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 Ca buffers).

Methods And Results: We measured the major K currents (, , and ) and their Ca- 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 Ca 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 and were significantly upregulated in HF under action potential clamp, but only when cytosolic Ca was not buffered. CaMKII (Ca/calmodulin-dependent protein kinase II) inhibition abolished upregulation in HF, but it did not affect . response to β-adrenergic stimulation was also significantly diminished in HF. was also decreased in HF regardless of Ca buffering, CaMKII inhibition, or β-adrenergic stimulation.

Conclusions: At baseline Ca-dependent upregulation of and in HF counterbalances the reduced , maintaining repolarization reserve (especially at higher heart rates) in physiological conditions, unlike conditions of strong cytosolic Ca buffering. However, under β-adrenergic stimulation, reduced responsiveness severely limits integrated repolarizing K current and repolarization reserve in HF. This would increase arrhythmia propensity in HF, especially during adrenergic stress.