{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:02:51Z","timestamp":1792645371228,"version":"4.5.0"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:00:00Z","timestamp":1682899200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>After myocardial infarction, the infarct border zone (BZ) is the dominant source of life-threatening arrhythmias, where fibrosis and abnormal repolarization create a substrate for reentry. We examined whether repolarization abnormalities are heterogeneous within the BZ in vivo and could be related to heterogeneous cardiomyocyte remodeling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Myocardial infarction was induced in domestic pigs by 120-minute ischemia followed by reperfusion. After 1 month, remodeling was assessed by magnetic resonance imaging, and electroanatomical mapping was performed to determine the spatial distribution of activation-recovery intervals. Cardiomyocytes were isolated and tissue samples collected from the BZ and remote regions. Optical recording allowed assessment of action potential duration (di-8-ANEPPS, stimulation at 1 Hz, 37\u2009\u00b0C) of large cardiomyocyte populations while gene expression in cardiomyocytes was determined by single nuclear RNA sequencing.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              In vivo, activation-recovery intervals in the BZ tended to be longer than in remote with increased spatial heterogeneity evidenced by a greater local SD (3.5\u00b11.3 ms versus remote: 2.0\u00b10.5 ms,\n              <jats:italic>P<\/jats:italic>\n              =0.036, n\n              <jats:sub>pigs<\/jats:sub>\n              =5). Increased activation-recovery interval heterogeneity correlated with enhanced arrhythmia susceptibility. Cellular population studies (n\n              <jats:sub>cells<\/jats:sub>\n              =635\u2013862 cells per region) demonstrated greater heterogeneity of action potential duration in the BZ (SD, 105.9\u00b117.0 ms versus remote: 73.9\u00b18.6 ms;\n              <jats:italic>P<\/jats:italic>\n              =0.001; n\n              <jats:sub>pigs<\/jats:sub>\n              =6), which correlated with heterogeneity of activation-recovery interval in vivo. Cell-cell gene expression heterogeneity in the BZ was evidenced by increased Euclidean distances between nuclei of the BZ (12.1 [9.2\u201315.0] versus 10.6 [7.5\u201311.6] in remote;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0001). Differentially expressed genes characterizing BZ cardiomyocyte remodeling included hypertrophy-related and ion channel\u2013related genes with high cell-cell variability of expression. These gene expression changes were driven by stress-responsive TFs (transcription factors). In addition, heterogeneity of left ventricular wall thickness was greater in the BZ than in remote.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Heterogeneous cardiomyocyte remodeling in the BZ is driven by uniquely altered gene expression, related to heterogeneity in the local microenvironment, and translates to heterogeneous repolarization and arrhythmia vulnerability in vivo.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.122.011677","type":"journal-article","created":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T09:00:38Z","timestamp":1683018038000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Heterogeneity of Repolarization and Cell-Cell Variability of Cardiomyocyte Remodeling Within the Myocardial Infarction Border Zone Contribute to Arrhythmia Susceptibility"],"prefix":"10.1161","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3691-3058","authenticated-orcid":true,"given":"Matthew","family":"Amoni","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Sciences, Experimental Cardiology (M.A., S.E.-T., R.D.P., G.G., M.Y., R.W., H.L.R., K.R.S.), KU Leuven, Belgium."},{"name":"Division of Cardiology, University Hospitals, Leuven, Belgium (M.A., R.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8769-783X","authenticated-orcid":true,"given":"Dylan","family":"Vermoortele","sequence":"additional","affiliation":[{"name":"Imaging and Cardiovascular Dynamics, Department of Cardiovascular Sciences (D.V., P.C.), KU Leuven, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samaneh","family":"Ekhteraei-Tousi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Experimental Cardiology (M.A., S.E.-T., R.D.P., G.G., M.Y., R.W., H.L.R., K.R.S.), KU Leuven, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9230-6765","authenticated-orcid":true,"given":"Rosa","family":"Do\u00f1ate Puertas","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Experimental Cardiology (M.A., S.E.-T., R.D.P., G.G., M.Y., R.W., H.L.R., K.R.S.), KU Leuven, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Gilbert","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Experimental Cardiology (M.A., S.E.-T., R.D.P., G.G., M.Y., R.W., H.L.R., K.R.S.), KU Leuven, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Youness","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Experimental Cardiology (M.A., S.E.-T., R.D.P., G.G., M.Y., R.W., H.L.R., K.R.S.), KU Leuven, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8772-6845","authenticated-orcid":true,"given":"Bernard","family":"Thienpont","sequence":"additional","affiliation":[{"name":"Laboratory for Functional Epigenetics, Department of Human Genetics (B.T.), KU Leuven, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5469-9609","authenticated-orcid":true,"given":"Rik","family":"Willems","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Experimental Cardiology (M.A., S.E.-T., R.D.P., G.G., M.Y., R.W., H.L.R., K.R.S.), KU Leuven, Belgium."},{"name":"Division of Cardiology, University Hospitals, Leuven, Belgium (M.A., R.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-3523","authenticated-orcid":true,"given":"H. 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