RATIONALE: Spontaneous Ca(2+) 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 Ca(2+) 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, Ca(2+)/calmodulin-dependent protein kinase II inhibition, or by using Mg(2+) or flecainide eliminated delayed afterdepolarizations and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring L-type Ca(2+) current (I(CaL)) with and without previous SCR indicated that I(CaL) was increased during Ca(2+)-induced Ca(2+) 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 Ca(2+)-induced Ca(2+) 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.
RATIONALE: Spontaneous Ca(2+) 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 Ca(2+) 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, Ca(2+)/calmodulin-dependent protein kinase II inhibition, or by using Mg(2+) or flecainide eliminated delayed afterdepolarizations and decreased BVR independent of effects on AP duration. Computational analyses and voltage-clamp experiments measuring L-type Ca(2+) current (I(CaL)) with and without previous SCR indicated that I(CaL) was increased during Ca(2+)-induced Ca(2+) 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 Ca(2+)-induced Ca(2+) 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.
Authors: Norbert Szentandrássy; Kornél Kistamás; Bence Hegyi; Balázs Horváth; Ferenc Ruzsnavszky; Krisztina Váczi; János Magyar; Tamás Bányász; András Varró; Péter P Nánási Journal: Pflugers Arch Date: 2014-08-02 Impact factor: 3.657
Authors: Bence Hegyi; Julie Bossuyt; Kenneth S Ginsburg; Lynette M Mendoza; Linda Talken; William T Ferrier; Steven M Pogwizd; Leighton T Izu; Ye Chen-Izu; Donald M Bers Journal: Circ Arrhythm Electrophysiol Date: 2018-02
Authors: Bence Hegyi; Julie Bossuyt; Leigh G Griffiths; Rafael Shimkunas; Zana Coulibaly; Zhong Jian; Kristin N Grimsrud; Claus S Sondergaard; Kenneth S Ginsburg; Nipavan Chiamvimonvat; Luiz Belardinelli; András Varró; Julius G Papp; Piero Pollesello; Jouko Levijoki; Leighton T Izu; W Douglas Boyd; Tamás Bányász; Donald M Bers; Ye Chen-Izu Journal: Proc Natl Acad Sci U S A Date: 2018-03-12 Impact factor: 11.205
Authors: Bence Hegyi; Ye Chen-Izu; Leighton T Izu; Sridharan Rajamani; Luiz Belardinelli; Donald M Bers; Tamás Bányász Journal: Circ Arrhythm Electrophysiol Date: 2020-03-23
Authors: Mathias Baumert; Alberto Porta; Marc A Vos; Marek Malik; Jean-Philippe Couderc; Pablo Laguna; Gianfranco Piccirillo; Godfrey L Smith; Larisa G Tereshchenko; Paul G A Volders Journal: Europace Date: 2016-01-27 Impact factor: 5.214
Authors: Jordi Heijman; Antonio Zaza; Daniel M Johnson; Yoram Rudy; Ralf L M Peeters; Paul G A Volders; Ronald L Westra Journal: PLoS Comput Biol Date: 2013-08-22 Impact factor: 4.475