{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:56:58Z","timestamp":1763578618215,"version":"3.45.0"},"reference-count":67,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Patients with abbreviated cardiac repolarization are at increased risk of cardiac arrhythmias including ventricular and atrial fibrillation (AF). In this computational simulation study, we investigated pro-arrhythmic effects of loss-of-function missense mutations in\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    (A39V and G490R Cav1.2) identified in patients with a phenotype combining Brugada syndrome with shorter-than-normal QT intervals. Biophysically-detailed computational models of human atrial cells were modified to incorporate the functional impact of the\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    encoded A39V and G490R mutations on the reduction of the maximal conductance (g\n                    <jats:sub>CaL<\/jats:sub>\n                    ) of L-type calcium channels (LTCC). Varying levels of g\n                    <jats:sub>CaL<\/jats:sub>\n                    reduction were considered. Effects of deficient LTCC on atrial excitation and propagation were investigated by using cellular and multi-dimensional tissue models that included a one-dimensional atrial strand, a two-dimensional idealized atrial sheet and three-dimensional human atria with realistic anatomical structure and detailed electrophysiology. Our results showed that reduced LTCC activity from the\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    A39V and G490R mutations accelerated atrial repolarization, leading to shortened action potential duration and effective refractory period, as well as the loss of their rate-dependence. At the tissue level, decreased g\n                    <jats:sub>CaL<\/jats:sub>\n                    shortened the wavelength of atrial excitation waves, slowed down atrial conduction velocity (CV) at low pacing rates but increased it at high pacing rates. It also showed bi-phasic arrhythmogenic effects in One-dimensional (1D), Two-dimensional (2D) and Three-dimensional (3D) tissue simulations. A large reduction in I\n                    <jats:sub>CaL<\/jats:sub>\n                    increased tissue susceptibility to initiation and maintenance of atrial re-entrant excitation waves, while a moderate reduction showed anti-arrhythmic effects due to an increased meandering area of re-entrant excitation waves that led to early self-termination of the reentry. In conclusion, this study provides new mechanistic insights into understanding of biphasic effects of loss-of-function LTCC mutations on atrial pro-arrhythmias.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1013616","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:40:47Z","timestamp":1763577647000},"page":"e1013616","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biphasic effects on human atrial arrhythmogenicity of L-type calcium channel mutations associated with a Brugada\/Short QT overlap syndrome - insights from a multiscale simulation study"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6887-5610","authenticated-orcid":true,"given":"Yirong","family":"Xiang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jules 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