{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:10:22Z","timestamp":1790640622691,"version":"4.1.0"},"reference-count":93,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T00:00:00Z","timestamp":1598400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL69071"],"award-info":[{"award-number":["R01 HL69071"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL116906"],"award-info":[{"award-number":["R01 HL116906"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL147064"],"award-info":[{"award-number":["R01 HL147064"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UL1 TR001082"],"award-info":[{"award-number":["UL1 TR001082"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1K23HI067915"],"award-info":[{"award-number":["1K23HI067915"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL109209"],"award-info":[{"award-number":["R01HL109209"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["AHA17GRNT33670495"],"award-info":[{"award-number":["AHA17GRNT33670495"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["14-CVD 03"],"award-info":[{"award-number":["14-CVD 03"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination of titin are the most common genetic cause of dilated cardiomyopathy. Modifications of titin, which change protein length, and relative stiffness affect resting tension of the ventricle and are associated with acquired forms of heart failure. Transcriptional and post-translational changes that increase titin\u2019s length and extensibility, making the sarcomere longer and softer, are associated with systolic dysfunction and left ventricular dilation. Modifications of titin that decrease its length and extensibility, making the sarcomere shorter and stiffer, are associated with diastolic dysfunction in animal models. There has been significant progress in understanding the mechanisms by which titin is modified. As molecular pathways that modify titin\u2019s mechanical properties are elucidated, they represent therapeutic targets for treatment of both systolic and diastolic dysfunction. In this article, we review titin\u2019s contribution to normal cardiac physiology, the pathophysiology of titin truncation variations leading to dilated cardiomyopathy, and transcriptional and post-translational modifications of titin. Emphasis is on how modification of titin can be utilized as a therapeutic target for treatment of heart failure.<\/jats:p>","DOI":"10.3390\/jcm9092770","type":"journal-article","created":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T09:05:37Z","timestamp":1598432737000},"page":"2770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure"],"prefix":"10.3390","volume":"9","author":[{"given":"Charles","family":"Tharp","sequence":"first","affiliation":[{"name":"Adult Medical Genetics Program, Cardiovascular Institute, University of Colorado Anschutz Medical Campus, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1116-2286","authenticated-orcid":false,"given":"Luisa","family":"Mestroni","sequence":"additional","affiliation":[{"name":"Adult Medical Genetics Program, Cardiovascular Institute, University of Colorado Anschutz Medical Campus, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9043-0810","authenticated-orcid":false,"given":"Matthew","family":"Taylor","sequence":"additional","affiliation":[{"name":"Adult Medical Genetics Program, Cardiovascular Institute, University of Colorado Anschutz Medical Campus, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,26]]},"reference":[{"key":"ref_1","first-page":"e6","article-title":"Heart disease and stroke statistics\u20142013 update: A report from the American Heart Association","volume":"127","author":"Go","year":"2013","journal-title":"Circulation"},{"key":"ref_2","first-page":"P9","article-title":"Clinical epidemiology of heart failure: Public and private health burden","volume":"19","author":"McMurray","year":"1998","journal-title":"Eur. 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