Xue Genlong, Yang Xiaolei, Zhan Ge, Wang Xin, Gao Jinghan, Zhao Yong, Wang Xinying, Li Jiatian, Pan Zhenwei, Xia Yunlong
Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Front Pharmacol. 2022 Oct 14;13:988408. doi: 10.3389/fphar.2022.988408. eCollection 2022.
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. 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. 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. 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 [Ca] 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 [Ca] at baseline and after EMPA (10 umol/L) infusion. EMPA perfusion did not change the APD and CaT 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 ( < 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. 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.
近期临床试验表明，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可改善心肌梗死（MI）患者的心血管结局，但其潜在机制尚不清楚。由于心律失常常发生于心肌梗死期间，它是主要的死亡原因。本研究的目的是探讨SGLT2抑制剂恩格列净（EMPA）对心肌梗死小鼠心脏电生理重塑和心律失常易感性的影响。在心肌梗死后1周从小鼠获取心电图以测定QT间期。在电生理研究中，进行光学标测以评估EMPA的作用及小鼠心肌梗死后的潜在机制。EMPA治疗显著缩短了MI小鼠的QT间期（MI + EMPA组为50.24毫秒，MI组为64.68毫秒）。使用光学标测技术从13个MI心脏和5个正常心脏记录膜电位和细胞内钙[Ca]。采用动态起搏方案测定基线及EMPA（10微摩尔/升）输注后动作电位时程和[Ca]。EMPA灌注对正常心室的动作电位时程和钙瞬变无影响，但在MI心脏的梗死区、边缘区和远隔区，在200毫秒、150毫秒、120毫秒和100毫秒起搏周期长度下可使其缩短。梗死心室的传导速度在基线时为0.278米/秒，正常心室为0.533米/秒（P<0.05）。给予EMPA后，梗死心室的传导速度增至0.363米/秒，而正常心室未观察到显著变化。EMPA灌注后梗死心室的动作电位上升时间、钙瞬变上升时间和钙瞬变衰减时间得到改善，而正常心室未观察到显著变化。EMPA可减少梗死心室的早期后去极化、室性早搏和心室颤动（VF）。EMPA显著降低了梗死心室在心室颤动期间的相奇点数量（基线时为6.26，EMPA时为3.25）、主导频率（20.52对10.675赫兹）和心室颤动持续时间（1.072对0.361秒）。EMPA治疗改善了MI后电生理重塑并减少了MI小鼠VF的基质。SGLT2抑制剂可能是一类预防慢性MI后室性心律失常的新型药物。
