Acute atrial arrhythmogenicity and altered Ca2+ homeostasis in murine RyR2-P2328S hearts

Yanmin Zhang, James A. Fraser, Kamalan Jeevaratnam, Xiaojin Hao, Sandeep S. Hothi, Andrew A. Grace, Ming Lei, Christopher L H Huang

    Research output: Contribution to journalArticlepeer-review


    Aims: The experiments explored for atrial arrhythmogenesis and its possible physiological background in recently developed hetero-(RyR2+/S) and homozygotic (RyR2S/S) RyR2-P2328S murine models for catecholaminergic polymorphic ventricular tachycardia (VT) for the first time. They complement previous clinical and experimental reports describing increased ventricular arrhythmic tendencies associated with physical activity, stress, or catecholamine infusion, potentially leading to VT and ventricular fibrillation. Methods and results: Atrial arrhythmogenic properties were compared at the whole animal, Langendorff-perfused heart, and single, isolated atrial myocyte levels using electrophysiological and confocal fluorescence microscopy methods. This demonstrated that: (i) electrocardiographic parameters in intact anaesthetized wild-type (WT), RyR2+/S and RyR2S/S mice were statistically indistinguishable both before and after addition of isoproterenol apart from increases in heart rates. (ii) Bipolar electrogram and monophasic action potential recordings showed significantly higher incidences of arrhythmogenesis in isolated perfused RyR2S/S, but not RyR2 +/S, relative to WT hearts during either regular pacing or programmed electrical stimulation. The addition of isoproterenol increased such incidences in all three groups. (iii) However, there were no accompanying differences in cardiac anatomy or action potential durations at 90% repolarization and refractory periods. (iv) In contrast, episodes of diastolic Ca2+ release were observed under confocal microscopy in isolated fluo-3-loaded RyR2S/S, but not RyR2+/S or WT, atrial myocytes. The introduction of isoproterenol resulted in significant diastolic Ca2+ release in all three groups. Conclusions: These findings establish acute atrial arrhythmogenic properties in RyR2-P2328S hearts and correlate these with altered Ca2+ homeostasis in an absence of repolarization abnormalities for the first time. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2010.
    Original languageEnglish
    Pages (from-to)794-804
    Number of pages10
    JournalCardiovascular research
    Issue number4
    Publication statusPublished - 1 Mar 2011


    • Atrial arrhythmia
    • Calcium
    • Electrocardiography
    • Monophasic action potentials
    • RyR2


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