Effects of SGLT2 inhibition on cardiac remodeling and heart failure development in rats with aortic stenosis Academic Article uri icon


  • Abstract Introduction Aortic stenosis prevalence has been increasing as population ages. Currently, no medical therapies influence the natural history of aortic stenosis. Sodium glucose co-transporter 2 inhibitors (SGLT2i) have reduced heart failure hospitalization and cardiovascular mortality in heart failure patients with both reduced and preserved ejection fraction. The aim of this study was to evaluate the effects of SGLT2 inhibitor empagliflozin (EMPA) on cardiac remodeling and heart failure development in aortic stenosis rats. Methods Eighteen weeks after supra-aortic banding surgery, male Wistar rats were divided in four groups: Sham (n=15); sham + EMPA (Sham-EMPA, n=16); aortic stenosis (AS, n=27); and aortic stenosis + EMPA (AS-EMPA, n=27). Empagliflozin (10 mg/kg/day) was added to rat chow for 8 weeks. Echocardiogram was performed to evaluate cardiac structure and function. Myocardial collagen content was quantified by histology; activity of antioxidant enzymes and enzymes involved in energy metabolism was assessed by spectrophotometry. Protein expression was quantified by Western blot, and matrix metalloproteinase (MMP) activity by zymography. Statistical analysis: ANOVA and Bonferroni or Kruskal-Wallis and Dunn (p>0.05). Results AS-EMPA group had a lower frequency of anatomopathological heart failure features, a lower left ventricular (LV) dilatation (LV diastolic diameter: Sham 8.390.57; Sham-EMPA 8.250.38; AS 9.800.53; AS-EMPA 9.080.87 mm; LV systolic diameter: Sham 4.240.68; Sham-EMPA 4.190.57; AS 5.720.74; AS-EMPA 5.091.08 mm) and LV mass (Sham 0.850.11; Sham-EMPA 0.820.07; AS 2.190.27; AS-EMPA 1.760.34 g), and better diastolic function (isovolumetric relaxation time: Sham 28.62.28; Sham-EMPA 29.83.04; AS 18.92.59; AS-EMPA 22.95.02 ms) than AS. Systolic function was impaired in both AS and AS-EMPA compared to their respective controls and did not differ between AS-EMPA and AS. AS and AS-EMPA had larger myocyte diameter, higher interleukin-6 protein expression and lower catalase activity than Sham and Sham-EMPA, respectively. AS and AS-EMPA groups had lower enzyme activity from energy metabolism than their respective controls. AS presented higher lipid hydroperoxide concentration, collagen III and p65 NF-kB protein expression, and lower glutathione peroxidase activity than Sham. AS-EMPA had higher collagen I expression and inactive MMP-2 than Sham-EMPA. AS-EMPA presented higher glutathione peroxidase and intermediary active MMP-2, and lower interstitial collagen fraction (Sham 2.680.59; Sham-EMPA 3.160.33; AS 5.680.97; AS-EMPA 3.550.70 %) than AS. Conclusion Empagliflozin improves cardiac remodeling, diastolic function and myocardial oxidative stress, and reduces heart failure feature frequency and interstitial collagen fraction in aortic stenosis rats.

published proceedings

  • European Heart Journal

author list (cited authors)

  • Pagan, L. U., Gomes, M. J., Damatto, F. C., Oliveira, J., Gatto, M., Souza, L. M., ... Okoshi, K.

citation count

  • 0

complete list of authors

  • Pagan, L Urbano||Gomes, MJ||Damatto, FC||Oliveira, JPG||Gatto, M||Souza, LM||Santos, ACC||Borim, PA||Rodrigues, EA||Mota, GAF||Campos, DHS||Murata, GM||Polegato, BF||Okoshi, MP||Okoshi, K

publication date

  • November 2023