Author + information
- Received November 19, 2018
- Revision received April 23, 2019
- Accepted April 27, 2019
- Published online September 23, 2019.
- Rio P. Juni, PhDa,
- Diederik W.D. Kuster, PhDa,
- Max Goebel, MSca,
- Michiel Helmes, PhDa,b,
- René J.P. Musters, PhDa,
- Jolanda van der Velden, PhDa,c,
- Pieter Koolwijk, PhDa,
- Walter J. Paulus, MD, PhDa and
- Victor W.M. van Hinsbergh, PhDa,c,∗ ()
- aAmsterdam Cardiovascular Sciences, Department of Physiology, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- bCytoCypher B.V., Wageningen, the Netherlands
- cNetherlands Heart Institute, Utrecht, the Netherlands
- ↵∗Address for correspondence:
Dr. Victor W.M. van Hinsbergh, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Department of Physiology, O|2 Research Building, Room 11W53, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
• CMECs exert a direct positive effect on cardiomyocyte contraction and relaxation, which is mainly mediated by endothelial-derived NO.
• Pro-inflammatory stimulation of CMECs by pre-incubation with TNF-α or interleukin-1β abrogates the positive regulatory function of these cells on cardiomyocyte contractile property.
• Mechanistically, pro-inflammatory activation of CMECs leads to mitochondrial and cytoplasmic ROS accumulation that results in the scavenging of NO.
• Empagliflozin directly restores the beneficial effect of CMECs on cardiomyocyte contraction and relaxation by reducing TNF-α-induced mitochondrial and cytoplasmic ROS accumulation, which leads to reinstatement of CMEC-derived NO delivery.
The positive findings of the EMPA-REG OUTCOME trial (Randomized, Placebo-Controlled Cardiovascular Outcome Trial of Empagliflozin) on heart failure (HF) outcome in patients with type 2 diabetes mellitus suggest a direct effect of empagliflozin on the heart. These patients frequently have HF with preserved ejection fraction (HFpEF), in which a metabolic risk-related pro-inflammatory state induces cardiac microvascular endothelial cell (CMEC) dysfunction with subsequent cardiomyocyte (CM) contractility impairment. This study showed that CMECs confer a direct positive effect on contraction and relaxation of CMs, an effect that requires nitric oxide, is diminished after CMEC stimulation with tumor necrosis factor-α, and is restored by empagliflozin. Our findings on the effect of empagliflozin on CMEC-mediated preservation of CM function suggests that empagliflozin can be used to treat the cardiac mechanical implications of microvascular dysfunction in HFpEF.
- contraction and relaxation
- endothelial cell–derived nitric oxide
- heart failure
- oxidative stress
This project is funded by the Netherlands Heart Foundation (CVON-RECONNECT consortium, no. 2014-11). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received November 19, 2018.
- Revision received April 23, 2019.
- Accepted April 27, 2019.
- 2019 The Authors