{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:47:29Z","timestamp":1792507649702,"version":"4.5.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,10,29]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Inflammation is a prominent feature of arrhythmogenic cardiomyopathy (ACM), but whether it contributes to the disease phenotype is not known.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>To define the role of inflammation in the pathogenesis of ACM, we characterized nuclear factor-\u03baB signaling in ACM models in vitro and in vivo and in cardiac myocytes from patient induced pluripotent stem cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Activation of nuclear factor-\u03baB signaling, indicated by increased expression and nuclear accumulation of phospho-RelA\/p65, occurred in both an in vitro model of ACM (expression of\n                      <jats:italic>\n                        JUP\n                        <jats:sup>2157del2<\/jats:sup>\n                      <\/jats:italic>\n                      in neonatal rat ventricular myocytes) and a robust murine model of ACM (homozygous knock-in of mutant desmoglein-2 [\n                      <jats:italic>Dsg2<\/jats:italic>\n                      <jats:sup>\n                        mut\/mu\n                        <jats:italic>t<\/jats:italic>\n                      <\/jats:sup>\n                      ]) that recapitulates the cardiac manifestations seen in patients with ACM. Bay 11-7082, a small-molecule inhibitor of nuclear factor-\u03baB signaling, prevented the development of ACM disease features in vitro (abnormal redistribution of intercalated disk proteins, myocyte apoptosis, release of inflammatory cytokines) and in vivo (myocardial necrosis and fibrosis, left ventricular contractile dysfunction, electrocardiographic abnormalities). Hearts of\n                      <jats:italic>Dsg2<\/jats:italic>\n                      <jats:sup>mut\/mut<\/jats:sup>\n                      mice expressed markedly increased levels of inflammatory cytokines and chemotactic molecules that were attenuated by Bay 11-7082. Salutary effects of Bay 11-7082 correlated with the extent to which production of selected cytokines had been blocked. Nuclear factor-\u03baB signaling was also activated in cardiac myocytes derived from a patient with ACM. These cells produced and secreted abundant inflammatory cytokines under basal conditions, and this was also greatly reduced by Bay 11-7082.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Inflammatory signaling is activated in ACM and drives key features of the disease. Targeting inflammatory pathways may be an effective new mechanism-based therapy for ACM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.119.040676","type":"journal-article","created":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T05:00:21Z","timestamp":1568869221000},"page":"1491-1505","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":192,"title":["Therapeutic Modulation of the Immune Response in Arrhythmogenic Cardiomyopathy"],"prefix":"10.1161","volume":"140","author":[{"given":"Stephen P.","family":"Chelko","sequence":"first","affiliation":[{"name":"Departments of Medicine (S.P.C., D.B., N.A.-A., P.A.), Johns Hopkins School of Medicine, Baltimore, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki","family":"Asimaki","sequence":"additional","affiliation":[{"name":"St. George\u2019s University of London, UK (A.A., C.B.-B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Lowenthal","sequence":"additional","affiliation":[{"name":"Biomedical Engineering (J.L., L.T.), Johns Hopkins School of Medicine, Baltimore, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Bueno-Beti","sequence":"additional","affiliation":[{"name":"St. George\u2019s University of London, UK (A.A., C.B.-B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djahida","family":"Bedja","sequence":"additional","affiliation":[{"name":"Departments of Medicine (S.P.C., D.B., N.A.-A., P.A.), Johns Hopkins School of Medicine, Baltimore, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Scalco","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Italy (A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Amat-Alarcon","sequence":"additional","affiliation":[{"name":"Departments of Medicine (S.P.C., D.B., N.A.-A., P.A.), Johns Hopkins School of Medicine, Baltimore, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Andersen","sequence":"additional","affiliation":[{"name":"Departments of Medicine (S.P.C., D.B., N.A.-A., P.A.), Johns Hopkins School of Medicine, Baltimore, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Judge","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical University of South Carolina, Charleston (D.P.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Tung","sequence":"additional","affiliation":[{"name":"Biomedical Engineering (J.L., L.T.), Johns Hopkins School of Medicine, Baltimore, 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