RESUMO
RATIONALE: Fibro-fatty infiltration of subepicardial layers of the atrial wall has been shown to contribute to the substrate of atrial fibrillation. OBJECTIVE: Here, we examined if the epicardium that contains multipotent cells is involved in this remodeling process. METHODS AND RESULTS: One hundred nine human surgical right atrial specimens were evaluated. There was a relatively greater extent of epicardial thickening and dense fibro-fatty infiltrates in atrial tissue sections from patients aged over 70 years who had mitral valve disease or atrial fibrillation when compared with patients aged less than 70 years with ischemic cardiomyopathy as indicated using logistic regression adjusted for age and gender. Cells coexpressing markers of epicardial progenitors and fibroblasts were detected in fibro-fatty infiltrates. Such epicardial remodeling was reproduced in an experimental model of atrial cardiomyopathy in rat and in Wilms tumor 1 (WT1)CreERT2/+;ROSA-tdT+/- mice. In the latter, genetic lineage tracing demonstrated the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of human adult epicardial-derived cells expressing PDGFR (platelet-derived growth factor receptor)-α were isolated and differentiated into myofibroblasts in the presence of Ang II (angiotensin II). Furthermore, single-cell RNA-sequencing analysis identified several clusters of adult epicardial-derived cells and revealed their specification from adipogenic to fibrogenic cells in the rat model of atrial cardiomyopathy. CONCLUSIONS: Epicardium is reactivated during the formation of the atrial cardiomyopathy. Subsets of adult epicardial-derived cells, preprogrammed towards a specific cell fate, contribute to fibro-fatty infiltration of subepicardium of diseased atria. Our study reveals the biological basis for chronic atrial myocardial remodeling that paves the way of atrial fibrillation.
Assuntos
Tecido Adiposo/patologia , Fibrilação Atrial/etiologia , Remodelamento Atrial , Cardiomiopatias/complicações , Átrios do Coração/patologia , Miocárdio/patologia , Pericárdio/patologia , Potenciais de Ação , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/metabolismo , Idoso , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Linhagem da Célula , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Frequência Cardíaca , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/metabolismo , Pericárdio/metabolismo , Pericárdio/fisiopatologia , Ratos Wistar , Células-Tronco/metabolismo , Células-Tronco/patologia , Proteínas WT1/genética , Proteínas WT1/metabolismoRESUMO
BACKGROUND: Serum cholesterol efflux capacity, a biomarker that integrates contributors and modulators of the initial step of the reverse cholesterol transport, has been associated with atherosclerosis independently of high-density lipoprotein (HDL) cholesterol level. OBJECTIVES: The authors evaluated the prognostic impact of serum cholesterol efflux capacity on mortality in a large cohort of patients hospitalized for an acute myocardial infarction (MI). METHODS: Serum cholesterol efflux capacity, cholesteryl ester transfer protein (CETP) activity, total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, and triglyceride levels were measured in 1,609 consecutive patients admitted with an acute MI. The primary endpoint was all-cause mortality evaluated at 6 years with a median follow-up of 1.9 years (interquartile range: 1.5 to 4.2 years). An analysis by quartile of serum cholesterol efflux capacity was also performed. RESULTS: In a fully adjusted model that included age, sex, traditional cardiovascular risk factors including lipid levels, and prognostic factors of MI, serum cholesterol efflux capacity was a strong predictor of survival (adjusted hazard ratio for mortality per 1-SD increase in serum cholesterol efflux capacity, 0.79; 95% confidence interval: 0.66 to 0.95; p = 0.0132). Patients displaying an elevated serum cholesterol efflux capacity had a marked lower rate of mortality at 6 years (adjusted hazard ratio: 0.54 [0.32 to 0.89]; p = 0.0165) as compared with patients with reduced serum cholesterol efflux capacity. CONCLUSIONS: Serum cholesterol efflux capacity, an integrative marker of reverse cholesterol transport pathway and efficacy, was inversely associated with all-cause mortality in MI patients independently of HDL cholesterol level and other risk factors.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Triglicerídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Colesterol/sangue , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnósticoRESUMO
BACKGROUND: Atrial fibrillation is associated with an atrial cardiomyopathy composed mainly of fibrosis and adipose tissue accumulation. We hypothesized that MRI, when used in an optimal ex vivo setting allowing high spatial resolution without motion artifacts, can help characterizing the complex 3D left atrial (LA) wall composition in human myocardial samples, as compared to histology. METHODS: This prospective case-control study was approved by the institutional review board. 3D MRI acquisitions including saturation-recovery T1 mapping and DIXON imaging was performed at 4.0 T on 9 human LA samples collected from patients who underwent cardiac surgery. Histological quantification of fibrosis and fat was obtained. MRI T1 maps were clustered based on a Gaussian Mixture Model allowing quantification of total, interstitial and fatty fibrosis components. Fat maps were computed from DIXON images and fat fractions were calculated. MRI measurements were performed on the same location as the histological analysis (plane) and on the entire sample volume (3D). RESULTS: High correlations and levels of agreement were observed between MRI and histology for total (r = 0.93), interstitial (r = 0.93) and fatty fibrosis (r = 0.98) and fat (r = 0.96). Native T1 correlated with the amount of fibrosis from MRI and histology. The 3D MRI total, interstitial and fatty fibrosis ranges were between 6% and 23%, 4% and 17.3%; and 1.4% and 19.7% respectively. CONCLUSION: High Field ex vivo MRI was able to quantify different LA myocardial components with high agreement in 2D with histology and moreover to provide 3D quantification of such components whereas in vivo application remains a challenge.
Assuntos
Tecido Adiposo/diagnóstico por imagem , Fibrose/diagnóstico por imagem , Átrios do Coração/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Imageamento por Ressonância Magnética , Miocárdio/patologia , Tecido Adiposo/patologia , Estudos de Casos e Controles , Diagnóstico Diferencial , Fibrose/patologia , Cardiopatias/patologia , Cardiopatias/cirurgia , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento Tridimensional , Estudos ProspectivosRESUMO
Purpose To determine whether left atrial (LA) strain quantification with cardiac magnetic resonance (MR) imaging feature tracking is associated with the severity of LA fibrofatty myocardial remodeling at histologic analysis. Materials and Methods This prospective case-control study was approved by the institutional review board. LA strain was evaluated with cardiac MR feature tracking between January 2014 and March 2015 in 13 consecutive patients (mean age, 61 years ± 19; nine male) with mitral regurgitation in the 24 hours before mitral valve surgery and 13 age- and sex-matched healthy control subjects. LA strain parameters were compared first between control subjects and patients and then according to atrial fibrillation and mitral regurgitation status. Associations between LA strain and histology of preoperative biopsies were reported by using receiver operating characteristic curve analysis and Spearman correlation. Results Peak longitudinal atrial strain (PLAS) was significantly lower in patients with mitral regurgitation than in healthy control subjects (P < .001). Increased LA remodeling was significantly related to altered LA strain, and the strongest association was found between PLAS and the degree of fibrofatty myocardial replacement at histologic analysis (r = -0.75, P = .017). LA end-diastolic volume was increased in patients with mitral regurgitation when compared with that in healthy volunteers (P < .001) because of volume overload; however, volume did not correlate with the histologic degree of LA fibrofatty replacement (r = -0.35, P = .330). Conclusion LA strain, especially PLAS, correlates strongly with the degree of fibrofatty replacement at histologic analysis. Such functional imaging biomarker in combination with LA volumetry could help to guide clinical decisions, since myocardial structural remodeling is a known morphologic substrate of LA dysfunction leading to atrial fibrillation with adverse outcome. © RSNA, 2017 Online supplemental material is available for this article.
Assuntos
Tecido Adiposo/diagnóstico por imagem , Remodelamento Atrial , Átrios do Coração/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodos , Tecido Adiposo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Fibrose/diagnóstico por imagem , Fibrose/patologia , Átrios do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/patologia , Estudos ProspectivosRESUMO
AIMS: Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors. METHODS AND RESULTS: We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7-41%] vs. 64% [95% CI 43-82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations. CONCLUSION: A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members.
Assuntos
Síndrome do QT Longo , Eletrocardiografia , Feminino , França , Testes Genéticos , Humanos , Itália , Japão , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers). We determined grandparental and parental origins of variant alleles in 1903 children and 624 grandchildren, and the grandparental origin of normal alleles in healthy children from 44 three-generation control families. LQTS alleles were more of maternal than paternal origin (61 vs 39%, P<0.001). The ratio of maternally transmitted alleles in LQT1 (66%) was higher than in LQT2 (56%, P<0.001) and LQT3 (57%, P=0.03). Unlike the Mendelian distribution of grandparental alleles seen in control families, variant grandparental LQT1 and LQT2 alleles in grandchildren showed an excess of maternally transmitted grandmother alleles. For LQT1, maternal transmission differs according to the variant level of dysfunction with 68% of maternal transmission for dominant negative or unknown functional consequence variants vs 58% for non-dominant negative and variants leading to haploinsufficiency, P<0.01; however, for LQT2 or LQT3 this association was not significant. An excess of disease-causing alleles of maternal origin, most pronounced in LQT1, was consistently found across ethnic groups. This observation does not seem to be linked to an imbalance in transmission of the LQTS subtype-specific grandparental allele, but to the potential degree of potassium channel dysfunction.
Assuntos
Canal de Potássio KCNQ1/genética , Síndrome do QT Longo/genética , Mutação , Herança Paterna , Adulto , Alelos , Criança , Feminino , Haploinsuficiência , Humanos , Masculino , LinhagemRESUMO
AIMS: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. METHODS AND RESULTS: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970). CONCLUSION: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.
Assuntos
Síndrome de Brugada/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Polimorfismo de Nucleotídeo Único , Potenciais de Ação , Adulto , Idoso , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatologia , Estudos de Casos e Controles , Linhagem Celular , Biologia Computacional , Análise Mutacional de DNA , Bases de Dados Genéticas , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Razão de Chances , Linhagem , Fenótipo , Fatores de Risco , Arábia Saudita , Transfecção , Estados UnidosRESUMO
BACKGROUND: Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS. METHODS AND RESULTS: In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 (0.19-0.61; P<0.0002) and with shorter QTc (P<0.0001) in the combined discovery and replication cohorts. CONCLUSIONS: We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS.
Assuntos
Canal de Potássio KCNQ1/genética , Síndrome do QT Longo/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Genéticas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/genética , Feminino , Frequência do Gene , Genótipo , Heterozigoto , Humanos , Síndrome do QT Longo/etiologia , Masculino , Fatores de RiscoRESUMO
AIMS: Brugada syndrome (BrS) is an inherited cardiac disease characterized by ST segment elevation in V1-V3 ECG leads. Mutations SCN5A gene encoding for the cardiac voltage-gated Na(+) channel are found in some BrS patients, but also in family members with isolated conduction disturbances. However, some patients show coved ST elevation in the inferior or lateral leads whose association with SCN5A and familial conduction disturbances are poorly known. METHODS AND RESULTS: Two novel SCN5A mutations, D1430N and Q1476X, were identified in two unrelated families comprising patients with Brugada-like ST elevation located in the inferior leads or isolated conduction disturbances. Wild-type (WT) and D1430N mutant channels were expressed in tsA201 cells. Patch clamp electrophysiological experiments revealed total absence of Na(+) current resulting from Nav1.5 mutant when compared to WT channels. Treatments known to restore trafficking defect (incubation at low temperature, with mexiletine or lidocaine) did not restore Na(+) current supporting that Nav1.5 mutation is not a defective trafficking mutation. Furthermore, immunocytolabelling indicates the membrane localisation of both WT and mutant channels confirming what we observed in our patch clamp experiments. This suggests that the mutation may induce a complete block of Na(+) permeation. The nonsense mutation Q1476X was leading to a premature stop codon and was not expressed. CONCLUSION: Brugada-like ST elevation in the inferior ECG leads or isolated conduction disturbances were found in two unrelated families and associated with two novel SCN5A mutations. The missense and nonsense mutations are both resulting in a complete loss of ventricular Na(+) current explaining the phenotypes.
Assuntos
Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Eletrocardiografia/métodos , Predisposição Genética para Doença/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Diagnóstico Diferencial , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Adulto JovemRESUMO
BACKGROUND: Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Na(v)1.5. However, ≈ 20% of probands have SCN5A mutations, suggesting the implication of other genes. MOG1 recently was described as a new partner of Na(v)1.5, playing a potential role in the regulation of its expression and trafficking. We investigated whether mutations in MOG1 could cause BrS. METHODS AND RESULTS: MOG1 was screened by direct sequencing in patients with BrS and idiopathic ventricular fibrillation. A missense mutation p.Glu83Asp (E83D) was detected in a symptomatic female patient with a type-1 BrS ECG but not in 281 controls. Wild type (WT)- and mutant E83D-MOG1 were expressed in HEK Na(v)1.5 stable cells and studied using patch-clamp assays. Overexpression of WT-MOG1 alone doubled sodium current (I(Na)) density compared to control conditions (P<0.01). In contrast, overexpression of mutant E83D alone or E83D+WT failed to increase I(Na) (P<0.05), demonstrating the dominant-negative effect of the mutant. Microscopy revealed that Na(v)1.5 channels failed to properly traffic to the cell membrane in the presence of the mutant. Silencing endogenous MOG1 demonstrated a 54% decrease in I(Na) density. CONCLUSIONS: Our results support the hypothesis that dominant-negative mutations in MOG1 can impair the trafficking of Na(v)1.5 to the membrane, leading to I(Na) reduction and clinical manifestation of BrS. Moreover, silencing MOG1 reduced I(Na), demonstrating that MOG1 is likely to be important in the surface expression of Na(v)1.5 channels. All together, our data support MOG1 as a new susceptibility gene for BrS.
Assuntos
Síndrome de Brugada/genética , Predisposição Genética para Doença , Proteína ran de Ligação ao GTP/genética , Sequência de Aminoácidos , Animais , Análise Mutacional de DNA , Eletrocardiografia , Feminino , Células HEK293 , Humanos , Dados de Sequência Molecular , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5 , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Alinhamento de Sequência , Canais de Sódio/genética , TransfecçãoRESUMO
BACKGROUND: Loss-of-function mutations in the gene KCNQ1 encoding the Kv7.1 K(+) channel cause long QT syndrome type 1 (LQT1), whereas gain-of-function mutations are associated with short QT syndrome as well as familial atrial fibrillation (FAF). However, KCNQ1 mutation pleiotropy, which is capable of expressing both LQT1 and FAF, has not been demonstrated for a discrete KCNQ1 mutation. The genotype-phenotype relationship for a family with FAF suggests a possible association with the LQT1 p.Arg231Cys-KCNQ1 (R231C-Q1) mutation. OBJECTIVE: The purpose of this study was to determine whether R231C-Q1 also can be linked to FAF. METHODS: The R231C-Q1 proband with AF underwent genetic testing for possible mutations in 10 other AF-linked genes plus KCNH2 and SCN5A. Sixteen members from five other R231C-positive LQT1 families were genetically tested for 21 single nucleotide polymorphisms (SNPs) to determine if the FAF family had discriminatory SNPs associated with AF. R231C-Q1 was expressed with KCNE1 (E1) in HEK293 cells, and Q1E1 currents (I(Q1E1)) were analyzed using the whole-cell patch-clamp technique. RESULTS: Genetic analyses revealed no additional mutations or discriminatory SNPs. Cells expressing WT-Q1 and R231C-Q1 exhibited some constitutively active I(Q1E1) and smaller maximal I(Q1E1) compared to cells expressing WT-Q1. CONCLUSION: Constitutively active I(Q1E1) and a smaller peak I(Q1E1) are common features of FAF-associated and LQT1-associated mutations, respectively. These data suggest that the mixed functional properties of R231C-Q1 may predispose some families to LQT1 or FAF. We conclude that R231C is a pleiotropic missense mutation capable of LQT1 expression, AF expression, or both.
Assuntos
Pleiotropia Genética/genética , Predisposição Genética para Doença/genética , Canal de Potássio KCNQ1/genética , Mutação de Sentido Incorreto , Síndrome de Romano-Ward/genética , Adulto , Fibrilação Atrial/genética , Biologia Computacional , Feminino , Humanos , Masculino , Técnicas de Patch-Clamp , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype. OBJECTIVE: This study sought to perform a retrospective analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS. METHODS: Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously. RESULTS: A total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions. CONCLUSION: This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.
Assuntos
Síndrome de Brugada/genética , Testes Genéticos , Saúde Global , Internacionalidade , Proteínas Musculares/genética , Canais de Sódio/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome de Brugada/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Bases de Dados Genéticas , Morte Súbita Cardíaca/epidemiologia , Éxons/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.5 , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait. METHODS: We investigated the distribution of alleles for the long-QT syndrome in 484 nuclear families with type 1 disease and 269 nuclear families with type 2 disease, all with fully genotyped offspring. The families were recruited in five European referral centers for the long-QT syndrome. Mutation segregation, sex ratio, and parental transmission were analyzed after correction for single ascertainment. RESULTS: Classic mendelian inheritance ratios were not observed in the offspring of either female carriers of the long-QT syndrome type 1 or male and female carriers of the long-QT syndrome type 2. Among the 1534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%, P<0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476 [55%]) than to male offspring (394 [45%], P=0.005). Increased maternal transmission of the long-QT syndrome mutations to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long-QT syndrome. CONCLUSIONS: Positive selection of the mutated alleles that cause the long-QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the offspring of affected families. Alleles for the long-QT syndrome are more often transmitted to daughters than to sons.
Assuntos
Padrões de Herança , Síndrome do QT Longo/genética , Razão de Masculinidade , Distribuição de Qui-Quadrado , Feminino , Genes Dominantes , Genótipo , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Estudos RetrospectivosRESUMO
The QT interval (QT) reflects cardiac ventricular repolarization and varies according to various known factors such as heart rate, gender and age. Nevertheless, a high intrasubject stability of the QT-RR pattern also suggests that a genetic component contributes to individual QT length. To determine whether single nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels were associated with the heart-rate corrected QT (QTc) length, we analyzed two groups of 200 subjects presenting the shortest and the longest QTc from a cohort of 2,008 healthy subjects. A total of 17 polymorphisms were genotyped; they were all in the Hardy-Weinberg equilibrium in both groups. Neither allele nor haplotype frequencies of the 10 KCNQ1 SNPs showed a significant difference between the two groups. In contrast, KCNH2 2690 C (K897T) and SCN5A 5457 T (D1819D) minor alleles were significantly more frequent in the group with the shortest QTc interval, whereas KCNE1 253 A (D85N), SCN5A 1673 G (H558R) and 1141-3 A minor alleles were significantly more frequent in the group with the longest QTc interval. Interestingly, an interaction was also found between the KCNH2 2690 A>C SNP and the KCNQ1 2031+ 932 A>G SNP suggesting that the effect of the KCNH2 2690 C allele on QTc length may occur within a particular genetic background. This suggests that genetic determinants located in KCNQ1, KCNE1, KCNH2 and SCN5A influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular diseases.
Assuntos
Canais de Potássio Éter-A-Go-Go/genética , Canal de Potássio KCNQ1/genética , Proteínas Musculares/genética , Polimorfismo Genético/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Canais de Sódio/genética , Sístole/genética , Adulto , Canal de Potássio ERG1 , Eletrocardiografia , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.5 , Valores de ReferênciaRESUMO
QT and Tp/Te intervals were longer in patients with LQT1 (n = 67) than in nonaffected subjects (n = 52) but did not differentiate symptomatic (n = 21) from asymptomatic patients (n = 46). At fast heart rate, the time to accumulate the last part of total T-wave area (the t50-97 interval) was longer in symptomatic carriers compared with asymptomatic patients (119 +/- 19 vs 106 +/- 15 ms, p <0.01). The latter group had significantly longer t50-97 intervals than nonaffected subjects (96 +/- 14 ms, p <0.01).
Assuntos
Frequência Cardíaca/fisiologia , Síndrome do QT Longo/genética , Síndrome do QT Longo/fisiopatologia , Adolescente , Adulto , Idoso , Portador Sadio , Distribuição de Qui-Quadrado , Criança , Eletrocardiografia Ambulatorial , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genéticaRESUMO
OBJECTIVE: KCNQ1 mutations lead to the long QT syndrome (LQTS), characterized by a prolonged QT interval, syncopes and sudden death. However, some mutations are associated with non-penetrant phenotype (no symptoms, QTc normal or borderline). The objective of this study was to determine whether KCNQ1 variants are associated with borderline QTc prolongation in a general population and to evaluate the frequency of carriers. METHODS: We selected 2008 unrelated and untreated healthy individuals from a non-patient population. The KCNQ1 gene was screened by denaturing high-performance liquid chromatography (dHPLC) in 50 men and 50 women presenting the longest QTc intervals (403 to 443 ms). RESULTS: We identified a nonsense mutation, Y148X, and an in-frame deletion of the serine residue 276 (DeltaS276), in S2 and S5 transmembrane domains, respectively. DeltaS276 KvLQT1 channels expressed in COS-7 cells failed to conduct any K+ current in the homozygous state. Besides, a slight reduction in channel activity was observed when coexpressed with WT KvLQT1 and IsK. Confocal microscopy performed on transfected COS-7 cells revealed that DeltaS276 KvLQT1 was retained in the endoplasmic reticulum, whereas WT KvLQT1 was localized in the cell membrane. The two mutation carriers presented borderline QTc interval prolongation at slow heart rate but a 24-h ECG recording revealed a marked QTc prolongation at higher heart rate for the Y148X carrier. CONCLUSIONS: In this population, two subjects with borderline QTc prolongations (438 and 443 ms) were carriers of KCNQ1 mutations leading to haploinsufficiency and are potentially at risk of developing drug-induced arrhythmia. The study provides the first demonstration of a defective cell surface localization of a KvLQT1 mutant missing one amino acid in a transmembrane domain.
Assuntos
Síndrome do QT Longo/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Adulto , Animais , Células COS , Códon sem Sentido , Feminino , Deleção de Genes , Haplótipos , Humanos , Canais de Potássio KCNQ , Canal de Potássio KCNQ1 , Síndrome do QT Longo/fisiopatologia , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Técnicas de Patch-Clamp , Análise de Sequência de DNARESUMO
OBJECTIVES: We hypothesized that neonatal long QT syndrome (LQTS) with 2:1 atrioventricular block (AVB) could be related to HERG mutations. BACKGROUND: Early onset of LQTS is rare but carries a high risk of life-threatening events such as ventricular arrhythmias and conduction disorders. There are no data on possible gene specificity. METHODS: We analyzed the characteristics and outcomes of 23 neonate probands from our LQTS population. Samples of DNA were available in 18 cases. RESULTS: Long QT syndrome was diagnosed because of corrected QT interval (QTc) prolongation (mean QTc of 558 +/- 62 ms) and neonatal bradycardia attributable to sinus bradycardia (n = 8) or 2:1 AVB (n = 15). Symptoms included syncope (n = 2), torsades de pointes (n = 7), and hemodynamic failure (n = 6). Three infants with 2:1 AVB died during the first month of life. During the neonatal period, all living patients received beta-blockers (BB) and 13 had a combination of BB and permanent cardiac pacing. Under treatment, patients remained asymptomatic, with a mean follow-up of seven years. Mutations were identified in HERG (n = 8) and KCNQ1 (n = 8), and one child had three mutations (HERG, KCNQ1, and SCN5A). Conduction disorders were associated with LQT2, whereas sinus bradycardia was associated with LQT1. CONCLUSIONS: Two-to-one AVB seems preferentially associated with HERG mutations, either isolated or combined. Long QT syndrome with relative bradycardia attributable to 2:1 AVB has a poor prognosis during the first month of life. In contrast, sinus bradycardia seems to be associated with KCNQ1 mutations, with a good short-term prognosis under BB therapy.