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Arrhythmogenic cardiomyopathy is associated with fibrotic remodeling, and it accounts for most cases of stress-related arrhythmic sudden death. Here we develop a correlative imaging approach to integrate macroscale cardiac electrophysiology with three-dimensional microscale reconstructions of the ventricles. We apply this tool to a desmoglein-2 mutant mouse model to characterize the dynamics of conduction wavefronts and relate them to the underlying structural substrate. We observed that conduction through fibrotic tissue areas shows a frequency-dependent behavior, where conduction fails at high stimulation frequencies; this promotes reentrant arrhythmias, even in regions that were electrophysiologically inconspicuous at lower stimulation rates. We found that fibrotic areas undergo electrophysiological remodeling that acts as a low-pass filter for conduction, quantitatively explained by computational models informed by structural data. Collectively, our study provides a structure\u2013function mapping pipeline and describes a pro-arrhythmogenic mechanism in arrhythmogenic cardiomyopathy.<\/jats:p>","DOI":"10.1038\/s44161-025-00728-9","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T09:04:02Z","timestamp":1759741442000},"page":"1466-1486","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Correlative imaging integrates electrophysiology with three-dimensional murine heart reconstruction to reveal electrical coupling between cell types"],"prefix":"10.1038","volume":"4","author":[{"given":"Francesco","family":"Giardini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8391-571X","authenticated-orcid":false,"given":"Camilla","family":"Olianti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7353-0235","authenticated-orcid":false,"given":"Gerard A.","family":"Marchal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Romanelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Steyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3637-2546","authenticated-orcid":false,"given":"Josef","family":"Madl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1239-8031","authenticated-orcid":false,"given":"Roberto","family":"Piersanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Arecchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Induja","family":"Perumal Vanaja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Biasci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva A.","family":"Rog-Zielinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Nesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie M.","family":"Loew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Cerbai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1675-5945","authenticated-orcid":false,"given":"Stephen P.","family":"Chelko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Regazzoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2487-4744","authenticated-orcid":false,"given":"Axel","family":"Loewe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6237-1902","authenticated-orcid":false,"given":"Martin J.","family":"Bishop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Mongillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0416-6270","authenticated-orcid":false,"given":"Peter","family":"Kohl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3702-3818","authenticated-orcid":false,"given":"Tania","family":"Zaglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6773-9884","authenticated-orcid":false,"given":"Callum M.","family":"Zgierski-Johnston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9320-5085","authenticated-orcid":false,"given":"Leonardo","family":"Sacconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"728_CR1","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.yjmcc.2013.10.018","volume":"70","author":"TP Nguyen","year":"2014","unstructured":"Nguyen, T. 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