{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:27:53Z","timestamp":1788362873438,"version":"build-2803163510"},"reference-count":75,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,5,5]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Pathogenic variants in\n                      <jats:italic toggle=\"no\">PKP2<\/jats:italic>\n                      are the most common cause of familial arrhythmogenic right ventricular cardiomyopathy. This study tests whether plakophilin\u20102 (PKP2) deficiency only in cardiomyocytes is sufficient to provoke premature aging and proinflammatory senescence in nonmyocyte, cardiac resident cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">We studied mice with cardiomyocyte\u2010specific, tamoxifen\u2010activated loss of PKP2 (cardiomyocyte\u2010specific conditional knockout of plakophilin\u20102) using conventional and multiplex imaging, cytokine arrays, epigenetic clocks, spatial transcriptomics, expansion and structured illumination microscopy, and correlative data analysis. We examined nonmyocytes and cardiomyocytes for premature aging and senescence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">We observed senescence\u2010associated heterochromatin foci in nonmyocytes, predominantly in cells positive for \u03b1\u2010smooth muscle actin staining. Cytokines in media of nonmyocyte cells were consistent with senescence\u2010associated secretory phenotype. Epigenetic clocks identified premature aging. Multiplex immunohistochemistry showed nonmyocyte cells in niches, intermingled with cardiomyocytes. Spatial transcriptomics showed overrepresentation of senescence\u2010associated secretory phenotype\u2013related transcripts, predominantly in myocyte\u2010rich areas of the left ventricle. Senescence\u2010associated heterochromatin foci and increased epigenetic age were not found in cardiomyocytes from cardiomyocyte\u2010specific conditional knockout of plakophilin\u20102 hearts, although we observed structural features associated with premature aging. Cross\u2010reference analysis showed correlation between the cardiomyocyte\u2010specific conditional knockout of plakophilin\u20102 cardiac proteome and that of mice 5 or 6 times their chronological age, as well as transcriptional signatures of neurodegenerative diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Loss of PKP2 expression only in adult cardiac myocytes is sufficient to induce proinflammatory senescence in nonmyocytes, and overall premature cardiac aging. This is the first study to intersect cellular senescence and premature aging with desmosomal arrhythmogenic cardiomyopathies. We speculate that cell\u2010agnostic molecular signatures, biomarkers, and pharmacology of senescence and of neurodegenerative diseases may be relevant to diagnose or treat PKP2 arrhythmogenic right ventricular cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.047447","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T09:55:00Z","timestamp":1777370100000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Cardiomyocyte\u2010Specific Plakophilin\u20102 Loss Is Sufficient to Induce Aging and Senescence of Nonmyocytes: Relevance to Arrhythmogenic Cardiomyopathy"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5352-253X","authenticated-orcid":false,"given":"Giorgia","family":"Bertoli","sequence":"first","affiliation":[{"name":"New York University Grossman School of Medicine","place":["New 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