Altered Repolarization Reserve in Failing Rabbit Ventricular Myocytes: Calcium and β-Adrenergic Effects on Delayed-...

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).

We measured the major K⁺ currents (I_Kr, I_Ks, and I_K1) 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 I_Kr and I_Ks 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 I_Ks upregulation in HF, but it did not affect I_Kr. I_Ks response to β-adrenergic stimulation was also significantly diminished in HF. I_K1 was also decreased in HF regardless of Ca²⁺ buffering, CaMKII inhibition, or β-adrenergic stimulation.

At baseline Ca²⁺-dependent upregulation of I_Kr and I_Ks in HF counterbalances the reduced I_K1, maintaining repolarization reserve (especially at higher heart rates) in physiological conditions, unlike conditions of strong cytosolic Ca²⁺ buffering. However, under β-adrenergic stimulation, reduced I_Ks responsiveness severely limits integrated repolarizing K⁺ current and repolarization reserve in HF. This would increase arrhythmia propensity in HF, especially during adrenergic stress.