Background and Aims The ecto–nucleoside triphosphate diphosphohydrolases of the CD39 family degrade ATP and ADP into AMP, which is converted into adenosine by the extracellular CD73/ecto-5-nucleotidase. This pathway has been explored in antithrombotic treatments but little in myocardial protection. We have investigated whether the administration of solCD39L3 (AZD3366) confers additional cardioprotection to that of ticagrelor alone in a pre-clinical model of myocardial infarction (MI). Methods Ticagrelor-treated pigs underwent balloon-induced MI (90 min) and, before reperfusion, received intravenously either vehicle, 1 mg/kg AZD3366 or 3 mg/kg AZD3366. All animals received ticagrelor twice daily for 42 days. A non-treated MI group was run as a control. Serial cardiac magnetic resonance (baseline, Day 3 and Day 42 post-MI), light transmittance aggregometry, bleeding time, and histological and molecular analyses were performed. Results Ticagrelor reduced oedema formation and infarct size at Day 3 post-MI vs. controls. A 3 mg/kg AZD3366 provided an additional 45% reduction in oedema and infarct size compared with ticagrelor and a 70% reduction vs. controls (P < .05). At Day 42, infarct size declined in all ticagrelor-administered pigs, particularly in 3 mg/kg AZD3366-treated pigs (P < .05). Left ventricular ejection fraction was diminished at Day 3 in placebo pigs and worsened at Day 42, whereas it remained unaltered in ticagrelor ± AZD3366-administered animals. Pigs administered with 3 mg/kg AZD3366 displayed higher left ventricular ejection fraction upon dobutamine stress at Day 3 and minimal dysfunctional segmental contraction at Day 42 (χ2 P < .05 vs. all). Cardiac and systemic molecular readouts supported these benefits. Interestingly, AZD3366 abolished ADP-induced light transmittance aggregometry without affecting bleeding time. Conclusions Infusion of AZD3366 on top of ticagrelor leads to enhanced cardioprotection compared with ticagrelor alone.

中文翻译：

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CD39L3 和替格瑞洛的重组人可溶性结构域：对实验性心肌梗死的心脏保护作用

背景和目的 CD39 家族的胞外核苷三磷酸二磷酸水解酶将 ATP 和 ADP 降解为 AMP，AMP 被胞外 CD73/胞外 5-核苷酸酶转化为腺苷。该途径已在抗血栓治疗中进行了探索，但在心肌保护方面却很少。我们研究了在心肌梗死 (MI) 临床前模型中，给予 solCD39L3 (AZD3366) 是否比单独使用替格瑞洛具有额外的心脏保护作用。方法 替格瑞洛治疗的猪接受球囊诱导的 MI（90 分钟），并在再灌注前静脉注射载体、1 mg/kg AZD3366 或 3 mg/kg AZD3366。所有动物每天两次接受替格瑞洛治疗，持续 42 天。将未治疗的 MI 组作为对照。进行了连续心脏磁共振（基线、MI后第3天和第42天）、透光率聚集测量、出血时间以及组织学和分子分析。结果 与对照组相比，替格瑞洛在 MI 后第 3 天减少了水肿形成和梗塞面积。与替格瑞洛相比，3 mg/kg AZD3366 使水肿和梗塞面积额外减少 45%，与对照相比减少 70%（P < .05）。在第42天，所有接受替卡格雷的猪的梗塞面积均下降，特别是接受3mg/kg AZD3366治疗的猪（P＜0.05）。安慰剂猪的左心室射血分数在第 3 天降低，并在第 42 天恶化，而在替格瑞洛 ± AZD3366 给药的动物中左心室射血分数保持不变。给予3 mg/kg AZD3366的猪在第3天的多巴酚丁胺应激下表现出较高的左心室射血分数，并且在第42天表现出最小的功能失调节段性收缩（相对于全部，χ2 P <0.05）。心脏和全身分子读数支持了这些益处。有趣的是，AZD3366 消除了 ADP 引起的透光率聚集测量，而不影响出血时间。结论 与单独使用替格瑞洛相比，在替格瑞洛基础上输注 AZD3366 可增强心脏保护作用。