Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used for the treatment of type 2 diabetes mellitus (T2DM). Recent data unveiled beneficial effects of SGLT2 inhibitors on cardiovascular events in heart failure with preserved ejection fraction (HFpEF), including diabetic cardiomyopathy. Besides Empagliflozin, the highly potent selective SGLT2 inhibitor Dapagliflozin (DAPA) was shown to reduce the risk of cardiovascular events and hospitalization in HF. Nevertheless, the described pathophysiological mechanism of beneficial effects are still a matter of debate. Concerning this, experimental models in rodents revealed modulatory effects of DAPA on the cardiac calcium (Ca²⁺) handling in diabetes. However, its effect on the cardiomyocytes affected by diabetic cardiomyopathy is rather speculative.

Methods: To confirm diabetic cardiomyopathy, echocardiography was performed at baseline (18 weeks) and at two different stages of diabetic cardiomyopathy (36 and 44 weeks of age). Cytosolic and mitochondrial Ca²⁺ transients were analyzed in isolated rat ventricular cardiomyocytes from the diabetic cardiomyopathy rat model of Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Upon continuous contraction in a field stimulation chamber, the fluorescent signals (Fluo-4, AM and Rhod-2, AM) of 10 µM DAPA and 1 µM DAPA treated myocytes as well as untreated cells were recorded at 37°C.

Results: Echocardiography indicated a significant decrease but still preserved ejection fraction (EF) in our rat model (EF>75%). Importantly, a marked increase in intraventricular septum thickness (IVS) as well as a biatriale enlargement were observed after 36 weeks, as well as 46 weeks of age, indicating diastolic dysfunction. Interestingly, in 36 weeks rats, Ca²⁺ transient measurements unveiled a significant reduction of intracellular Ca²⁺ currents when treated with 10 µM DAPA (p=0.0009), while mitochondrial Ca²⁺ currents were not influenced by the DAPA treatment (p=0.1543). Also at the age of 44 weeks, DAPA was shown to significantly reduce cytosolic Ca²⁺ currents when treated with 10 µM DAPA (p=0.0046) or 1 µM DAPA (p=0.0020) in comparison to untreated cells, respectively. In addition to that, DAPA was shown to reduce the duration of rapid depolarizing Ca²⁺ influx as well as the time of cytosolic Ca²⁺ decay. The 10-fold reduction of the DAPA concentration (from 10 µM to 1 µM) was shown to have a minor impact on the Ca²⁺ transients measured.

Conclusion: In our model of diabetic cardiomyopathy with HFpEF, DAPA treatment seems to reduce cytosolic but not mitochondrial Ca²⁺ transients. These results indicate major alterations of Ca²⁺ handling in diabetic cardiomyocytes. Further, studies need to investigate the effect of SGLT-2 inhibitors, in particular DAPA, on the cardiomyocytes’ function as well as their electrophysiological properties.

This study was supported by Paracelsus Medical University (R-018/02/105/-JIR).