Empagliflozin prevents doxorubicin-induced myocardial dysfunction

Abstract

Background: Empagliflozin showed efficacy in controlling glycaemia, leading to reductions in HbA1c levels, weight loss and blood pressure, compared to standard treatment. Moreover, the EMPA-REG OUTCOME trial demonstrated a 14% reduction of major adverse cardiovascular events (MACE), a 38% reduction in cardiovascular (CV) death and a 35% reduction in the hospitalization rate for heart failure (HF). These beneficial effect on HF were apparently independent from glucose control. However, no mechanistic in vivo studies are available to explain these results, yet. We aimed to determine the effect of empagliflozin on left ventricular (LV) function in a mouse model of doxorubicin-induced cardiomyopathy (DOX-HF).

Methods: Male C57Bl/6 mice were randomly assigned to the following groups: controls (CTRL, n = 7), doxorubicin (DOX, n = 14), DOX plus empagliflozin (DOX + EMPA, n = 14), or DOX plus furosemide (DOX + FURO group, n = 7). DOX was injected intraperitoneally. LV function was evaluated at baseline and after 6 weeks of treatment using high-resolution echocardiography with 2D speckle tracking (Vevo 2100). Histological assessment was obtained using Haematoxylin and Eosin and Masson's Goldner staining.

Results: A significant decrease in both systolic and diastolic LV function was observed after 6 weeks of treatment with doxorubicin. EF dropped by 32% (p = 0.002), while the LS was reduced by 42% (p < 0.001) and the CS by 50% (p < 0.001). However, LV function was significantly better in the DOX + EMPA group, both in terms of EF (61.30 ± 11% vs. 49.24 ± 8%, p = 0.007), LS (- 17.52 ± 3% vs. - 13.93 ± 5%, p = 0.04) and CS (- 25.75 ± 6% vs. - 15.91 ± 6%, p < 0.001). Those results were not duplicated in the DOX + FURO group. Hearts from the DOX + EMPA group showed a 50% lower degree of myocardial fibrosis, compared to DOX mice (p = 0.03). No significant differences were found between the DOX + FURO and the DOX group (p = 0.103).

Conclusion: Empagliflozin attenuates the cardiotoxic effects exerted by doxorubicin on LV function and remodelling in nondiabetic mice, independently of glycaemic control. These findings support the design of clinical studies to assess their relevance in a clinical setting.

Keywords: Cardiotoxicity; Heart failure; Left ventricular function.

Fig. 1

LV systolic function. Mice treated with DOX presented a significant reduction of LV function parameters compared to baseline. On the other hand, mice in the DOX + EMPA group had a significantly better LV function compared to the DOX group

Fig. 2

Speckle tracking analysis. LV strain parameters were severely impaired in the DOX group compared to baseline. Moreover, DOX + EMPA mice had significantly better longitudinal and circumferential strains values compared to the DOX group

Fig. 3

LV diastolic function. a Shows results of E/A Ratio across the groups. b Shows results of E/Eʹ ratio

Fig. 4

Histological sections. The figure shows the effects on myocardial fibrosis and remodelling in the different study groups compared to controls (CTRL)

Fig. 5

SGLT2 in mice heart. a Shows the expression of SGLT2 at western blot (the insert report a cropped picture of the blotting plate). b Reports results of RT-PCR analysis

Fig. 6

LV ERK activity. The bar graph reports mean ERK Activity across all study groups