{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:31:21Z","timestamp":1792042281966,"version":"4.4.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,8,3]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Sarcomere gene mutations lead to cardiomyocyte hypertrophy and pathological myocardial remodeling. However, there is considerable phenotypic heterogeneity at both the cellular and the organ level, suggesting modifiers regulate the effects of these mutations. We hypothesized that sarcomere dysfunction leads to cardiomyocyte genotoxic stress, and this modifies pathological ventricular remodeling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Using a murine model deficient in the sarcomere protein, Mybpc3\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              (cardiac myosin\u2010binding protein 3), we discovered that there was a surge in cardiomyocyte nuclear DNA damage during the earliest stages of cardiomyopathy. This was accompanied by a selective increase in ataxia telangiectasia and rad3\u2010related phosphorylation and increased p53 protein accumulation. The cause of the DNA damage and DNA damage pathway activation was dysregulated cardiomyocyte DNA synthesis, leading to replication stress. We discovered that selective inhibition of ataxia telangiectasia and rad3 related or cardiomyocyte deletion of p53 reduced pathological left ventricular remodeling and cardiomyocyte hypertrophy in Mybpc3\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              animals. Mice and humans harboring other types of sarcomere gene mutations also had evidence of activation of the replication stress response, and this was associated with cardiomyocyte aneuploidy in all models studied.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Collectively, our results show that sarcomere mutations lead to activation of the cardiomyocyte replication stress response, which modifies pathological myocardial remodeling in sarcomeric cardiomyopathy.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.121.021768","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T09:05:44Z","timestamp":1627549544000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Replication Stress Response Modifies Sarcomeric Cardiomyopathy Remodeling"],"prefix":"10.1161","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3873-0450","authenticated-orcid":false,"given":"Soumojit","family":"Pal","sequence":"first","affiliation":[{"name":"Division of Cardiology Department of Medicine Heart, Lung Blood and Vascular Medicine InstituteSchool of MedicineUniversity of PittsburghUniversity of Pittsburgh Medical Center PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin R.","family":"Nixon","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Medicine Heart, Lung Blood and Vascular Medicine InstituteSchool of MedicineUniversity of PittsburghUniversity of Pittsburgh Medical Center PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Glennon","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Medicine Heart, Lung Blood and Vascular Medicine InstituteSchool of MedicineUniversity of PittsburghUniversity of Pittsburgh Medical Center PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puneeth","family":"Shridhar","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Medicine Heart, Lung Blood and Vascular Medicine InstituteSchool of MedicineUniversity of PittsburghUniversity of Pittsburgh Medical Center PA"},{"name":"Department of Bioengineering Swanson School of Engineering University of Pittsburgh PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidney L.","family":"Satterfield","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Medicine Heart, Lung Blood and Vascular Medicine InstituteSchool of MedicineUniversity of PittsburghUniversity of Pittsburgh Medical Center PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan Ru","family":"Su","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Medicine Vanderbilt University Medical Center Nashville TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2107-8179","authenticated-orcid":false,"given":"Jason R.","family":"Becker","sequence":"additional","affiliation":[{"name":"Division of Cardiology Department of Medicine Heart, Lung Blood and Vascular Medicine InstituteSchool of MedicineUniversity of PittsburghUniversity of Pittsburgh Medical Center 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