Abstract
Ectopic heartbeats can trigger reentrant arrhythmias, leading to ventricular fibrillation and sudden cardiac death. Such events have been attributed to perturbed Ca2+ handling in cardiac myocytes leading to spontaneous Ca2+ release and delayed afterdepolarizations (DADs). However, the ways in which perturbation of specific molecular mechanisms alters the probability of ectopic beats is not understood. We present a multiscale model of cardiac tissue incorporating a biophysically detailed three-dimensional model of the ventricular myocyte. This model reproduces realistic Ca2+ waves and DADs driven by stochastic Ca2+ release channel (RyR) gating and is used to study mechanisms of DAD variability. In agreement with previous experimental and modeling studies, key factors influencing the distribution of DAD amplitude and timing include cytosolic and sarcoplasmic reticulum Ca2+ concentrations, inwardly rectifying potassium current (IK1) density, and gap junction conductance. The cardiac tissue model is used to investigate how random RyR gating gives rise to probabilistic triggered activity in a one-dimensional myocyte tissue model. A novel spatial-average filtering method for estimating the probability of extreme (i.e. rare, high-amplitude) stochastic events from a limited set of spontaneous Ca2+ release profiles is presented. These events occur when randomly organized clusters of cells exhibit synchronized, high amplitude Ca2+ release flux. It is shown how reduced IK1 density and gap junction coupling, as observed in heart failure, increase the probability of extreme DADs by multiple orders of magnitude. This method enables prediction of arrhythmia likelihood and its modulation by alterations of other cellular mechanisms.
Highlights
In cardiac myocytes, dyads are sites where the junctional sarcoplasmic reticulum (JSR) membrane closely approaches (~ 15 nm) invaginations of the cell membrane known as transverse tubules (TTs)
Arrhythmias are electrical abnormalities of the heart that can degenerate into fibrillation, preventing normal heartbeats and leading to sudden cardiac death
While incidental afterdepolarizations in a large number of myocytes is highly improbable on any given beat, it may be feasible over a long time frame, explaining the unpredictability of arrhythmias
Summary
Dyads are sites where the junctional sarcoplasmic reticulum (JSR) membrane closely approaches (~ 15 nm) invaginations of the cell membrane known as transverse tubules (TTs). The resulting local increases of dyad Ca2+ concentration ([Ca2+]d) increase RyR open probability, which when open allow flux of Ca2+ ions from the JSR into the dyad This process, known as Ca2+-induced Ca2+ release (CICR), causes brief, spatially localized release events known as a Ca2+ sparks [1]. Spontaneous Ca2+ release events generate an inward current via the Na+/Ca2+ exchanger (NCX), which transports 3 Na+ ions into the cell for every Ca2+ ion extruded, and in canine myocytes via the Ca2+-activated chloride channel [5] In diastole, this produces a net inward current, resulting in an elevation of cell membrane potential (V) known as a delayed afterdepolarization (DAD) [6]. Understanding Ca2+ dynamics in ventricular myocytes and the Ca2+ handling instability that arises under pathological conditions is fundamental to our understanding of cardiac arrhythmogenesis
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