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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12933-020-01208-z |
| _version_ | 1818844885434761216 |
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| author | David Bode Lukas Semmler Paulina Wakula Niklas Hegemann Uwe Primessnig Nicola Beindorff David Powell Raphael Dahmen Hartmut Ruetten Christian Oeing Alessio Alogna Daniel Messroghli Burkert M. Pieske Frank R. Heinzel Felix Hohendanner |
| author_facet | David Bode Lukas Semmler Paulina Wakula Niklas Hegemann Uwe Primessnig Nicola Beindorff David Powell Raphael Dahmen Hartmut Ruetten Christian Oeing Alessio Alogna Daniel Messroghli Burkert M. Pieske Frank R. Heinzel Felix Hohendanner |
| author_sort | David Bode |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T05:20:52Z |
| format | Article |
| id | doaj.art-57d4817c45a544b8a94b775a2cf0aec3 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-12-19T05:20:52Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-57d4817c45a544b8a94b775a2cf0aec32022-12-21T20:34:30ZengBMCCardiovascular Diabetology1475-28402021-01-0120111410.1186/s12933-020-01208-zDual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEFDavid Bode0Lukas Semmler1Paulina Wakula2Niklas Hegemann3Uwe Primessnig4Nicola Beindorff5David Powell6Raphael Dahmen7Hartmut Ruetten8Christian Oeing9Alessio Alogna10Daniel Messroghli11Burkert M. Pieske12Frank R. Heinzel13Felix Hohendanner14Department of Internal Medicine and Cardiology, Charité University MedicineDepartment of Internal Medicine and Cardiology, Charité University MedicineDepartment of Internal Medicine and Cardiology, Charité University MedicineDepartment of Internal Medicine and Cardiology, Charité University MedicineDepartment of Internal Medicine and Cardiology, Charité University MedicineBerlin Experimental Radionuclide Imaging Center (BERIC), Charité-Universitaetsmedizin BerlinLexicon Pharmaceuticals, Metabolism ResearchSanofi-Aventis Deutschland GmbH, Research & DevelopmentSanofi-Aventis Deutschland GmbH, Research & DevelopmentDepartment of Internal Medicine and Cardiology, Charité University MedicineDepartment of Internal Medicine and Cardiology, Charité University MedicineDepartment of Internal Medicine and Cardiology, Charité University MedicineDepartment of Internal Medicine and Cardiology, Charité University MedicineDepartment of Internal Medicine and Cardiology, Charité University MedicineDepartment of Internal Medicine and Cardiology, Charité University MedicineAbstract 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.https://doi.org/10.1186/s12933-020-01208-zAtrial cardiomyopathyHeart failure with preserved ejection fractionSGLT inhibitionAtrial remodelingLeft atrial cardiomyocytesCalcium cycling |
| spellingShingle | David Bode Lukas Semmler Paulina Wakula Niklas Hegemann Uwe Primessnig Nicola Beindorff David Powell Raphael Dahmen Hartmut Ruetten Christian Oeing Alessio Alogna Daniel Messroghli Burkert M. Pieske Frank R. Heinzel Felix Hohendanner Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF Cardiovascular Diabetology Atrial cardiomyopathy Heart failure with preserved ejection fraction SGLT inhibition Atrial remodeling Left atrial cardiomyocytes Calcium cycling |
| title | Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF |
| title_full | Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF |
| title_fullStr | Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF |
| title_full_unstemmed | Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF |
| title_short | Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF |
| title_sort | dual sglt 1 and sglt 2 inhibition improves left atrial dysfunction in hfpef |
| topic | Atrial cardiomyopathy Heart failure with preserved ejection fraction SGLT inhibition Atrial remodeling Left atrial cardiomyocytes Calcium cycling |
| url | https://doi.org/10.1186/s12933-020-01208-z |
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