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JCI Insight ; 5(18)2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32841220

RESUMO

Atrial fibrillation (AF) is the most common cardiac arrhythmia, yet the molecular signature of the vulnerable atrial substrate is not well understood. Here, we delineated a distinct transcriptional signature in right versus left atrial cardiomyocytes (CMs) at baseline and identified chamber-specific gene expression changes in patients with a history of AF in the setting of end-stage heart failure (AF+HF) that are not present in heart failure alone (HF). We observed that human left atrial (LA) CMs exhibited Notch pathway activation and increased ploidy in AF+HF but not in HF alone. Transient activation of Notch signaling within adult CMs in a murine genetic model is sufficient to increase ploidy in both atrial chambers. Notch activation within LA CMs generated a transcriptomic fingerprint resembling AF, with dysregulation of transcription factor and ion channel genes, including Pitx2, Tbx5, Kcnh2, Kcnq1, and Kcnip2. Notch activation also produced distinct cellular electrophysiologic responses in LA versus right atrial CMs, prolonging the action potential duration (APD) without altering the upstroke velocity in the left atrium and reducing the maximal upstroke velocity without altering the APD in the right atrium. Our results support a shared human/murine model of increased Notch pathway activity predisposing to AF.


Assuntos
Potenciais de Ação , Fibrilação Atrial/patologia , Biomarcadores/metabolismo , Regulação da Expressão Gênica , Átrios do Coração/patologia , Insuficiência Cardíaca/patologia , Miócitos Cardíacos/patologia , Animais , Fibrilação Atrial/genética , Átrios do Coração/metabolismo , Insuficiência Cardíaca/genética , Humanos , Camundongos , Miócitos Cardíacos/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transcriptoma
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