{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:27:54Z","timestamp":1788362874839,"version":"build-2803163510"},"reference-count":49,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T00:00:00Z","timestamp":1729728000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["836632"],"award-info":[{"award-number":["836632"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF19SA0059305"],"award-info":[{"award-number":["NNF19SA0059305"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF20OC0059767"],"award-info":[{"award-number":["NNF20OC0059767"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Atrial arrhythmias occur in 20\u201340% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and are associated with an increased risk of sustained ventricular arrhythmias and inappropriate implantable cardioverter\u2010defibrillator shocks. The pathophysiology of atrial arrhythmias in ARVC remains unclear. Most cases of gene\u2010positive ARVC are linked to pathogenic variants in the desmosomal gene\n                      <jats:italic>plakophilin\u20102<\/jats:italic>\n                      (PKP2). Here, we test the hypothesis that loss of PKP2 expression leads to pro\u2010arrhythmic changes in atrial cardiomyocytes. Atrial cells\/tissue were obtained from a cardiac\u2010specific, tamoxifen\u2010activated model of PKP2 deficiency (PKP2cKO). By contrast to PKP2cKO ventricular myocytes, PKP2cKO atrial cardiomyocytes presented no significant differences in intracellular calcium (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      <jats:sub>i<\/jats:sub>\n                      ) transient dynamics, sarcoplasmic reticulum load or action potential morphology. PKP2cKO atrial cardiomyocytes showed elevated reactive oxygen species levels, increased frequency and amplitude of Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sparks, and increased diastolic [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      compared to control; the latter two parameters were further increased by isoproterenol exposure and reversed by exposure to ryanodine receptor blocker dantrolene. We speculate that these isoproterenol\u2010dependent effects may impact on the exercise\u2010related atrial arrhythmia risk in ARVC patients. Despite absence of changes in Ca\n                      <jats:sup>2+<\/jats:sup>\n                      <jats:sub>i<\/jats:sub>\n                      transient dynamics, PKP2cKO atrial cardiomyocytes showed enhanced sarcomere shortening and impaired sarcomere relaxation. Orthogonal transcriptomic analysis of human(GTEx) and PKP2cKO atrial tissue led to identification of 41 transcripts depending on PKP2 expression. Biochemical follow\u2010up confirmed reduced abundance of sarcomeric protein myosin binding protein C, potentially playing a role in cellular shortening and relaxation changes observed. Our findings provide novel insights into the role of PKP2 in atrial myocardium with potential implications to therapeutic management of atrial fibrillation in patients with PKP2\u2010related ARVC.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16374-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Atrial arrhythmias occur in a large group of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a cardiac disease mostly caused by pathogenic variants in the desmosomal gene plakophilin\u20102 (PKP2). Exercise is considered to be an independent risk factor for arrhythmias consequent to PKP2 deficiency.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            We\u00a0show that loss of PKP2 expression affects cellular calcium handling and electrophysiology differently in left atrial\n                            <jats:italic>vs<\/jats:italic>\n                            . ventricular myocardium and causes extensive atrial fibrosis.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PKP2\u2010deficient atrial cardiomyocytes present increased spontaneous sarcoplasmic reticulum calcium release events, further\u00a0enhanced\u00a0by isoproterenol exposure and reversible\u00a0by\u00a0a ryanodine receptor blocker\u00a0(dantrolene). In addition, PKP2\u2010deficient atrial myocytes exhibit impaired relaxation and enhanced sarcomere shortening, most probably related to reduced abundance of myosin binding protein C.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We speculate that cellular effects reported upon isoproterenol impact on the exercise\u2010related atrial arrhythmia risk in ARVC patients.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We further propose that therapeutic approaches aimed at mitigating ventricular damage may be effective to treat the atrial disease in ARVC.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp286985","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T11:05:21Z","timestamp":1729767921000},"page":"4951-4972","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Atrial cardiomyopathy resulting from loss of plakophilin\u20102 expression: Response to adrenergic stimulation and implications for the exercise response"],"prefix":"10.1113","volume":"603","author":[{"given":"Kavya","family":"Phadke","sequence":"first","affiliation":[{"name":"The Leon Charney Division of Cardiology New York University Grossmann School of Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1349-5157","authenticated-orcid":false,"given":"Sergio","family":"D'Anna","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefania","family":"Torres Vega","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhua","family":"Xiao","sequence":"additional","affiliation":[{"name":"The Leon Charney Division of Cardiology New York University Grossmann School of Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianming","family":"Lin","sequence":"additional","affiliation":[{"name":"The Leon Charney Division of Cardiology New York University Grossmann School of Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Leon Charney Division of Cardiology New York University Grossmann School of Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Sall","sequence":"additional","affiliation":[{"name":"DART Microscopy Laboratory New York University Grossmann School of Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0037-4590","authenticated-orcid":false,"given":"Feng\u2010Xia","family":"Liang","sequence":"additional","affiliation":[{"name":"DART Microscopy Laboratory New York University Grossmann School of Medicine  New York NY USA"},{"name":"Department of Cell Biology New York University Grossmann School of Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Park","sequence":"additional","affiliation":[{"name":"The Leon Charney Division of Cardiology New York University Grossmann School of Medicine  New York NY 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