Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

Abstract

Background Sodium–glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF. Methods 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student’s t-test, as applicable. Results Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium–calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition. Conclusion The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.

Implications of SGLT Inhibition on Redox Signalling in Atrial Fibrillation

“…Investigation of human heart tissue from healthy controls and different cardiac diseases found expression of SGLT 1, but not of SGLT 2 [ 80 , 81 ]. Conversely, we and others have observed expression of SGLT 2 in rat hearts [ 37 , 70 ]. Inhibition of the Na + /H + exchanger and subsequent decrease in cellular [Na + ] has been described in different animal models [ 76 , 78 ].…”

“…Similar effects (accelerated Ca 2+ removal, restored SR Ca 2+ load) were observed in a rat model of carbohydrate-induced metabolic syndrome after 2 weeks of Dapagliflozin treatment [ 38 ]. In left atrial cardiomyocytes, we have been able to observe a reduction in cytosolic [Ca 2+ ] and release amplitude of spontaneous Ca 2+ release events in a rat model of metabolic heart failure with preserved ejection fraction (HFpEF) [ 70 ]. Interestingly, in murine and human cardiomyocytes, 24 h incubation with Empagliflozin in vitro reduced CaMKII activity [ 71 ].…”

“…The effect of SGLTi on intracellular Na + balance in cardiomyocytes is matter of debate [ 76 , 77 ]. Studies in animal models suggest a decrease in cytosolic [Na + ] after treatment with Empagliflozin, to which inhibition of the cardiac Na + /H + exchanger and SGLT-1/2 have been proposed as central mechanisms [ 70 , 76 , 78 , 79 ]. However, conflicting evidence on the expression of SGLT subtypes 1 and 2 in the heart are present, which may be subject to species difference.…”

“…However, experiments in rat ventricular cardiomyocytes did not find an effect of SGLTi on Na + /H + exchanger activity [ 77 ]. A cascade where SGLTi lower [Na + ] and foster NCX dependent Ca 2+ efflux have been suggested [ 70 ]. However, there is demand for further research given the contradictory reports on Na + /H + exchanger activity and Na + balance.…”

“…Following 6 weeks treatment of Sotagliflozin in a rat model of HFpEF, left atrial cardiomyocytes exhibited decreased ROS production in a glucose-fasted state. This observation was accompanied by increased mitochondrial Ca 2+ influx and improved mitochondrial swelling in response to Ca 2+ [ 70 ].…”