{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:08:29Z","timestamp":1791637709601,"version":"4.3.4"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2023,10,3]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Sarcoidosis is an inflammatory, granulomatous disease of unknown cause affecting multiple organs, including the heart. Untreated, unresolved granulomatous inflammation can lead to cardiac fibrosis, arrhythmias, and eventually heart failure. Here we characterize the cardiac phenotype of mice with chronic activation of mammalian target of rapamycin (mTOR) complex 1 signaling in myeloid cells known to cause spontaneous pulmonary sarcoid\u2010like granulomas.<\/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                      The cardiac phenotype of mice with conditional deletion of the\n                      <jats:italic>tuberous sclerosis 2<\/jats:italic>\n                      (\n                      <jats:italic>TSC2<\/jats:italic>\n                      ) gene in CD11c\n                      <jats:sup>+<\/jats:sup>\n                      cells (TSC2\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      CD11c\u2010Cre; termed\n                      <jats:italic>TSC2<\/jats:italic>\n                      <jats:sup>KO<\/jats:sup>\n                      ) and controls (\n                      <jats:italic>TSC2<\/jats:italic>\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      ) was determined by histological and immunological stains. Transthoracic echocardiography and invasive hemodynamic measurements were performed to assess myocardial function.\n                      <jats:italic>TSC2<\/jats:italic>\n                      <jats:sup>KO<\/jats:sup>\n                      animals were treated with either everolimus, an mTOR inhibitor, or Bay11\u20107082, a nuclear factor\u2010kB inhibitor. Activation of mTOR signaling was evaluated on myocardial samples from sudden cardiac death victims with a postmortem diagnosis of cardiac sarcoidosis. Chronic activation of mTORC1 signaling in CD11c\n                      <jats:sup>+<\/jats:sup>\n                      cells was sufficient to initiate progressive accumulation of granulomatous infiltrates in the heart, which was associated with increased fibrosis, impaired cardiac function, decreased plakoglobin expression, and abnormal connexin 43 distribution, a substrate for life\u2010threatening arrhythmias. Mice treated with the mTOR inhibitor everolimus resolved granulomatous infiltrates, prevented fibrosis, and improved cardiac dysfunction. In line, activation of mTOR signaling in CD68\n                      <jats:sup>+<\/jats:sup>\n                      macrophages was detected in the hearts of sudden cardiac death victims who suffered from cardiac sarcoidosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">To our best knowledge this is the first animal model of cardiac sarcoidosis that recapitulates major pathological hallmarks of human disease. mTOR inhibition may be a therapeutic option for patients with cardiac sarcoidosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.123.030478","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T07:59:57Z","timestamp":1695715197000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["An mTORC1\u2010Dependent Mouse Model for Cardiac Sarcoidosis"],"prefix":"10.1161","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4626-1276","authenticated-orcid":false,"given":"Carlos","family":"Bueno\u2010Beti","sequence":"first","affiliation":[{"name":"Clinical Cardiology Academic Group, Molecular and Clinical Research Science Institute St George\u2019s University of London London United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7297-0055","authenticated-orcid":false,"given":"Clarice X.","family":"Lim","sequence":"additional","affiliation":[{"name":"Center for Pathobiochemistry and Genetics Medical University of Vienna Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8595-7212","authenticated-orcid":false,"given":"Alexandros","family":"Protonotarios","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Science, Clinical 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