{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:30:49Z","timestamp":1793197849413,"version":"4.5.0"},"reference-count":67,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While \u224850% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCM\n              <jats:sub>SMP<\/jats:sub>\n              ), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCM\n              <jats:sub>SMN<\/jats:sub>\n              ). Genotype-specific differences have been reported in cardiac function. Moreover, HCM\n              <jats:sub>SMN<\/jats:sub>\n              patients have later disease onset and a better prognosis than HCM\n              <jats:sub>SMP<\/jats:sub>\n              patients. To define if genotype-specific derailments at the protein level may explain the heterogeneity in disease development, we performed a proteomic analysis in cardiac tissue from a clinically well-phenotyped HCM patient group.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              A proteomics screen was performed in cardiac tissue from 39 HCM\n              <jats:sub>SMP<\/jats:sub>\n              patients, 11HCM\n              <jats:sub>SMN<\/jats:sub>\n              patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel\n              <jats:italic>MYBPC3<\/jats:italic>\n              <jats:sub>2373insG<\/jats:sub>\n              mouse model was used to confirm functional relevance of our proteomic findings.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              In all HCM patient samples, we found lower levels of metabolic pathway proteins and higher levels of extracellular matrix proteins. Levels of total and detyrosinated \u03b1-tubulin were markedly higher in HCM\n              <jats:sub>SMP<\/jats:sub>\n              than in HCM\n              <jats:sub>SMN<\/jats:sub>\n              and controls. Higher tubulin detyrosination was also found in 2 unrelated\n              <jats:italic>MYBPC3<\/jats:italic>\n              mouse models and its inhibition with parthenolide normalized contraction and relaxation time of isolated cardiomyocytes.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Our findings indicate that microtubules and especially its detyrosination contribute to the pathomechanism of patients with HCM\n              <jats:sub>SMP<\/jats:sub>\n              . This is of clinical importance since it represents a potential treatment target to improve cardiac function in patients with HCM\n              <jats:sub>SMP<\/jats:sub>\n              , whereas a beneficial effect may be limited in patients with HCM\n              <jats:sub>SMN<\/jats:sub>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circheartfailure.120.007022","type":"journal-article","created":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T13:13:24Z","timestamp":1610457204000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":105,"title":["Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9401-6190","authenticated-orcid":true,"given":"Maike","family":"Schuldt","sequence":"first","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Physiology, Amsterdam Cardiovascular Sciences, The Netherlands (M.S., L.M.D., J.v.d.V., D.W.D.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Pei","sequence":"additional","affiliation":[{"name":"Division Heart and Lungs, Department of Cardiology (J.P., M.H., F.W.A.), University Medical Center Utrecht, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7293-1029","authenticated-orcid":true,"given":"Magdalena","family":"Harakalova","sequence":"additional","affiliation":[{"name":"Division Heart and Lungs, Department of Cardiology (J.P., M.H., F.W.A.), University Medical Center Utrecht, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4045-9321","authenticated-orcid":true,"given":"Larissa M.","family":"Dorsch","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Physiology, Amsterdam Cardiovascular Sciences, The Netherlands (M.S., L.M.D., J.v.d.V., D.W.D.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8329-6198","authenticated-orcid":true,"given":"Saskia","family":"Schlossarek","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Germany (S.S., L.C.)."},{"name":"DZHK (German Centre for Cardiovascular Research), partner site Hamburg\/Kiel\/L\u00fcbeck, Hamburg, Germany (S.S., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5298-4852","authenticated-orcid":true,"given":"Michal","family":"Mokry","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology, Wilhelmina Children\u2019s Hospital (M. Morky), University Medical Center Utrecht, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaco C.","family":"Knol","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, OncoProteomics Laboratory, VUmc-Cancer Center Amsterdam, The Netherlands (J.C.K., T.V.P., T.S., S.R.P., C.R.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0333-2492","authenticated-orcid":true,"given":"Thang V.","family":"Pham","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, OncoProteomics Laboratory, VUmc-Cancer Center Amsterdam, The Netherlands (J.C.K., T.V.P., T.S., S.R.P., C.R.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3444-0971","authenticated-orcid":true,"given":"Tim","family":"Schelfhorst","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, OncoProteomics Laboratory, VUmc-Cancer Center Amsterdam, The Netherlands (J.C.K., T.V.P., T.S., S.R.P., C.R.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7262-3395","authenticated-orcid":true,"given":"Sander R.","family":"Piersma","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, OncoProteomics Laboratory, VUmc-Cancer Center Amsterdam, The Netherlands (J.C.K., T.V.P., T.S., S.R.P., C.R.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1052-7490","authenticated-orcid":true,"given":"Cris","family":"dos Remedios","sequence":"additional","affiliation":[{"name":"Sydney Heart Bank, Discipline of Anatomy, Bosch Institute, University of Sydney, Australia (C.d.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel","family":"Dalinghaus","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology (M.D.), Erasmus Medical Center Rotterdam, The Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6432-0431","authenticated-orcid":true,"given":"Michelle","family":"Michels","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Thorax Center (M. 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