Sodium–glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction

Salva R. Yurista, Herman H.W. Silljé, Silke U. Oberdorf-Maass, Elisabeth Maria Schouten, Mario G. Pavez Giani, Jan Luuk Hillebrands, Harry van Goor, Dirk J. van Veldhuisen, Rudolf A. de Boer, B. Daan Westenbrink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

236 Citations (Scopus)

Abstract

Aims: Sodium–glucose co-transporter 2 (SGLT2) inhibition reduces heart failure hospitalizations in patients with diabetes, irrespective of glycaemic control. We examined the effect of SGLT2 inhibition with empagliflozin (EMPA) on cardiac function in non-diabetic rats with left ventricular (LV) dysfunction after myocardial infarction (MI). Methods and results: Non-diabetic male Sprague–Dawley rats underwent permanent coronary artery ligation to induce MI, or sham surgery. Rats received chow containing EMPA that resulted in an average daily intake of 30 mg/kg/day or control chow, starting before surgery (EMPA-early) or 2 weeks after surgery (EMPA-late). Cardiac function was assessed using echocardiography and histological and molecular markers of cardiac remodelling and metabolism were assessed in the left ventricle. Renal function was assessed in metabolic cages. EMPA increased urine production by two-fold without affecting creatinine clearance and serum electrolytes. EMPA did not influence MI size, but LV ejection fraction (LVEF) was significantly higher in the EMPA-early and EMPA-late treated MI groups compared to the MI group treated with vehicle (LVEF 54%, 52% and 43%, respectively, all P < 0.05). EMPA also attenuated cardiomyocyte hypertrophy, diminished interstitial fibrosis and reduced myocardial oxidative stress. EMPA treatment reduced mitochondrial DNA damage and stimulated mitochondrial biogenesis, which was associated with the normalization of myocardial uptake and oxidation of glucose and fatty acids. EMPA increased circulating ketone levels as well as myocardial expression of the ketone body transporter and two critical ketogenic enzymes, indicating that myocardial utilization of ketone bodies was increased. Together these metabolic changes were associated with an increase in cardiac ATP production. Conclusion: Empagliflozin favourably affects cardiac function and remodelling in non-diabetic rats with LV dysfunction after MI, associated with substantial improvements in cardiac metabolism and cardiac ATP production. Importantly, it did so without renal adverse effects. Our data suggest that EMPA might be of benefit in heart failure patients without diabetes.

Original languageEnglish
Pages (from-to)862-873
Number of pages12
JournalEuropean Journal of Heart Failure
Volume21
Issue number7
DOIs
Publication statusPublished - Jul 2019
Externally publishedYes

Bibliographical note

Funding Information:
Dr. Yurista is supported by a grant from the Indonesia Endowment Fund for Education (LPDP no. 20150722083422). Dr. de Boer is supported by the Netherlands Heart Foundation (CVON DOSIS, grant 2014-40, CVON SHE-PREDICTS-HF, grant 2017-21, and CVON RED-CVD, grant 2017-11); and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VIDI, grant 917.13.350). Dr. Westenbrink is supported by The Netherlands Organisation for Scientific Research (NWO VENI, grant 016.176.147). Conflict of interest: The UMCG, which employs Dr. de Boer, has received research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Roche, Trevena, and ThermoFisher GmbH. R.A.d.B. is a minority shareholder of scPharmaceuticals, Inc., and received personal fees from MandalMed Inc., Novartis, and Servier. The other authors do not report conflicts of interest.

Funding Information:
Dr. Yurista is supported by a grant from the Indonesia Endowment Fund for Education (LPDP no. 20150722083422). Dr. de Boer is supported by the Netherlands Heart Foundation (CVON DOSIS, grant 2014-40, CVON SHE-PREDICTS-HF, grant 2017-21, and CVON RED-CVD, grant 2017-11); and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VIDI, grant 917.13.350). Dr. Westenbrink is supported by The Netherlands Organisation for Scientific Research (NWO VENI, grant 016.176.147). Conflict of interest: The UMCG, which employs Dr. de Boer, has received research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Roche, Trevena, and ThermoFisher GmbH. R.A.d.B. is a minority shareholder of scPharmaceuticals, Inc., and received personal fees from MandalMed Inc., Novartis, and Servier. The other authors do not report conflicts of interest. We acknowledge Boehringer Ingelheim for supplying empagliflozin and control chow, and thank Dr. Eric Mayoux for support and expert advice throughout the project. We thank Janny Takens and Martin Dokter for expert technical assistance and advice.

Publisher Copyright:
© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

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