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

Rio P Juni; Diederik W D Kuster; Max Goebel; Michiel Helmes; René J P Musters; Jolanda van der Velden; Pieter Koolwijk; Walter J Paulus; Victor W M van Hinsbergh

doi:10.1016/j.jacbts.2019.04.003

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. eCollection 2019 Sep.

Authors

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.

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.