Empagliflozin attenuates arrhythmogenesis via inhibition of O-GlcNAcylation in diastolic phase of diabetic cardiomyopathy

Abstract Background Diabetic cardiomyopathy is an important complication of diabetes mellitus (DM) and reported to increase the risk fatal ventricular arrhythmias. Recent clinical trials showed that empagliflozin (EMPA), a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, improved cardiovascular outcomes regardless presence traditional factors. Despite promising benefit EMPA on heart failure treatment, its beneficial effect in context anti-arrhythmic therapy has not been fully examined. We therefore aimed examine acute treatment especially onto calcium (Ca2+) handling diabetic cardiomyocytes. Methods assessed echocardiography, hemodynamic study, electrophysiology, Ca2+ protein expression C57BLKS/J-leprdb/db mice (db/db mice), leptin receptor-deficient model obesity Type diabetes, their non-diabetic lean heterozygous Leprdb/+ littermates (db/+ mice). Results The 16-week-old db/db had preserved systolic function but exhibited diastolic dysfunction. In arrhythmia induction using ex-vivo Langendorff-perfused hearts, significantly increased premature complex (PVC) by 2x 1μM isoproterenol load than control, which was attenuated perfusion (1 μM). cardiomyocytes frequency spontaneous sparks waves, decreased transient amplitude sarcoplasmic reticulum (SR) content. decay tau time 50% were prolonged These data indicating impaired normalized administration μM), while NHE inhibitor (Cariporide 10 μM) did show significant differences. analysis, CaMKII Thr287 autophosphorylation CaMKII-dependent RyR2 S2814 phosphorylation inhibited short-term (30 min) expressions SERCA2a phospholamban different among three groups. Lastly, whole hearts O-GlcNAcylation, one post translational modifications, reduced treatment. Conclusion intracellular arrhythmogenesis with at dysfunction phase, suggesting may exhibit this normalization via inhibiting O-GlcNAcylation. Funding Acknowledgement funding sources: Private grant(s) and/or Sponsorship. Main source(s): Boehringer Ingelheim