{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T18:07:28Z","timestamp":1784657248458,"version":"3.55.0"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Alterations in microtubule dynamics have been shown to affect cardiomyocyte membrane stiffness and modulate ion channels, including the cardiac sodium channel. While conditions, such as heart failure and Duchenne muscular dystrophy, are associated with increased detyrosination of microtubules and reduced sodium current, a potential role for microtubule detyrosination in arrhythmogenic cardiomyopathy has not been explored. We here investigated the impact of microtubule detyrosination on membrane stiffness, cardiac sodium channel distribution, and function in mouse and human models of arrhythmogenic cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Isolated ventricular cardiomyocytes from mice with cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 (plakophilin-2), as well as\n                      <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n                      -c.2013delC, and isogenic control human-induced pluripotent stem cell\u2013derived-cardiomyocytes were incubated for 2 to 4 hours with compounds known to decrease microtubule detyrosination (parthenolide, 10 \u00b5mol\/L; EpoY, 20 \u00b5mol\/L) or vehicle (dimethyl sulfoxide). Immunocytochemistry, mechano-scanning ion conductance microscopy, patch-clamp analysis, and stochastic optical reconstruction microscopy were performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes displayed increased microtubule detyrosination and membrane stiffness, which were both attenuated by parthenolide treatment. Parthenolide significantly increased whole-cell sodium current density in cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes, with macropatch measurements demonstrating that this increase occurred both at the intercalated disc and lateral membrane. Stochastic optical reconstruction microscopy analysis revealed that parthenolide increased cardiac sodium channel cluster density at the intercalated disc of cardiomyocyte-specific, tamoxifen-activated knockout of PKP2 mouse cardiomyocytes. In contrast, parthenolide had no effect on sodium current density, cardiac sodium channel cluster size, or density in cardiomyocytes from control mice.\n                      <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n                      -c.2013delC human-induced pluripotent stem cell\u2013derived-cardiomyocytes displayed increased microtubule detyrosination and reduced sodium current density compared with isogenic control human-induced pluripotent stem cell\u2013derived-cardiomyocytes, which were both prevented by parthenolide and EpoY.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Increased microtubule detyrosination secondary to loss of PKP2 impacts cardiomyocyte (dys)function beyond the desmosome, contributing to both electrical and mechanical alterations in the setting of arrhythmogenic cardiomyopathy. Our findings identify microtubule detyrosination as a novel therapeutic target in pathophysiological conditions, such as arrhythmogenic cardiomyopathy, aimed at improving both contractile and electrical function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circep.125.014354","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T09:00:16Z","timestamp":1782723616000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Decreasing Microtubule Detyrosination Improves Cardiac Mechanics and Sodium Channel Function in Arrhythmogenic Cardiomyopathy"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8485-4446","authenticated-orcid":true,"given":"Giovanna","family":"Nasilli","sequence":"first","affiliation":[{"name":"Department of Experimental Cardiology, Heart Center, Amsterdam University Medical Center, Academic Medical Center (AMC), University of Amsterdam, The Netherlands (G.N., S.C., C.A.R.)."},{"name":"Amsterdam Cardiovascular Sciences, Cardiomyopathy and Arrhythmias, the Netherlands (G.N., S.C., C.A.R.)."},{"name":"Division of Cardiology (G.N., X.L., M.P.-H., M.Z., M.D.), NYU Grossman School of Medicine, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3638-8137","authenticated-orcid":true,"given":"Xianming","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Cardiology (G.N., X.L., M.P.-H., M.Z., M.D.), NYU Grossman School of Medicine, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Swiatlowska","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, United Kingdom (P.S., J.L.S.-A., J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9571-0309","authenticated-orcid":true,"given":"Viviana","family":"Meraviglia","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Embryology, Leiden University Medical Center, the Netherlands (V.M., M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6119-103X","authenticated-orcid":true,"given":"Marta","family":"P\u00e9rez-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Division of Cardiology (G.N., X.L., M.P.-H., M.Z., M.D.), NYU Grossman School of Medicine, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7600-3821","authenticated-orcid":true,"given":"Mingliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cardiology (G.N., X.L., M.P.-H., M.Z., M.D.), NYU Grossman School of Medicine, New York, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2942-0079","authenticated-orcid":true,"given":"Jose L.","family":"Sanchez-Alonso","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College London, United Kingdom (P.S., J.L.S.-A., J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5380-6743","authenticated-orcid":true,"given":"Milena","family":"Bellin","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Embryology, Leiden University Medical Center, the Netherlands (V.M., M.B.)."},{"name":"The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, the Netherlands (M.B.)."},{"name":"Department of Biology, University of Padua, Italy 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