Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release

Niall Macquaide, Hoang-Trong Minh Tuan, Jun-Ichi Hotta, Wouter Sempels, Ilse Lenaerts, Patricia Holemans, Johan Hofkens, M. Saleet Jafri, Rik Willems, Karin R. Sipido*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

AIMS: In atrial fibrillation (AF), abnormalities in Ca(2+) release contribute to arrhythmia generation and contractile dysfunction. We explore whether ryanodine receptor (RyR) cluster ultrastructure is altered and is associated with functional abnormalities in AF.

METHODS AND RESULTS: Using high-resolution confocal microscopy (STED), we examined RyR cluster morphology in fixed atrial myocytes from sheep with persistent AF (N = 6) and control (Ctrl; N = 6) animals. RyR clusters on average contained 15 contiguous RyRs; this did not differ between AF and Ctrl. However, the distance between clusters was significantly reduced in AF (288 ± 12 vs. 376 ± 17 nm). When RyR clusters were grouped into Ca(2+) release units (CRUs), i.e. clusters separated by <150 nm, CRUs in AF had more clusters (3.43 ± 0.10 vs. 2.95 ± 0.02 in Ctrl), which were more dispersed. Furthermore, in AF cells, more RyR clusters were found between Z lines. In parallel experiments, Ca(2+) sparks were monitored in live permeabilized myocytes. In AF, myocytes had >50% higher spark frequency with increased spark time to peak (TTP) and duration, and a higher incidence of macrosparks. A computational model of the CRU was used to simulate the morphological alterations observed in AF cells. Increasing cluster fragmentation to the level observed in AF cells caused the observed changes, i.e. higher spark frequency, increased TTP and duration; RyR clusters dispersed between Z-lines increased the occurrence of macrosparks.

CONCLUSION: In persistent AF, ultrastructural reorganization of RyR clusters within CRUs is associated with overactive Ca(2+) release, increasing the likelihood of propagating Ca(2+) release.

Original languageEnglish
Pages (from-to)387-398
Number of pages12
JournalCardiovascular Research
Volume108
Issue number3
Early online date21 Oct 2015
DOIs
Publication statusPublished - 1 Dec 2015

Keywords

  • Animals
  • Atrial Fibrillation/metabolism
  • Calcium Signaling
  • Computer Simulation
  • Disease Models, Animal
  • Heart Atria/metabolism
  • Kinetics
  • Microscopy, Confocal
  • Models, Cardiovascular
  • Models, Molecular
  • Myocytes, Cardiac/metabolism
  • Protein Conformation
  • Ryanodine Receptor Calcium Release Channel/metabolism
  • Sheep
  • Structure-Activity Relationship

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