{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T02:35:00Z","timestamp":1783650900252,"version":"3.55.0"},"reference-count":65,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T00:00:00Z","timestamp":1682380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>After myocardial infarction (MI), a significant portion of heart muscle is replaced with scar tissue, progressively leading to heart failure. Human pluripotent stem cell\u2010derived cardiomyocytes (hPSC\u2010CM) offer a promising option for improving cardiac function after MI. However, hPSC\u2010CM transplantation can lead to engraftment arrhythmia (EA). EA is a transient phenomenon arising shortly after transplantation then spontaneously resolving after a few weeks. The underlying mechanism of EA is unknown. We hypothesize that EA may be explained partially by time\u2010varying, spatially heterogeneous, graft\u2013host electrical coupling. Here, we created computational slice models derived from histological images that reflect different configuration of grafts in the infarcted ventricle. We ran simulations with varying degrees of connection imposed upon the graft\u2013host perimeter to assess how heterogeneous electrical coupling affected EA with non\u2010conductive scar, slow\u2010conducting scar and scar replaced by host myocardium. We also quantified the effect of variation in intrinsic graft conductivity. Susceptibility to EA initially increased and subsequently decreased with increasing graft\u2013host coupling, suggesting the waxing and waning of EA is regulated by progressive increases in graft\u2013host coupling. Different spatial distributions of graft, host and scar yielded markedly different susceptibility curves. Computationally replacing non\u2010conductive scar with host myocardium or slow\u2010conducting scar, and increasing intrinsic graft conductivity both demonstrated potential means to blunt EA vulnerability. These data show how graft location, especially relative to scar, along with its dynamic electrical coupling to host, can influence EA burden; moreover, they offer a rational base for further studies aimed to define the optimal delivery of hPSC\u2010CM injection.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15534-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Human pluripotent stem cell\u2010derived cardiomyocytes (hPSC\u2010CM) hold great cardiac regenerative potential but can also cause engraftment arrhythmias (EA).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Spatiotemporal evolution in the pattern of electrical coupling between injected hPSC\u2010CMs and surrounding host myocardium may explain the dynamics of EA observed in large animal models.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We conducted simulations in histology\u2010derived 2D slice computational models to assess the effects of heterogeneous graft\u2013host electrical coupling on EA propensity, with or without scar tissue.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our findings suggest spatiotemporally heterogeneous graft\u2013host coupling can create an electrophysiological milieu that favours graft\u2010initiated host excitation, a surrogate metric of EA susceptibility. Removing scar from our models reduced but did not abolish the propensity for this phenomenon. Conversely, reduced intra\u2010graft electrical connectedness increased the incidence of graft\u2010initiated host excitation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The computational framework created for this study can be used to generate new hypotheses, targeted delivery of hPSC\u2010CMs.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp284244","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T12:26:27Z","timestamp":1680611187000},"page":"2733-2749","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Graft\u2013host coupling changes can lead to engraftment arrhythmia: a computational study"],"prefix":"10.1113","volume":"601","author":[{"given":"Chelsea E.","family":"Gibbs","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Marchian\u00f3","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine University of Washington  Seattle WA USA"},{"name":"Department of Laboratory Medicine &amp; Pathology University of Washington  Seattle WA USA"},{"name":"Center for Cardiovascular Biology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiulan","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine University of Washington  Seattle WA USA"},{"name":"Department of Laboratory Medicine &amp; Pathology University of Washington  Seattle WA USA"},{"name":"Center for Cardiovascular Biology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles E.","family":"Murry","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Washington  Seattle WA USA"},{"name":"Institute for Stem Cell and Regenerative Medicine University of Washington  Seattle WA USA"},{"name":"Department of Laboratory Medicine &amp; Pathology University of Washington  Seattle WA USA"},{"name":"Center for Cardiovascular Biology University of Washington  Seattle WA USA"},{"name":"Division of Cardiology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9048-1239","authenticated-orcid":false,"given":"Patrick M.","family":"Boyle","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Washington  Seattle WA USA"},{"name":"Institute for Stem Cell and Regenerative Medicine University of Washington  Seattle WA USA"},{"name":"Center for Cardiovascular Biology University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,25]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11437"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2017.09.015"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1109\/TBME.2020.2976924"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164680"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-018-0079-8"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.64213"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2019.01.010"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-019-0437-9"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.07.054"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13233"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.16977"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.4137\/CMC.S39708"},{"issue":"4","key":"e_1_2_5_14_1","first-page":"765","article-title":"Mind the Gap: A semicontinuum model for discrete electrical propagation in cardiac tissue","volume":"63","author":"Costa C. 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