Altered Repolarization Reserve in Failing Rabbit Ventricular Myocytes

Altered Repolarization Reserve in Failing Rabbit Ventricular Myocytes Background: Electrophysiological remodeling and increased susceptibility for cardiac arrhythmias are hallmarks of heart failure (HF). Ventricular action potential duration (APD) is typically prolonged in HF, with reduced repolarization reserve. However, underlying K+ current changes are often measured in nonphysiological conditions (voltage clamp, low pacing rates, cytosolic Ca2+ buffers). Methods and Results: We measured the major K+ currents (IKr, IKs, and IK1) and their Ca2+- and β-adrenergic dependence in rabbit ventricular myocytes in chronic pressure/volume overload–induced HF (versus age-matched controls). APD was significantly prolonged only at lower pacing rates (0.2–1 Hz) in HF under physiological ionic conditions and temperature. However, when cytosolic Ca2+ was buffered, APD prolongation in HF was also significant at higher pacing rates. Beat-to-beat variability of APD was also significantly increased in HF. Both IKr and IKs were significantly upregulated in HF under action potential clamp, but only when cytosolic Ca2+ was not buffered. CaMKII (Ca2+/calmodulin-dependent protein kinase II) inhibition abolished IKs upregulation in HF, but it did not affect IKr. IKs response to β-adrenergic stimulation was also significantly diminished in HF. IK1 was also decreased in HF regardless of Ca2+ buffering, CaMKII inhibition, or β-adrenergic stimulation. Conclusions: At baseline Ca2+-dependent upregulation of IKr and IKs in HF counterbalances the reduced IK1, maintaining repolarization reserve (especially at higher heart rates) in physiological conditions, unlike conditions of strong cytosolic Ca2+ buffering. However, under β-adrenergic stimulation, reduced IKs responsiveness severely limits integrated repolarizing K+ current and repolarization reserve in HF. This would increase arrhythmia propensity in HF, especially during adrenergic stress. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Circulation: Arrhythmia & Electrophysiology Wolters Kluwer Health

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Publisher
Wolters Kluwer
Copyright
© 2018 American Heart Association, Inc.
ISSN
1941-3149
eISSN
1941-3084
D.O.I.
10.1161/CIRCEP.117.005852
Publisher site
See Article on Publisher Site

Abstract

Background: Electrophysiological remodeling and increased susceptibility for cardiac arrhythmias are hallmarks of heart failure (HF). Ventricular action potential duration (APD) is typically prolonged in HF, with reduced repolarization reserve. However, underlying K+ current changes are often measured in nonphysiological conditions (voltage clamp, low pacing rates, cytosolic Ca2+ buffers). Methods and Results: We measured the major K+ currents (IKr, IKs, and IK1) and their Ca2+- and β-adrenergic dependence in rabbit ventricular myocytes in chronic pressure/volume overload–induced HF (versus age-matched controls). APD was significantly prolonged only at lower pacing rates (0.2–1 Hz) in HF under physiological ionic conditions and temperature. However, when cytosolic Ca2+ was buffered, APD prolongation in HF was also significant at higher pacing rates. Beat-to-beat variability of APD was also significantly increased in HF. Both IKr and IKs were significantly upregulated in HF under action potential clamp, but only when cytosolic Ca2+ was not buffered. CaMKII (Ca2+/calmodulin-dependent protein kinase II) inhibition abolished IKs upregulation in HF, but it did not affect IKr. IKs response to β-adrenergic stimulation was also significantly diminished in HF. IK1 was also decreased in HF regardless of Ca2+ buffering, CaMKII inhibition, or β-adrenergic stimulation. Conclusions: At baseline Ca2+-dependent upregulation of IKr and IKs in HF counterbalances the reduced IK1, maintaining repolarization reserve (especially at higher heart rates) in physiological conditions, unlike conditions of strong cytosolic Ca2+ buffering. However, under β-adrenergic stimulation, reduced IKs responsiveness severely limits integrated repolarizing K+ current and repolarization reserve in HF. This would increase arrhythmia propensity in HF, especially during adrenergic stress.

Journal

Circulation: Arrhythmia & ElectrophysiologyWolters Kluwer Health

Published: Feb 1, 2018

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