Pabel, Steffen and Wagner, Stefan and Bollenberg, Hannah and Bengel, Philipp and Kovacs, Arpad and Schach, Christian and Tirilomis, Petros and Mustroph, Julian and Renner, Andre and Gummert, Jan and Fischer, Thomas and Van Linthout, Sophie and Tschoepe, Carsten and Streckfuss-Boemeke, Katrin and Hasenfuss, Gerd and Maier, Lars S. and Hamdani, Nazha and Sossalla, Samuel (2018) Empagliflozin directly improves diastolic function in human heart failure. EUROPEAN JOURNAL OF HEART FAILURE, 20 (12). pp. 1690-1700. ISSN 1388-9842, 1879-0844
Full text not available from this repository. (Request a copy)Abstract
Aims Empagliflozin, a clinically used oral antidiabetic drug that inhibits the sodium-dependent glucose co-transporter 2, has recently been evaluated for its cardiovascular safety. Surprisingly, empagliflozin reduced mortality and hospitalization for heart failure (HF) compared to placebo. However, the underlying mechanisms remain unclear. Therefore, our study aims to investigate whether empagliflozin may cause direct pleiotropic effects on the myocardium. Methods and results In order to assess possible direct myocardial effects of empagliflozin, we performed contractility experiments with in toto-isolated human systolic end-stage HF ventricular trabeculae. Empagliflozin significantly reduced diastolic tension, whereas systolic force was not changed. These results were confirmed in murine myocardium from diabetic and non-diabetic mice, suggesting independent effects from diabetic conditions. In human HF cardiomyocytes, empagliflozin did not influence calcium transient amplitude or diastolic calcium level. The mechanisms underlying the improved diastolic function were further elucidated by studying myocardial fibres from patients and rats with diastolic HF (HF with preserved ejection fraction, HFpEF). Empagliflozin beneficially reduced myofilament passive stiffness by enhancing phosphorylation levels of myofilament regulatory proteins. Intravenous injection of empagliflozin in anaesthetized HFpEF rats significantly improved diastolic function measured by echocardiography, while systolic contractility was unaffected. Conclusion Empagliflozin causes direct pleiotropic effects on the myocardium by improving diastolic stiffness and hence diastolic function. These effects were independent of diabetic conditions. Since pharmacological therapy of diastolic dysfunction and HF is an unmet need, our results provide a rationale for new translational studies and might also contribute to the understanding of the EMPA-REG OUTCOME trial.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-KINASE-II; DYSFUNCTION; INHIBITION; STIFFNESS; PHOSPHORYLATION; Heart failure; Empagliflozin; Diastolic dysfunction; Contractility |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2019 08:45 |
| Last Modified: | 04 Oct 2019 08:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13413 |
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