{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:34:32Z","timestamp":1791196472990,"version":"4.1.0"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2013,10,29]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>The role of right ventricular (RV) diastolic stiffness in pulmonary arterial hypertension (PAH) is not well established. Therefore, we investigated the presence and possible underlying mechanisms of RV diastolic stiffness in PAH patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      Single-beat RV pressure-volume analyses were performed in 21 PAH patients and 7 control subjects to study RV diastolic stiffness. Data are presented as mean\u00b1SEM. RV diastolic stiffness (\u03b2) was significantly increased in PAH patients (PAH, 0.050\u00b10.005 versus control, 0.029\u00b10.003;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.05) and was closely associated with disease severity. Subsequently, we searched for possible underlying mechanisms using RV tissue of PAH patients undergoing heart\/lung transplantation and nonfailing donors. Histological analyses revealed increased cardiomyocyte cross-sectional areas (PAH, 453\u00b131 \u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      versus control, 218\u00b121 \u03bcm\n                      <jats:sup>2<\/jats:sup>\n                      ;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.001), indicating RV hypertrophy. In addition, the amount of RV fibrosis was enhanced in PAH tissue (PAH, 9.6\u00b10.7% versus control, 7.2\u00b10.6%;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.01). To investigate the contribution of stiffening of the sarcomere (the contractile apparatus of RV cardiomyocytes) to RV diastolic stiffness, we isolated and membrane-permeabilized single RV cardiomyocytes. Passive tension at different sarcomere lengths was significantly higher in PAH patients compared with control subjects (&gt;200%;\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>interaction<\/jats:sub>\n                      &lt;0.001), indicating stiffening of RV sarcomeres. An important regulator of sarcomeric stiffening is the sarcomeric protein titin. Therefore, we investigated titin isoform composition and phosphorylation. No alterations were observed in titin isoform composition (N2BA\/N2B ratio: PAH, 0.78\u00b10.07 versus control, 0.91\u00b10.08), but titin phosphorylation in RV tissue of PAH patients was significantly reduced (PAH, 0.16\u00b10.01 arbitrary units versus control, 0.20\u00b10.01 arbitrary units;\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>RV diastolic stiffness is significantly increased in PAH patients, with important contributions from increased collagen and intrinsic stiffening of the RV cardiomyocyte sarcomeres.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.113.001873","type":"journal-article","created":{"date-parts":[[2013,9,21]],"date-time":"2013-09-21T02:12:01Z","timestamp":1379729521000},"page":"2016-2025","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":346,"title":["Right Ventricular Diastolic Impairment in Patients With Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"128","author":[{"given":"Silvia","family":"Rain","sequence":"first","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Louis","family":"Handoko","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Trip","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Tji-Joong","family":"Gan","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"Westerhof","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ger J.","family":"Stienen","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"Paulus","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coen A.C.","family":"Ottenheijm","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Tim","family":"Marcus","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dorfm\u00fcller","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Guignabert","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Humbert","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"MacDonald","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cris","family":"dos Remedios","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piet E.","family":"Postmus","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandra","family":"Saripalli","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos G.","family":"Hidalgo","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk L.","family":"Granzier","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Vonk-Noordegraaf","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; Universit\u00e9 Paris-Sud, Le Kremlin-Bic\u00eatre, France (P.D., C.G., M.H.); INSERM UMR 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (P.D., C.G., M.H.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanda","family":"van der Velden","sequence":"additional","affiliation":[{"name":"From the Departments of Pulmonology (S.R., P.T., C.T.-J.G., N.W., P.E.P., A.V.-N., F.S.d.M.), Physiology (S.R., M.L.H., N.W., G.J.S., W.J.P., C.A.C.O., J.v.d.V., F.S.d.M.), Cardiology (M.L.H.), and Medical Physics (J.T.M.), VU University Medical Center\/Institute for Cardiovascular Research, Amsterdam, the Netherlands; 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