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.
['Hegyi|Bence|B|', 'Bossuyt|Julie|J|', 'Ginsburg|Kenneth S|KS|', 'Mendoza|Lynette M|LM|', 'Talken|Linda|L|', 'Ferrier|William T|WT|', 'Pogwizd|Steven M|SM|', 'Izu|Leighton T|LT|', 'Chen-Izu|Ye|Y|', 'Bers|Donald M|DM|']
D000200:Action Potentials D000318:Adrenergic beta-Agonists D000818:Animals D002118:Calcium D004195:Disease Models, Animal D006333:Heart Failure D006352:Heart Ventricles D008297:Male D032383:Myocytes, Cardiac D011188:Potassium D011817:Rabbits
electrophysiology heart failure action potential calcium/calmodulin-dependent protein kinase II potassium channels