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However, the optimal programming settings for ventriculo-ventricular delay (VVD) for LOT-CRT are unknown. We aim to investigate how to optimally program VVD for LOT-CRT in the presence of various LV conduction substrates using computational modelling.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We simulated ventricular activation on 24 anatomies and validated the model against clinical data. Diffuse LV conduction system and intra-myocardial delay were simulated by slowing the conduction velocity of the LV His-Purkinje system and myocardium, respectively, alone or in combination with proximal left bundle branch block (LBBB). We simulated LOT-CRT with selective or myocardial capture (LV septal pacing, LVSP) with VVD ranging between \u2212100\u2005ms (LBBP\/LVSP ahead) and +100\u2005ms [LV epicardial lead (LVepiP), ahead]. Response was quantified with 95% LV activation times (LVAT95). In the presence of diffuse LV conduction system delay, the optimal VVD for LOT-CRT was always negative (LBBB: \u221242.5 \u00b1 6.6\u2005ms; no LBBB: \u221236.2 \u00b1 5.6\u2005ms), as delivering LBBP ahead of LVepiP compensates for the slow LV His-Purkinje. In the presence of LV intra-myocardial disease, the shortest LVAT95 with LOT-CRT was achieved by pacing the coronary sinus LV first (optimal VVD for LBBB: 23.3 \u00b1 8.5\u2005ms; no LBBB: 79.2 \u00b1 18.0\u2005ms). The type of capture for LOT-CRT affected the optimal VVD, with myocardial capture favouring negative VVDs (LVSP ahead).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The optimal VVD for LOT-CRT depends on the mechanism of delayed LV activation and type of capture achieved, highlighting the importance of VVD optimization.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euaf089","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T06:02:13Z","timestamp":1747807333000},"source":"Crossref","is-referenced-by-count":9,"title":["An <i>in silico<\/i> guide for ventriculo-ventricular delay programming for left bundle branch-optimized cardiac resynchronization therapy"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1312-251X","authenticated-orcid":false,"given":"Marina","family":"Strocchi","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London , 72 Du Cane Road, London W12 0NN ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9090-9610","authenticated-orcid":false,"given":"Jack W","family":"Samways","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London , 72 Du Cane Road, London W12 0NN ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1681-2981","authenticated-orcid":false,"given":"Akriti","family":"Naraen","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London , 72 Du Cane Road, London W12 0NN ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3169-4776","authenticated-orcid":false,"given":"Nadine","family":"Ali","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London , 72 Du Cane Road, London W12 0NN ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1179-0867","authenticated-orcid":false,"given":"Matthew J","family":"Shun-Shin","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London , 72 Du Cane Road, London W12 0NN ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0420-5375","authenticated-orcid":false,"given":"Karli","family":"Gillette","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Division of Medical Physics and Biophysics, Medical University of Graz , Graz ,","place":["Austria"]},{"name":"Department of Biomedical Engineering, University of Utah , Salt Lake City, UT ,","place":["USA"]},{"name":"Scientific Computing and Imaging Institute, University of Utah , Salt Lake City, UT ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3930-1957","authenticated-orcid":false,"given":"Christopher Aldo","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering and Imaging Sciences, King\u2019s College London , London ,","place":["UK"]},{"name":"Cardiovascular Department, Guys\u2019 and St Thomas\u2019 NHS Foundation Trust , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7597-0170","authenticated-orcid":false,"given":"Ahran D","family":"Arnold","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London , 72 Du Cane Road, London W12 0NN ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7380-6908","authenticated-orcid":false,"given":"Gernot","family":"Plank","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Division of Medical Physics and Biophysics, Medical University of Graz , Graz ,","place":["Austria"]},{"name":"BioTechMed-Graz , Graz ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1388-3589","authenticated-orcid":false,"given":"Edward J","family":"Vigmond","sequence":"additional","affiliation":[{"name":"IHU Liryc, Electrophysiology and Heart Modeling Institute, Fondation University Bordeaux , Pessac-Bordeaux ,","place":["France"]},{"name":"Institute of Mathematics of Bordeaux, UMR 5251, University of Bordeaux , Bordeaux, Talence 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