{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:05:29Z","timestamp":1792670729619,"version":"4.5.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>Obesity and diabetes mellitus are important metabolic risk factors and frequent comorbidities in heart failure with preserved ejection fraction. They contribute to myocardial diastolic dysfunction (DD) through collagen deposition or titin modification. The relative importance for myocardial DD of collagen deposition and titin modification was investigated in obese, diabetic ZSF1 rats after heart failure with preserved ejection fraction development at 20 weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      Four groups of rats (Wistar-Kyoto, n=11; lean ZSF1, n=11; obese ZSF1, n=11, and obese ZSF1 with high-fat diet, n=11) were followed up for 20 weeks with repeat metabolic, renal, and echocardiographic evaluations and hemodynamically assessed at euthanization. Myocardial collagen, collagen cross-linking, titin isoforms, and phosphorylation were also determined. Resting tension (F\n                      <jats:sub>passive<\/jats:sub>\n                      )\u2013sarcomere length relations were obtained in small muscle strips before and after KCl\u2013KI treatment, which unanchors titin and allows contributions of titin and extracellular matrix to F\n                      <jats:sub>passive<\/jats:sub>\n                      to be discerned. At 20 weeks, the lean ZSF1 group was hypertensive, whereas both obese ZSF1 groups were hypertensive and diabetic. Only the obese ZSF1 groups had developed heart failure with preserved ejection fraction, which was evident from increased lung weight, preserved left ventricular ejection fraction, and left ventricular DD. The underlying myocardial DD was obvious from high muscle strip stiffness, which was largely (\u00b180%) attributable to titin hypophosphorylation. The latter occurred specifically at the S3991 site of the elastic N2Bus segment and at the S12884 site of the PEVK segment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>Obese ZSF1 rats developed heart failure with preserved ejection fraction during a 20-week time span. Titin hypophosphorylation importantly contributed to the underlying myocardial DD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.113.000539","type":"journal-article","created":{"date-parts":[[2013,9,7]],"date-time":"2013-09-07T01:31:13Z","timestamp":1378517473000},"page":"1239-1249","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":300,"title":["Myocardial Titin Hypophosphorylation Importantly Contributes to Heart Failure With Preserved Ejection Fraction in a Rat Metabolic Risk Model"],"prefix":"10.1161","volume":"6","author":[{"given":"Nazha","family":"Hamdani","sequence":"first","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantijn","family":"Franssen","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Louren\u00e7o","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas","family":"Falc\u00e3o-Pires","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dulce","family":"Fontoura","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Leite","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Plettig","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bego\u00f1a","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coen A.","family":"Ottenheijm","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Moritz","family":"Becher","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arantxa","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, 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Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang A.","family":"Linke","sequence":"additional","affiliation":[{"name":"From the Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (N.H., C.F., C.A.O., W.J.P.); Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany (N.H., L.P., W.A.L.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (A.L., I.F.-P., D.F., S.L., A.F.L.-M.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, 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