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Delayed afterdepolarization-induced triggered activity in cardiac purkinje cells mediated through cytosolic calcium diffusion waves.

ABSTRACT: Cardiac Purkinje cells (PCs) are more susceptible to action potential abnormalities as compared to ventricular myocytes (VMs), which could be associated with their distinct intracellular calcium handling. We developed a detailed biophysical model of a mouse cardiac PC, which importantly reproduces the experimentally observed biphasic cytosolic calcium waves. The model includes a stochastic gating formulation for the opening and closing of ryanodine receptor (RyR) channels, simulated with a Monte Carlo method, to accurately reproduce cytosolic calcium wave propagation and the effects of spontaneous calcium release events. Simulations predict that during an action potential, smaller cytosolic calcium wavelets propagated from the sarcolemma towards the center of the cell and initiated larger magnitude cell-wide calcium waves via a calcium-induced-calcium release mechanism. In the presence of RyR mutations, frequent spontaneous calcium leaks from sarcoplasmic reticulum (SR) initiated calcium waves, which upon reaching the cell periphery produced delayed afterdepolarizations (DADs) via sodium-calcium exchanger (NCX) and T-type calcium (I_CaT ) channel activation. In the presence of isoproterenol-mediated effects, DADs induced triggered activity by reactivation of fast sodium channels. Based on our model, we found that the activation of either L-type calcium channels (I_CaL ), I_CaT , sodium-potassium exchanger (I_NaK ) or NCX is sufficient for occurrence of triggered activity; however, a partial blockade of I_CaT or I_NaK is essential for its successful termination. Our modeling study highlights valuable insights into the mechanisms of DAD-induced triggered activity mediated via cytosolic calcium waves in cardiac PCs and may elucidate the increased arrhythmogeneity in PCs.

SUBMITTER: Shah C

PROVIDER: S-EPMC6928245 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Delayed afterdepolarization-induced triggered activity in cardiac purkinje cells mediated through cytosolic calcium diffusion waves.

Shah Chirag C Jiwani Sohel S Limbu Bijay B Weinberg Seth S Deo Makarand M

Physiological reports 20191201 24

Cardiac Purkinje cells (PCs) are more susceptible to action potential abnormalities as compared to ventricular myocytes (VMs), which could be associated with their distinct intracellular calcium handling. We developed a detailed biophysical model of a mouse cardiac PC, which importantly reproduces the experimentally observed biphasic cytosolic calcium waves. The model includes a stochastic gating formulation for the opening and closing of ryanodine receptor (RyR) channels, simulated with a Monte ...[more]

PMID: 31872561

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Project description:In normal atrial and ventricular tissue, the electrical wavefronts are mediated by the fast sodium current (I(Na)), whereas in sinoatrial and atrioventricular nodal tissue, conduction is mediated by the slow L-type calcium current (I(Ca,L)). However, it has not been shown whether the same tissue can exhibit both the I(Na)-mediated and the I(Ca,L)-mediated conduction.This study sought to test the hypothesis that bi-stable cardiac wave conduction, mediated by I(Na) and I(Ca,L), respectively, can occur in the same tissue under conditions promoting early afterdepolarizations (EADs), and to study how this novel wave dynamics is related to the mechanisms of EAD-mediated arrhythmias.Computer models of two-dimensional (2D) tissue with a physiologically detailed action potential model were used to study the bi-stable wave dynamics. Theoretical predictions were tested experimentally by optical mapping in neonatal rat ventricular myocyte monolayers.In the same 2D homogeneous tissue, we could induce spiral waves that are mediated by either I(Na) or I(Ca,L) under conditions in which the action potential model exhibited EADs. This bi-stable wave propagation behavior was similar to bi-stability shown in many other nonlinear systems. Because the bi-stable states are also excitable, we call this novel behavior bi-excitability. In a 2D heterogeneous tissue, the I(Ca,L)-mediated spiral wave meanders, giving rise to a twisting electrocardiographic QRS axis, resembling torsades de pointes, whereas the coexistence and interplay between the I(Na)-mediated wavefronts and I(Ca,L)-mediated wavefronts give rise to polymorphic ventricular tachycardia. We also present experimental evidence for bi-excitability under EAD-promoting conditions in neonatal rat ventricular myocyte monolayers exposed to BayK8644 and isoproterenol.Under EAD-prone conditions, both I(Na)-mediated conduction and I(Ca,L)-mediated conduction can occur in the same tissue. These novel wave dynamics may be responsible for certain EAD-mediated arrhythmias, such as torsades de pointes and polymorphic ventricular tachycardia.

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Delayed afterdepolarization-induced triggered activity in cardiac purkinje cells mediated through cytosolic calcium diffusion waves.

Publications

Delayed afterdepolarization-induced triggered activity in cardiac purkinje cells mediated through cytosolic calcium diffusion waves.

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