{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:48:36Z","timestamp":1790927316036,"version":"4.1.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,7,7]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in \u03b2-cardiac myosin heavy chain (\u03b2-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle\/environmental differences between subjects even from the same family.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>To characterize disease caused by \u03b2-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>Unlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC\/+) or Arg719Trp (RW\/+), VM\/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM\/VM mice were indistinguishable from wild-type animals, whereas RC\/RC- and RW\/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM\/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM\/RC hearts was severely impaired already before the onset of cardiac remodeling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>The VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.115.303178","type":"journal-article","created":{"date-parts":[[2014,5,15]],"date-time":"2014-05-15T09:12:45Z","timestamp":1400145165000},"page":"227-237","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["\u03b2-Myosin Heavy Chain Variant Val606Met Causes Very Mild Hypertrophic Cardiomyopathy in Mice, but Exacerbates HCM Phenotypes in Mice Carrying Other HCM Mutations"],"prefix":"10.1161","volume":"115","author":[{"given":"Robert","family":"Blankenburg","sequence":"first","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, W\u00fcrzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital D\u00fcsseldorf and Cardiovascular Research Institute D\u00fcsseldorf (CARID), Heinrich-Heine-University, D\u00fcsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, MA (C.E.S.); Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.); and Bio-Medical Research Center..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Hackert","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, W\u00fcrzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital D\u00fcsseldorf and Cardiovascular Research Institute D\u00fcsseldorf (CARID), Heinrich-Heine-University, D\u00fcsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, MA (C.E.S.); Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.); and Bio-Medical Research Center..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Wurster","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, W\u00fcrzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital D\u00fcsseldorf and Cardiovascular Research Institute D\u00fcsseldorf (CARID), Heinrich-Heine-University, D\u00fcsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, MA (C.E.S.); Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.); and Bio-Medical Research Center..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Deenen","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, W\u00fcrzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital D\u00fcsseldorf and Cardiovascular Research Institute D\u00fcsseldorf (CARID), Heinrich-Heine-University, D\u00fcsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, MA (C.E.S.); Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.); and Bio-Medical Research Center..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.G.","family":"Seidman","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, W\u00fcrzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital D\u00fcsseldorf and Cardiovascular Research Institute D\u00fcsseldorf (CARID), Heinrich-Heine-University, D\u00fcsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, MA (C.E.S.); Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.); and Bio-Medical Research Center..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine E.","family":"Seidman","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, W\u00fcrzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital D\u00fcsseldorf and Cardiovascular Research Institute D\u00fcsseldorf (CARID), Heinrich-Heine-University, D\u00fcsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, MA (C.E.S.); Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.); and Bio-Medical Research Center..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Lohse","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, W\u00fcrzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital D\u00fcsseldorf and Cardiovascular Research Institute D\u00fcsseldorf (CARID), Heinrich-Heine-University, D\u00fcsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, MA (C.E.S.); Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.); and Bio-Medical Research Center..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim P.","family":"Schmitt","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology, University of W\u00fcrzburg, W\u00fcrzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital D\u00fcsseldorf and Cardiovascular Research Institute D\u00fcsseldorf (CARID), Heinrich-Heine-University, D\u00fcsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, MA (C.E.S.); 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