{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T18:32:55Z","timestamp":1774377175632,"version":"3.50.1"},"reference-count":35,"publisher":"American Physiological Society","issue":"1","funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)","doi-asserted-by":"publisher","award":["R01 HL59301"],"award-info":[{"award-number":["R01 HL59301"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2016,7,1]]},"abstract":"<jats:p>The sarcomere is the functional unit of the heart. Alterations in sarcomere activation lead to disease states such as hypertrophic and restrictive cardiomyopathy (HCM\/RCM). Mutations in many of the sarcomeric genes are causal for HCM\/RCM. In most cases, these mutations result in increased Ca<jats:sup>2+<\/jats:sup>sensitivity of the sarcomere, giving rise to altered systolic and diastolic function. There is emerging evidence that small-molecule sarcomere neutralization is a potential therapeutic strategy for HCM\/RCM. To pursue proof-of-concept, W7 was used here because of its well-known Ca<jats:sup>2+<\/jats:sup>desensitizer biochemical effects at the level of cardiac troponin C. Acute treatment of adult cardiac myocytes with W7 caused a dose-dependent (1\u201310 \u03bcM) decrease in contractility in a Ca<jats:sup>2+<\/jats:sup>-independent manner. Alkalosis was used as an in vitro experimental model of acquired heightened Ca<jats:sup>2+<\/jats:sup>sensitivity, resulting in increased live cell contractility and decreased baseline sarcomere length, which were rapidly corrected with W7. As an inherited cardiomyopathy model, R193H cardiac troponin I (cTnI) transgenic myocytes showed significant decreased baseline sarcomere length and slowed relaxation that were rapidly and dose-dependently corrected by W7. Langendorff whole heart pacing stress showed that R193H cTnI transgenic hearts had elevated end-diastolic pressures at all pacing frequencies compared with hearts from nontransgenic mice. Acute treatment with W7 rapidly restored end-diastolic pressures to normal values in R193H cTnI hearts, supporting a sarcomere intrinsic mechanism of dysfunction. The known off-target effects of W7 notwithstanding, these results provide further proof-of-concept that small-molecule-based sarcomere neutralization is a potential approach to remediate hyper-Ca<jats:sup>2+<\/jats:sup>-sensitive sarcomere function.<\/jats:p>","DOI":"10.1152\/ajpheart.00981.2015","type":"journal-article","created":{"date-parts":[[2016,5,14]],"date-time":"2016-05-14T04:44:29Z","timestamp":1463201069000},"page":"H36-H43","source":"Crossref","is-referenced-by-count":17,"title":["Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca<sup>2+<\/sup>-sensitive myofilaments"],"prefix":"10.1152","volume":"311","author":[{"given":"Brian R.","family":"Thompson","sequence":"first","affiliation":[{"name":"Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, 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