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Inhibition of sodium–glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization

  • Hana E. Baker
  • Alexander M. Kiel
  • Samuel T. Luebbe
  • Blake R. Simon
  • Conner C. Earl
  • Ajit Regmi
  • William C. Roell
  • Kieren J. Mather
  • Johnathan D. Tune
  • Adam G. GoodwillEmail author
Original Contribution

Abstract

The goal of the present study was to evaluate the effects of SGLT2i on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion injury in normal, metabolically healthy swine. Lean swine received placebo or canagliflozin (300 mg PO) 24 h prior to and the morning of an invasive physiologic study protocol. Hemodynamic and cardiac function measurements were obtained at baseline, during a 30-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, coronary flow, and myocardial oxygen consumption were unaffected by canagliflozin treatment. Ventricular volumes remained unchanged in controls throughout the protocol. At the onset of ischemia, canagliflozin produced acute large increases in left ventricular end-diastolic and systolic volumes which returned to baseline with reperfusion. Canagliflozin-mediated increases in end-diastolic volume were directly associated with increases in stroke volume and stroke work relative to controls during ischemia. Canagliflozin also increased cardiac work efficiency during ischemia relative to control swine. No differences in myocardial uptake of glucose, lactate, free fatty acids or ketones, were noted between treatment groups at any time. In separate experiments using a longer 60 min coronary occlusion followed by 2 h of reperfusion, canagliflozin increased end-diastolic volume and stroke volume and significantly diminished myocardial infarct size relative to control swine. These data demonstrate that SGLT2i with canagliflozin preserves cardiac contractile function and efficiency during regional myocardial ischemia and provides ischemia protection independent of alterations in myocardial substrate utilization.

Keywords

Pig SGLT2 inhibition Myocardial ischemia Cardiac function Fuel selection Infarct 

Notes

Acknowledgements

The authors wish to thank Joshua Sturek for his assistance in performing the described studies.

Author contributions

HB, AK, AR, WR, and AG performed studies and reviewed/edited the manuscript. HB and AG wrote the manuscript. JD and KM contributed to discussion, study design and reviewed/edited the manuscript. SL, BS, and CE performed studies and quantified infarct data. AG is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

This work was funded by Eli Lilly and Company. Eli Lilly and Company had no role in study design, data collection, data analysis, data interpretation, or writing of the report. BS and SL were supported by T35HL110854. AK was supported by T32DK101001. 

Compliance with ethical standards

Conflict of interest

No conflicts of interest to disclose for AK, KM, JD, SL, BS, CE, and AG. HB is a full-time graduate student at Indiana University and an employee of Eli Lilly and Co., but received no compensation from Eli Lilly for the work performed in this study. AR and WR are both employees of Eli Lilly and Co.

Supplementary material

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Supplementary material 1 (TIFF 819 kb)
395_2019_733_MOESM2_ESM.tif (718 kb)
Supplementary material 2 (TIFF 717 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Hana E. Baker
    • 1
  • Alexander M. Kiel
    • 1
    • 3
  • Samuel T. Luebbe
    • 1
  • Blake R. Simon
    • 1
  • Conner C. Earl
    • 1
    • 3
  • Ajit Regmi
    • 4
  • William C. Roell
    • 4
  • Kieren J. Mather
    • 2
  • Johnathan D. Tune
    • 1
  • Adam G. Goodwill
    • 1
    Email author
  1. 1.Department of Cellular and Integrative PhysiologyIndiana University School of MedicineIndianapolisUSA
  2. 2.Department of MedicineIndiana University School of MedicineIndianapolisUSA
  3. 3.Weldon School of Biomedical EngineeringPurdue UniversityWest LafayetteUSA
  4. 4.Diabetes and Complications Research, Lilly Research LaboratoriesEli Lilly and CompanyIndianapolisUSA

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