Modeling the Effects of Distinct Calcium Dynamics in Purkinje Cells in Delayed Afterdepolarization-Induced Triggered Activity

Abstract

<h3>Background</h3> Recent mouse experiments demonstrated that Purkinje cells (PC) are more vulnerable to delayed afterdepolarizations (DADs) than ventricular myocytes (VM). PCs exhibit a distinct calcium (Ca) activation process, which in the presence of ryanodine receptor (RyR2) mutations may facilitate DADs and triggered activity. However, the exact mechanisms are poorly understood. We hypothesize that cytosolic Ca diffusion together with T-type Ca (I_CaT) channel reopening as a result of leaky RyR2 lead to DAD-induced triggered activity in PCs. <h3>Methods</h3> A detailed mathematical model of a mouse PC (Figure A) involving spatiotemporal diffusion of cytosolic Ca was developed. Two components of the Ca activation—radial subsarcolemmal wavelets (C1) and longitudinal cell-wide waves (C2), as observed in literature—were modeled (Figure B). RyR2 mutations were simulated by reducing the threshold for sarcoplasmic reticulum (SR) Ca release in the presence of isoproterenol effects. <h3>Results</h3> During 1-Hz pacing, sarcolemmal (SL) Ca channels trigger C1 propagating toward the core of the cell, which then triggers C2. SR Ca leaks initiated wavelets propagating in the reverse direction. Increased amplitudes of the L-type Ca current (I_CaL) (150%) and I_CaT (200%) were sufficient to cause DADs due to reactivation of I_CaT and sodium/calcium exchanger (Figure C). Further increase in I_CaT (300%) led to DAD-induced triggered activity (Figure D), which was not observed with increased I_CaL alone. <h3>Conclusions</h3> Our simulations suggest that characteristic two-dimensional cytosolic Ca diffusion along with reactivation of I_CaT lead to DAD-induced triggered activity caused by leaky SR in PCs.