Altered Repolarization Reserve in Failing Rabbit Ventricular Myocytes: Calcium and β-Adrenergic Effects on Delayed- and Inward-Rectifier Potassium Currents

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.