Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Heterogeneity of the action potential duration is required for sustained atrial fibrillation
Uma Mahesh R. Avula, … , Steven O. Marx, Elaine Y. Wan
Uma Mahesh R. Avula, … , Steven O. Marx, Elaine Y. Wan
Published April 25, 2019
Citation Information: JCI Insight. 2019;4(11):e128765. https://doi.org/10.1172/jci.insight.128765.
View: Text | PDF
Research Article Cardiology Cell biology

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

  • Text
  • PDF
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 potentially 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 required 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.

Authors

Uma Mahesh R. Avula, Jeffrey Abrams, Alexander Katchman, Sergey Zakharov, Sergey Mironov, Joseph Bayne, Daniel Roybal, Anirudh Gorti, Lin Yang, Vivek Iyer, Marc Waase, Deepak Saluja, Edward J. Ciaccio, Hasan Garan, Andrew R. Marks, Steven O. Marx, Elaine Y. Wan

×

Figure 1

Inhomogeneity of APD in mice and humans with AF.

Options: View larger image (or click on image) Download as PowerPoint
Inhomogeneity of APD in mice and humans with AF.
(A) Representative limb...
(A) Representative limb lead surface ECGs of isoflurane-anesthetized littermate control mouse in sinus rhythm (top row) and of F1759A-dTG mouse in AF (lower row). (B) Representative snapshots from phase movies of Langendorff-perfused F1759A-dTG hearts demonstrating simultaneous rotors in the right atrium (RA) and left atrium (LA), a predominant rotor in the RA, and wavebreaks and fibrillatory conduction in the LA. (C and D) Representative optical APD maps (C) and optical action potential tracings (D) from littermate control and F1759A-dTG mice. APD maps (pacing at 10 Hz) for F1759A-dTG mice were obtained after hyperkalemia-induced conversion to sinus rhythm. The circle marks the region corresponding to the optical action potential tracings in D. Scale bar: 1 mm. (E) Graph showing maximal (max) and mean APD50 in LA and RA of littermate control (n = 4) and F1759A-dTG mice (n = 7). Mean ± SEM. ***P < 0.001; 2-tailed Student’s t test. (F) Representative all-points histograms of APD. (G) Graphs of APD50 dispersion. Mean ± SEM for littermate control and F1759A-dTG mice. **P < 0.01; ***P < 0.01; 2-tailed Student’s t test. (H) Electro-anatomical voltage map (upper) and MAP recordings in sinus rhythm (lower) with APD90 measurement for the corresponding regions for 5 patients undergoing AF ablation. For the electro-anatomical voltage map, red color (0.2 mV) is indicative of low-voltage area consistent with scarred tissue, and purple (0.5–1.0 mV) is indicative of normal healthy tissue. LIPV, linferior pulmonary vein; RIPV, right inferior pulmonary vein; LSPV, eft superior pulmonary vein; and RSPV: right superior pulmonary vein.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts