Aims: SK channels are small conductance calcium-activated potassium channels that are upregulated in ventricular myocytes under heart failure (HF). In a previous in silico study, SK channel block was found to increase transmural dispersion of repolarization, suggesting an antiarrhythmic role for these channels. However, previous research did not consider the β-adrenergic remodeling and the loss of T-tubular cellular domains characteristic of HF. The current study investigates how SK channel block affects repolarization dispersion and inotropy under β-adrenergic stimulation (β-AS) in the failing ventricle.
Methods: We updated a human ventricular HF electrophysiological model that includes SK channel activity by incorporating the loss of T-tubular domains and a β-adrenergic HF-remodeled signaling module. Simulations were conducted for endocardial, mid-myocardial and epicardial cells at 1 Hz pacing. Action potential duration (APD), CaT peak (CaT_max), CaT duration from maximum upstroke to 80% recovery (CaTD_80), and the difference CaTD_80 - APD_80 were calculated for combinations of β-AS (none vs. full isoproterenol-equivalent β-AS) and SK channel activity (active vs. full block).
Results: Without β-AS, SK block prolonged APD_90 by 20.5%, 18.8%, and 21.9% in epicardial, mid-myocardial, and endocardial cells, respectively. Under β-AS, the prolongation was 14.6% (epicardial) and 16.5% (endocardial), while mid-myocardial cells developed early afterdepolarizations (EADs). SK block increased ∆APD_90 (endo-epi) and decreased CaTD_80 - APD_80 in all cell types, both with and without β-AS.
Conclusion: SK channels block may affect arrhythmicity under both basal and β-AS in HF. On one hand, SK block increased transmural repolarization heterogeneity and, under β-AS, provoked EADs in mid-myocardial cells. Conversely, SK block decreased the CaTD_80 - APD_80 interval across all cell types, which may be protective against delayed afterdepolarizations (DADs).