Author + information
- Ven G. Lim, MRCPa,∗,
- Robert M. Bell, PhDa,∗,
- S. Arjun, PhDa,
- Maria Kolatsi-Joannou, PhDb,
- David A. Long, PhDb and
- Derek M. Yellon, PhD, DSca,∗ ()
- aThe Hatter Cardiovascular Institute, University College London, London, United Kingdom
- bDevelopmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
- ↵∗Address for correspondence:
Prof. Derek M. Yellon, The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, United Kingdom.
• Long-term SGLT2 inhibition with dietary canagliflozinin diabetic and nondiabetic rats attenuates myocardial ischemia/reperfusion injury ex vivo.
• This suggests that the improvement in myocardial infarct size by SGLT2 inhibition may occur independent of the glycemic status.
• Canagliflozin improved hyperglycemia in diabetic rats but importantly did not cause hypoglycemia in nondiabetic rats.
• Short-term perfusion of the nondiabetic heart with canagliflozin, solubilized in the Langendorff perfusion buffer, had no impact on the myocardial infarct size.
The authors hypothesized that despite similar cardiovascular event rates, the improved cardiovascular survival from SGLT2 inhibition, seen clinically, could be via a direct cytoprotective effect, including protection against myocardial ischemia/reperfusion injury. Langendorff-perfused hearts, from diabetic and nondiabetic rats, fed long-term for 4 weeks with canagliflozin, had lower infarct sizes; this being the first demonstration of canagliflozin’s cardioprotective effect against ischemia/reperfusion injury in both diabetic and nondiabetic animals. By contrast, direct treatment of isolated nondiabetic rat hearts with canagliflozin, solubilized in the isolated Langendorff perfusion buffer, had no impact on infarct size. This latter study demonstrates that the infarct-sparing effect of long-term treatment with canagliflozin results from either a glucose-independent effect or up-regulation of cardiac prosurvival pathways. These results further suggest that SGLT2 inhibitors could be repurposed as novel cardioprotective interventions in high-risk cardiovascular patients irrespective of diabetic status.
↵∗ Drs. Lim and Bell contributed equally to this work and are joint first authors.
Janssen-Cilag provided funding support for this study and the formulated treatment diets for the long-term oral administration study and the treatment drug for the ex vivo administration study. Dr. Bell is supported by the National Institute of Health (NIHR) University College London Biomedical Research Centre (BRC) and work is supported by the British Heart Foundation (PG/18/10/33550). Dr. Long’s laboratory is supported by a Medical Research Council (MR/P018629/1), Diabetes UK (13/0004763, 15/0005283), Kidney Research UK (RP36/2015), and by the NIHR BRC at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. Prof. Yellon has served on a global advisory board for Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received August 29, 2018.
- Revision received October 11, 2018.
- Accepted October 11, 2018.
- 2019 The Authors