RESUMO
KChIP2, a gene encoding three auxiliary subunits of Kv4.2 and Kv4.3, is preferentially expressed in the adult heart, and its expression is downregulated in cardiac hypertrophy. Mice deficient for KChIP2 exhibit normal cardiac structure and function but display a prolonged elevation in the ST segment on the electrocardiogram. The KChIP2(-/-) mice are highly susceptible to the induction of cardiac arrhythmias. Single-cell analysis revealed a substrate for arrhythmogenesis, including a complete absence of transient outward potassium current, I(to), and a marked increase in action potential duration. These studies demonstrate that a defect in KChIP2 is sufficient to confer a marked genetic susceptibility to arrhythmias, establishing a novel genetic pathway for ventricular tachycardia via a loss of the transmural gradient of I(to).
Assuntos
Proteínas de Ligação ao Cálcio/genética , Predisposição Genética para Doença , Miocárdio/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Potássio/metabolismo , Taquicardia Ventricular/genética , Potenciais de Ação/fisiologia , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Ligação ao Cálcio/química , Proteínas de Ligação ao Cálcio/metabolismo , Eletrocardiografia , Embrião de Mamíferos/metabolismo , Marcação de Genes , Humanos , Hibridização In Situ , Proteínas Interatuantes com Canais de Kv , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Dados de Sequência Molecular , Miocárdio/citologia , Técnicas de Patch-Clamp , Canais de Potássio/genética , Canais de Potássio/metabolismo , Isoformas de Proteínas , Canais de Potássio Shal , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologiaRESUMO
HF-1 b, an SP1 -related transcription factor, is preferentially expressed in the cardiac conduction system and ventricular myocytes in the heart. Mice deficient for HF-1 b survive to term and exhibit normal cardiac structure and function but display sudden cardiac death and a complete penetrance of conduction system defects, including spontaneous ventricular tachycardia and a high incidence of AV block. Continuous electrocardiographic recordings clearly documented cardiac arrhythmogenesis as the cause of death. Single-cell analysis revealed an anatomic substrate for arrhythmogenesis, including a decrease and mislocalization of connexins and a marked increase in action potential heterogeneity. Two independent markers reveal defects in the formation of ventricular Purkinje fibers. These studies identify a novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages.