P4230Empagliflozin reduces the doxorubicine-induced myocardial dysfunction

Abstract

Background: Empagliflozin (empa), a selective inhibitor of the sodium glucose co-transporter 2, showed very effective in controlling glycaemia, compared to standard treatment. Moreover, the EMPA-REG OUTCOME trial found a 14% reduction in MACE, a 38% reduction in cardiovascular (CV) death and a 35% reduction in the hospitalization rate for heart failure (HF). Hence, multiple mechanisms have been suggested to explain this dramatic improvement in CV outcomes. In particular, the beneficial effect on HF was apparently independent from glucose control. However, no mechanistic in vivo studies are available to explain these results, yet. Purpose: In this context, we aimed to determine the effect of empa on LV function in doxorubicin-induced cardiomyopathy (DOX-HF) in mice. Methods: Male C57Bl/6 mice were randomly assigned to one of the following treatments: saline plus DOX (n=10), or EMPA plus DOX (n=10). DOX was injected intraperitoneally at weekly doses of 5 mg/kg. EMPA (10 mg/kg) was administered daily by oral gavage for 5 weeks. Cardiac function was evaluated at baseline and 5 weeks later, by Vevo 2100 (Visualsonics). Global Longitudinal Strain (GLS) was evaluated by 2D speckle tracking. After echocardiography, mice were euthanized, and hearts were processed for histological evaluations (Haematoxylin and eosin and Masson's Goldner staining). Results: A significant decrease in LV function was observed after the 5 weeks treatment with DOXO. LV ejection fraction (EF) dropped from 75±5% to 56±13% (p<0.05), while GLS changed from -21±4% to -14%±4% (p<0.05). LV function (64±9% vs 47±3%; p=0.028) and LV fractional shortening (p=0.09) were significantly better in EMPA mice, compared to controls. Hystological evaluation revealed that, compared to controls, hearts from EMPAtreated mice showed a 1.5-fold lower degree of myocardial fibrosis and a 2.5- fold reduction of attenuation of fibrillar bands. Moreover, advanced disarray of myocardial fibers (75% vs. 40%), presence of wavy myocardial fibers (100% vs 40%) and vacuolization of myocytes (100% vs. 60%) were all substantial reduced in EMPA mice compared to controls. Of note, no significant differences were found between EMPA-treated mice and controls, at the end of treatment, in systolic (p=0.99) or diastolic blood pressure (p=0.69), as well as in weight (p=0.28). No significant difference in glycaemia were found between the two groups at the end of treatment (p=0.38). Finally, Empagliflozin treatment was not associated to significant changes in blood glucose and diuresis volume in euglycemic mice. Conclusions: Empagliflozin attenuates the cardiotoxic side effects of doxorubicin in a mouse model of chemotherapy-induced cardiac dysfunction. Interestingly, the protective effect of empagliflozin could be documented both on functional echocardiographical indices and on several structural remodelling parameters, as evidenced at the histological evaluation.