Voltage and Calcium Coupling in the Genesis of Cardiac Afterdepolarizations

Abstract

Early (EADs) and delayed (DADs) afterdepolarizations are triggers of cardiac arrhythmias. While DADs are caused by spontaneous Ca releases, EADs can originate from either voltage oscillations or Ca oscillations. In addition, in many situations, both EADs and DADs occur simultaneously. However, voltage and Ca are bi-directionally coupled, how this coupling affects EADs and the interactions between EADs and DADs are not well understood. Here we use an action potential (AP) model of ventricular myocytes with detailed spatiotemporal Ca cycling regulation to investigate the effects of voltage-Ca coupling on EAD and DAD genesis and their interactions. We increased the Ca window current or the late Na current to promote voltage oscillations and changed the RyR leakness and SERCA pump activity to promote Ca oscillations. By scanning the parameter space of voltage and Ca cycling, we found that: 1) EADs can be caused by either voltage oscillations or Ca oscillations. Ca oscillations also promote DADs and triggered activity; 2) An EAD can result from a secondary Ca release event due to transient SR Ca overload caused by very fast Ca re-uptake and/or a lengthened AP; when AP is short, this secondary release results in a DAD; 3) For certain parameters, partially decoupling voltage and Ca by removing the Ca-dependence of IKs suppresses both EADs and DADs, indicating that Ca and voltage interact synergistically to promote EADs and DADs; and 4) Ca oscillations are markedly reduced under voltage clamp conditions, further suggesting that Ca oscillations and voltage oscillations promote each other in a synergistic manner. In conclusion, the coupling of voltage and Ca promotes the formation of EADs and DADs and generates large amplitude EADs that are arrhythmogenic.