Dual effects of the small-conductance Ca2+-activated K+ current on human atrial electrophysiology and Ca2+-driven arrhythmogenesis: an in silico study

Nathaniel T Herrera, Xianwei Zhang, Haibo Ni, Mary M Maleckar, Jordi Heijman, Dobromir Dobrev, Eleonora Grandi*, Stefano Morotti*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

By sensing changes in intracellular Ca , small-conductance Ca -activated K (SK) channels dynamically regulate the dynamics of the cardiac action potential (AP) on a beat-to-beat basis. Given their predominance in atria vs. ventricles, SK channels are considered a promising atrial-selective pharmacological target against atrial fibrillation (AF), the most common cardiac arrhythmia. However, the precise contribution of SK current (I ) to atrial arrhythmogenesis is poorly understood, and may potentially involve different mechanisms that depend on species, heart rates, and degree of AF-induced atrial remodeling. Both reduced and enhanced I have been linked to AF. Similarly, both SK channel up- and downregulation have been reported in chronic AF (cAF) vs. normal sinus rhythm (nSR) patient samples. Here, we use our multi-scale modeling framework to obtain mechanistic insights into the contribution of I in human atrial cardiomyocyte electrophysiology. We simulate several protocols to quantify how I modulation affects the regulation of AP duration (APD), Ca transient, refractoriness, and occurrence of alternans and delayed afterdepolarizations (DADs). Our simulations show that I activation shortens the APD and atrial effective refractory period, limits Ca cycling, and slightly increases the propensity for alternans in both nSR and cAF conditions. We also show that increasing I counteracts DAD development by enhancing the repolarization force that opposes the Ca -dependent depolarization. Taken together, our results suggest that increasing I in human atrial cardiomyocytes could promote reentry, while protecting against triggered activity. Depending on the leading arrhythmogenic mechanism, I inhibition may thus be a beneficial or detrimental anti-AF strategy.
Original languageEnglish
Pages (from-to)H896-H908
Number of pages13
JournalAmerican Journal of Physiology-heart and Circulatory Physiology
Volume325
Issue number4
DOIs
Publication statusPublished - 25 Oct 2023

Keywords

  • arrhythmia
  • atrial fibrillation
  • atrial myocyte electrophysiology
  • mathematical model
  • small-conductance Ca2+-activated K+ current

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