2. Academic Validation
  3. Empagliflozin Blunts Worsening Cardiac Dysfunction Associated With Reduced NLRP3 (Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation in Heart Failure

Empagliflozin Blunts Worsening Cardiac Dysfunction Associated With Reduced NLRP3 (Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation in Heart Failure

  • Circ Heart Fail. 2020 Jan;13(1):e006277. doi: 10.1161/CIRCHEARTFAILURE.119.006277.
Nikole J Byrne 1 2 3,  Nobutoshi Matsumura 1 2 3 4,  Zaid H Maayah 1 2 3,  Mourad Ferdaoussi 1 2 3,  Shingo Takahara 1 2 3 4,  Ahmed M Darwesh 4,  Jody L Levasseur 1 2,  James Won Suk Jahng 5,  Dyonne Vos 1,  Nirmal Parajuli 1 2 6,  Ayman O S El-Kadi 7,  Branko Braam 8 9,  Martin E Young 10,  Subodh Verma 11,  Peter E Light 1 2 12,  Gary Sweeney 5,  John M Seubert 1 12 7,  Jason R B Dyck 1 2 3
Affiliations

Affiliations

  • 1 Cardiovascular Research Centre, Faculty of Medicine and Dentistry (N.J.B., N.M., Z.H.M., M.F., S.T., J.L.L., D.V., N.P., P.E.L., J.M.S., J.R.B.D.), University of Alberta, Edmonton, Canada.
  • 2 Alberta Diabetes Institute, Faculty of Medicine and Dentistry (N.J.B., N.M., Z.H.M., M.F., S.T., J.L.L., N.P., P.E.L., J.R.B.D.), University of Alberta, Edmonton, Canada.
  • 3 Department of Pediatrics, Faculty of Medicine and Dentistry (N.J.B., N.M., Z.H.M., M.F., S.T., J.R.B.D.), University of Alberta, Edmonton, Canada.
  • 4 Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (N.M., S.T., A.M.D.).
  • 5 Deparment of Biology, York University, Toronto, Canada (J.W.S.J., G.S.).
  • 6 Division of Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion (N.P.).
  • 7 Faculty of Pharmacy and Pharmaceutical Sciences (A.O.S.E.-K., J.M.S.), University of Alberta, Edmonton, Canada.
  • 8 Division of Nephrology, Faculty of Medicine and Dentistry (B.B.), University of Alberta, Edmonton, Canada.
  • 9 Department of Medicine, Faculty of Medicine and Dentistry (B.B.), University of Alberta, Edmonton, Canada.
  • 10 Department of Medicine, University of Alabama at Birmingham (M.E.Y.).
  • 11 Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Canada (S.V.).
  • 12 Department of Pharmacology, Faculty of Medicine and Dentistry (P.E.L., J.M.S.), University of Alberta, Edmonton, Canada.
PMID: 31957470 DOI: 10.1161/CIRCHEARTFAILURE.119.006277
Abstract

Background: Although empagliflozin was shown to profoundly reduce cardiovascular events in diabetic patients and blunt the decline in cardiac function in nondiabetic mice with established heart failure (HF), the mechanism of action remains unknown.

Methods and results: We treated 2 rodent models of HF with 10 mg/kg per day empagliflozin and measured activation of the NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome in the heart. We show for the first time that beneficial effects of empagliflozin in HF with reduced ejection fraction (HF with reduced ejection fraction [HFrEF]; n=30-34) occur in the absence of changes in circulating ketone bodies, cardiac ketone oxidation, or increased cardiac ATP production. Of note, empagliflozin attenuated activation of the NLRP3 inflammasome and expression of associated markers of sterile inflammation in hearts from mice with HFrEF, implicating reduced cardiac inflammation as a mechanism of empagliflozin that contributes to sustained function in HFrEF in the absence of diabetes mellitus. In addition, we validate that the beneficial cardiac effects of empagliflozin in HF with preserved ejection fraction (HFpEF; n=9-10) are similarly associated with reduced activation of the NLRP3 inflammasome. Lastly, the ability of empagliflozin to reduce inflammation was completely blunted by a calcium (CA2+) ionophore, suggesting that empagliflozin exerts its benefit upon restoring optimal cytoplasmic CA2+ levels in the heart.

Conclusions: These data provide evidence that the beneficial cardiac effects of empagliflozin are associated with reduced cardiac inflammation via blunting activation of the NLRP3 inflammasome in a CA2+-dependent manner and hence may be beneficial in treating HF even in the absence of diabetes mellitus.

Keywords

animals; heart failure; humans; inflammation; mice.

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