Julia Moellmann1, Barbara M Klinkhammer2, Patrick Droste2, Ben Kappel1, Elias Haj-Yehia1, Sebastian Maxeiner1, Anna Artati3, Jerzy Adamski4, Peter Boor2, Katharina Schütt1, Gary D Lopaschuk5, Subodh Verma6, Nikolaus Marx7, Michael Lehrke8. 1. Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany. 2. Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany. 3. Research Unit Molecular Endocrinology and Metabolism, Helmholtz Centrum Munich, German Research Center for Environmental Health (GmbH), Munich-Neuherberg, Germany. 4. Research Unit Molecular Endocrinology and Metabolism, Helmholtz Centrum Munich, German Research Center for Environmental Health (GmbH), Munich-Neuherberg, Germany; Chair of Experimental Genetics, Technical University of Munich, Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD e.V.), Munich-Neuherberg, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 5. Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada. 6. Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, ON, Canada. 7. Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany. Electronic address: nmarx@ukaachen.de. 8. Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany. Electronic address: mlehrke@ukaachen.de.
Abstract
OBJECTIVES: Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy. BACKGROUND: SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart. METHODS: We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress. RESULTS: Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected. CONCLUSIONS: In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.
OBJECTIVES: Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy. BACKGROUND:SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart. METHODS: We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress. RESULTS: Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected. CONCLUSIONS: In a murine model of severe diabetesempagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.
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