Myocardial Titin Hypophosphorylation Importantly Contributes to Heart Failure With Preserved Ejection Fraction in a Rat Metabolic Risk Model
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 co...
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| Published in | Circulation. Heart failure Vol. 6; no. 6; pp. 1239 - 1249 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
01.11.2013
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1941-3289 1941-3297 1941-3297 |
| DOI | 10.1161/CIRCHEARTFAILURE.113.000539 |
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| Abstract | 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.
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 (Fpassive)-sarcomere length relations were obtained in small muscle strips before and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellular matrix to Fpassive 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 (±80%) 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.
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. |
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| AbstractList | 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.BACKGROUNDObesity 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.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 (Fpassive)-sarcomere length relations were obtained in small muscle strips before and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellular matrix to Fpassive 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 (±80%) 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.METHODS AND RESULTSFour 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 (Fpassive)-sarcomere length relations were obtained in small muscle strips before and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellular matrix to Fpassive 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 (±80%) 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.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.CONCLUSIONSObese ZSF1 rats developed heart failure with preserved ejection fraction during a 20-week time span. Titin hypophosphorylation importantly contributed to the underlying myocardial DD. 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. 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 (Fpassive)-sarcomere length relations were obtained in small muscle strips before and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellular matrix to Fpassive 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 (±80%) 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. 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. |
| Author | Plettig, Luisa Paulus, Walter J. Lourenço, André Díez, Javier López, Begoña González, Arantxa Linke, Wolfgang A. Becher, Peter Moritz Tschöpe, Carsten Fontoura, Dulce Hamdani, Nazha Leite-Moreira, Adelino F. Franssen, Constantijn Falcão-Pires, Inês Ottenheijm, Coen A. Leite, Sara |
| Author_xml | – sequence: 1 givenname: Nazha surname: Hamdani fullname: Hamdani, Nazha organization: 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 – sequence: 2 givenname: Constantijn surname: Franssen fullname: Franssen, Constantijn organization: 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 – sequence: 3 givenname: André surname: Lourenço fullname: Lourenço, André organization: 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 – sequence: 4 givenname: Inês surname: Falcão-Pires fullname: Falcão-Pires, Inês organization: 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 – sequence: 5 givenname: Dulce surname: Fontoura fullname: Fontoura, Dulce organization: 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 – sequence: 6 givenname: Sara surname: Leite fullname: Leite, Sara organization: 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 – sequence: 7 givenname: Luisa surname: Plettig fullname: Plettig, Luisa organization: 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 – sequence: 8 givenname: Begoña surname: López fullname: López, Begoña organization: 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 – sequence: 9 givenname: Coen A. surname: Ottenheijm fullname: Ottenheijm, Coen A. organization: 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 – sequence: 10 givenname: Peter Moritz surname: Becher fullname: Becher, Peter Moritz organization: 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 – sequence: 11 givenname: Arantxa surname: González fullname: González, Arantxa organization: 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 – sequence: 12 givenname: Carsten surname: Tschöpe fullname: Tschöpe, Carsten organization: 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 – sequence: 13 givenname: Javier surname: Díez fullname: Díez, Javier organization: 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 – sequence: 14 givenname: Wolfgang A. surname: Linke fullname: Linke, Wolfgang A. organization: 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 – sequence: 15 givenname: Adelino F. surname: Leite-Moreira fullname: Leite-Moreira, Adelino F. organization: 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 – sequence: 16 givenname: Walter J. surname: Paulus fullname: Paulus, Walter J. organization: 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 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24014826$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1016/j.jacc.2009.06.067 10.1161/circulationaha.111.025270 10.1161/circulationaha.110.011031 10.1085/jgp.200409177 10.1161/hypertensionaha.112.202705 10.1016/j.jjcc.2009.10.001 10.1007/s10974-006-9090-5 10.1161/circheartfailure.110.959890 10.1161/CIRCRESAHA.108.184408 10.1016/j.yjmcc.2009.01.004 10.1016/j.jsb.2006.02.017 10.1016/j.jacc.2011.11.040 10.1016/S0006-3495(95)80278-X 10.1161/circulationaha.105.587519 10.1161/circresaha.111.300105 10.1016/0735-1097(88)90364-6 10.1016/j.jacc.2010.04.040 10.1161/circulationaha.111.063412 10.1161/01.cir.0000164273.57823.26 10.1161/CIRCRESAHA.108.193326 10.1093/cvr/cvs353 10.1007/s00392-011-0305-4 10.1161/CIRCULATIONAHA.109.860171 10.1016/j.jacc.2011.09.062 10.1161/circresaha.109.198465 10.1007/s00395-009-0014-6 10.1093/cvr/cvt144 10.1161/circulationaha.111.076075 10.1161/circulationaha.107.728550 10.1016/j.jacc.2010.03.077 10.1074/jbc.M112.372839 10.1093/eurheartj/ehq426 10.1016/j.ejheart.2007.12.010 10.1016/j.jacc.2010.04.041 10.1161/CIRCULATIONAHA.111.048520 10.1093/eurheartj/ehm037 10.1161/01.RES.0000021115.24712.99 |
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| SubjectTerms | Animals Connectin - metabolism Disease Models, Animal Disease Progression Heart Failure - etiology Heart Failure - metabolism Heart Failure - physiopathology Male Myocardium - metabolism Obesity - complications Obesity - metabolism Phosphorylation Rats Rats, Inbred WKY Stroke Volume - physiology Ventricular Dysfunction, Left - complications Ventricular Dysfunction, Left - metabolism Ventricular Dysfunction, Left - physiopathology |
| Title | Myocardial Titin Hypophosphorylation Importantly Contributes to Heart Failure With Preserved Ejection Fraction in a Rat Metabolic Risk Model |
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