Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Johnson, DM; Heijman, J; Bode, EF; Greensmith, DJ; van der Linde, H; Abi-Gerges, N; Eisner, DA; Trafford, AW; Volders, PGA.
Diastolic Spontaneous Calcium Release From the Sarcoplasmic Reticulum Increases Beat-to-Beat Variability of Repolarization in Canine Ventricular Myocytes After β-Adrenergic Stimulation
CIRC RES. 2013; 112(2): 246-+.
Doi: 10.1161/CIRCRESAHA.112.275735
Web of Science
PubMed
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- Co-authors Med Uni Graz
- Heijman Jordi
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- Abstract:
- Rationale: Spontaneous Ca2+ release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations and triggered activity, contributing to arrhythmogenesis during beta-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 beta-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 beta-adrenergic stimulation besides triggered activity and illustrate the importance of I-Ks function in preventing excessive BVR. (Circ Res. 2013;112:246-256.)
- Find related publications in this database (Keywords)
- action potentials
- arrhythmia
- beta-adrenergic receptors
- calcium
- sarcoplasmic reticulum