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Leveraging on the experimental <jats:italic>in vitro<\/jats:italic> 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 <jats:inline-formula><jats:alternatives><jats:tex-math>$$\\hbox {Ca}^{2+}$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:msup>\n                    <mml:mtext>Ca<\/mml:mtext>\n                    <mml:mrow>\n                      <mml:mn>2<\/mml:mn>\n                      <mml:mo>+<\/mml:mo>\n                    <\/mml:mrow>\n                  <\/mml:msup>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula> 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, <jats:inline-formula><jats:alternatives><jats:tex-math>$$\\hbox {Ca}^{2+}$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:msup>\n                    <mml:mtext>Ca<\/mml:mtext>\n                    <mml:mrow>\n                      <mml:mn>2<\/mml:mn>\n                      <mml:mo>+<\/mml:mo>\n                    <\/mml:mrow>\n                  <\/mml:msup>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula> 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\u2019s 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.<\/jats:p>","DOI":"10.1038\/s41598-024-80726-2","type":"journal-article","created":{"date-parts":[[2024,11,30]],"date-time":"2024-11-30T06:58:11Z","timestamp":1732949891000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel computational model of swine ventricular myocyte reveals new insights into disease mechanisms and therapeutic approaches in Timothy Syndrome"],"prefix":"10.1038","volume":"14","author":[{"given":"Alessandro","family":"Trancuccio","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Tarifa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossana","family":"Bongianino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia G.","family":"Priori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Demetrio J.","family":"Santiago","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,30]]},"reference":[{"key":"80726_CR1","doi-asserted-by":"crossref","unstructured":"Splawski, I. et al. 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