Background. Sodium/glucose co-transporter 2 (SGLT-2) inhibitors improve the outcome of patients with diabetes, heart failure and chronic kidney disease, respectively. The underlying mechanisms are, however, unresolved. SGLP2-inhibitors are also the first class of drugs that improves outcome in patients with heart failure and preserved ejection fraction (HFpEF). Since obesity is an important risk factor for the development and in particular, of HFpEF, we evaluated its impact on excitation-contraction coupling and mitochondrial energetics in a rat model with diet-induced obesity.

Methods and results. Male Wistar rats were fed a high fat, high fructose diet (HFD) for 8 weeks to induce obesity. Afterwards, rats received either the SGLT2-inhibitor empagliflozin (Empa; 10mg/kg/day via drinking water) or regular tap water (CO) for 8-weeks, and could choose between HFD and low fat diet. After 16 weeks, there was no difference in fructosamine levels (0.83 vs. 0.77 mmol/l, p = 0.9). Cardiac ventricular myocytes and mitochondria were isolated from n=3 or 6 rats per group, respectively. Sarcomere length, cytosolic Ca²⁺ (Indo1, AM), mitochondrial redox state (autofluorescence of NAD(P)H and FAD), membrane potential (TMRM) and ROS (DCF) were determined in myocytes using an automatic Ionoptix fluorescence setup. Pacing at 0.3 Hz, followed by β-adrenergic stimulation and increasing stimulation rate to 3 Hz for 3 minutes was employed to subject cardiac myocytes to simulate a physiological increase in workload. Empa treatment lowered [Ca²⁺]_i, but had no effect on the magnitude of cytosolic Ca²⁺-transients (n=70/60 CO/empa). Diastolic sarcomere length (n=100/69 CO/empa) was extended, although fractional sarcomere shortening increased. ROS generation (n=56/30 CO/empa), mitochondrial redox state (n=46/52 CO/empa) and membrane potential (n=69/60 CO/empa) were unaffected. In isolated mitochondria, complex I (pyruvate/malate) or complex II respiration (with succinate), Ca²⁺-retention capacity detected by Calcium-Green, mitochondrial membrane potential using TMRM as well as NAD(P)H levels were unaltered after Empa compared to CO treatment.

Conclusion. In a rat model of diet-induced obesity, in vivo treatment with empagliflozin lowers cytosolic Ca²⁺ concentrations and thereby improves diastolic sarcomere function, while fractional sarcomere shortening is modestly improved without adverse effects on mitochondrial redox state, membrane potential or ROS. These data warrant further studies into the impact of empagliflozin on mechano-energetic coupling also in rats in which obesity is combined with hypertension to induce HFpEF.