Atrial arrhythmia, triggering events and conduction abnormalities in isolated murine RyR2-P2328S hearts

• Published in: Acta Physiologica 2013-02, Vol.207 (2), p.308-323
• Main Authors: King, J. H., Zhang, Y., Lei, M., Grace, A. A., Huang, C. L.-H., Fraser, J. A.
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - physiopathology; atrial fibrillation; Biological and medical sciences; calcium; Calcium - metabolism; conduction velocity; Electrocardiography; Fundamental and applied biological sciences. Psychology; Heart Atria - metabolism; Heart Atria - physiopathology; Mice; Mice, Mutant Strains; Organ Culture Techniques; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; RyR2; triggered activity; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 1748-1708; 1748-1716
• DOI: 10.1111/apha.12006

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.