Dataset Information

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.

SUBMITTER: Bode D

PROVIDER: S-EPMC7792219 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Bode David D Semmler Lukas L Wakula Paulina P Hegemann Niklas N Primessnig Uwe U Beindorff Nicola N Powell David D Dahmen Raphael R Ruetten Hartmut H Oeing Christian C Alogna Alessio A Messroghli Daniel D Pieske Burkert M BM Heinzel Frank R FR Hohendanner Felix F

Cardiovascular diabetology 20210107 1

<h4>Background</h4>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 tre ...[more]

PMID: 33413413

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Project description:PurposeTo assess the impact of left ventricular (LV) diastolic dysfunction on left atrial (LA) phasic volume and function using dual-source CT (DSCT) and to find a viable alternative prognostic parameter of CT for LV diastolic dysfunction through quantitative evaluation of LA phasic volume and function in patients with LV diastolic dysfunction.Materials and methodsSeventy-seven patients were examined using DSCT and Doppler echocardiography on the same day. Reservoir, conduit, and contractile function of LA were evaluated by measuring LA volume (LAV) during different cardiac phases and all parameters were normalized to body surface area (BSA). Patients were divided into four groups (normal, impaired relaxation, pseudonormal, and restrictive LV diastolic filling) according to echocardiographic findings. The LA phasic volume and function in different stages of LV diastolic function was compared using one-way ANOVA analysis. The correlations between indexed volume of LA (LAVi) and diastolic function in different stages of LV were evaluated using Spearman correlation analysis.ResultsLA ejection fraction (LAEF), LA contraction, reservoir, and conduit function in patients in impaired relaxation group were not different from those in the normal group, but they were lower in patients in the pseudonormal and restrictive LV diastolic dysfunction groups (P < 0.05). For LA conduit function, there were no significant differences between the patients in the pseudonormal group and restrictive filling group (P = 0.195). There was a strong correlation between the indexed maximal left atrial volume (LAVmax, r = 0.85, P < 0.001), minimal left atrial volume (LAVmin, r = 0.91, P < 0.001), left atrial volume at the onset of P wave (LAVp, r = 0.84, P < 0.001), and different stages of LV diastolic function. The LAVi increased as the severity of LV diastolic dysfunction increased.ConclusionsLA remodeling takes place in patients with LV diastolic dysfunction. At the same time, LA phasic volume and function parameters evaluated by DSCT indicated the severity of the LV diastolic dysfunction. Quantitative analysis of LA phasic volume and function parameters using DSCT could be a viable alternative prognostic parameter of LV diastolic function.

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Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

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