Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and Restored by Empagliflozin

  • JACC Basic Transl Sci. 2019 Sep 4;4(5):575-591. doi: 10.1016/j.jacbts.2019.04.003.
Rio P Juni  1 ,  Diederik W D Kuster  1 ,  Max Goebel  1 ,  Michiel Helmes  1  2 ,  René J P Musters  1 ,  Jolanda van der Velden  1  3 ,  Pieter Koolwijk  1 ,  Walter J Paulus  1 ,  Victor W M van Hinsbergh  1  3
Affiliations
  • 1. Amsterdam Cardiovascular Sciences, Department of Physiology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
  • 2. CytoCypher B.V., Wageningen, the Netherlands.
  • 3. Netherlands Heart Institute, Utrecht, the Netherlands.
PMID: 31768475 DOI: 10.1016/j.jacbts.2019.04.003
Abstract

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.

Keywords
CM, cardiomyocyte; CMEC, cardiac microvascular endothelial cell; Ca, calcium; DM, diabetes mellitus; DPPH, 1,1-diphenyl-picrylhydrazyl; EC, endothelial cell; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; JNK, Jun N-terminal kinase; L-NAME, N(ω)-nitro-L-arginine methyl ester; LV, left ventricular; NK-κB, nuclear factor-κB; NO, nitric oxide; ROS, reactive oxygen species; SGLT2, sodium glucose transporter 2; contraction and relaxation; eNOS, endothelial nitric oxide synthase; empagliflozin; endothelial cell–derived nitric oxide; heart failure; oxidative stress.
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