Dataset Information

Acute atrial arrhythmogenicity and altered Ca(2+) homeostasis in murine RyR2-P2328S hearts.

ABSTRACT:

Aims

The experiments explored for atrial arrhythmogenesis and its possible physiological background in recently developed hetero-(RyR2(+/S)) and homozygotic (RyR2(S/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 RyR2(S/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 RyR2(S/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 Ca(2+) release were observed under confocal microscopy in isolated fluo-3-loaded RyR2(S/S), but not RyR2(+/S) or WT, atrial myocytes. The introduction of isoproterenol resulted in significant diastolic Ca(2+) release in all three groups.

Conclusions

These findings establish acute atrial arrhythmogenic properties in RyR2-P2328S hearts and correlate these with altered Ca(2+) homeostasis in an absence of repolarization abnormalities for the first time.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3039245 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Publications

Acute atrial arrhythmogenicity and altered Ca(2+) homeostasis in murine RyR2-P2328S hearts.

Zhang Yanmin Y Fraser James A JA Jeevaratnam Kamalan K Hao Xiaojin X Hothi Sandeep S SS Grace Andrew A AA Lei Ming M Huang Christopher L-H CL

Cardiovascular research 20100709 4

<h4>Aims</h4>The experiments explored for atrial arrhythmogenesis and its possible physiological background in recently developed hetero-(RyR2(+/S)) and homozygotic (RyR2(S/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 ...[more]

PMID: 20621925

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Project description:The clinically established proarrhythmic effect of bradycardia and antiarrhythmic effect of lidocaine (10 microM) were reproduced in hypokalaemic (3.0 mM K(+)) Langendorff-perfused murine hearts paced over a range (80-180 ms) of baseline cycle lengths (BCLs). Action potential durations (at 90% repolarization, APD(90)s), transmural conduction times and ventricular effective refractory periods (VERPs) were then determined from monophasic action potential records obtained during a programmed electrical stimulation procedure in which extrasystolic stimuli were interposed following regular stimuli at successively decreasing coupling intervals. A novel graphical analysis of epicardial and endocardial, local and transmural relationships between APD(90), corrected for transmural conduction time where appropriate, and VERP yielded predictions in precise agreement with the arrhythmogenic findings obtained over the entire range of BCLs studied. Thus, in normokalaemic (5.2 mM K(+)) hearts a statistical analysis confirmed that all four relationships were described by straight lines of gradients not significantly (P > 0.05) different from unity that passed through the origin and thus subtended constant critical angles, theta with the abscissa (45.8 degrees +/- 0.9 degrees , 46.6 degrees +/- 0.5 degrees , 47.6 degrees +/- 0.5 degrees and 44.9 degrees +/- 0.8 degrees , respectively). Hypokalaemia shifted all points to the left of these reference lines, significantly (P < 0.05) increasing theta at BCLs of 80-120 ms where arrhythmic activity was not observed ( approximately 63 degrees , approximately 54 degrees , approximately 55 degrees and approximately 58 degrees , respectively) and further significantly (P < 0.05) increasing theta at BCLs of 140-180 ms where arrhythmic activity was observed ( approximately 68 degrees , approximately 60 degrees , approximately 61 degrees and approximately 65 degrees , respectively). In contrast, the antiarrhythmic effect of lidocaine treatment was accompanied by a significant (P < 0.05) disruption of this linear relationship and decreases in theta in both normokalaemic ( approximately 40 degrees , approximately 33 degrees , approximately 39 degrees and approximately 41 degrees , respectively) and hypokalaemic ( approximately 40 degrees , approximately 44 degrees , approximately 50 degrees and approximately 48 degrees , respectively) hearts. This extended a previous approach that had correlated alterations in transmural repolarization gradients with arrhythmogenicity in murine models of the congenital long QT syndrome type 3 and hypokalaemia at a single BCL. Thus, the analysis in terms of APD(90) and VERP provided a more sensitive indication of the effect of lidocaine than one only considering transmural repolarization gradients and may be particularly applicable in physiological and pharmacological situations in which these parameters diverge.

Project description:Ryanodine receptor (RyR2) is the major Ca(2+) channel of the cardiac sarcoplasmic reticulum (SR) and plays a crucial role in the generation of myocardial force. Changes in RyR2 gating properties and resulting increases in its open probability (Po) are associated with Ca(2+) leakage from the SR and arrhythmias; however, the effects of RyR2 dysfunction on myocardial contractility are unknown. Here, we investigated the possibility that a RyR2 mutation associated with catecholaminergic polymorphic ventricular tachycardia, R4496C, affects the contractile function of atrial and ventricular myocardium. We measured isometric twitch tension in left ventricular and atrial trabeculae from wild-type mice and heterozygous transgenic mice carrying the R4496C RyR2 mutation and found that twitch force was comparable under baseline conditions (30°C, 2 mM [Ca(2+)]o, 1 Hz). However, the positive inotropic responses to high stimulation frequency, 0.1 µM isoproterenol, and 5 mM [Ca(2+)]o were decreased in R4496C trabeculae, as was post-rest potentiation. We investigated the mechanisms underlying inotropic insufficiency in R4496C muscles in single ventricular myocytes. Under baseline conditions, the amplitude of the Ca(2+) transient was normal, despite the reduced SR Ca(2+) content. Under inotropic challenge, however, R4496C myocytes were unable to boost the amplitude of Ca(2+) transients because they are incapable of properly increasing the amount of Ca(2+) stored in the SR because of a larger SR Ca(2+) leakage. Recovery of force in response to premature stimuli was faster in R4496C myocardium, despite the unchanged rates of recovery of L-type Ca(2+) channel current (ICa-L) and SR Ca(2+) content in single myocytes. A faster recovery from inactivation of the mutant R4496C channels could explain this behavior. In conclusion, changes in RyR2 channel gating associated with the R4496C mutation could be directly responsible for the alterations in both ventricular and atrial contractility. The increased RyR2 Po and fractional Ca(2+) release from the SR induced by the R4496C mutation preserves baseline contractility despite a slight decrease in SR Ca(2+) content, but cannot compensate for the inability to increase SR Ca(2+) content during inotropic challenge.

Dataset Information

Acute atrial arrhythmogenicity and altered Ca(2+) homeostasis in murine RyR2-P2328S hearts.

Aims

Methods and results

Conclusions

Publications

Acute atrial arrhythmogenicity and altered Ca(2+) homeostasis in murine RyR2-P2328S hearts.

Similar Datasets

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