长期西地那非治疗慢性血栓栓塞性肺动脉高压

    英国剑桥Ppworth医院Suntharalingam博士开展的一项研究显示，长期使用西地那非治疗不能手术的慢性血栓栓塞性肺动脉高压有一定的疗效。

    在这项双盲安慰剂对照中，19例不能手术的慢性血栓性肺动脉高压患者，随机接受西地那非40mg，一日2次，或安慰剂，连续12周。结果显示，主要终点方面，西地那非组患者的6分钟步行距离长于安慰剂组，但无显著性差异。在次终点方面，西地那非组患者的WHO功能分级和肺血管阻力(PVR)明显改善。17例患者完成12个月的研究。结果显示，6分钟步行距离、心肺血液动力学、心脏指数、生活质量(QOL)评分、肺血管阻力、N端前脑钠素(NT-proBNP)均显著改善。

Long-term Use of Sildenafil in Inoperable Chronic Thromboembolic Pulmonary Hypertension

Tay Suntharalingam, MRCP,Carmen M.Treacy, BSc, et al. CHEST.2008,134(2):229-236.

Background: There are currently no licensed medical therapies for inoperable chronic thromboembolic pulmonary hypertension (CTEPH).

Methods: In this double-blind, placebo-controlled pilot study, 19 subjects with inoperable CTEPH were randomly assigned to sildenafil or placebo for 12 weeks. The primary end point was change in 6-min walking distance (6MWD). Secondary end points included changes in World Health Organization (WHO) class, cardiopulmonary hemodynamics, quality of life (QOL) scores, and N-terminal pro brain natriuretic peptide (NT-proBNP). All subjects were transferred to open-label sildenafil at the end of the study and offered repeat assessment at 12 months.

Results: There were no significant differences between the two groups with respect to change in exercise capacity. However significant improvements were seen in WHO class and pulmonary vascular resistance (PVR). Seventeen subjects were eligible for reassessment at 12 months and demonstrated significant improvements in 6MWD, activity and symptom components of QOL, cardiac index, PVR, and NT-proBNP.

Conclusions: Although this pilot study was insufficiently powered to test the primary end point, it did suggest beneficial effects in favor of sildenafil in several secondary end points at both 3 months and 12 months. Further larger-scale trials of sildenafil in inoperable CTEPH are required to confirm these findings and potentially increase the treatment options available for this devastating disease.

解说：

慢性血慢性血栓栓塞性肺动脉高压

    慢性血慢性血栓栓塞性肺动脉高压栓栓塞性肺动脉高压是指肺动脉及其主要分支由于血栓栓塞所导致的血流受阻，长期不能缓解或进行性加重，导致肺动脉高压。它是肺血栓栓塞症中的一种特殊类型，是血栓不能完全溶解，或者是在深静脉血栓形成反复脱落的基础上继发反复多次栓塞肺动脉，血栓机化，肺动脉内膜慢性炎症并增厚，发展为慢性肺栓塞。它最终导致慢性肺动脉高压和肺的通气/血流灌注失衡，进一步发展会出现呼吸功能不全、低氧血症和右心衰竭。

    急性肺血栓栓塞发生后的解剖学和血流动力学的不完全恢复；肺血栓栓塞的反复发作及与之伴发肺动脉原位血栓形成；血栓机化以及与之伴发的肺血管重塑是慢性血栓栓塞性肺动脉高压形成中的三个重要阶段。这三个阶段顺次或同时出现，在发生、发展过程中相互重叠、相互作用。

     参与肺动脉高压发生的病理生理学机制主要有两个方面：肺动脉的部分阻塞和由于涡流导致的血管活性物质释放。1.在慢性血栓栓塞性肺动脉高压发展过程中，由于肺动脉慢性栓塞，肺血流减少，肺动脉管腔闭塞或狭窄可致肺通气/血流比例失衡；持续的栓子阻塞数周到数月可能会导致慢性肺动脉高压；肺血栓栓塞的反复发作，原位血栓形成，非阻塞部位远端小血管的重塑会导致肺动脉高压进一步加重。2.血栓的部分阻塞和其他原因导致的肺动脉血管内皮的刺激，可以触发肺动脉发生一系列的变化，包括粥样硬化、血管重塑等。血管重塑通常会累及阻塞动脉远端血管，导致压力变化。血栓阻塞与血管重塑协同作用可以使肺动脉压力进一步升高。3.肺内血栓可释放缩血管活性物质，血小板和粥样硬化斑的相互作用可以导致血管活性物质的释放；多种影响因素如低氧血症，内源性血管收缩剂和炎性细胞因子的释放可以维持这一过程，使全肺阻力进一步升高，右心后负荷加重可致右心衰竭。

    对于慢性血栓栓塞性肺动脉高压的诊断与治疗需要多个学科的通力协作，其中包括心胸外科、呼吸科、重症监护病房、心脏科、麻醉和放射科。慢性肺血栓栓塞引起的肺动脉高压内科治疗往往是姑息性的。严重的慢性血栓栓塞性肺支店高压病例，若阻塞部位处于手术可及的肺动脉近端，可考虑行肺动脉血栓内膜剥脱术。慢性大血管栓塞性肺动脉高压，肺血管阻力超过临界值且不适合手术的患者及慢性小血管栓塞性肺动脉高压，临床症状明显药物治疗无效者，可以考虑进行肺移植。