{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T01:48:21Z","timestamp":1790214501563,"version":"4.1.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Mutations in\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              encoding nuclear envelope proteins lamin A\/C cause dilated cardiomyopathy. Activation of the AKT\/mTOR (RAC-\u03b1 serine\/threonine-protein kinase\/mammalian target of rapamycin) pathway is implicated as a potential pathophysiologic mechanism. The aim of this study was to assess whether pharmacological inhibition of mTOR signaling has beneficial effects on heart function and prolongs survival in a mouse model of the disease, after onset of heart failure.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We treated male\n              <jats:italic toggle=\"yes\">Lmna<\/jats:italic>\n              <jats:sup>H222P\/H222P<\/jats:sup>\n              mice, after the onset of heart failure, with placebo or either of 2 orally bioavailable mTOR inhibitors: everolimus or NV-20494, a rapamycin analog highly selective against mTORC1. We examined left ventricular remodeling, and the cell biological, biochemical, and histopathologic features of cardiomyopathy, potential drug toxicity, and survival.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Everolimus treatment (n=17) significantly reduced left ventricular dilatation and increased contractility on echocardiography, with a 7% (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.018) reduction in left ventricular end-diastolic diameter and a 39% (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.0159) increase fractional shortening compared with placebo (n=17) after 6 weeks of treatment. NV-20494 treatment (n=15) yielded similar but more modest and nonsignificant changes. Neither drug prevented the development of cardiac fibrosis. Drug treatment reactivated suppressed autophagy and inhibited mTORC1 signaling in the heart, although everolimus was more potent. With regards to drug toxicity, everolimus alone led to a modest degree of glucose intolerance during glucose challenge. Everolimus (n=20) and NV-20494 (n=20) significantly prolonged median survival in\n              <jats:italic toggle=\"yes\">Lmna<\/jats:italic>\n              <jats:sup>H222P\/H222P<\/jats:sup>\n              mice, by 9% (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.0348) and 11% (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.0206), respectively, compared with placebo (n=20).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              These results suggest that mTOR inhibitors may be beneficial in patients with cardiomyopathy caused by\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              mutations and that further study is warranted.\n            <\/jats:p>\n          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