{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T18:39:33Z","timestamp":1784745573213,"version":"3.55.0"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Arrhythmogenic cardiomyopathy (ACM) is an inherited disease that is characterized by lethal ventricular arrhythmias stemming from myocyte dysfunction. ACM is associated with considerable subepicardial fibrosis and inflammation with right ventricle predominance. Most cases of gene-positive ACM are caused by a desmosome protein mutation, with plakophilin-2 (\n                      <jats:italic toggle=\"yes\">Pkp2<\/jats:italic>\n                      ) mutations being the most common. We hypothesized that\n                      <jats:italic toggle=\"yes\">Pkp2<\/jats:italic>\n                      -deficiency in epicardium-derived cells (EPDCs) contributes to fibro-inflammatory signaling and ACM pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We developed transgenic mice that lack\n                      <jats:italic toggle=\"yes\">Pkp2<\/jats:italic>\n                      in cardiomyocytes (Pkp2-cKO), in EPDC (Pkp2-eKO), or in both cardiomyocyte and EPDC (Pkp2-ceKO) via the tissue-specific expression of tamoxifen-inducible Cre recombinase. Nonmyocyte populations were isolated 21 days posttamoxifen injection for single-cell RNA-sequencing. Immunohistochemistry, flow cytometry, quantitative reverse transcription polymerase chain reaction, and echocardiography were used to interrogate cardiac physiology and cellular composition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We identified a population of epicardium-derived fibroblasts characterized by the expression of\n                      <jats:italic toggle=\"yes\">Ccl2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Ccl7<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Thbs1<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Ptx3<\/jats:italic>\n                      that accumulated on\n                      <jats:italic toggle=\"yes\">Pkp2<\/jats:italic>\n                      deletion in both cardiomyocytes and EPDC.\n                      <jats:italic toggle=\"yes\">Pkp2<\/jats:italic>\n                      deletion in cardiomyocytes induced a moderate fibro-inflammatory EPDC phenotype, while deletion in EPDC did not elicit a pathological phenotype, suggesting cardiomyocyte involvement is necessary for ACM pathogenesis. Proinflammatory fibroblasts acquired the senescence-associated secretory phenotype, correlating with elevated senescence associated-\u03b2gal staining in the right ventricle. Gene expression, flow cytometry, and histological data also revealed an exaggerated inflammatory response in Pkp2-ceKO mice, which progresses from right to left ventricular predominance. Importantly, macrophages and B cells accumulate in both Pkp2-cKO and Pkp2-ceKO mice compared with controls. Although B cell depletion delays the early inflammatory and fibrosis response, it did not alter end-stage cardiac physiology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Pkp2<\/jats:italic>\n                      deletion in EPDC facilitates the emergence of a fibro-inflammatory phenotype that may contribute to ACM pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.125.013966","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T09:00:19Z","timestamp":1780650019000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Epicardial Contributions to Fibro-Inflammatory Signaling in a Pkp2-Deficient Arrhythmogenic Cardiomyopathy Model"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6742-915X","authenticated-orcid":true,"given":"Daniel D.","family":"Han","sequence":"first","affiliation":[{"name":"Aab Cardiovascular Research Institute, Department of Medicine (D.D.H., A.C.B., R.A.D., D.M.M., E.M.S.), University of Rochester School of Medicine and Dentistry, NY."},{"name":"Department of Pathology and Laboratory Medicine (D.D.H., E.M.S.), University of Rochester School of Medicine and Dentistry, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0927-0835","authenticated-orcid":true,"given":"Alan C.","family":"Brooks","sequence":"additional","affiliation":[{"name":"Aab Cardiovascular Research Institute, Department of Medicine (D.D.H., A.C.B., R.A.D., D.M.M., E.M.S.), University of Rochester School of Medicine and Dentistry, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3792-4317","authenticated-orcid":true,"given":"Cameron D.","family":"Baker","sequence":"additional","affiliation":[{"name":"Genomics Research Center (C.D.B., J.M.A.), University of Rochester School of Medicine and Dentistry, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8450-8719","authenticated-orcid":true,"suffix":"Jr","given":"Ronald A.","family":"Dirkx","sequence":"additional","affiliation":[{"name":"Aab Cardiovascular Research Institute, Department of Medicine (D.D.H., A.C.B., R.A.D., D.M.M., E.M.S.), University of Rochester School of Medicine and Dentistry, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7730-9012","authenticated-orcid":true,"given":"Deanne M.","family":"Mickelsen","sequence":"additional","affiliation":[{"name":"Aab Cardiovascular Research Institute, Department of Medicine (D.D.H., A.C.B., R.A.D., D.M.M., E.M.S.), University of Rochester School of Medicine and Dentistry, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4561-0895","authenticated-orcid":true,"given":"Benjamin","family":"Fisler","sequence":"additional","affiliation":[{"name":"Center for Advanced Light Microscopy and Nanoscopy (B.F.), University of Rochester School of Medicine and Dentistry, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7831-9310","authenticated-orcid":true,"given":"Kavya","family":"Phadke","sequence":"additional","affiliation":[{"name":"The Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine (K.P., M.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9875-5994","authenticated-orcid":true,"given":"John M.","family":"Ashton","sequence":"additional","affiliation":[{"name":"Genomics Research Center (C.D.B., J.M.A.), University of Rochester School of Medicine and Dentistry, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2085-5589","authenticated-orcid":true,"given":"Mario","family":"Delmar","sequence":"additional","affiliation":[{"name":"The Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine (K.P., M.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8593-0343","authenticated-orcid":true,"given":"Eric M.","family":"Small","sequence":"additional","affiliation":[{"name":"Aab Cardiovascular Research Institute, Department of Medicine (D.D.H., A.C.B., R.A.D., D.M.M., E.M.S.), University of Rochester School of Medicine and Dentistry, NY."},{"name":"Department of Pathology and Laboratory Medicine (D.D.H., E.M.S.), University of Rochester School of Medicine and Dentistry, NY."},{"name":"Department of Medicine (E.M.S.), University of Rochester School of Medicine and Dentistry, NY."},{"name":"Department of Pharmacology and Physiology (E.M.S.), University of Rochester School of Medicine and Dentistry, NY."},{"name":"Department of Biomedical Engineering, University of Rochester, NY 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