Atrial cardiomyocytes have a less well-developed T-tubule system than ventricular cells, resulting in intracellular calcium waves propagating from the membrane to the center via centripetal calcium diffusion. Failure of centripetal calcium-wave propagation (‘calcium silencing’) has been observed in a rabbit model of rapid atrial pacing and in patients with atrial fibrillation, but the underlying mechanisms remain incompletely understood. The goal of this study was to develop a novel computational model of the rabbit atrial cardiomyocyte that incorporates detailed compartmentalization of intracellular calcium dynamics, which can be used to investigate the mechanisms underpinning calcium silencing.
We incorporated ion-current formulations reflecting rabbit electrophysiology into a previously published human atrial cardiomyocyte model. The model was validated with published experimental data and the effects of altered rate of calcium diffusion between the calcium-release-unit space and the cytosol (τdiff) were investigated. τdiff modulates local calcium levels available to activate neighboring calcium-release sites, affecting wave propagation.
Simulation results showed that calcium-wave propagation was highly sensitive to τdiff during normal pacing at 2 Hz. We observed impaired calcium-wave propagation for a range of values of τdiff, with full calcium-wave propagation for values of τdiff exceeding 12.7 ms, and calcium silencing for values of τdiff below 10.6 ms due to insufficient local positive feedback for calcium-induced calcium release to maintain centripetal wave propagation. We also observed calcium alternans between propagating and non-propagating waves for intermediate values of τdiff.
This study provided new insight into the mechanisms of calcium-wave propagation failure in rabbit atrial cardiomyocytes and motivates further investigation of the effects of altered calcium diffusion on wave-propagation abnormalities and calcium-dependent arrhythmogenesis. Moreover, the newly developed model will be a useful tool for studying conditions which permit restoration of normal calcium wave propagation.