Cardiac Alternans Occurs through the Synergy of Voltage- and Calcium-Dependent Mechanisms

Abstract

Cardiac alternans is characterized by alternating weak and strong beats of the heart. This signaling at the cellular level may appear as alternating long and short action potentials (APs) that occur in synchrony with alternating large and small calcium transients, respectively. Previous studies have suggested that alternans manifests itself through either a voltage dependent mechanism based upon action potential restitution or as a calcium dependent mechanism based on refractoriness of calcium release. We use a novel model of cardiac excitation-contraction (EC) coupling in the rat ventricular myocyte that includes 20,000 calcium release units (CRU) each with 49 ryanodine receptors (RyR2s) and 7 L-type calcium channels that are all stochastically gated. The model suggests that at the cellular level in the case of alternans produced by rapid pacing, the mechanism requires a synergy of voltage- and calcium-dependent mechanisms. The rapid pacing reduces AP duration and magnitude reducing the number of L-type calcium channels activating individual CRUs during each AP and thus increases the population of CRUs that can be recruited stochastically. Elevated myoplasmic and sarcoplasmic reticulum (SR) calcium, [Ca2+]myo and [Ca2+]SR respectively, increases ryanodine receptor open probability (Po) according to our model used in this simulation and this increased the probability of activating additional CRUs. A CRU that opens in one beat is less likely to open the subsequent beat due to refractoriness caused by incomplete refilling of the junctional sarcoplasmic reticulum (jSR). Furthermore, the model includes estimates of changes in Na+ fluxes and [Na+]i and thus provides insight into how changes in electrical activity, [Na+]i and sodium-calcium exchanger activity can modulate alternans. The model thus tracks critical elements that can account for rate-dependent changes in [Na+]i and [Ca2+]myo and how they contribute to the generation of Ca2+ signaling alternans in the heart.

Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives

“…This model also indicated the importance of realistic (and variable) dyad distribution on the specific dynamics of both CaT alternans and SCRE, providing spatial constraints on the randomness of both. These results are further supported by the recent sub-micron, type 1 model of Hoang-Trong et al (2021) which included experimentally influenced spatial distributions of multiple Ca 2+ -flux channels, explicit modeling of transverse-and axial-tubules, and Ca 2+ -CaM interactions. This study highlighted the importance of CRU distribution and the presence of rogue (non-junctional or orphaned) RyRs on Ca 2+ -spark propagation and wave dynamics.…”

“…It is worth highlighting that the models of single nanodomains do not reproduce well experimentally measured values for the full width half maximum (FWHM) of Ca 2+ , generally resulting in values of ∼1 µm which are below the 1.8-2.2 µm in experiment. Hoang-Trong et al (2021) for example did simulate a realistic feature of 1.85 µm, but this required using a large RyR cluster combined with two smaller satellite clusters. However, due to spatio-temporal limits on the resolution of functional imaging experiments, sparks smaller than given sizes are not detected experimentally with any given accuracy.…”

“…Spatial coupling is solved using FDM [equation ( 40)] on regular structured grids or using the more complex finite element method (FEM) on structured or unstructured meshes. They can be discretized at different choices of resolution, generally between 0.05 and 0.2 µm (Nivala et al, 2012a(Nivala et al, , 2015Colman et al, 2017b;Echebarria, 2018, 2020;Hoang-Trong et al, 2021), although there are other intermediary approaches, such as Sutanto et al ( 2018) which uses the CRU-grid approach in the transverse direction but is discretized at half-CRU distance in the longitudinal direction.…”

A Stochastic Spatiotemporal Model of Rat Ventricular Myocyte Calcium Dynamics Demonstrated Necessary Features for Calcium Wave Propagation

“…Based on a previously published compartmental model for a rat ventricular myocyte, we created a spatial model [36]. The rat ventricular myocyte is represented as a rectangular solid with dimensions of 120 µm × 20.8 µm × 10 µm, yielding a total cell volume of 24.96 pL, which is consistent with the cell volume with 20,000 CRUs [1,37,38].…”

“…The volume ratio λ ds = V ds /V myo was incorporated into the fluxes to address the volume differences between model compartments. The model used for this study is based on our published work where the reader can find all the details of the ionic currents and other details [36].…”