Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice
Background: Recent clinical trials indicate that sodium–glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in myocardial infarction (MI) patients, but the underlying mechanisms remain unknown. As arrhythmia often occurs during myocardial infarction, it is the main cause of de...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-10-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.988408/full |
| _version_ | 1811241414066962432 |
|---|---|
| author | Genlong Xue Xiaolei Yang Xiaolei Yang Ge Zhan Xin Wang Xin Wang Jinghan Gao Yong Zhao Xinying Wang Jiatian Li Zhenwei Pan Yunlong Xia Yunlong Xia |
| author_facet | Genlong Xue Xiaolei Yang Xiaolei Yang Ge Zhan Xin Wang Xin Wang Jinghan Gao Yong Zhao Xinying Wang Jiatian Li Zhenwei Pan Yunlong Xia Yunlong Xia |
| author_sort | Genlong Xue |
| collection | DOAJ |
| description | Background: Recent clinical trials indicate that sodium–glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in myocardial infarction (MI) patients, but the underlying mechanisms remain unknown. As arrhythmia often occurs during myocardial infarction, it is the main cause of death.Objective: The purpose of this study was to investigate the influence of empagliflozin (EMPA), an SGLT2 inhibitor, on cardiac electrophysiological remodeling and arrhythmia susceptibility of myocardial infarction mice.Methods: ECG was obtained from mice 1 week after MI to determine the QT interval. In an electrophysiological study and optical mapping was performed to evaluate the function of EMPA and underlying mechanisms of post-myocardial-infarction in mice.Results: EMPA treatment significantly reduced the QT interval of MI mice (MI + EMPA 50.24 ms vs. MI 64.68 ms). The membrane potential and intracellular Ca [Cai] were mapped from 13 MI hearts and five normal hearts using an optical mapping technique. A dynamic pacing protocol was used to determine action potential duration and [Cai] at baseline and after EMPA (10 umol/L) infusion. EMPA perfusion did not change the APD80 and CaT80 in normal ventricles while shortening them in an infarct zone, bordering zone, and remote zone of MI hearts at 200 ms, 150 ms, 120 ms, and 100 ms pacing cycle length. The conduction velocity of infarcted ventricles was 0.278 m/s and 0.533 m/s in normal ventricles at baseline (p < 0.05). After EMPA administration, the conduction velocity of infarcted ventricles increased to 0.363 m/s, whereas no significant changes were observed in normal ventricles. The action potential rise time, CaT rise time, and CaT tau time were improved after EMPA perfusion in infarcted ventricles, whereas no significant changes were observed in normal ventricles. EMPA decreases early afterdepolarizations premature ventricular beats, and ventricular fibrillation (VF) in infarcted ventricles. The number of phase singularities (baseline versus EMPA, 6.26 versus 3.25), dominant frequency (20.52 versus 10.675 Hz), and ventricular fibrillation duration (1.072 versus 0.361 s) during ventricular fibrillation in infarcted ventricles were all significantly decreased by EMPA.Conclusion: Treatment with EMPA improved post-MI electrophysiological remodeling and decreased substrate for VF of MI mice. The inhibitors of SGLT2 may be a new class of agents for the prevention of ventricle arrhythmia after chronic MI. |
| first_indexed | 2024-04-12T13:35:47Z |
| format | Article |
| id | doaj.art-b2b91f3d75f24c0c8bf0cc605461b89e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T13:35:47Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-b2b91f3d75f24c0c8bf0cc605461b89e2022-12-22T03:31:01ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-10-011310.3389/fphar.2022.988408988408Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in miceGenlong Xue0Xiaolei Yang1Xiaolei Yang2Ge Zhan3Xin Wang4Xin Wang5Jinghan Gao6Yong Zhao7Xinying Wang8Jiatian Li9Zhenwei Pan10Yunlong Xia11Yunlong Xia12Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Ultrasound, The Affiliated Hospital of Innermongolia Medical University, Huhhot, ChinaInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, ChinaInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, ChinaBackground: Recent clinical trials indicate that sodium–glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in myocardial infarction (MI) patients, but the underlying mechanisms remain unknown. As arrhythmia often occurs during myocardial infarction, it is the main cause of death.Objective: The purpose of this study was to investigate the influence of empagliflozin (EMPA), an SGLT2 inhibitor, on cardiac electrophysiological remodeling and arrhythmia susceptibility of myocardial infarction mice.Methods: ECG was obtained from mice 1 week after MI to determine the QT interval. In an electrophysiological study and optical mapping was performed to evaluate the function of EMPA and underlying mechanisms of post-myocardial-infarction in mice.Results: EMPA treatment significantly reduced the QT interval of MI mice (MI + EMPA 50.24 ms vs. MI 64.68 ms). The membrane potential and intracellular Ca [Cai] were mapped from 13 MI hearts and five normal hearts using an optical mapping technique. A dynamic pacing protocol was used to determine action potential duration and [Cai] at baseline and after EMPA (10 umol/L) infusion. EMPA perfusion did not change the APD80 and CaT80 in normal ventricles while shortening them in an infarct zone, bordering zone, and remote zone of MI hearts at 200 ms, 150 ms, 120 ms, and 100 ms pacing cycle length. The conduction velocity of infarcted ventricles was 0.278 m/s and 0.533 m/s in normal ventricles at baseline (p < 0.05). After EMPA administration, the conduction velocity of infarcted ventricles increased to 0.363 m/s, whereas no significant changes were observed in normal ventricles. The action potential rise time, CaT rise time, and CaT tau time were improved after EMPA perfusion in infarcted ventricles, whereas no significant changes were observed in normal ventricles. EMPA decreases early afterdepolarizations premature ventricular beats, and ventricular fibrillation (VF) in infarcted ventricles. The number of phase singularities (baseline versus EMPA, 6.26 versus 3.25), dominant frequency (20.52 versus 10.675 Hz), and ventricular fibrillation duration (1.072 versus 0.361 s) during ventricular fibrillation in infarcted ventricles were all significantly decreased by EMPA.Conclusion: Treatment with EMPA improved post-MI electrophysiological remodeling and decreased substrate for VF of MI mice. The inhibitors of SGLT2 may be a new class of agents for the prevention of ventricle arrhythmia after chronic MI.https://www.frontiersin.org/articles/10.3389/fphar.2022.988408/fullsodium–glucose cotransporter 2empagliflozinmyocardial infarctionmembrane potentialintracellular Ca2+ |
| spellingShingle | Genlong Xue Xiaolei Yang Xiaolei Yang Ge Zhan Xin Wang Xin Wang Jinghan Gao Yong Zhao Xinying Wang Jiatian Li Zhenwei Pan Yunlong Xia Yunlong Xia Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice Frontiers in Pharmacology sodium–glucose cotransporter 2 empagliflozin myocardial infarction membrane potential intracellular Ca2+ |
| title | Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice |
| title_full | Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice |
| title_fullStr | Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice |
| title_full_unstemmed | Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice |
| title_short | Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice |
| title_sort | sodium glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post myocardial infarction in mice |
| topic | sodium–glucose cotransporter 2 empagliflozin myocardial infarction membrane potential intracellular Ca2+ |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.988408/full |
| work_keys_str_mv | AT genlongxue sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT xiaoleiyang sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT xiaoleiyang sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT gezhan sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT xinwang sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT xinwang sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT jinghangao sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT yongzhao sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT xinyingwang sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT jiatianli sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT zhenweipan sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT yunlongxia sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice AT yunlongxia sodiumglucosecotransporter2inhibitorempagliflozindecreasesventriculararrhythmiasusceptibilitybyalleviatingelectrophysiologicalremodelingpostmyocardialinfarctioninmice |