JACC: Basic to Translational Science (Sep 2019)

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

  • Rio P. Juni, PhD,
  • Diederik W.D. Kuster, PhD,
  • Max Goebel, MSc,
  • Michiel Helmes, PhD,
  • René J.P. Musters, PhD,
  • Jolanda van der Velden, PhD,
  • Pieter Koolwijk, PhD,
  • Walter J. Paulus, MD, PhD,
  • Victor W.M. van Hinsbergh, PhD

Journal volume & issue
Vol. 4, no. 5
pp. 575 – 591

Abstract

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Summary: 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. Key Words: contraction and relaxation, endothelial cell–derived nitric oxide, empagliflozin, heart failure, oxidative stress