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

MacQuaide, N. , Tuan, H.-T. M., Hotta, J.-I., Sempels, W., Lenaerts, I., Holemans, P., Hofkens, J., Jafri, M. S., Willems, R. and Sipido, K. R. (2015) Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release. Cardiovascular Research, 108(3), pp. 387-398. (doi: 10.1093/cvr/cvv231) (PMID:26490742) (PMCID:PMC4648199)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacQuaide, Dr Niall
Authors: MacQuaide, N., Tuan, H.-T. M., Hotta, J.-I., Sempels, W., Lenaerts, I., Holemans, P., Hofkens, J., Jafri, M. S., Willems, R., and Sipido, K. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Cardiovascular Research
Publisher:Oxford University Press
ISSN:0008-6363
ISSN (Online):1755-3245
Published Online:21 October 2015
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Cardiovascular Research 108(3):387-398
Publisher Policy:Reproduced under a Creative Commons License

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