Speaker
Description
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are widely used to investigate inherited and acquired cardiac disorders in a patient-specific context. However, their immature electrophysiological phenotype requires quantitatively calibrated dynamical models capable of mechanistically describing nonlinear calcium–voltage coupling across multiple temporal scales.
We develop a ventricular hiPSC-CM ionic model formulated as a stiff system of 28 coupled nonlinear first-order ordinary differential equations. Building upon the Paci2020 framework, we replace the original Hodgkin–Huxley description of the L-type calcium current (ICaL) with a finite-state Markovian scheme. This formulation separates voltage-dependent and calcium-dependent inactivation into two interconnected four-state loops, with channel transitions governed by voltage- and calcium-dependent rates that ensure probability conservation.
Mathematically, the resulting system defines a high-dimensional nonlinear dynamical flow characterized by tight coupling among membrane voltage, gating variables, and intracellular calcium compartments. Such ionic models display marked sensitivity to parameter variations and initial conditions: small perturbations in conductances or transition rates may produce substantial changes in action potential morphology, repolarization dynamics, or oscillatory behavior, reflecting the complex stability structure of the nonlinear system.
Parameter identification is performed through automatic optimization in two stages. First, the Markovian ICaL submodel is calibrated by minimizing a weighted least-squares objective via the Nelder–Mead simplex algorithm. Second, global optimization is carried out against experimental biomarkers of spontaneous action potentials and calcium transients obtained from in vitro patch-clamp recordings.
Pharmacological and genetic perturbations are modeled as structured modifications of transition rates within the Markov framework, enabling consistent interpretation within the same nonlinear system. The resulting model provides a robust and quantitatively identified platform for studying calcium-mediated arrhythmogenesis and supports scalable multiscale cardiac electrophysiology investigations.
References
[1] Francesca Simone, et al. A novel computational model of human iPSC-derived ventricular myocytes with improved [l]-type calcium current for application to Timothy syndrome. Scientific Reports, February 2026.