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
Demkes, Evelyne J.; Wenker, Steven; Silvis, Max J.M.; van Nieuwburg, Martijn M.J.; Visser, M. Joyce; Jansen, Marlijn S.; Brans, Maike A.D.; Velema, Evelyn; Sluijter, Joost P.G.; Hoefer, Imo E.; de Kleijn, Dominique P.V.; Timmers, Leo; de Jager, Saskia C.A.
(2021) Frontiers in Pharmacology, volume 12
(Article)
Abstract
Background: 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
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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. Methods and Results: Forty female Topigs Norsvin pigs were subjected to 150 min 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 weeks with a continued high dose via 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 weeks. In line, left ventricular volume and function assessed by three-dimensional (3D) echocardiography (baseline, 7 days and 8 weeks), and cardiac magnetic resonance imaging (CMR, 8 weeks) 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 via intravenous injection, followed by continued treatment via placement of osmotic mini-pumps for 28 days. Global cardiac function, assessed by 3D echocardiography performed at baseline, 7, 14, and 28 days, 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. Conclusion: 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.
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Keywords: cardiac function, chronic heart failure, glucagon-like peptide-1 agonist, mineralocorticoid receptor antagonist, mouse, myocardial infarction, porcine, Pharmacology, Pharmacology (medical)
ISSN: 1663-9812
Publisher: Frontiers Media S. A.
Note: Funding Information: This work was financially supported by the Genesis Pharma, Athens, Greece. Funding Information: The authors gratefully acknowledge Petra van der Kraak and Marian Wesseling from University Medical Center Utrecht, Netherlands for their help regarding histology. Publisher Copyright: © Copyright © 2021 Demkes, Wenker, Silvis, van Nieuwburg, Visser, Jansen, Brans, Velema, Sluijter, Hoefer, de Kleijn, Timmers and de Jager.
(Peer reviewed)