The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Canada.
The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Canada; Toronto General Hospital, Canada.
Life Sci. 2021 Jul 1;276:119440. doi: 10.1016/j.lfs.2021.119440. Epub 2021 Mar 27.
Empagliflozin (EMPA) reduces heart failure hospitalization and mortality. The benefit in terms of ventricular arrhythmia and contractility has not been explored.
To determine the direct effects of EMPA on ventricular arrhythmia and cardiac contractility in an ex-vivo model of global ischemia-reperfusion (I/R).
Langendorff-perfused rabbit hearts were subjected to 30 min of complete perfusion arrest and reperfusion. Either EMPA (1 μM) or normal saline (controls) was then infused into the perfusate in a randomized fashion. Ten minutes following drug infusion, calcium imaging was performed. At the end of each experiment, the heart was electrically stimulated 5 times to assess the inducibility of ventricular fibrillation (VF). In a separate series of experiments, left ventricular (LV) pressure and epicardial NADH fluorescence were simultaneously recorded. LV specimens were then collected for western blotting.
Post-ischemia, EMPA treatment was associated with reduction in the induction of VF >10s (rate of induction: 16.7 ± 3.3% vs. 60 ± 8.7% in control hearts, p = 0.003), improvement of LV developed pressure (LVDP; 68.10 ± 9.02% vs. 47.61 ± 5.15% in controls, p = 0.03) and reduction of NADH fluorescence (87.42 ± 2.79% vs. 112.88 ± 2.27% in control hearts, p = 0.04) along with an increase in NAD+/NADH ratio (2.75 ± 0.55 vs. 1.09 ± 0.32 in the control group, p = 0.04) A higher calcium amplitude alternans threshold was also observed with EMPA-treatment (5.42 ± 0.1 Hz vs. 4.75 ± 0.1 Hz in controls, p = 0.006). Sodium-glucose co-transporter-2 (SGLT2) expression was not detected in LV tissues.
EMPA treatment reduced ventricular arrhythmia vulnerability and mitigated contractile dysfunction in the global I/R model while improving calcium cycling and mitochondrial redox by SGLT2-independent mechanisms.
恩格列净（EMPA）可降低心力衰竭住院和死亡率。但尚未探讨其在室性心律失常和收缩性方面的益处。
在体外全心缺血再灌注（I/R）模型中，确定 EMPA 对室性心律失常和心脏收缩力的直接影响。
采用 Langendorff 灌注兔心，完全停搏 30 分钟，再灌注。然后以随机方式将 EMPA（1μM）或生理盐水（对照）注入灌流液。药物输注 10 分钟后进行钙成像。在每个实验结束时，对心脏进行 5 次电刺激以评估室颤（VF）的诱导率。在另一组实验中，同时记录左心室（LV）压力和心外膜 NADH 荧光。然后收集 LV 标本进行 Western blot 分析。
缺血后，EMPA 治疗可降低 >10 秒 VF 的诱导率（诱导率：对照组为 16.7±3.3%，而 EMPA 组为 60±8.7%，p=0.003），改善 LV 发展压（LVDP；对照组为 68.10±9.02%，而 EMPA 组为 47.61±5.15%，p=0.03），降低 NADH 荧光（对照组为 112.88±2.27%，而 EMPA 组为 87.42±2.79%，p=0.04），并增加 NAD+/NADH 比值（对照组为 1.09±0.32，而 EMPA 组为 2.75±0.55，p=0.04）。还观察到 EMPA 治疗时钙振幅alternans 阈值升高（对照组为 4.75±0.1Hz，而 EMPA 组为 5.42±0.1Hz，p=0.006）。LV 组织中未检测到钠-葡萄糖共转运蛋白-2（SGLT2）表达。
EMPA 治疗可降低全心 I/R 模型中的室性心律失常易感性，并通过 SGLT2 非依赖性机制减轻收缩功能障碍，同时改善钙循环和线粒体氧化还原。
