Exploring Dynamical Instabilities in Cardiac Myocytes: A Four-Variable Model of Calcium Cycling and L-type Calcium Channel Regulation

Shang-Jung Wu¹, Yi-Ting Shen¹, Shigeyuki Komura³, Hsuan-Yi Chen⁴, Daisuke Sato², Kuo-An Wu^1*

¹Department of Physics, National Tsing Hua University, Hsinchu, Taiwan
²Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
³Department of Physics, National Central University, Jhongli, Taiwan
⁴Department of Pharmacology, University of California, Davis, California, USA

* Presenter:Kuo-An Wu, email:kuoan.wu@gmail.com

Cardiac arrhythmias, like ventricular fibrillation and tachycardia, arise from instabilities in heart cell electrical activity. While ionic models capture these dynamics with impressive detail, their intricacy can make it challenging to pinpoint the crucial factors driving instabilities. We propose a four-variable model, focusing on bulk and junctional calcium concentrations, release currents, and the L-type calcium channel’s q gate, to simplify and explore these instabilities. The proposed model replicates the period-doubling bifurcation and both concordant and discordant alternans observed in full models and in experiments. Analyzing its corresponding two-dimensional iterated map reveals that the difference in release current between two cycles is the primary instability driver to alternans. In addition to the understanding of the role of calcium-dependent inactivation q gate in the transition of electromechanically concordant and discordant alternans, the four-variable model further elucidates how changes in calcium release sensitivity and L-type channel gating dynamics affect instability and phase transitions. Furthermore, we find there exists a concordant and discordant phase boundary around the physiologically relevant parameters, indicating a highly unstable phase domain. How the concordant and discordant phase domains change with the sensitivity of calcium release and the relaxation time constant of the f gate of the L-type calcium channel will be discussed.

Keywords: Cardiac arrhythmias, Cardiac Myocyte, Concordant/Discordant Alternans, Calcium Induced Instability