Department of Cardiology, Skåne University Hospital, Lund, Sweden.
BMC Cardiovasc Disord. 2010 Sep 27;10:45. doi: 10.1186/1471-2261-10-45.
Polymorphonuclear neutrophils, stimulated by the activated complement factor C5a, have been implicated in cardiac ischemia/reperfusion injury. ADC-1004 is a competitive C5a receptor antagonist that has been shown to inhibit complement related neutrophil activation. ADC-1004 shields the neutrophils from C5a activation before they enter the reperfused area, which could be a mechanistic advantage compared to previous C5a directed reperfusion therapies. We investigated if treatment with ADC-1004, according to a clinically applicable protocol, would reduce infarct size and microvascular obstruction in a large animal myocardial infarct model.
In anesthetized pigs (42-53 kg), a percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 minutes, followed by 4 hours of reperfusion. Twenty minutes after balloon inflation the pigs were randomized to an intravenous bolus administration of ADC-1004 (175 mg, n = 8) or saline (9 mg/ml, n = 8). Area at risk (AAR) was evaluated by ex vivo SPECT. Infarct size and microvascular obstruction were evaluated by ex vivo MRI. The observers were blinded to the treatment at randomization and analysis.
ADC-1004 treatment reduced infarct size by 21% (ADC-1004: 58.3 ± 3.4 vs control: 74.1 ± 2.9%AAR, p = 0.007). Microvascular obstruction was similar between the groups (ADC-1004: 2.2 ± 1.2 vs control: 5.3 ± 2.5%AAR, p = 0.23). The mean plasma concentration of ADC-1004 was 83 ± 8 nM at sacrifice. There were no significant differences between the groups with respect to heart rate, mean arterial pressure, cardiac output and blood-gas data.
ADC-1004 treatment reduces myocardial ischemia-reperfusion injury and represents a novel treatment strategy of myocardial infarct with potential clinical applicability.
被激活的补体因子 C5a 刺激的多形核粒细胞被认为与心肌缺血/再灌注损伤有关。ADC-1004 是一种竞争性 C5a 受体拮抗剂，已被证明可抑制补体相关的中性粒细胞激活。ADC-1004 在中性粒细胞进入再灌注区域之前阻止它们被 C5a 激活，与以前的 C5a 定向再灌注治疗相比，这可能是一种机制优势。我们研究了根据临床适用方案用 ADC-1004 治疗是否会减少大型动物心肌梗死模型中的梗死面积和微血管阻塞。
在麻醉猪（42-53 公斤）中，在前降支动脉内充气经皮冠状动脉介入球囊 40 分钟，然后再灌注 4 小时。球囊充气后 20 分钟，猪随机静脉推注 ADC-1004（175mg，n=8）或生理盐水（9mg/ml，n=8）。通过体外 SPECT 评估危险区（AAR）。通过体外 MRI 评估梗死面积和微血管阻塞。观察者在随机分组和分析时对治疗情况不知情。
ADC-1004 治疗使梗死面积减少 21%（ADC-1004：58.3±3.4% vs 对照组：74.1±2.9%AAR，p=0.007）。两组间微血管阻塞无显著差异（ADC-1004：2.2±1.2% vs 对照组：5.3±2.5%AAR，p=0.23）。处死时 ADC-1004 的平均血浆浓度为 83±8 nM。两组间心率、平均动脉压、心输出量和血气数据无显著差异。
ADC-1004 治疗可减少心肌缺血/再灌注损伤，代表了一种具有潜在临床适用性的心肌梗死新治疗策略。
