{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T22:09:37Z","timestamp":1791670177432,"version":"4.3.4"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,6,2]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Primary valvular heart disease is a prevalent cause of morbidity and mortality in both industrialized and developing countries. Although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart diseases centers around valve repair or replacement rather than prevention or reversal of myocardial dysfunction. This is particularly evident in primary mitral regurgitation (MR), which invariably results in eccentric hypertrophy and left ventricular (LV) failure in the absence of timely valve repair or replacement. The mechanism of LV dysfunction in primary severe MR is entirely unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Here, we developed the first mouse model of severe MR. Valvular damage was achieved by severing the mitral valve leaflets and chords with iridectomy scissors, and MR was confirmed by echocardiography. Serial echocardiography was performed to follow up LV morphology and systolic function. Analysis of cardiac tissues was subsequently performed to evaluate valve deformation, cardiomyocyte morphology, LV fibrosis, and cell death. Finally, dysregulated pathways were assessed by RNA-sequencing analysis and immunofluorescence.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>In the ensuing 15 weeks after the induction of MR, gradual LV dilatation and dysfunction occurred, resulting in severe systolic dysfunction. Further analysis revealed that severe MR resulted in a marked increase in cardiac mass and increased cardiomyocyte length but not width, with electron microscopic evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe MR resulted in activation of multiple components of both the mammalian target of rapamycin and calcineurin pathways. Inhibition of mammalian target of rapamycin signaling preserved sarcomeric structure and prevented LV remodeling and systolic dysfunction. Immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator Crb2 (crumbs homolog 2) along the longitudinal axis of cardiomyocytes and close to the intercalated disks in the MR hearts. Electron microscopy images demonstrated a significant increase in polysome localization in close proximity to the intercalated disks and some areas along the longitudinal axis in the MR hearts.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>These results indicate that LV dysfunction in response to severe MR is a form of maladaptive eccentric cardiomyocyte hypertrophy and outline the link between cell polarity regulation and spatial localization protein synthesis as a pathway for directional cardiomyocyte growth.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.043939","type":"journal-article","created":{"date-parts":[[2020,4,10]],"date-time":"2020-04-10T09:01:37Z","timestamp":1586509297000},"page":"1787-1799","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation"],"prefix":"10.1161","volume":"141","author":[{"given":"Shujuan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pediatric Cardiology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (S.L.)."},{"name":"NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China (S.L.)."},{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngoc Uyen Nhi","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Menendez-Montes","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Nakada","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilson Lek Wen","family":"Tan","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, National University of Singapore (W.L.W.T., C.G.A.-N., R.S.F.)."},{"name":"Genome Institute of Singapore (W.L.W.T., C.G.A.-N., R.S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chukwuemeka George","family":"Anene-Nzelu","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, National University of Singapore (W.L.W.T., C.G.A.-N., R.S.F.)."},{"name":"Genome Institute of Singapore (W.L.W.T., C.G.A.-N., R.S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger S.","family":"Foo","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, National University of Singapore (W.L.W.T., C.G.A.-N., R.S.F.)."},{"name":"Genome Institute of Singapore (W.L.W.T., C.G.A.-N., R.S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suwannee","family":"Thet","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisson Campos","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas."},{"name":"Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, S\u00e3o Paulo (A.C.C., A.H.M.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waleed M.","family":"Elhelaly","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., J.A.H., H.A.S.), University of Texas Southwestern Medical Center, Dallas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas T.","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (S.L., N.U.N.N., F.X., I.M.-M., Y.N., S.T., A.C.C., P.W., W.M.E., N.T.L., A.H.M.P., 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