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Necrostatin‐1 alleviates reperfusion injury following acute myocardial infarction in pigs
Author(s) -
Koudstaal Stefan,
Oerlemans Martinus I. F. J.,
Van der Spoel Tycho I. G.,
Janssen Aafke W. F.,
Hoefer Imo E.,
Doevendans Pieter A.,
Sluijter Joost P. G.,
Chamuleau Steven A. J.
Publication year - 2015
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/eci.12391
Subject(s) - medicine , ejection fraction , myocardial infarction , contractility , reperfusion injury , infarction , ischemia , anesthesia , cardiology , heart failure
Background In rodents, it has previously been shown that necrostatin‐1 (Nec‐1) inhibits RIP 1, 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 ( LC x). 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 CTRL s ( 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 ( ESV 100 )] 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.