A novel computational model of swine ventricular myocyte reveals new insights into disease mechanisms and therapeutic approaches in Timothy Syndrome.

Timothy syndrome type 1 (TS1), a malignant variant of Long QT Syndrome, is caused by L-type Ca2+ Channel (LTCC) inactivation defects secondary to the p.Gly406Arg mutation in the CACNA1C gene. Leveraging on the experimental in vitro data from our TS1 knock-in swine model and their wild-type (WT) littermates, we first developed a mathematical model of WT large white swine ventricular cardiomyocyte electrophysiology that reproduces a wide range of experimental data, including ionic current properties, action potential (AP) dynamics, and handling. A sensitivity analysis tested robustness and facilitated comparison with the parent ORd human model. Introducing 22% of TS1-mutated LTCCs, the model faithfully reproduced key disease features, including marked AP prolongation, steeper rate-dependent adaptation of AP duration, overload, and CaMKII-mediated decreased upstroke velocity. Translational relevance of the TS1 model was investigated by: dissecting the roles of primary and secondary contributors to TS1 phenotype; demonstrating the arrhythmogenic potential of TS1 vs. WT cells; and evaluating the model's capability to identify novel pharmacological targets which could modulate the cellular phenotype. In conclusion, we developed a mathematical large white swine ventricular myocyte model, demonstrating its utility in exploring arrhythmogenic mechanisms and therapeutic interventions in cardiac diseases, such as TS1.