Empagliflozin improves diastolic function in obese ZSF1 rats by restoring the cardiac mitochondrial respiratory capacity

Abstract

Abstract Background Clinical studies demonstrated beneficial effects of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) on the combined risk of cardiovascular death or heart failure hospitalization in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes leading to cardioprotection remain unclear. Purpose The present study aimed to elucidate the impact of Empagliflozin on myocardial function and metabolism in a rat model (ZSF1 rat) with established HFpEF and to analyze underlying mechanisms. Methods 24 week old, obese ZSF1 rats were randomized either receiving standard care (obese) or Empagliflozin (Empa, 30 mg/kg/d p.o.). ZSF1 lean rats (lean) served as healthy controls. All animals underwent a baseline, intermediate and final echocardiography. After 8 weeks of treatment, hemodynamics were measured invasively, blood samples were taken, cardiac mitochondrial function was assessed and left ventricular tissue was collected for molecular and histological analyses or for transmission electron microscopy (TEM). Results Compared to the obese control Empa treated obese rats demonstrated a significantly improved diastolic function already at 4 weeks of treatment (E/é: lean: 17.9 ± 0.8; obese: 23.7 ± 0.7, p<0.001 vs. lean; Empa: 21.0 ± 1.1, p<0.05 vs. lean; p<0.05 vs. obese), which reached the level of healthy controls after 8 weeks of treatment (E/é: lean: 17.5 ± 0.7; obese: 24.4 ± 1.1, p<0.001 vs. lean; Empa: 19.4 ± 0.8, p<0.001 vs. obese). This was accompanied by reduced hypertrophy, fibrosis, left ventricular stiffness and inflammation as well as by improved hemodynamics. Except for a slightly improved myocardial ketone body utilization in Empa treated rats, there was no shift in metabolic substrate preference between groups. Cardiac mitochondrial respiratory function observed in untreated obese rats was significantly impaired compared to healthy controls but restored by Empa treatment (Vmax of complex II: lean: 0.15 ± 0.007 nmol O2/s/mg, obese: 0.12 ± 0.004 nmol O2/s/mg, p<0.01 vs. lean; Empa: 0.17 ± 0.006 nmol O2/s/mg, p<0.05 vs. lean, p<0.001 vs. obese). Moreover, mitochondrial respiratory capacity correlated with diastolic function, suggesting a pivotal role of restored respiratory function for improved diastolic relaxation. TEM revealed reduced size of cardiac mitochondria in obese rats, which was significantly restored by Empa. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation and antioxidant metabolism. Conclusions The present study demonstrates for the first time beneficial effects of Empaglifozin on cardiac remodeling, diastolic function and hemodynamics in an obese rat model of HFpEF. These effects were accompanied by improved mitochondrial respiratory function, enhanced ketone body utilization and improved antioxidant capacity.