Empagliflozin halts deleterious right ventricular remodeling in a model of rats with right ventricular dysfunction

Abstract Background Right ventricular (RV) dysfunction, a frequent condition in the spectrum of heart failure (HF) that is associated with worse outcome, still lacks a specific therapy with a beneficial impact on RV remodeling. Empagliflozin has showed beneficial effects in patients with HF, regardless of ejection fraction, especially on the left chambers. Yet, there is no pre-clinical data regarding the potential effects of empagliflozin on the RV. Aims To assess the effect of empagliflozin (EMPA, 10 mg/kg/day) on the RV in a model of rats with RV dysfunction compared to loop diuretic (furosemide, FURO, 10 mg/kg/day). Methods After an intraperitoneal injection of monocrotaline (MCT, 50 mg/kg), wistar male rats (aged 3 months) were randomized into four groups : sham (n=12, without MCT), MCT (n=12), MCT+EMPA (n=12), MCT+FURO (n=12). Treatment, either EMPA or FURO, began seven days after the MCT injection and the rats were prospectively assessed. The whole cohort was serially assessed by echocardiography (Vevo3100 Fujifilm), stress test, metabolic cage, invasively explored by a right heart catheterization, before sacrifice and histological investigations. Results Compared to the other groups, including MCT+FURO, the MCT+EMPA groups was more likely to have higher diuresis and glycosuria (all, p0.05). Regarding echocardiography, the use of EMPA was associated with a significant improvement in RV function (TAPSE, S wave and fractional area change) and a decrease in RV and right atrial dimensions (Figure, p0.01). Using right heart catheterization, rats from MCT+EMPA group were more likely to have lower right atrial pressure and RV end-diastolic pressure (Figure, p0.05). There was a trend for lower RV fibrosis (red Sirius coloration) in the group MCT+EMPA compared to the other groups (ANOVA p=0.08) as well as regarding survival analyses (ANOVA, p=0.09). Conclusion Empagliflozin seems to halt RV deleterious remodeling in the context of RV dysfunction, reinforcing its interest in HF and particularly in patients with solely predominant RV dysfunction. On-going histological, immune-histological and PCR analyses will allow to better understand cellular pathways involved in this process.