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We showed an association between atrial fibrillation and rare loss-of-function (LOF) variants in the cardiac splicing regulator RBM20 in 2 independent cohorts. In a rat model with loss of RBM20, we demonstrated altered splicing of sarcomere genes (NEXN, TTN, TPM1, MYOM1, and LDB3), and differential expression in key cardiac genes. We identified altered sarcomere and mitochondrial structure on electron microscopy imaging and found compromised mitochondrial function. Finally, we demonstrated that 3 novel LOF variants in RBM20, identified in patients with atrial fibrillation, lead to significantly reduced splicing activity. Our results implicate alternative splicing as a novel proarrhythmic mechanism in the atria.
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BACKGROUND: Plasma levels of YKL-40 are elevated in patients with atrial fibrillation (AF). We hypothesized that a single nucleotide polymorphism (SNP) that affects YKL-40 plasma levels is associated to the risk of lone AF. FINDINGS: We included 178 young patients with lone AF and the first episode before the age of 40 years, and a control group of 875 healthy individuals. We analyzed a promoter SNP (-131CG) (rs4950928) in the Chitinase 3-like 1 (CHI3L1) gene encoding YKL-40, which had previously been associated with elevated levels of YKL-40. CONCLUSIONS: The (-131CG) genotype was not associated with increased risk of AF. Genetically increased YKL-40 levels were not associated to AF.
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Adipocinas/sangue , Fibrilação Atrial/genética , Lectinas/sangue , Polimorfismo de Nucleotídeo Único , Adulto , Idade de Início , Estudos de Casos e Controles , Proteína 1 Semelhante à Quitinase-3 , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Regiões Promotoras GenéticasRESUMO
INTRODUCTION: Systemic inflammation is associated with atrial fibrillation (AF) and inflammatory processes are involved in the pathophysiology of AF. We hypothesized that genetic polymorphisms, which determine the rate of inflammatory cytokines, are associated with increased risk of AF. MATERIALS AND METHODS: We included 158 patients with AF and 188 healthy controls. All patients were genotyped for common single nucleotide polymorphisms (SNPs) in selected inflammatory genes. RESULTS: A case-control analysis of the investigated SNPs (IL1A-889, TNF-308, IL1B-511, IL10-592, IL10-1082, IL18-137 and IL18-607) revealed no significant differences in the frequencies of genotypes between the AF patients and the healthy controls.
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Fibrilação Atrial/genética , Fibrilação Atrial/imunologia , Inflamação/genética , Inflamação/imunologia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: Genome wide association studies have shown an association between rs2200733 at 4q25 and atrial fibrillation (AF). In this case-control study we investigate the association of rs2200733 and lone AF in young patients. METHODS: We included 196 young patients with lone AF and the first episode before the age of 40 years. We analyzed the single nucleotide polymorphism (SNP) rs2200733 for the lone AF patients and compared them to a control group of 176 age matched healthy individuals. RESULTS: No significant differences, in neither genotype distribution, nor minor allele frequencies were found between the lone AF patients and the healthy controls. CONCLUSION: Our results suggest that the rs220733 is not a risk factor for AF in patients with no other cardiovascular disease and with early onset of the arrhythmia.
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Fibrilação Atrial/genética , Cromossomos Humanos Par 4 , Polimorfismo de Nucleotídeo Único , Adulto , Idade de Início , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Dinamarca/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Razão de Chances , Fenótipo , Medição de Risco , Fatores de RiscoRESUMO
We tested the hypothesis that arterial reactivity to noradrenaline is augmented in congestive heart failure (CHF), which could contribute to the deleterious changes in peripheral vascular resistance and compliance in this condition. From male Wistar rats with post-infarction CHF and sham-operated rats, skeletal muscle conductance and resistance arteries (mean lumen diameters: 514 and 186 microm) were isolated and mounted on wire myographs, and wall tension was recorded in response to cumulative application of acetylcholine and noradrenaline to the vessel segments. In a subset of experiments, wall tension and cytosolic free calcium ion concentration [Ca(2+)](i) were recorded simultaneously during noradrenaline application, using wire myography and the FURA-2 technique. No significant differences were found in the arterial baseline levels of [Ca(2+)](i) or tension between CHF and sham rats. In the resistance arteries of CHF rats, the noradrenaline-induced increases in [Ca(2+)](i) were significantly enhanced (P=0.003). Despite the augmented [Ca(2+)](i) levels, the tension responses to noradrenaline were unaltered in these arteries. In the conductance arteries, there were no significant differences in noradrenaline-induced [Ca(2+)](i) or tension responses between CHF and control rats. CHF did not alter vascular morphology or change vascular relaxations to acetylcholine in either type of artery. In conclusion, these results do not support the contention that arterial reactivity to noradrenaline is augmented in the skeletal muscle vascular bed in CHF. On the contrary, the unchanged contractile responsiveness in the resistance arteries despite the enhanced levels of [Ca(2+)](i) during noradrenaline application suggests that the contractile function of these vessels is compromised in CHF. Neither vascular remodeling, endothelial dysfunction nor changes in baseline vascular tone could be demonstrated in the skeletal muscle vascular bed of this animal model of heart failure.
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Artérias/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Norepinefrina/farmacologia , Acetilcolina/farmacologia , Animais , Artérias/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Endotélio Vascular/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Contração Isométrica/efeitos dos fármacos , Masculino , Músculo Esquelético/fisiologia , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
In this study we tested the hypothesis that arterial myofilament Ca(2+) sensitivity and/or the Ca(2+) sensitising effect of noradrenaline (NA) is enhanced in post-infarction congestive heart failure (CHF), which could contribute to the high peripheral vascular resistance in this condition. Femoral skeletal muscle resistance and conductance arteries (mean lumen diameters of 159 and 519 microm) from rats with CHF and sham-operated control rats were used. Isometric tension development and intracellular free calcium concentration ([Ca(2+)](i)) were measured simultaneously in isolated vessel segments using wire myography and the FURA-2 fluorescence technique. In conductance and resistance arteries, the resting levels of [Ca(2+)](i) and tension in physiological saline solution (PSS) and active tension in response to single doses of 125 mM K(+) (KPSS) were unaffected by CHF. During cumulative application of extracellular Ca(2+) to arteries depolarised with 125 mM K(+) or activated with 30 microM NA, [Ca(2+)](i) and vessel wall tension were similar in CHF and control rats. However, the conductance arteries showed significantly higher calcium sensitivity than resistance arteries in these experiments. We conclude that an abnormality in the sensitivity of the contractile apparatus to Ca(2+), or in NA-induced Ca(2+) sensitisation in arterial vascular smooth muscle cells is unlikely to contribute to the ubiquitously elevated vascular resistance associated with CHF. However, our data demonstrate significant differences in vascular Ca(2+) handling, myofilament Ca(2+) sensitivity and tension development between resistance and conductance arteries, regardless of CHF.
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Cálcio/metabolismo , Artéria Femoral/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Contração Muscular , Infarto do Miocárdio/metabolismo , Norepinefrina/farmacologia , Vasoconstritores/farmacologia , Animais , Artéria Femoral/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Wistar , Resistência VascularRESUMO
Arrhythmogenic right ventricular cardiomyopathy is an inherited disease of the cardiomyocyte. The disease is diagnosed as a syndrome based on criteria that include ventricular arrhythmias, electrocardiographic findings, imaging, tissue characteristics and family history. An implantable cardioverter-defibrillator is generally recommended. Novel insight into the molecular genetic background has established that the disease may be associated with mutation in the genes encoding desmosomal proteins. Genetic testing is expected to facilitate the diagnostic workup and treatment of patients and their families.
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Displasia Arritmogênica Ventricular Direita/diagnóstico , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/terapia , Criança , Desfibriladores Implantáveis , Diagnóstico Diferencial , Eletrocardiografia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Placofilinas/genética , Medição de Risco , SíndromeRESUMO
BACKGROUND: Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation. METHODS AND RESULTS: A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%, P<0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes. CONCLUSIONS: All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF.