Stochastic spontaneous calcium release events and sodium channelopathies promote ventricular arrhythmias.

Fernando O Campos,Yohannes Shiferaw,Gernot Plank,Edward J Vigmond

doi:10.1063/1.4999612

Abstract

Premature ventricular complexes (PVCs), the first initiating beats of a variety of cardiac arrhythmias, have been associated with spontaneous calcium release (SCR) events at the cell level. However, the mechanisms underlying the degeneration of such PVCs into arrhythmias are not fully understood. The objective of this study was to investigate the conditions under which SCR-mediated PVCs can lead to ventricular arrhythmias. In particular, we sought to determine whether sodium (Na+) current loss-of-function in the structurally normal ventricles provides a substrate for unidirectional conduction block and reentry initiated by SCR-mediated PVCs. To achieve this goal, a stochastic model of SCR was incorporated into an anatomically accurate compute model of the rabbit ventricles with the His-Purkinje system (HPS). Simulations with reduced Na+ current due to a negative-shift in the steady-state channel inactivation showed that SCR-mediated delayed afterdepolarizations led to PVC formation in the HPS, where the electrotonic load was lower, conduction block, and reentry in the 3D myocardium. Moreover, arrhythmia initiation was only possible when intrinsic electrophysiological heterogeneity in action potential within the ventricles was present. In conclusion, while benign in healthy individuals SCR-mediated PVCs can lead to life-threatening ventricular arrhythmias when combined with Na+ channelopathies.

Highlights

Triggered activity in cardiac myocytes occurs when action potentials (APs) are elicited by oscillations in the transmembrane potential, Vm, referred to as afterdepolarizations, which are assumed to be caused by abnormalities at the subcellular scale
We sought to determine the conditions under which premature ventricular complexes (PVCs) resulting from stochastic subcellular spontaneous calcium (Ca2þ) release (SCR) events can lead to ventricular arrhythmias, how Naþ current reduction can accentuate the occurrence of subthreshold delayed afterdepolarizations (DADs) in the 3D myocardium causing conduction block of PVCs and reentry
This study makes use of a mathematical model of SCR events coupled to an anatomically accurate model of rabbit ventricles and His-Purkinje system (HPS) to investigate the origin of triggered arrhythmias

Summary

Introduction

Triggered activity in cardiac myocytes occurs when action potentials (APs) are elicited by oscillations in the transmembrane potential, Vm, referred to as afterdepolarizations, which are assumed to be caused by abnormalities at the subcellular scale. Such afterdepolarizations may manifest either early during the plateau phase of the AP – classified as early afterdepolarizations (EADs) – or later, after the AP has repolarized to resting potential levels, in which case they are referred to as delayed afterdepolarizations (DADs).. During the course of an AP, Ca2þ sparks arise throughout the cell due to the opening of Ryanodine receptor (RyR) channels located in the sarcoplasmic reticulum (SR) within the dyadic clefts forming a Ca2þ release unit. Such random RyR openings can induce spontaneous Ca2þ sparks, which propagate between

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