A Clinical Trial of Aspirin and Simvastatin in Pulmonary Arterial Hypertension

内皮功能障碍和血小板聚集引起肺动脉血管收缩，有丝分裂， 肺动脉高压（PAH）中血栓形成和血管闭塞的异常识别 类花生酸代谢和内皮素-1（ET-1）的产生增加是认识 PAH的病理生理学。胃肠外前列环素类似物和ET-1受体拮抗剂现在是治疗前列腺癌的最佳药物。 PAH的标准治疗。虽然这些疗法干预内皮功能障碍的下游效应， 没有一种方法能够充分解决近端内皮损伤或血小板应答。 HMG-CoA还原酶抑制剂（他汀类药物）和阿司匹林是非常安全，高效的心血管 数百万人使用的疗法。辛伐他汀降低胆固醇，稳定内皮细胞层， 增加一氧化氮的生物利用度，减少氧化应激，并减少炎症。阿司匹林 阻止血小板血栓素A2的产生，抑制血小板聚集。我们研究了辛伐他汀， 阿司匹林在动物模型和PAH患者中的应用结果令人鼓舞。增加一氧化氮， 减少血小板聚集将可能降低肺血管阻力并增加心输出量， 从而改善PAH的结局。我们已经设计了一个II期试验，以启动这两个研究 具有最大效率和最小费用的潜在有用的疗法。我们提出了一个随机的， 安慰剂对照的辛伐他汀和阿司匹林的2 × 2析因试验，招募128例患者回答这些问题 具体目标： 1)确定辛伐他汀是否影响PAH患者6个月时的运动功能。 2)确定阿司匹林是否影响PAH患者6个月时的运动功能。 我们假设，辛伐他汀和阿司匹林将增加患者在6分钟内步行的距离， 呸。 3)为了确定辛伐他汀是否影响6个月时血管内皮功能障碍和损伤， 呸。我们假设辛伐他汀会增加肱动脉血流介导的扩张，降低血管紧张素转换酶活性。 与安慰剂相比的Willebrand因子。 4)确定阿司匹林是否影响PAH患者的血小板功能。 我们假设阿司匹林会降低可溶性P-选择素、血清血栓素B2和/或血栓球蛋白。 PAH患者与安慰剂相比，6个月内。 PAH袭击年轻人，大大缩短他们的寿命。我们的目标是研究安全但创新的 可以重塑肺血管并改善这种目前无法治愈的疾病的结局的疗法 疾病

Endothelial dysfunction and platelet aggregation cause pulmonary artery vasoconstriction, mitogenesis, thrombosis, and vascular obliteration in pulmonary arterial hypertension (PAH) The recognition of abnormal eicosanoid metabolism and increased endothelin-1 (ET-1) production were major advances in understanding the pathophysiology of PAH. Parenteral prostacyclin analogs and ET-1 receptor antagonists are now the standard of care for PAH. While these therapies intervene on downstream effects of endothelial dysfunction, none adequately addresses the proximal endothelial insult or the platelet response. HMG-CoA reductase inhibitors (statins) and aspirin are very safe, highly-effective cardiovascular therapies used by millions of people. Simvastatin decreases cholesterol, stabilizes the endothelial cell layer, increases the bioavailability of nitric oxide, reduces oxidative stress, and decreases inflammation. Aspirin arrests platelet thromboxane A2 production, inhibiting platelet aggregation. We have studied simvastatin and aspirin in animal models and humans with PAH with encouraging results. Increasing nitric oxide and reducing platelet aggregation will likely decrease pulmonary vascular resistance and increase cardiac output, therefore improving outcomes in PAH. We have designed a Phase II trial to initiate the study of these two potentially useful therapies with maximum efficiency and minimum expense. We propose a randomized, placebo-controlled 2 X 2 factorial trial of simvastatin and aspirin enrolling 128 patients to answer these Specific Aims: 1) To determine whether simvastatin affects exercise function at six months in patients with PAH. 2) To determine whether aspirin affects exercise function at six months in patients with PAH. We hypothesize that simvastatin and aspirin will increase the distance walked in six minutes in patients with PAH. 3) To determine whether simvastatin affects endothelial dysfunction and injury at six months in patients with PAH. We hypothesize that simvastatin will increase brachial artery flow-mediated dilatation and lower von Willebrand factor compared to placebo. 4) To determine whether aspirin affects platelet function in patients with PAH. We hypothesize that aspirin will decrease soluble P-selectin, serum thromboxane B2, and /Mhromboglobulin in patients with PAH compared to placebo over six months. PAH strikes young individuals, drastically shortening their lifespan. We aim to investigate safe but innovative therapies which could remodel the pulmonary vasculature and improve outcomes in this currently incurable disease.