Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure

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Abstract
The precise mechanisms by which oxidative stress (OS) causes atrial fibrillation (AF) are not known. Since AF frequently originates in the posterior left atrium (PLA), we hypothesized that OS, via calmodulin-dependent protein kinase II (CaMKII) signaling, creates a fertile substrate in the PLA for triggered activity and reentry. In a canine heart failure (HF) model, OS generation and oxidized-CaMKII–induced (Ox-CaMKII–induced) RyR2 and Na v 1.5 signaling were increased preferentially in the PLA (compared with left atrial appendage). Triggered Ca 2+ waves (TCWs) in HF PLA myocytes were particularly sensitive to acute ROS inhibition. Computational modeling confirmed a direct relationship between OS/CaMKII signaling and TCW generation. CaMKII phosphorylated Na v 1.5 (CaMKII-p-Na v 1.5 [S571]) was located preferentially at the intercalated disc (ID), being nearly absent at the lateral membrane. Furthermore, a decrease in ankyrin-G (AnkG) in HF led to patchy dropout of CaMKII-p-Na v 1.5 at the ID, causing its distribution to become spatially heterogeneous; this corresponded to preferential slowing and inhomogeneity of conduction noted in the HF PLA. Computational modeling illustrated how conduction slowing (e.g., due to increase in CaMKII-p-Na v 1.5) interacts with fibrosis to cause reentry in the PLA. We conclude that OS via CaMKII leads to substrate for triggered activity and reentry in HF PLA by mechanisms independent of but complementary to fibrosis.
Funding Information
  • National Heart, Lung, and Blood Institute (HL093490)
  • National Heart, Lung, and Blood Institute (HL140061)
  • National Heart, Lung, and Blood Institute (HL119095)
  • National Heart, Lung, and Blood Institute (HL114893)
  • National Heart, Lung, and Blood Institute (HL134824)
  • National Heart, Lung, and Blood Institute (HL135096)
  • National Heart, Lung, and Blood Institute (HL114383)
  • National Heart, Lung, and Blood Institute (HL135096)
  • National Heart, Lung, and Blood Institute (HL139348)
  • Northwestern University (Proof-of-concept biomedical award)
  • Northwestern Memorial Foundation (Dixon Award)

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