UC Davis

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 (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.

Conclusions

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.