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There are two major hypotheses for EAD genesis based on experimental observations, i.e., the voltage (\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    )-driven and intracellular calcium (Ca)-driven mechanisms. In ventricular myocytes, Ca and\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    are bidirectionally coupled, which can affect each other\u2019s dynamics and result in new dynamics, however, the roles of Ca cycling and its coupling with\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    in the genesis of EADs have not been well understood. In this study, we use an action potential model that is capable of independent\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    and Ca oscillations to investigate the roles of\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    and Ca coupling in EAD genesis. Four different mechanisms of EADs are identified, which are either driven by\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    oscillations or Ca oscillations alone, or oscillations caused by their interactions. We also use 5 other ventricular action potential models to assess these EAD mechanisms and show that EADs in these models are mainly\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    -driven. These mechanistic insights from our simulations provide a theoretical base for understanding experimentally observed EADs and EAD-related arrhythmogenesis.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1011930","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T13:37:35Z","timestamp":1709127455000},"page":"e1011930","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dissecting the roles of calcium cycling and its coupling with voltage in the genesis of early afterdepolarizations in cardiac myocyte models"],"prefix":"10.1371","volume":"20","author":[{"given":"Rui","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5217-6022","authenticated-orcid":true,"given":"Zhilin","family":"Qu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1524-5919","authenticated-orcid":true,"given":"Xiaodong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"issue":"4","key":"pcbi.1011930.ref001","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1161\/01.RES.41.4.415","article-title":"Action potentials, afterdepolarizations, and arrhythmias","volume":"41","author":"PF Cranefield","year":"1977","journal-title":"Circ Res"},{"key":"pcbi.1011930.ref002","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/cvr\/cvt104","article-title":"Early afterdepolarizations in cardiac myocytes: beyond reduced repolarization reserve","volume":"99","author":"Z Qu","year":"2013","journal-title":"Cardiovasc Res"},{"key":"pcbi.1011930.ref003","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/j.1749-6632.1984.tb20776.x","article-title":"The clinical relevance of afterdepolarizations","volume":"427","author":"MR Rosen","year":"1984","journal-title":"Ann N Y Acad Sci"},{"issue":"6","key":"pcbi.1011930.ref004","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1111\/j.1540-8159.1988.tb06016.x","article-title":"Torsade de pointes and other pause-induced ventricular tachycardias: The short-long-short sequence and early afterdepolarizations","volume":"11","author":"PF Cranefiled","year":"1988","journal-title":"Pacing Clin Electrophysiol"},{"issue":"5","key":"pcbi.1011930.ref005","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1111\/j.1540-8159.1998.tb00148.x","article-title":"Taking the \u201cIdio\u201d out of \u201cIdiosyncratic\u201d: Predicting Torsadesde Pointes","volume":"21","author":"DM Roden","year":"1998","journal-title":"Pacing Clin Electrophysiol"},{"issue":"12","key":"pcbi.1011930.ref006","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1016\/j.hrthm.2010.09.017","article-title":"Early afterdepolarizations and cardiac arrhythmias","volume":"7","author":"JN Weiss","year":"2010","journal-title":"Heart Rhythm"},{"issue":"1","key":"pcbi.1011930.ref007","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev-physiol-021014-071622","article-title":"Mechanisms of ventricular arrhythmias: From molecular fluctuation to electrical turbulence","volume":"77","author":"Z Qu","year":"2015","journal-title":"Ann Rev Physiol"},{"issue":"3","key":"pcbi.1011930.ref008","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1161\/01.RES.62.3.563","article-title":"A model for early afterdepolarizations: induction with the Ca2+ channel agonist Bay K 8644","volume":"62","author":"CT January","year":"1988","journal-title":"Circ Res"},{"issue":"5","key":"pcbi.1011930.ref009","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1161\/01.RES.64.5.977","article-title":"Early afterdepolarizations: mechanism of induction and block. 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