Diastolic Spontaneous Calcium Release From the Sarcoplasmic Reticulum Increases Beat-to-Beat Variability of Repolarization in Canine Ventricular Myocytes After β-Adrenergic Stimulation

Johnson, Daniel M.; Heijman, Jordi; Bode, Elizabeth F.; Greensmith, David J.; van der Linde, Henk; Abi-Gerges, Najah; Eisner, David A.; Trafford, Andrew W. and Volders, Paul G.A. (2013). Diastolic Spontaneous Calcium Release From the Sarcoplasmic Reticulum Increases Beat-to-Beat Variability of Repolarization in Canine Ventricular Myocytes After β-Adrenergic Stimulation. Circulation Research, 112(2) pp. 246–256.

DOI: https://doi.org/10.1161/CIRCRESAHA.112.275735

Abstract

Rationale:
Spontaneous Ca₂₊ release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations and triggered activity, contributing to arrhythmogenesis during β-adrenergic stimulation. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased during intense β-adrenergic stimulation, leading to SCR.

Objective:
We aimed to determine ionic mechanisms controlling BVR under these conditions.

Methods and Results:
Membrane potentials and cell shortening or Ca²⁺ transients were recorded from isolated canine left ventricular myocytes in the presence of isoproterenol. Action-potential (AP) durations after delayed afterdepolarizations were significantly prolonged. Addition of slowly activating delayed rectifier K⁺ current (I^Ks) blockade led to further AP prolongation after SCR, and this strongly correlated with exaggerated BVR. Suppressing SCR via inhibition of ryanodine receptors, Ca2+/calmodulin-dependent protein kinase II inhibition, or by using Mg²⁺ or flecainide eliminated delayed afterdepolarizations and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring L-type Ca²⁺ current (I_CaL) with and without previous SCR indicated that I_CaL was increased during Ca²⁺-induced Ca²⁺ release after SCR, and this contributes to AP prolongation. Prolongation of QT, T_peak-T_end intervals, and left ventricular monophasic AP duration of beats after aftercontractions occurred before torsades de pointes in an in vivo dog model of drug-induced long-QT1 syndrome.

Conclusions:
SCR contributes to increased BVR by interspersed prolongation of AP duration, which is exacerbated during I_Ks blockade. Attenuation of Ca₂₊-induced Ca₂₊ release by SCR underlies AP prolongation via increased I_CaL. These data provide novel insights into arrhythmogenic mechanisms during β-adrenergic stimulation besides triggered activity and illustrate the importance of I^Ks function in preventing excessive BVR.

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About

• Item ORO ID
• 68854
• Item Type
• Journal Item
• ISSN
• 0009-7330
• Project Funding Details

• Funded Project Name	Project ID	Funding Body
  Not Set	Not Set	AstraZeneca Ltd.

• Keywords
• calcium; action potentials; arrhythmia; sarcoplasmic reticulum; β-adrenergic receptors
• Academic Unit or School
• Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
  Faculty of Science, Technology, Engineering and Mathematics (STEM)
• Copyright Holders
• © 2013 American Heart Association, Inc.
• Depositing User
• Daniel Johnson