{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T05:02:52Z","timestamp":1794114172493,"version":"4.8.0"},"reference-count":67,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Dilated cardiomyopathy caused by\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      mutations is a severe cardiac condition marked by arrhythmias, contractile dysfunction, and excessive myocardial fibrosis, which collectively impair left ventricular function and increase the risk of heart failure. Although the disease has been well characterized, a lack of insight into the pathogenesis has impeded the development of therapies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Here, we employed human induced pluripotent stem cells (hiPSCs) derived from a patient carrying a\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      point mutation (c.665A&gt;C, p.His222Pro), alongside a murine model carrying the same mutation, to investigate the functional and molecular abnormalities driving dilated cardiomyopathy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We demonstrated that\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      patient-derived cardiomyocytes and engineered heart tissues exhibited elevated diastolic calcium levels and reduced sensitivity to external calcium, respectively, as well as hypocontractility. These cells also displayed nuclear shape abnormalities in 2-dimensional and 3-dimensional, a hallmark of\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      -associated dilated cardiomyopathy, associated with disrupted chromosome spatial organization and altered gene expression profiles. Transcriptomic analysis revealed dysregulation of extracellular matrix remodeling and significant upregulation of Loxl2 in mutated hiPSC\u2013cardiomyocytes, hiPSC\u2013engineered heart tissues, and mice. Treatment with Simtuzumab, a Loxl2 inhibitor, effectively prevented cardiac dysfunction and fibrosis in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Taken together, our findings underscore the crucial role of Loxl2 as a therapeutic target and suggest that its inhibition could be a promising strategy to preserve cardiac function in\n                      <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n                      -associated dilated cardiomyopathy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.125.013806","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T17:00:43Z","timestamp":1773766843000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in\n                    <i>LMNA<\/i>\n                    Mutation-Induced Dilated Cardiomyopathy"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1543-9044","authenticated-orcid":true,"given":"Marie","family":"Kervella","sequence":"first","affiliation":[{"name":"Institute of Myology, Center of Research in Myology, Sorbonne University, Inserm, Paris, France (M.K., C.P., Z.G., F.G., A.F., A.M.)."},{"name":"PhyMedExp, University of Montpellier, Inserm, CNRS, France (M.K., A.C., R.A., A.C.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6698-0572","authenticated-orcid":true,"given":"Charlotta S.","family":"Behrens","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Germany (C.S.B., S.R.S., T.E.)."},{"name":"German 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