Necrostatin-1 alleviates reperfusion injury following acute myocardial infarction in pigs

Background: In rodents, it has previously been shown that necrostatin-1 (Nec-1) inhibits RIP1, a central regulator of programmed necrosis, thereby decreasing cell death and reducing infarct size (IS) after ischaemia/reperfusion (I/R) injury. To address unanswered questions on feasibility and efficacy of Nec-1 in a large animal model, we assessed the effects of Nec-1 in a porcine I/R model, relevant to human disease. Materials and methods: In Dalland landrace pigs (69 ± 3 kg), I/R injury was induced by a 75-min surgical ligation of the left circumflex coronary artery (LCx). Ten minutes prior to reperfusion, pigs were randomly allocated to different Nec-1 doses (1·0 mg/kg or 3·3 mg/kg) or vehicle treatment (control, CTRL). Functional endpoints and immunohistological analyses were performed 24 h after reperfusion. Results: Nec-1 3·3 mg/kg significantly reduced IS (n = 6; 24·4 ± 15·6%) compared to Nec-1 1·0 mg/kg (n = 5; 54·8 ± 16·9%) or CTRLs (n = 6; 62·1 ± 26·6%; P = 0·016). In line, LV ejection fraction (LVEF) was significantly higher in Nec-1 3·3 mg/kg, compared to Nec-1 1·0 mg/kg or CTRL treated animals (50·0 ± 12·0% vs. 32·5 ± 12·9% vs. 31·9 ± 6·6%, respectively, P = 0·015). Hemodynamically, a preserved contractility was observed [end-systolic volume at 100 mmHg (ESV100)] at 24-h follow-up (87·6 ± 17·3 mL vs. 74·5 ± 41·1 mL vs. 56·8 ± 11·8 mL, respectively, P = 0·032), reflecting improved cardiac function. Conclusions: In the pig model of I/R injury, intravenous administration of Nec-1 prior to reperfusion was an effective and above all practical therapeutic strategy that significantly reduced IS and preserved left ventricular function. These data highlight the potential of cardioprotection as a promising adjuvant therapy in the setting of early reperfusion following I/R injury.