis. Although long remains the way to personalized medicine against BrS, the high phenotype variability encountered in familial forms of the disease may partly find an explanation into this specific genetic architecture.
RESUMO
BACKGROUND AND AIMS: Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by decreased plasma levels of LDL-cholesterol and apolipoprotein B (ApoB). Currently, genetic diagnosis in FHBL relies largely on Sanger sequencing to identify APOB and PCSK9 gene mutations and on western blotting to detect truncated ApoB species. METHODS: Here, we applied targeted enrichment and next-generation sequencing (NGS) on a panel of three FHBL genes and two abetalipoproteinemia genes (APOB, PCSK9, ANGPTL3, MTTP and SAR1B). RESULTS: In this study, we identified five likely pathogenic heterozygous rare variants. These include four novel nonsense mutations in APOB (p.Gln845*, p.Gln2571*, p.Cys2933* and p.Ser3718*) and a rare variant in PCSK9 (Minor Allele Frequency <0.1%). The affected family members tested were shown to be carriers, suggesting co-segregation with low LDL-C. CONCLUSIONS: Our study further demonstrates that NGS is a reliable and practical approach for the molecular screening of FHBL-causative genes that may provide a mean for deciphering the genetic basis in FHBL.