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1.
Sci Rep ; 10(1): 1453, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996765

RESUMO

Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Its pathogenesis is complex and poorly understood. Whole exome sequencing of Danish families with AF revealed a novel four nucleotide deletion c.1041_1044del in CLCN2 shared by affected individuals. We aimed to investigate the role of genetic variation of CLCN2 encoding the inwardly rectifying chloride channel ClC-2 as a risk factor for the development of familiar AF. The effect of the CLCN2 variant was evaluated by electrophysiological recordings on transiently transfected cells. We used quantitative PCR to assess CLCN2 mRNA expression levels in human atrial and ventricular tissue samples. The nucleotide deletion CLCN2 c.1041_1044del results in a frame-shift and premature stop codon. The truncated ClC-2 p.V347fs channel does not conduct current. Co-expression with wild-type ClC-2, imitating the heterozygote state of the patients, resulted in a 50% reduction in macroscopic current, suggesting an inability of truncated ClC-2 protein to form channel complexes with wild type channel subunits. Quantitative PCR experiments using human heart tissue from healthy donors demonstrated that CLCN2 is expressed across all four heart chambers. Our genetic and functional data points to a possible link between loss of ClC-2 function and an increased risk of developing AF.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31748945

RESUMO

The use of cardiovascular magnetic resonance imaging left atrial late gadolinium enhancement (LA LGE) is increasing for fibrosis evaluation though the use is still limited to specialized centres due to complex image acquisition and lack of consensus on image analyses. Analysis of LA LGE with image intensity ratio (IIR) (pixel intensity of atrial wall normalized by blood pool intensity) provides an objective method to obtain quantitative data on atrial fibrosis. A threshold between healthy myocardium and fibrosis of 1.2 has previously been established in 3T scans. The aim of the study was to reaffirm this threshold in 1.5T scans. LA LGE was performed using a 1.5T magnetic resonance scanner on: 11 lone-AF patients, 11 age-matched healthy volunteers (aged 27-44) and 11 elderly patients without known history of AF but varying degrees of comorbidities. Mean values of IIR for all healthy volunteers +2SD were set as upper limit of normality and was reproduced to 1.21 and the original IIR-threshold of 1.20 was maintained. The degree of fibrosis in lone-AF patients [median 9.0% (IQR 3.9-12.0)] was higher than in healthy volunteers [2.8% (1.3-8.3)] and even higher in elderly non-AF [20.1% (10.2-35.8), p = 0.001]. The previously established IIR-threshold of 1.2 was reaffirmed in 1.5T LA LGE scans. Patients with lone AF presented with increased degrees of atrial fibrosis compared to healthy volunteers in the same age-range. Elderly patients with no history of AF showed significantly higher degrees of fibrosis compared to both groups with younger individuals.

3.
Cardiovasc Res ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31504264

RESUMO

AIMS: Atrial Fibrillation (AF) is the most common type of cardiac arrhythmias, whose incidence is likely to increase with the aging of the population. It is considered a progressive condition, frequently observed as a complication of other cardiovascular disorders. However, recent genetic studies revealed the presence of several mutations and variants linked to AF, findings that define AF as a multifactorial disease. Due to the complex genetics and paucity of models, molecular mechanisms underlying the initiation of AF are still poorly understood.Here we investigate the pathophysiological mechanisms of a familial form of AF, with particular attention to the identification of putative triggering cellular mechanisms, using patient's derived cardiomyocytes differentiated from induced pluripotent stem cells (iPSC). METHODS AND RESULTS: Here we report the clinical case of three siblings with untreatable persistent AF whose whole-exome sequence analysis revealed several mutated genes. To understand the pathophysiology of this multifactorial form of AF we generated three iPSC clones from two of these patients and differentiated these cells toward the cardiac lineage. Electrophysiological characterization of patient-derived cardiomyocytes (AF-CMs) revealed that they have higher beating rates compared to control (CTRL)-CMs. The analysis showed an increased contribution of the If and ICaL currents. No differences were observed in the repolarizing current IKr and in the sarcoplasmic reticulum calcium handling. Paced AF-CMs presented significantly prolonged action potentials and, under stressful conditions, generated both delayed afterdepolarizations of bigger amplitude and more ectopic beats than CTRL cells. CONCLUSIONS: Our results demonstrate that the common genetic background of the patients induces functional alterations of If and ICaL currents leading to a cardiac substrate more prone to develop arrhythmias under demanding conditions. To our knowledge this is the first report that, using patient-derived CMs differentiated from iPSC, suggests a plausible cellular mechanism underlying this complex familial form of AF.

4.
Heart ; 105(15): 1160-1167, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129608

RESUMO

OBJECTIVES: Electrocardiographic bundle branch block (BBB) is common but the prognostic implications in primary care are unclear. We sought to investigate the relationship between electrocardiographic BBB subtypes and the risk of cardiovascular (CV) outcomes in a primary care population free of major CV disease. METHODS: Retrospective cohort study of primary care patients referred for electrocardiogram (ECG) recording between 2001 and 2011. Cox regression models were used to estimate hazard ratios (HR) as well as absolute risks of CV outcomes based on various BBB subtypes. RESULTS: We included 202 268 individuals with a median follow-up period of 7.8 years (Inter-quartile range [IQR] 4.9-10.6). Left bundle branch block (LBBB) was associated with heart failure (HF) in both men (HR 3.96, 95% CI 3.30 to 4.76) and women (HR 2.51, 95% CI 2.15 to 2.94) and with CV death in men (HR 1.80, 95% CI 1.38 to 2.35). Right bundle branch block (RBBB) was associated with pacemaker implantation in both men (HR 3.26, 95% CI 2.74 to 3.89) and women (HR 3.69, 95% CI 2.91 to 4.67), HF in both sexes and weakly associated with CV death in men. Regarding LBBB, we found an increasing hazard of HF with increasing QRS-interval duration (HR 1.25, 95% CI 1.11 to 1.42 per 10 ms increase in men and HR 1.23, 95% CI 1.08 to 1.40 per 10 ms increase in women). Absolute 10-year risk predictions across age-specific and sex-specific subgroups revealed clinically relevant differences between having various BBB subtypes. CONCLUSIONS: Opportunistic findings of BBB subtypes in primary care patients without major CV disease should be considered warnings of future HF and pacemaker implantation.

5.
Per Med ; 15(2): 93-102, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29714131

RESUMO

AIM: We investigated the effect of variants in genes encoding sodium channel modifiers SNTA1 and GPD1L found in early onset atrial fibrillation (AF) patients. PATIENTS & METHODS: Genetic screening in patients with early onset lone AF revealed three variants in GPD1L and SNTA1 in three AF patients. Functional analysis was performed by patch-clamp electrophysiology. RESULTS: Co-expression of GPD1L or its p.A326E variant with NaV1.5 did not alter INa density or current kinetics. SNTA1 shifted the peak-current by -5 mV. The SNTA1-p.A257G variant significantly increased INa. SNTA1-p.P74L did not produce functional changes. CONCLUSION: Although genetic variation of sodium channel modifiers may contribute to development of AF at a molecular level, it is unlikely a monogenic cause of the disease.


Assuntos
Fibrilação Atrial/genética , Proteínas de Ligação ao Cálcio/genética , Glicerolfosfato Desidrogenase/genética , Proteínas de Membrana/genética , Proteínas Musculares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Análise Mutacional de DNA/métodos , Dinamarca , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Variação Genética/genética , Glicerolfosfato Desidrogenase/metabolismo , Humanos , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Mutação , Canais de Sódio/genética
6.
Stem Cell Res ; 24: 29-32, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29034891

RESUMO

Atrial fibrillation (AF) is the most common sustained arrhythmia associated with several cardiac risk factors, but increasing evidences indicated a genetic component. Indeed, genetic variations of the atrial specific KCNA5 gene have been identified in patients with early-onset lone AF. To investigate the molecular mechanisms underlying AF, we reprogrammed to pluripotency polymorphonucleated leukocytes isolated from the blood of a patient carrying a KCNA5 p.D322H mutation, using a commercially available non-integrating system. The generated iPSCs expressed pluripotency markers and differentiated toward cells belonging to the three embryonic germ layers. Moreover, the cells showed a normal karyotype and retained the p.D322H mutation.


Assuntos
Fibrilação Atrial/terapia , Células-Tronco Pluripotentes Induzidas/metabolismo , Adulto , Diferenciação Celular , Humanos , Masculino , Mutação
7.
Stem Cell Res ; 24: 8-11, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29034898

RESUMO

Atrial fibrillation (AF) is the most common sustained arrhythmia associated with several cardiac risk factors, but increasing evidences indicated a genetic component. Indeed, genetic variations of the specific PITX2 gene have been identified in patients with early-onset AF. To investigate the molecular mechanisms underlying AF, we reprogrammed to pluripotency polymorphonucleated leukocytes isolated from the blood of a patient carrying a PITX2 p.M200V mutation, using a commercially available non-integrating expression system. The generated iPSCs expressed pluripotency markers and differentiated toward cells belonging to the three embryonic germ layers. Moreover, the cells showed a normal karyotype and retained the PITX2 p.M200V mutation.


Assuntos
Fibrilação Atrial/terapia , Células-Tronco Pluripotentes Induzidas/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Fibrilação Atrial/genética , Diferenciação Celular , Genótipo , Humanos , Masculino , Mutação
8.
Can J Cardiol ; 33(5): 674-681, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28449838

RESUMO

BACKGROUND: Because of ambiguous reports in the literature, we aimed to investigate the association between PR interval and the risk of all-cause and cardiovascular death, heart failure, and pacemaker implantation, allowing for a nonlinear relationship. METHODS: We included 293,111 individuals, corresponding to one-third of the population in the greater region of Copenhagen. These individuals had a digital electrocardiogram recorded in a general practitioner's core facility from 2001-2011. Data on drug use, comorbidities, and outcomes were collected from Danish registries. We divided the population into 7 groups based on the population PR interval distribution. Cox models were used, with reference to a PR interval between 152 and 161 ms (40th to < 60th percentile). RESULTS: During follow-up, we identified 34,783 deaths from all causes, 9867 cardiovascular deaths, 9526 cases of incident heart failure, and 1805 pacemaker implantations. A short PR interval (< 125 ms; hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.08-1.41; P = 0.001) as well as a long PR interval (> 200 ms; HR, 1.23; 95% CI, 1.14-1.32; P < 0.001) was associated with an increased risk of cardiovascular death after multivariable adjustment. A long PR interval conferred an increased risk of heart failure (> 200 ms; HR, 1.31; 95% CI, 1.22-1.42; P < 0.001). An increasing PR interval conferred an increased risk of pacemaker implantation, in a dose-response manner, with the highest risk associated with a PR interval > 200 ms (HR, 3.49; 95% CI, 2.96-4.11; P < 0.001). CONCLUSIONS: PR interval was significantly associated with the risk of the adverse outcomes investigated. The nonlinear relationships, in combination with relatively weak associations, could contribute to previously reported conflicting results on the subject.


Assuntos
Doenças Cardiovasculares , Eletrocardiografia , Sistema de Condução Cardíaco , Insuficiência Cardíaca/epidemiologia , Marca-Passo Artificial/estatística & dados numéricos , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Dinamarca/epidemiologia , Eletrocardiografia/métodos , Eletrocardiografia/estatística & dados numéricos , Feminino , Sistema de Condução Cardíaco/diagnóstico por imagem , Sistema de Condução Cardíaco/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Sistema de Registros , Medição de Risco/métodos , Fatores de Risco
9.
J Mol Cell Cardiol ; 97: 24-35, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27103460

RESUMO

The two-pore domain potassium (K(+)) channel TWIK-1 (or K2P1.1) contributes to background K(+) conductance in diverse cell types. TWIK-1, encoded by the KCNK1 gene, is present in the human heart with robust expression in the atria, however its physiological significance is unknown. To evaluate the cardiac effects of TWIK-1 deficiency, we studied zebrafish embryos after knockdown of the two KCNK1 orthologues, kcnk1a and kcnk1b. Knockdown of kcnk1a or kcnk1b individually caused bradycardia and atrial dilation (p<0.001 vs. controls), while ventricular stroke volume was preserved. Combined knockdown of both kcnk1a and kcnk1b resulted in a more severe phenotype, which was partially reversed by co-injection of wild-type human KCNK1 mRNA, but not by a dominant negative variant of human KCNK1 mRNA. To determine whether genetic variants in KCNK1 might cause atrial fibrillation (AF), we sequenced protein-coding regions in two independent cohorts of patients (373 subjects) and identified three non-synonymous variants, p.R171H, p.I198M and p.G236S, that were all located in highly conserved amino acid residues. In transfected mammalian cells, zebrafish and wild-type human TWIK-1 channels had a similar cellular distribution with predominant localization in the endosomal compartment. Two-electrode voltage-clamp experiments using Xenopus oocytes showed that both zebrafish and wild-type human TWIK-1 channels produced K(+) currents that are sensitive to external K(+) concentration as well as acidic pH. There were no effects of the three KCNK1 variants on cellular localization, current amplitude or reversal potential at pH7.4 or pH6. Our data indicate that TWIK-1 has a highly conserved role in cardiac function and is required for normal heart rate and atrial morphology. Despite the functional importance of TWIK-1 in the atrium, genetic variation in KCNK1 is not a common primary cause of human AF.


Assuntos
Remodelamento Atrial/genética , Estudos de Associação Genética , Átrios do Coração/metabolismo , Frequência Cardíaca/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Adulto , Idoso , Animais , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Feminino , Expressão Gênica , Técnicas de Inativação de Genes , Variação Genética , Átrios do Coração/anatomia & histologia , Átrios do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Canais de Potássio de Domínios Poros em Tandem/deficiência , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Transporte Proteico , Fatores de Risco , Peixe-Zebra
10.
J Cardiovasc Electrophysiol ; 26(7): 715-23, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25786344

RESUMO

INTRODUCTION: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of-function mutation in KCNQ1, the gene encoding the pore-forming α-subunit of the IKs channel (KV 7.1), was the first ion channel dysfunction to be associated with familial AF. We hypothesized that early-onset lone AF is associated with a high prevalence of mutations in KCNQ1. METHODS AND RESULTS: We bidirectionally sequenced the entire coding sequence of KCNQ1 in 209 unrelated patients with early-onset lone AF (<40 years) and investigated the identified mutations functionally in a heterologous expression system. We found 4 nonsynonymous KCNQ1 mutations (A46T, R195W, A302V, and R670K) in 4 unrelated patients (38, 31, 39, and 36 years, respectively). None of the mutations were present in the control group (n = 416 alleles). No other mutations were found in genes previously associated with AF. The mutations A46T, R195W, and A302V have previously been associated with long-QT syndrome. In line with previous reports, we found A302V to display a pronounced loss-of-function of the IKs current, while the other mutants exhibited a gain-of-function phenotype. CONCLUSIONS: Mutations in the IKs channel leading to gain-of-function have previously been described in familial AF, yet this is the first time a loss-of-function mutation in KCNQ1 is associated with early-onset lone AF. These findings suggest that both gain-of-function and loss-of-function of cardiac potassium currents enhance the susceptibility to AF.


Assuntos
Fibrilação Atrial/genética , Canal de Potássio KCNQ1/genética , Mutação , Potenciais de Ação , Adolescente , Adulto , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Estudos de Casos e Controles , Linhagem Celular , Análise Mutacional de DNA , Dinamarca , Eletrocardiografia , Feminino , Predisposição Genética para Doença , Frequência Cardíaca , Humanos , Canal de Potássio KCNQ1/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Fenótipo , Potássio/metabolismo , Transfecção , Adulto Jovem
11.
Cardiovasc Res ; 104(2): 355-63, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25053638

RESUMO

AIMS: To test the hypothesis that vulnerability to atrial fibrillation (AF) is associated with rare coding sequence variation in the SCN10A gene, which encodes the voltage-gated sodium channel isoform NaV1.8 found primarily in peripheral nerves and to identify potentially disease-related mechanisms in high-priority rare variants using in-vitro electrophysiology. METHODS AND RESULTS: We re-sequenced SCN10A in 274 patients with early onset AF from the Vanderbilt AF Registry to identify rare coding variants. Engineered variants were transiently expressed in ND7/23 cells and whole-cell voltage clamp experiments were conducted to elucidate their functional properties. Resequencing SCN10A identified 18 heterozygous rare coding variants (minor allele frequency ≤1%) in 18 (6.6%) AF probands. Four probands were carriers of two rare variants each and 14 were carriers of one coding variant. Based on evidence of co-segregation, initial assessment of functional importance, and presence in ≥1 AF proband, three variants (417delK, A1886V, and the compound variant Y158D-R814H) were selected for functional studies. The 417delK variant displayed near absent current while A1886V and Y158D-R814H exhibited enhanced peak and late (INa-L) sodium currents; both Y158D and R818H individually contributed to this phenotype. CONCLUSION: Rare SCN10A variants encoding Nav1.8 were identified in 6.6% of patients with early onset AF. In-vitro electrophysiological studies demonstrated profoundly altered function in 3/3 high-priority variants. Collectively, these data strongly support the hypothesis that rare SCN10A variants may contribute to AF susceptibility.


Assuntos
Fibrilação Atrial/metabolismo , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Sódio/metabolismo , Adolescente , Adulto , Idade de Início , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Linhagem Celular , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Frequência Cardíaca , Heterozigoto , Humanos , Masculino , Potenciais da Membrana , Pessoa de Meia-Idade , Mutação , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Fenótipo , Sistema de Registros , Tennessee , Fatores de Tempo , Transfecção , Adulto Jovem
12.
Biomark Med ; 8(4): 557-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24796621

RESUMO

AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Disturbances in cardiac potassium conductance are considered as one of the disease mechanisms in AF. We aimed to investigate if mutations in potassium-channel ß-subunits KCNE2 and KCNE3 are associated with early-onset lone AF. METHODS & RESULTS: The coding regions of KCNE2 and KCNE3 were bidirectionally sequenced in 192 unrelated patients diagnosed with early-onset lone AF (<40 years). Two nonsynonymous missense mutations were identified in KCNE2 (M23L and I57T). Both mutations were absent in a healthy control group (n=1500 alleles). Electrophysiological investigations were performed for both mutations in combination with candidate pore-forming α-subunits KV7.1, KV11.1, KV4.3 and KV1.5. A significant gain-of-function effect was observed upon coexpression with KV7.1 and KV7.1+KCNE1. Confocal imaging found no differences in subcellular localization. No disease-suspected mutations were identified in KCNE3. CONCLUSION: We identified two KCNE2 gain-of-function missense mutations that seem to increase the susceptibility of early-onset lone AF. These results confirm previous findings indicating that gain-of-function in the slow delayed rectifier potassium current might be involved in the pathogenesis of AF.


Assuntos
Fibrilação Atrial/diagnóstico , Fibrilação Atrial/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Adulto , Alelos , Sequência de Aminoácidos , Animais , Fibrilação Atrial/metabolismo , Sequência de Bases , Pressão Sanguínea , Células CHO , Cricetinae , Cricetulus , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Canal de Potássio KCNQ1/genética , Canal de Potássio KCNQ1/metabolismo , Masculino , Microscopia Confocal , Mutação de Sentido Incorreto , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo
13.
J Am Heart Assoc ; 3(3): e000549, 2014 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-24815495

RESUMO

BACKGROUND: We sought to perform a study assessing the association between electrocardiographic ST-segment deviations and cardiovascular death (CVD), in relation to sex and age (≥ and <65 years), in a large primary care population without overt ischemic heart disease. METHODS AND RESULTS: Using computerized analysis of ECGs from 285 194 persons, we evaluated the association between precordial ST-segment deviations and the risk of CVD. All data on medication, comorbidity, and outcomes were retrieved from Danish registries. After a median follow-up period of 5.8 years, there were 6679 cardiovascular deaths. Increasing ST-depression was associated with an increased risk of CVD in almost all of the precordial leads, with the most robust association seen in lead V5 to V6. ST-elevations in lead V2 to V6 were associated with increased risk of CVD in young women, but not in men. However, ST-elevations in V1 increased the risk for both genders and age groups, exemplified by a HR of 1.80 (95% CI [1.19 to 2.74], P=0.005) for men <65 years with ST-elevations ≥ 150 µV versus a nondeviating ST-segment (-50 µV to +50 µV). In contrast, for men <65 years, ST-elevations in lead V2 to V3 conferred a decreased risk of CVD with a HR of 0.77 (95% CI [0.62 to 0.96], P<0.001) for ST-elevations ≥ 150 µV in V2. CONCLUSION: We found that ST-depressions were associated with a dose-responsive increased risk of CVD in nearly all the precordial leads. ST-elevations conferred an increased risk of CVD in women and with regard to lead V1 also in men. However, ST-elevations in V2 to V3 were associated with a decreased risk of CVD in young men.


Assuntos
Doenças Cardiovasculares/mortalidade , Eletrocardiografia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/fisiopatologia , Dinamarca/epidemiologia , Feminino , Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais
14.
Circ Cardiovasc Genet ; 6(6): 615-23, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24200904

RESUMO

BACKGROUND: The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy. Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known. METHODS AND RESULTS: We identified the 2 novel variants DES-p.A120D (c.359C>A) and DES-p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D reveal a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation, whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type. CONCLUSIONS: Because of the functional in vivo and in vitro characterization, DES-p.A120D has to be regarded as a pathogenic mutation and DES-p.H326R as a rare variant with unknown significance. Presumably, the loss of the desmin-p. A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.


Assuntos
Morte Súbita Cardíaca , Desmina/genética , Filamentos Intermediários/genética , Mutação , Adulto , Sequência de Aminoácidos , Animais , Linhagem Celular , Linhagem Celular Tumoral , Análise Mutacional de DNA , Desmina/metabolismo , Desmossomos/metabolismo , Saúde da Família , Feminino , Células HeLa , Humanos , Filamentos Intermediários/metabolismo , Masculino , Microscopia de Força Atômica , Microscopia de Fluorescência , Dados de Sequência Molecular , Miocárdio/metabolismo , Miocárdio/patologia , Linhagem , Homologia de Sequência de Aminoácidos
15.
Nat Genet ; 45(9): 1044-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23872634

RESUMO

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Síndrome de Brugada/complicações , Síndrome de Brugada/genética , Morte Súbita Cardíaca/etiologia , Variação Genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Proteínas Repressoras/genética , Alelos , Animais , Estudos de Casos e Controles , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 6 , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Knockout , Razão de Chances , Polimorfismo de Nucleotídeo Único , Canais de Sódio/genética , Canais de Sódio/metabolismo
16.
Front Genet ; 4: 88, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23730307

RESUMO

Several studies have associated mutations in genes encoding potassium channels and accessory subunits involved in cardiac repolarization with increased susceptibility of atrial fibrillation (AF). Recently, the Krüppel-like factor 15 (Klf15) was found to transcriptionally control rhythmic expression of KChIP2, a critical subunit required for generating the transient outward potassium current (Ito), and that deficiency or excess of Klf15 increased the susceptibility of arrhythmias. On this basis we hypothesized that mutations in Klf15 could be associated with AF. A total of 209 unrelated Caucasian lone AF patients were screened for mutations in Klf15 by direct sequencing. No mutations in the lone AF cohort were found. In one patient we found a synonymous variant (c.36C > T). In NHLBI GO Exome Sequencing Project (ESP) the variant was present in 31 of 4269 Caucasian individuals and in 3 of 2200 African Americans. In our cohort Klf15 was not associated with lone AF.

17.
Heart Rhythm ; 10(9): 1249-56, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23608590

RESUMO

BACKGROUND: Prolongation of the PR interval has been associated with an increased risk of incident atrial fibrillation (AF). OBJECTIVE: To determine if there was a nonlinear relation between PR interval duration and the risk of AF. METHODS: We included 288,181 individuals, corresponding to one third of the population in the greater region of Copenhagen. These individuals had a digital electrocardiogram (ECG) recorded in a general practitioner's core facility from 2001 to 2010. Data on drug use, comorbidity, and outcomes were collected from Danish registries. RESULTS: During a median follow-up period of 5.7 years, 11,087 developed AF. Having a PR interval ≥95th percentile (≥196 ms for women, ≥204 ms for men) was associated with an increased risk of AF as evidenced by a multivariable-adjusted hazard ratio (HR) of 1.18 (95% confidence interval [CI] 1.06-1.30, P = .001) for women and 1.30 (1.17-1.44, P < .001) for men compared with the respective reference groups (PR interval between 40th and 60th percentile). Having a short PR interval <5th percentile (≤121 ms for women, ≤129 ms for men) was also associated with an increased risk of AF for women (HR 1.32, 95% CI 1.12-1.56, P = .001), but this was not significant for men (HR 1.09, 95% CI 0.92-1.29, P = .33). CONCLUSION: In this large ECG study, we found an increased risk of AF for longer PR intervals for both women and men. With respect to short PR intervals, we also observed an increased risk of AF for women.


Assuntos
Fibrilação Atrial/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Adulto , Idoso , Fibrilação Atrial/epidemiologia , Dinamarca/epidemiologia , Eletrocardiografia/métodos , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , Fatores Sexuais , População Urbana/estatística & dados numéricos
18.
J Am Coll Cardiol ; 61(25): 2557-64, 2013 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-23583581

RESUMO

OBJECTIVES: The aim of this study was to investigate whether the heart rate-corrected QT (QTc) interval on the electrocardiogram (ECG) is associated with the onset of atrial fibrillation (AF). BACKGROUND: Patients with hereditary short-QT or long-QT syndromes, representing the very extremes of the QT interval, both seem to have a high prevalence of AF. METHODS: A total of 281,277 subjects were included, corresponding to one-third of the population of the greater region of Copenhagen. These subjects underwent digital ECG recordings in a general practitioner's core facility from 2001 to 2010. Data on drug use, comorbidities, and outcomes were collected from Danish registries. RESULTS: After a median follow-up period of 5.7 years, 10,766 subjects had developed AF, of whom 1,467 (14%) developed lone AF. Having a QTc interval lower than the first percentile (≤372 ms) was associated with a multivariate-adjusted hazard ratio of 1.45 (95% confidence interval: 1.14 to 1.84; p = 0.002) of AF, compared with the reference group (411 to 419 ms). From the reference group and upward, the risk of AF increased with QTc interval duration in a dose-response manner, reaching a hazard ratio of 1.44 (95% confidence interval: 1.24 to 1.66, p < 0.001) for those with QTc intervals ≥99th percentile (≥464 ms). The association with respect to longer QTc intervals was stronger for the outcome of lone AF, as evidenced by a hazard ratio of 2.32 (95% confidence interval: 1.52 to 3.54, p < 0.001) for having a QTc interval ≥99th percentile (≥458 ms). CONCLUSIONS: In this large ECG study, a J-shaped association was found between QTc interval duration and risk of AF. This association was strongest with respect to the development of lone AF.


Assuntos
Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Eletrocardiografia , Frequência Cardíaca/fisiologia , Adulto , Idoso , Fibrilação Atrial/epidemiologia , Estudos de Coortes , Dinamarca/epidemiologia , Eletrocardiografia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo
19.
Cardiovasc Res ; 98(3): 488-95, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23400760

RESUMO

AIMS: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and early-onset lone AF has been linked to mutations in genes encoding ion channels. Mutations in the pore forming subunit KV4.3 leading to an increase in the transient outward potassium current (Ito) have previously been associated with the Brugada Syndrome. Here we aim to determine if mutations in KV4.3 or in the auxiliary subunit K(+) Channel-Interacting Protein (KChIP) 2 are associated with early-onset lone AF. METHODS AND RESULTS: Two hundred and nine unrelated early-onset lone AF patients (<40 years) were recruited. The entire coding sequence of KCND3 and KCNIP2 was bidirectionally sequenced. One novel non-synonymous mutation A545P was found in KCND3 and was neither present in the control group (n = 432 alleles) nor in any publicly available database. The proband had onset of persistent AF at the age of 22, and no mutations in genes previously associated with AF were found. Electrophysiological analysis of KV4.3-A545P expressed in CHO-K1 cells, revealed that peak-current density was increased and the onset of inactivation was slower compared with WT, resulting in a significant gain-of-function both in the absence and the presence of KChIP2. CONCLUSION: Gain-of-function mutations in KV4.3 have previously been described in Brugada Syndrome, however, this is the first report of a KV4.3 gain-of-function mutation in early-onset lone AF. This association of KV4.3 gain-of-function and early-onset lone AF further supports the hypothesis that increased potassium current enhances AF susceptibility.


Assuntos
Fibrilação Atrial/genética , Mutação , Canais de Potássio Shal/genética , Adulto , Idade de Início , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Células CHO , Estudos de Casos e Controles , Cricetinae , Cricetulus , Dinamarca , Eletrocardiografia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Proteínas Interatuantes com Canais de Kv/genética , Masculino , Potenciais da Membrana , Fenótipo , Potássio/metabolismo , Canais de Potássio Shal/metabolismo , Transfecção , Adulto Jovem
20.
J Cardiovasc Electrophysiol ; 23(10): 1092-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22882672

RESUMO

INTRODUCTION: Sudden unexplained death account for one-third of all sudden natural deaths in the young (1-35 years). Hitherto, the prevalence of genopositive cases has primarily been based on deceased persons referred for postmortem genetic testing. These deaths potentially may represent the worst of cases, thus possibly overestimating the prevalence of potentially disease causing mutations in the 3 major long-QT syndrome (LQTS) genes in the general population. We therefore wanted to investigate the prevalence of mutations in an unselected population of sudden unexplained deaths in a nationwide setting. METHODS: DNA for genetic testing was available for 44 cases of sudden unexplained death in Denmark in the period 2000-2006 (equaling 33% of all cases of sudden unexplained death in the age group). KCNQ1, KCNH2, and SCN5A were sequenced and in vitro electrophysiological studies were performed on novel mutations. RESULTS: In total, 5 of 44 cases (11%) carried a mutation in 1 of the 3 genes corresponding to 11% of all investigated cases (R190W KCNQ1, F29L KCNH2 (2 cases), P297S KCNH2 and P1177L SCN5A). P1177L SCN5A has not been reported before. In vitro electrophysiological studies of P1177L SCN5A revealed an increased sustained current suggesting a LQTS phenotype. CONCLUSION: In a nationwide setting, the genetic investigation of an unselected population of sudden unexplained death cases aged 1-35 years finds a lower than expected number of mutations compared to referred populations previously reported. We therefore conclude that the prevalence of mutations in the 3 major LQTS associated genes may not be as abundant as previously estimated.


Assuntos
Morte Súbita Cardíaca/etiologia , Canais de Potássio Éter-A-Go-Go/genética , Canal de Potássio KCNQ1/genética , Síndrome do QT Longo/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Adolescente , Adulto , Fatores Etários , Análise de Variância , Autopsia , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Morte Súbita Cardíaca/epidemiologia , Dinamarca , Canal de Potássio ERG1 , Técnicas Eletrofisiológicas Cardíacas , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Frequência do Gene , Predisposição Genética para Doença , Células HEK293 , Humanos , Lactente , Canal de Potássio KCNQ1/metabolismo , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/mortalidade , Masculino , Potenciais da Membrana , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Técnicas de Patch-Clamp , Linhagem , Fenótipo , Síndrome de Romano-Ward/genética , Síndrome de Romano-Ward/mortalidade , Transfecção , Adulto Jovem
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