The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Improves Graft Contractile Function following Heart Transplantation in Rats

Background: Heart transplantation (HTX) remains the gold standard treatment for patients with end-stage heart failure. Efforts have been taken to enhance the posttransplant graft function and reduce the ischemia/reperfusion injury (IRI) during HTX. Sodium-glucose cotransporter (SGLT)-2 inhibitors, used to treat type 2 diabetes mellitus, have been shown to protect against myocardial IRI in nondiabetic conditions. Hence, we hypothesized that canagliflozin (CANA), a SGLT-2 inhibitor, improves posttransplant graft function when given to the recipients in a rat model of HTX.

Method: The donor hearts from male Lewis rats were arrested, explanted, and stored for 1 hour in cold Custodiol solution before the implantation. Five minutes before the reperfusion, the recipient male Lewis rats received either saline (HTX + placebo, n = 8) or CANA (HTX + CANA, 10 µg/kg, n = 8) via inferior vena cava. Left ventricular (LV) graft function was evaluated after 1-hour reperfusion under different LV volumes via a Millar catheter. Additionally, the myocardial expression of 88 genes, involved in inflammation, apoptosis, and oxidative stress, was profiled using polymerase chain reaction (PCR) array.

Results: After HTX, a significantly improved graft systolic function was observed in the HTX + CANA group compared with HTX + placebo rats (LV systolic pressure 117 ± 7 vs. 94 ± 9 mm Hg; LV developed pressure 112 ± 7 vs. 89 ± 9 mm Hg, at the intraventricular volume of 170 μL, p < 0.05). Furthermore, the rate pressure product, used to determine the myocardial workload, was significantly increased in the HTX + CANA hearts compared with the HTX + placebo group (23,211 ± 1,922 vs. 18,727 ± 1,316 mm Hg*beats/min, at an intraventricular volume of 170 μL, p < 0.05). Among the tested genes, IRI significantly altered the expression of 17 genes, including that of Il1a, which was reduced 2-fold by CANA treatment. Furthermore, the overexpression of Hspa1a, was prevented by CANA.

Conclusion: CANA improves graft LV systolic function when administered to the heart transplant recipients in a small animal model.

Publication History

Article published online:
03 February 2022