Serruys Patrick W, García-García Héctor M, Buszman Pawel, Erne Paul, Verheye Stefan, Aschermann Michael, Duckers Henrikus, Bleie Oyvind, Dudek Dariusz, Bøtker Hans Erik, von Birgelen Clemens, D'Amico Don, Hutchinson Tammy, Zambanini Andrew, Mastik Frits, van Es Gerrit-Anne, van der Steen Antonius F W, Vince D Geoffrey, Ganz Peter, Hamm Christian W, Wijns William, Zalewski Andrew
Thoraxcenter, Ba583, Erasmus MC, Rotterdam, Netherlands.
Circulation. 2008 Sep 9;118(11):1172-82. doi: 10.1161/CIRCULATIONAHA.108.771899. Epub 2008 Sep 1.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture.
This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA(2) inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers.
=0.37). In contrast, Lp-PLA(2) activity was inhibited by 59% with darapladib (P<0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (P=0.22) or plasma high-sensitivity C-reactive protein (P=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5+/-17.9 mm(3); P=0.009), whereas darapladib halted this increase (-0.5+/-13.9 mm(3); P=0.71), resulting in a significant treatment difference of -5.2 mm(3) (P=0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (P=0.95).
Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA(2) inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA(2) inhibition may represent a novel therapeutic approach.
脂蛋白相关磷脂酶A2（Lp-PLA2）在冠状动脉病变的坏死核心中大量表达，其酶活性产物可能导致炎症和细胞死亡，使斑块易于破裂。
本研究比较了12个月的达拉匹林（一种口服Lp-PLA2抑制剂，每日160毫克）或安慰剂治疗对330例经血管造影证实患有冠心病患者的冠状动脉粥样硬化可变形性（血管内超声触诊）和血浆高敏C反应蛋白的影响。次要终点包括坏死核心大小（血管内超声射频）、粥样斑块大小（血管内超声灰阶）和血液生物标志物的变化。
=0.37）。相比之下，达拉匹林可使Lp-PLA2活性降低59%（与安慰剂相比，P<0.001）。12个月后，两组在斑块可变形性（P=0.22）或血浆高敏C反应蛋白（P=0.35）方面无显著差异。然而，在安慰剂治疗组中，坏死核心体积显著增加（4.5±17.9立方毫米；P=0.009），而达拉匹林阻止了这种增加（-0.5±13.9立方毫米；P=0.71），导致显著的治疗差异为-5.2立方毫米（P=0.012）。这些斑块内成分变化在总粥样斑块体积方面无显著治疗差异（P=0.95）。
尽管坚持高水平的标准治疗，但接受安慰剂的患者坏死核心仍在继续扩大。相比之下，用达拉匹林抑制Lp-PLA2可防止坏死核心扩大，而坏死核心扩大是斑块易损性的关键决定因素。这些发现表明，抑制Lp-PLA2可能代表一种新的治疗方法。
