{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:07:21Z","timestamp":1790482041906,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T00:00:00Z","timestamp":1617062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The angiotensin receptor\/neprilysin inhibitor Sacubitril\/Valsartan (Sac\/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac\/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac\/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac\/Val treatment reduced E\/\u00e9 ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac\/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac\/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.<\/jats:p>","DOI":"10.3390\/ijms22073570","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T09:57:04Z","timestamp":1617098224000},"page":"3570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Sacubitril\/Valsartan Improves Diastolic Function But Not Skeletal Muscle Function in a Rat Model of HFpEF"],"prefix":"10.3390","volume":"22","author":[{"given":"Antje","family":"Schauer","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7955-7324","authenticated-orcid":false,"given":"Volker","family":"Adams","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Augstein","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8047-2774","authenticated-orcid":false,"given":"Anett","family":"Jannasch","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Carl Gustav Carus Faculty of Medicine, Technische Universit\u00e4t Dresden, Heart Centre Dresden, Fetscherstrasse 76, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runa","family":"Draskowski","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Kirchhoff","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9244-6381","authenticated-orcid":false,"given":"Keita","family":"Goto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeniffer","family":"Mittag","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Carl Gustav Carus Faculty of Medicine, Technische Universit\u00e4t Dresden, Heart Centre Dresden, Fetscherstrasse 76, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0633-0321","authenticated-orcid":false,"given":"Roberta","family":"Galli","sequence":"additional","affiliation":[{"name":"Clinical Sensoring and Monitoring, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, TU Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"M\u00e4nnel","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy","family":"Barthel","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"Linke","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ephraim B.","family":"Winzer","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, TU Dresden, Heart Center Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s11897-015-0252-x","article-title":"Heart Failure in Women","volume":"12","author":"Taylor","year":"2015","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1093\/eurjhf\/hfq121","article-title":"Epidemiology and clinical course of heart failure with preserved ejection fraction","volume":"13","author":"Lam","year":"2011","journal-title":"Eur. J. Heart Fail."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s12471-016-0815-9","article-title":"Animal models of heart failure with preserved ejection fraction","volume":"24","author":"Conceicao","year":"2016","journal-title":"Neth. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1002\/ehf2.12915","article-title":"ZSF1 rat as animal model for HFpEF: Development of reduced diastolic function and skeletal muscle dysfunction","volume":"7","author":"Schauer","year":"2020","journal-title":"ESC Heart Fail."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S2213-8587(17)30087-6","article-title":"Effect of sacubitril\/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: A post-hoc analysis from the PARADIGM-HF trial","volume":"5","author":"Seferovic","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1056\/NEJMoa1313731","article-title":"Spironolactone for heart failure with preserved ejection fraction","volume":"370","author":"Pitt","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1056\/NEJMoa1908655","article-title":"Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction","volume":"381","author":"Solomon","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1001\/jama.2015.17346","article-title":"Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial","volume":"315","author":"Kitzman","year":"2016","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s00059-015-4346-8","article-title":"Effects of renin-angiotensin-aldosterone system inhibitors on mortality, hospitalization, and diastolic function in patients with HFpEF. A meta-analysis of 13 randomized controlled trials","volume":"41","author":"Zhang","year":"2016","journal-title":"Herz"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1016\/S0140-6736(07)60980-5","article-title":"Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: A randomised trial","volume":"369","author":"Solomon","year":"2007","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ijcard.2016.11.239","article-title":"The effect of beta-blockers on mortality in heart failure with preserved ejection fraction: A meta-analysis of observational cohort and randomized controlled studies","volume":"228","author":"Fukuta","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1007\/s12471-016-0814-x","article-title":"Is enhancing cGMP-PKG signalling a promising therapeutic target for heart failure with preserved ejection fraction?","volume":"24","author":"Alogna","year":"2016","journal-title":"Neth. Heart J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.jchf.2017.04.013","article-title":"Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction: Rationale and Design of the PARAGON-HF Trial","volume":"5","author":"Solomon","year":"2017","journal-title":"JACC. Heart Fail."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1161\/CIRCULATIONAHA.119.044491","article-title":"Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF","volume":"141","author":"McMurray","year":"2020","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1002\/ehf2.12694","article-title":"Angiotensin receptor neprilysin inhibition versus individualized RAAS blockade: Design and rationale of the PARALLAX trial","volume":"7","author":"Wachter","year":"2020","journal-title":"ESC Heart Fail."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Nguyen, I.T.N., Brandt, M.M., van de Wouw, J., van Drie, R.W.A., Wesseling, M., Cramer, M.J., de Jager, S.C.A., Merkus, D., Duncker, D.J., and Cheng, C. (2020). Both male and female obese ZSF1 rats develop cardiac dysfunction in obesity-induced heart failure with preserved ejection fraction. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0232399"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"H501","DOI":"10.1152\/ajpheart.00138.2005","article-title":"Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: A guide for clinical, translational, and basic researchers","volume":"289","author":"Burkhoff","year":"2005","journal-title":"Am. J. Physiol. Heart Circ. Physiol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1038\/nprot.2008.138","article-title":"Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats","volume":"3","author":"Pacher","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.jacc.2020.05.072","article-title":"Effect of Sacubitril\/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF","volume":"76","author":"Cunningham","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/j.jacbts.2020.07.006","article-title":"Differential Effects of Sacubitril\/Valsartan on Diastolic Function in Mice With Obesity-Related Metabolic Heart Disease","volume":"5","author":"Croteau","year":"2020","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1002\/ejhf.474","article-title":"LCZ696, an angiotensin receptor\u00d4\u00c7\u00f4neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice","volume":"18","author":"Suematsu","year":"2016","journal-title":"Eur. J. Heart Fail."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.jacbts.2020.08.001","article-title":"Trimming the Fat in HFpEF: Learning How to Target the Metabolic Disease Phenotype","volume":"5","author":"Schilling","year":"2020","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s11897-016-0292-x","article-title":"Neprilysin and Natriuretic Peptide Regulation in Heart Failure","volume":"13","year":"2016","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1016\/j.jacc.2020.08.031","article-title":"Targeting Cyclic Guanosine Monophosphate to Treat Heart Failure","volume":"76","author":"Emdin","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1161\/CIRCRESAHA.108.184408","article-title":"Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs","volume":"104","author":"Lang","year":"2009","journal-title":"Cir. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1161\/CIRCHEARTFAILURE.113.000539","article-title":"Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model","volume":"6","author":"Hamdani","year":"2013","journal-title":"Circ. Heart Fail."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Michel, K., Herwig, M., Werner, F., Spiranec Spes, K., Abe\u00dfer, M., Schuh, K., Dabral, S., M\u00fcgge, A., Baba, H.A., and Skryabin, B.V. (2020). C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness. JCI Insight, 5.","DOI":"10.1172\/jci.insight.139910"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1002\/ejhf.799","article-title":"Neprilysin inhibition in heart failure: Mechanisms and substrates beyond modulating natriuretic peptides","volume":"19","author":"Iacovoni","year":"2017","journal-title":"Eur. J. Heart Fail."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/ejhf.1617","article-title":"Myocardial adipose deposition and the development of heart failure with preserved ejection fraction","volume":"22","author":"Wu","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1161\/CIRCULATIONAHA.118.037077","article-title":"Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation","volume":"139","author":"Kang","year":"2019","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jacc.2013.02.092","article-title":"A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation","volume":"62","author":"Paulus","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ijcard.2018.08.087","article-title":"Endothelial function is disturbed in a hypertensive diabetic animal model of HFpEF: Moderate continuous vs. high intensity interval training","volume":"273","author":"Schmederer","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Leite, S., Cerqueira, R.J., Ibarrola, J., Fontoura, D., Fern+\u00edndez-Celis, A., Zannad, F., Falc+\u00fao-Pires, I., Paulus, W.J., Leite-Moreira, A.F., and Rossignol, P. (2019). Arterial Remodeling and Dysfunction in the ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction. Circ. Heart Fail., 12.","DOI":"10.1161\/CIRCHEARTFAILURE.118.005596"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jchf.2015.10.007","article-title":"Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction","volume":"4","author":"Franssen","year":"2016","journal-title":"JACC Heart Fail."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s11897-017-0361-9","article-title":"Skeletal muscle alterations in HFrEF vs HFpEF","volume":"14","author":"Adams","year":"2017","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Goto, K., Schauer, A., Augstein, A., Methawasin, M., Granzier, H., Halle, M., van Craenenbroeck, E.M., Rolim, N., Gielen, S., and Pieske, B. (2020). Muscular changes in animal models of heart failure with preserved ejection fraction: What comes closest to the patient?. ESC Heart Fail.","DOI":"10.1002\/ehf2.13142"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0033-0620(90)90018-W","article-title":"Clinical assessment of diastolic function","volume":"32","author":"Mirsky","year":"1990","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.jjcc.2012.06.009","article-title":"Coronary perivascular fibrosis is associated with impairment of coronary blood flow in patients with non-ischemic heart failure","volume":"60","author":"Dai","year":"2012","journal-title":"J. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1038\/nbt899","article-title":"Nonlinear magic: Multiphoton microscopy in the biosciences","volume":"21","author":"Zipfel","year":"2003","journal-title":"Nat. Biotechnol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.4022\/jafib.1644","article-title":"Label-free Imaging of Myocardial Remodeling in Atrial Fibrillation Using Nonlinear Optical Microscopy: A Feasibility Study","volume":"10","author":"Buttner","year":"2018","journal-title":"J. Atr. Fibrillation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nchembio.525","article-title":"Chemical contrast for imaging living systems: Molecular vibrations drive CARS microscopy","volume":"7","author":"Pezacki","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1146\/annurev-anchem-071114-040352","article-title":"Multimodal Imaging Spectroscopy of Tissue","volume":"8","author":"Vogler","year":"2015","journal-title":"Annu. Rev. Anal. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"60901","DOI":"10.1117\/1.JBO.17.6.060901","article-title":"Protein conformation and molecular order probed by second-harmonic-generation microscopy","volume":"17","author":"Vanzi","year":"2012","journal-title":"J. Biomed. Opt."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of bacteriophage T4","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3570\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:10:28Z","timestamp":1760364628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/7\/3570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,30]]},"references-count":45,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22073570"],"URL":"https:\/\/doi.org\/10.3390\/ijms22073570","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,30]]}}}