Abstract | AIMS: 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.
|
Authors | Steffen Pabel, Stefan Wagner, Hannah Bollenberg, Philipp Bengel, Árpád Kovács, Christian Schach, Petros Tirilomis, Julian Mustroph, André Renner, Jan Gummert, Thomas Fischer, Sophie Van Linthout, Carsten Tschöpe, Katrin Streckfuss-Bömeke, Gerd Hasenfuss, Lars S Maier, Nazha Hamdani, Samuel Sossalla |
Journal | European journal of heart failure
(Eur J Heart Fail)
Vol. 20
Issue 12
Pg. 1690-1700
(12 2018)
ISSN: 1879-0844 [Electronic] England |
PMID | 30328645
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | © 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology. |
Chemical References |
- Benzhydryl Compounds
- Glucosides
- Sodium-Glucose Transporter 2 Inhibitors
- empagliflozin
|
Topics |
- Animals
- Benzhydryl Compounds
(pharmacology)
- Biopsy
- Diastole
- Disease Models, Animal
- Echocardiography
- Female
- Glucosides
(pharmacology)
- Heart Failure
(drug therapy, pathology, physiopathology)
- Heart Ventricles
(diagnostic imaging, drug effects, physiopathology)
- Humans
- Male
- Mice
- Middle Aged
- Myocardial Contraction
(drug effects)
- Myocardium
(metabolism, pathology)
- Myocytes, Cardiac
(drug effects, metabolism, pathology)
- Rats
- Rats, Zucker
- Sodium-Glucose Transporter 2 Inhibitors
(pharmacology)
- Ventricular Function, Left
(drug effects)
|