Protective effect of canagliflozin on post-resuscitation myocardial function in a rat model of cardiac arrest

Abstract

Abstract Background Currently, most patients with cardiac arrest (CA) show reversible myocardial dysfunction, hemodynamic instability, systemic inflammation and other pathophysiological state in early stage of resuscitation, some patients may eventually progress to multiple organ failure. There is evidence that heart failure is the terminal stage in the development of various cardiovascular diseases. Although the cardio-protective effect of canagliflozin (CANA) has been confirmed in large clinical studies and recommended in domestic and international heart failure-related guidelines, the effectiveness of CANA after resuscitation remains unclear. In this study, we constructed a modified CA/CPR rat model to investigate whether CANA administered on post-resuscitation improves myocardial function. Methods Twenty-fourth healthy male Sprague–Dawley rats were randomized into four groups: (1) Sham + placebo group, (2) Sham + CANA group, (3) CPR + placebo group, and (4) CPR + CANA group. Ventricular fibrillation was induced by transcutaneous electrical stimulation on epicardium. After 6 min untreated ventricular fibrillation, chest compressions was initiated. The rats were received an injection of placebo or canagliflozin (3 ug/kg) randomly 15 min after restore of spontaneous circulation (ROSC). Electrocardiogram (ECG) and blood pressure were continuously detected in each group throughout the experiment. The rats were killed 6 h after ROSC to collected the arterial serum and myocardial tissue. Myocardial injury was estimated with concentrations of inflammatory factors, oxidative stress indexes and, apoptosis index, myocardial injury markers, echocardiography and myocardial pathological slices. Results After resuscitation, mean arterial pressure (MAP) were significantly increased after cardiopulmonary resuscitation in CANA group rats when compared with placebo group. Heart rate, body lactate returned and left ventricular ejection fraction (LVEF) to normal levels in a shorter time and the myocardial injury was obviously attenuated in CPR + CANA group. Inflammatory factors (IL-6, TNF-α) and oxidative stress indexes (MAD, SOD, CAT) were dramatically decreased with the administration of CANA. The expression of apoptosis index (BAX, caspase-3) were higher in CPR + placebo group and the expression of anti-apoptosis index (Bcl-2) was lower (P < 0.05). Conclusions The administration of CANA effectively reduces myocardial ischaemia/reperfusion (I/R) injury after cardiac arrest and cardiopulmonary resuscitation (CPR), and the underlying mechanism may be related to anti-inflammation, oxidative stress and apoptosis.

Keywords

• Canagliflozin
• Cardiac arrest
• Post-resuscitation myocardial function
• Myocardial ischaemia/reperfusion injury