1. Academic Validation
  2. Heterogeneity of the action potential duration is required for sustained atrial fibrillation

Heterogeneity of the action potential duration is required for sustained atrial fibrillation

  • JCI Insight. 2019 Apr 25;5(11):e128765. doi: 10.1172/jci.insight.128765.
Uma Mahesh R Avula 1 Jeffrey Abrams 1 Alexander Katchman 1 Sergey Zakharov 1 Sergey Mironov 2 Joseph Bayne 1 Daniel Roybal 1 Anirudh Gorti 1 Lin Yang 1 Vivek Iyer 3 Marc Waase 1 Deepak Saluja 1 Edward J Ciaccio 1 Hasan Garan 1 Andrew R Marks 4 5 Steven O Marx 1 Elaine Y Wan 1
Affiliations

Affiliations

  • 1 Division of Cardiology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
  • 2 Center for Arrhythmia Research, Division of Cardiology, University of Michigan, Ann Arbor, Michigan, USA.
  • 3 Marin General Hospital, Greenbrae, California, USA.
  • 4 The Wu Center for Molecular Cardiology, Columbia University, New York, New York, USA.
  • 5 Department of Physiology and Cellular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity and mortality. Recently, we created a mouse model with spontaneous and sustained AF caused by a mutation in the NaV1.5 channel (F1759A) that enhances persistent Na+ current, thereby enabling the investigation of molecular mechanisms that cause AF and the identification of novel treatment strategies. The mice have regional heterogeneity of action potential duration of the atria similar to observations in patients with AF. In these mice, we found that the initiation and persistence of the rotational reentrant AF arrhythmias, known as spiral waves or rotors, were dependent upon action potential duration heterogeneity. The centers of the rotors were localized to regions of greatest heterogeneity of the action potential duration. Pharmacologically attenuating the action potential duration heterogeneity reduced both spontaneous and pacing-induced AF. Computer-based simulations also demonstrated that the action potential duration heterogeneity is sufficient to generate rotors that manifest as AF. Taken together, these findings suggest that action potential duration heterogeneity in mice and humans is one mechanism by which AF is initiated and that reducing action potential duration heterogeneity can lessen the burden of AF.

Keywords

Arrhythmias; Cardiology; Cell Biology; Ion channels; Mouse models.

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