Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, C/Sant Antoni Mª Claret 167, Barcelona 08025, Spain.
Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.
Eur Heart J. 2024 May 7;45(17):1553-1567. doi: 10.1093/eurheartj/ehae107.
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).
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.
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 (χ2P < .05 vs. all). Cardiac and systemic molecular readouts supported these benefits. Interestingly, AZD3366 abolished ADP-induced light transmittance aggregometry without affecting bleeding time.
Infusion of AZD3366 on top of ticagrelor leads to enhanced cardioprotection compared with ticagrelor alone.
CD39 家族的外核苷酸三磷酸二磷酸水解酶将 ATP 和 ADP 降解为 AMP，然后由细胞外 CD73/外 5-核苷酸酶将 AMP 转化为腺苷。该途径已在抗血栓治疗中进行了探索，但在心肌保护方面研究较少。我们研究了在心肌梗死（MI）的临床前模型中，单独给予替格瑞洛与给予替格瑞洛联合 solCD39L3（AZD3366）是否可以提供额外的心脏保护。
接受 balloon-induced MI（90 分钟）的替格瑞洛治疗的猪，在再灌注前静脉内给予 vehicle、1mg/kg AZD3366 或 3mg/kg AZD3366。所有动物均接受替格瑞洛每日两次治疗 42 天。非治疗性 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）、透光比浊聚集测定、出血时间以及组织学和分子分析。
与对照组相比，替格瑞洛可减少 MI 后第 3 天的水肿形成和梗死面积。与替格瑞洛相比，3mg/kg AZD3366 可使水肿和梗死面积进一步减少 45%，与对照组相比可减少 70%（P<.05）。在第 42 天，所有接受替格瑞洛治疗的猪的梗死面积均下降，特别是接受 3mg/kg AZD3366 治疗的猪（P<.05）。安慰剂猪在第 3 天的左心室射血分数降低，在第 42 天恶化，而替格瑞洛±AZD3366 治疗的动物的左心室射血分数保持不变。接受 3mg/kg AZD3366 的猪在第 3 天给予多巴酚丁胺应激时的左心室射血分数更高，在第 42 天的功能障碍节段性收缩减少（χ2P<.05 与所有）。心脏和全身分子检测结果支持这些益处。有趣的是，AZD3366 消除了 ADP 诱导的透光比浊聚集，而不影响出血时间。
与单独使用替格瑞洛相比，替格瑞洛联合 AZD3366 可提供增强的心脏保护作用。
