Hu Z, Ju F, Du L, et al. - Subsequent severe lethal ventricular arrhythmia due to myocardial ischemia and reperfusion injury can be prevented by pretreatment with empagliflozin (a selective sodium–glucose cotransporter 2 inhibitor). These protective benefits may result from activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2)-dependent cell-survival signaling pathway in a glucose-independent manner.

• Experimental models were used to determine empagliflozin’s impact on myocardial ischemia/reperfusion-induced cardiac arrhythmia and sudden cardiac death in vivo.

• Male Sprague Dawley rats were randomized to sham-operated, control or empagliflozin groups, and all except for the sham-operated rats were subjected to 5-min left main coronary artery ligation followed by 20-min reperfusion.

• Baseline cardiac normal conduction activity was not modified by empagliflozin.

• However, empagliflozin not only removed myocardial vulnerability to sudden cardiac death (from 69.2% death rate in the control group to 0% in the empagliflozin group) but also decreased the susceptibility to reperfusion-induced arrhythmias after ischemia/reperfusion injury.

• Post-reperfusion injury, increased phosphorylation of cardiac ERK1/2 was brought about by empagliflozin.

• Anti-arrhythmic action of empagliflozin and ERK1/2 phosphorylation were abolished by using U0126 (ERK1/2 inhibitor).