{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T21:06:30Z","timestamp":1789679190779,"version":"4.0.1"},"reference-count":72,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2013,5,24]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      High-myofilament Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      To investigate whether high myofilament Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Cardiac samples from patients with HCM harboring mutations in genes encoding thick (\n                      <jats:italic>MYH7<\/jats:italic>\n                      ,\n                      <jats:italic>MYBPC3<\/jats:italic>\n                      ) and thin (\n                      <jats:italic>TNNT2<\/jats:italic>\n                      ,\n                      <jats:italic>TNNI3<\/jats:italic>\n                      ,\n                      <jats:italic>TPM1<\/jats:italic>\n                      ) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sensitivity was similar (\n                      <jats:italic>MYBPC3<\/jats:italic>\n                      <jats:sub>mut<\/jats:sub>\n                      ,\n                      <jats:italic>TPM1<\/jats:italic>\n                      <jats:sub>mut<\/jats:sub>\n                      , sarcomere mutation-negative HCM), higher (\n                      <jats:italic>MYH7<\/jats:italic>\n                      <jats:sub>mut<\/jats:sub>\n                      ,\n                      <jats:italic>TNNT2<\/jats:italic>\n                      <jats:sub>mut<\/jats:sub>\n                      ), or even significantly lower (\n                      <jats:italic>TNNI3<\/jats:italic>\n                      <jats:sub>mut<\/jats:sub>\n                      ) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating\n                      <jats:italic>MYBPC3<\/jats:italic>\n                      mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in\n                      <jats:italic>TNNT2<\/jats:italic>\n                      <jats:sub>mut<\/jats:sub>\n                      and\n                      <jats:italic>TNNI3<\/jats:italic>\n                      <jats:sub>mut<\/jats:sub>\n                      corrected length-dependent activation to donor values.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      High-myofilament Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein\u2013protein interactions, and represents a common pathomechanism in HCM.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.111.300436","type":"journal-article","created":{"date-parts":[[2013,3,19]],"date-time":"2013-03-19T00:38:40Z","timestamp":1363653520000},"page":"1491-1505","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":195,"title":["Perturbed Length-Dependent Activation in Human Hypertrophic Cardiomyopathy With Missense Sarcomeric Gene Mutations"],"prefix":"10.1161","volume":"112","author":[{"given":"Vasco","family":"Sequeira","sequence":"first","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.M.","family":"Wijnker","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise L.A.M.","family":"Nijenkamp","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diederik W.D.","family":"Kuster","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aref","family":"Najafi","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Rosalie","family":"Witjas-Paalberends","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A.","family":"Regan","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicky","family":"Boontje","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folkert J.","family":"ten Cate","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjeerd","family":"Germans","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Carrier","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakthivel","family":"Sadayappan","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon A.","family":"van Slegtenhorst","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruud","family":"Zaremba","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Brian","family":"Foster","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Murphy","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); 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Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ger J.M.","family":"Stienen","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn Y.","family":"Ho","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Michels","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL (D.W.D.K., S.S.); Department of Physiology, Molecular Cardiovascular Research Program, Sarver Heart Center, University of Arizona, Tucson (J.A.R.); Thorax Center,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanda","family":"van der Velden","sequence":"additional","affiliation":[{"name":"From the Laboratory for Physiology (V.S., P.J.M.W., L.L.A.M.N., D.W.D.K., A.N., E.R.W.-P., J.A.R., N.B., R.Z., G.J.M.S., J.v.d.V.) and Department of Cardiology (T.G.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; 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