Abstract
In atrial cardiomyocytes without a well-developed T-tubule system, calcium diffuses from the periphery toward the center creating a centripetal wave pattern. During atrial fibrillation, rapid activation of atrial myocytes induces complex remodeling in diffusion properties that result in failure of calcium to propagate in a fully regenerative manner toward the center; a phenomenon termed “calcium silencing.” This has been observed in rabbit atrial myocytes after exposure to prolonged rapid pacing. Although experimental studies have pointed to possible mechanisms underlying calcium silencing, their individual effects and relative importance remain largely unknown. In this study we used computational modeling of the rabbit atrial cardiomyocyte to query the individual and combined effects of the proposed mechanisms leading to calcium silencing and abnormal calcium wave propagation. We employed a population of models obtained from a newly developed model of the rabbit atrial myocyte with spatial representation of intracellular calcium handling. We selected parameters in the model that represent experimentally observed cellular remodeling which have been implicated in calcium silencing, and scaled their values in the population to match experimental observations. In particular, we changed the maximum conductances of ICaL, INCX, and INaK, RyR open probability, RyR density, Serca2a density, and calcium buffering strength. We incorporated remodeling in a population of 16 models by independently varying parameters that reproduce experimentally observed cellular remodeling, and quantified the resulting alterations in calcium dynamics and wave propagation patterns. The results show a strong effect of ICaL in driving calcium silencing, with INCX, INaK, and RyR density also resulting in calcium silencing in some models. Calcium alternans was observed in some models where INCX and Serca2a density had been changed. Simultaneously incorporating changes in all remodeled parameters resulted in calcium silencing in all models, indicating the predominant role of decreasing ICaL in the population phenotype.
Highlights
Models of cardiac electrophysiology are important tools for studying the mechanisms of heart disease and impaired cardiac cell function, and have been relevant in the study of arrhythmic events such as atrial fibrillation (AF) (Trayanova, 2014; Grandi and Maleckar, 2016; Vagos et al, 2018)
We have previously developed a model of the rabbit atrial myocyte with spatial calcium description (Vagos et al, 2020), which was parameterized to match experimentally observed rabbit-specific electrophysiology using a population of models approach
In this study we have proposed an approach for analyzing the effects of rapid atrial pacing remodeling in a population of healthy rabbit atrial myocytes
Summary
Models of cardiac electrophysiology are important tools for studying the mechanisms of heart disease and impaired cardiac cell function, and have been relevant in the study of arrhythmic events such as atrial fibrillation (AF) (Trayanova, 2014; Grandi and Maleckar, 2016; Vagos et al, 2018). Atrial cardiomyocytes have a less developed T-tubule system than their ventricular counterpart, and in many species this results in markedly different intracellular calcium dynamics. In both cell types calcium enters via L-type calcium channels, locally accumulates close to the membrane, and triggers calcium-induced calcium release from calcium release units (CRU) in the junctional sarcoplasmic reticulum (SR) into the cytosol. As one CRU is activated, calcium diffuses through the cytosol to cause a local concentration rise at the neighboring CRUs, which reaches the threshold level for activation and releases more calcium and the process repeats resulting in a centripetally propagating calcium wave
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