{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T15:51:51Z","timestamp":1762876311128,"version":"3.41.2"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Ischemia-reperfusion and cardiac remodeling is associated with cardiomyocyte death, excessive fibrosis formation, and functional decline, eventually resulting in heart failure (HF). Glucagon-like peptide (GLP)-1 agonists are reported to reduce apoptosis and myocardial infarct size after ischemia-reperfusion. Moreover, mineralocorticoid receptor antagonists (MRAs) have been described to reduce reactive fibrosis and improve cardiac function. Here, we investigated whether combined treatment with GLP-1R agonist exenatide and MRA potassium canrenoate could minimize cardiac injury and limit HF progression in animal models of chronic HF.<\/jats:p><jats:p><jats:bold>Methods and Results:<\/jats:bold> Forty female Topigs Norsvin pigs were subjected to 150\u00a0min balloon occlusion of the left anterior descending artery (LAD). Prior to reperfusion, pigs were randomly assigned to placebo or combination therapy (either low dose or high dose). Treatment was applied for two consecutive days or for 8\u00a0weeks with a continued high dose <jats:italic>via<\/jats:italic> a tunneled intravenous catheter. Using 2,3,5-Triphenyltetrazolium chloride (TTC) staining we observed that combination therapy did not affect the scar size after 8\u00a0weeks. In line, left ventricular volume and function assessed by three-dimensional (3D) echocardiography (baseline, 7\u00a0days and 8\u00a0weeks), and cardiac magnetic resonance imaging (CMR, 8\u00a0weeks) did not differ between experimental groups. In addition, 36 C57Bl\/6JRj mice underwent permanent LAD-occlusion and were treated with either placebo or combination therapy prior to reperfusion, for two consecutive days <jats:italic>via<\/jats:italic> intravenous injection, followed by continued treatment <jats:italic>via<\/jats:italic> placement of osmotic mini-pumps for 28\u00a0days. Global cardiac function, assessed by 3D echocardiography performed at baseline, 7, 14, and 28\u00a0days, did not differ between treatment groups. Also, no differences were observed in cardiac hypertrophy, assessed by heart weight\/bodyweight and heart weight\/tibia length ratio.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> In the current study, combined treatment with GLP-1R agonist exenatide and MR antagonist potassium canrenoate did not show beneficial effects on cardiac remodeling nor resulted in functional improvement in a small and large animal chronic HF model.<\/jats:p>","DOI":"10.3389\/fphar.2021.702326","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T11:58:05Z","timestamp":1627300685000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Neutral Effects of Combined Treatment With GLP-1R Agonist Exenatide and MR Antagonist Potassium Canrenoate on Cardiac Function in Porcine and Murine Chronic Heart Failure Models"],"prefix":"10.3389","volume":"12","author":[{"given":"Evelyne J.","family":"Demkes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Wenker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max J. M.","family":"Silvis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martijn M. J.","family":"van Nieuwburg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Joyce","family":"Visser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marlijn S.","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maike A. D.","family":"Brans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelyn","family":"Velema","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joost P. G.","family":"Sluijter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imo E.","family":"Hoefer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique P. V.","family":"de Kleijn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leo","family":"Timmers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saskia C. A.","family":"de Jager","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/s11886-017-0876-4","article-title":"Adverse Remodeling and Reverse Remodeling after Myocardial Infarction","volume":"19","author":"Bhatt","year":"2017","journal-title":"Curr. Cardiol. Rep."},{"key":"B2","first-page":"893","article-title":"Mineralocorticoid Excess, Dietary Sodium, and Myocardial Fibrosis","volume":"120","author":"Brilla","year":"1992","journal-title":"J. Lab. Clin. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.3892\/ijmm.2013.1475","article-title":"Cardioprotective Effects of Exenatide against Oxidative Stress-Induced Injury","volume":"32","author":"Chang","year":"2013","journal-title":"Int. J. Mol. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/s0008-6363(03)00251-7","article-title":"Aldosterone Receptor Blockade Improves Left Ventricular Remodeling and Increases Ventricular Fibrillation Threshold in Experimental Heart Failure","volume":"58","author":"Cittadini","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1016\/j.ahj.2005.03.032","article-title":"Effects of Canrenoate Plus Angiotensin-Converting Enzyme Inhibitors versus Angiotensin-Converting Enzyme Inhibitors Alone on Systolic and Diastolic Function in Patients with Acute Anterior Myocardial Infarction","volume":"150","author":"Di Pasquale","year":"2005","journal-title":"Am. Heart J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"54021","DOI":"10.3791\/54021","article-title":"Primary Outcome Assessment in a Pig Model of Acute Myocardial Infarction","volume":"116","author":"Ellenbroek","year":"2016","journal-title":"J. Vis. Exp."},{"key":"B7","first-page":"285","article-title":"Marked Interspecies Differences between Humans and Pigs in Cyclosporine and Prednisolone Disposition","volume":"16","author":"Frey","year":"1988","journal-title":"Drug Metab. Dispos"},{"key":"B8","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1111\/dom.13907","article-title":"Exenatide and Dapagliflozin Combination Improves Markers of Liver Steatosis and Fibrosis in Patients with Type 2 Diabetes","volume":"22","author":"Gastaldelli","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1528","DOI":"10.1007\/s00464-003-9295-2","article-title":"Effects of the Aldosterone Receptor Antagonist Potassium Canrenoate on Renal Blood Flow and Urinary Output during Prolonged Increased Intraabdominal Pressure (IAP) in Pigs","volume":"18","author":"Gudmundsson","year":"2004","journal-title":"Surg. Endosc."},{"key":"B10","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.hlc.2016.08.007","article-title":"Exenatide Prevents Morphological and Structural Changes of Mitochondria Following Ischaemia-Reperfusion Injury","volume":"26","author":"Lee","year":"2017","journal-title":"Heart Lung Circ."},{"key":"B11","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1161\/CIRCHEARTFAILURE.112.000074","article-title":"Impact of Mineralocorticoid Receptor Antagonists on Changes in Cardiac Structure and Function of Left Ventricular Dysfunction","volume":"6","author":"Li","year":"2013","journal-title":"Circ. Heart Fail."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1093\/eurheartj\/ehr309","article-title":"Exenatide Reduces Reperfusion Injury in Patients with ST-Segment Elevation Myocardial Infarction","volume":"33","author":"L\u00f8nborg","year":"2012","journal-title":"Eur. Heart J."},{"key":"B13","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1067\/mhj.2001.111258","article-title":"Aldosterone Inhibition Limits Collagen Synthesis and Progressive Left Ventricular Enlargement after Anterior Myocardial Infarction","volume":"141","author":"Modena","year":"2001","journal-title":"Am. Heart J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.matbio.2017.12.001","article-title":"Understanding Cardiac Extracellular Matrix Remodeling to Develop Biomarkers of Myocardial Infarction Outcomes","author":"Nielsen","year":"2019","journal-title":"Matrix Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"975","DOI":"10.2337\/db08-1193","article-title":"GLP-1R Agonist Liraglutide Activates Cytoprotective Pathways and Improves Outcomes after Experimental Myocardial Infarction in Mice","volume":"58","author":"Noyan-Ashraf","year":"2009","journal-title":"Diabetes"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1056\/NEJMoa030207","article-title":"Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction","volume":"348","author":"Pitt","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1056\/NEJM199909023411001","article-title":"The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure","volume":"341","author":"Pitt","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1136\/hrt.2010.219345","article-title":"Cardioprotection against Ischaemia Induced by Dobutamine Stress Using Glucagon-like Peptide-1 in Patients with Coronary Artery Disease","volume":"98","author":"Read","year":"2012","journal-title":"Heart"},{"key":"B19","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.ijcard.2016.06.283","article-title":"No Benefit of Additional Treatment with Exenatide in Patients with an Acute Myocardial Infarction","volume":"220","author":"Roos","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1093\/eurheartj\/ehp555","article-title":"Cardioprotective Effects of Mineralocorticoid Receptor Antagonists at Reperfusion","volume":"31","author":"Schmidt","year":"2010","journal-title":"Eur. Heart J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e356","DOI":"10.1136\/bmj.e356","article-title":"25 Year Trends in First Time Hospitalisation for Acute Myocardial Infarction, Subsequent Short and Long Term Mortality, and the Prognostic Impact of Sex and Comorbidity: a Danish Nationwide Cohort Study","volume":"344","author":"Schmidt","year":"2012","journal-title":"BMJ"},{"key":"B22","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1186\/s12872-021-01995-7","article-title":"Experimental Parameters and Infarct Size in Closed Chest Pig LAD Ischemia Reperfusion Models; Lessons Learned","volume":"21","author":"Silvis","year":"2021","journal-title":"BMC Cardiovasc. Disord."},{"key":"B23","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1291\/hypres.30.427","article-title":"Spironolactone Modulates Expressions of Cardiac Mineralocorticoid Receptor and 11.BETA.-Hydroxysteroid Dehydrogenase 2 and Prevents Ventricular Remodeling in Post-Infarct Rat Hearts","volume":"30","author":"Takeda","year":"2007","journal-title":"Hypertens. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.jacc.2008.10.033","article-title":"Exenatide Reduces Infarct Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury","volume":"53","author":"Timmers","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/s1071-9164(03)00578-5","article-title":"Role of a Selective Aldosterone Blocker in Mice with Chronic Heart Failure","volume":"10","author":"Wang","year":"2004","journal-title":"J. Card. Fail."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1056\/NEJMra071667","article-title":"Myocardial Reperfusion Injury","volume":"357","author":"Yellon","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1056\/NEJMoa1009492","article-title":"Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms","volume":"364","author":"Zannad","year":"2011","journal-title":"N. Engl. J. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.702326\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T11:58:10Z","timestamp":1627300690000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.702326\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,26]]},"references-count":27,"alternative-id":["10.3389\/fphar.2021.702326"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.702326","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2021,7,26]]},"article-number":"702326"}}