Journal
ACTA PHYSIOLOGICA
Volume 207, Issue 2, Pages 308-323Publisher
WILEY-BLACKWELL
DOI: 10.1111/apha.12006
Keywords
atrial fibrillation; calcium; conduction velocity; RyR2; triggered activity
Categories
Funding
- Biological Sciences Research Council (BBSRC)
- Medical Research Council (MRC)
- Raymond and Beverly Sackler Foundation
- MRC
- University of Cambridge School of Clinical Medicine
- BBSRC
- BBSRC [BB/F023863/1] Funding Source: UKRI
- MRC [G0100188] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F023863/1] Funding Source: researchfish
- Medical Research Council [G0100188] Funding Source: researchfish
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Aim RyR2 mutations are associated with catecholaminergic polymorphic tachycardia, a condition characterized by ventricular and atrial arrhythmias. The present experiments investigate the atrial electrophysiology of homozygotic murine RyR2-P2328S (RyR2S/S) hearts for ectopic triggering events and for conduction abnormalities that might provide a re-entrant substrate. Methods Electrocardiograph recordings were made from regularly stimulated RyR2S/S and wild type (WT) hearts, perfused using a novel modified Langendorff preparation. This permitted the simultaneous use of either floating intracellular microelectrodes to measure action potential (AP) parameters, or a multielectrode array to measure epicardial conduction velocity (CV). Results RyR2S/S showed frequent sustained tachyarrhythmias, delayed afterdepolarizations and ectopic APs, increased interatrial conduction delays, reduced epicardial CVs and reduced maximum rates of AP depolarization ((dV/dt)max), despite similar effective refractory periods, AP durations and AP amplitudes. Effective interatrial CVs and (dV/dt)max values of APs following ectopic (S2) stimulation were lower than those of APs following regular stimulation and decreased with shortening S1S2 intervals. However, although RyR2S/S atria showed arrhythmias over a wider range of S1S2 intervals, the interatrial CV and (dV/dt)max of S2 APs provoking such arrhythmias were similar in RyR2S/S and WT. Conclusions These results suggest that abnormal intracellular Ca2+ homoeostasis produces both arrhythmic triggers and a slow-conducting arrhythmic substrate in RyR2S/S atria. A similar mechanism might also contribute to arrhythmogenesis in other conditions, associated with diastolic Ca2+release, such as atrial fibrillation.
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