慢性血栓栓塞性肺动脉高压实验动物模型的建立

目的：建立操作简便,成功率高,接近人体生理学的慢性血栓栓塞性肺动脉高压的动物模型.方法：[1]实验于2004-12/2005-03在北京大学第一医院动物实验中心完成.选用健康杂种犬12只.[2]给予健康杂种犬戊巴比妥静脉麻醉后,取血50 mL,加入凝血酶静置制备成血栓.切开颈外静脉插入7 F导管,经导管向颈外静脉内注射自体血栓适量,同时监测生理指标.[3]达到实验标准后,缝合静脉切口及皮肤切口,给予抗生素,动物饲养15,30,60 d后,重复上述麻醉和注栓实验步骤.所有动物分别于第一次注栓前和注栓后第90天记录平均肺动脉压、肺毛细血管嵌压、心输出量、呼吸频率、潮气量、气体流速、胸内压.肺血管阻力=（平均肺动脉压-肺毛细血管嵌压）/心输出量.采用Amdur和Mead方法利用呼吸频率、潮气量、呼吸流速和胸内压计算肺气道阻力和肺动态顺应性.内皮素1水平测定用放射免疫非平衡法.[4]采用实验动物模型建立前后平均肺动脉压、肺血管阻力、肺气道阻力和肺动态顺应性,以及血浆内皮素1水平作为判定模型建立成功与否的标准.[5]显著性比较用配对t检验.结果：[1]动物模型建立成功率为83%（10/12）.[2]成活动物饲养第90天血浆内皮素1水平、肺动脉平均压、肺血管阻力、肺气道阻力明显高于注栓前[（35.3&;#177;7.2）pg/L,（28&;#177;5）mm Hg,（5.71&;#177;0.68）（mm Hg&;#183;min）/L,（128.47&;#177;34.32）Pa/（L&;#183;s）;（20.6&;#177;6.3）pg/L,（12&;#177;2）mm Hg,（2.71&;#177;0.23）（mm Hg&;#183;min）/L,（61.78&;#177;5.88）Pa/（L&;#183;s）,P＜0.05],肺动态顺应性明显低于注栓前[（1.23&;#177;0.36）,（1.68&;#177;0.20）mL/kPa,P＜0.05].结论：用自体血栓连续注射法建立慢性血栓栓塞性肺动脉高压动物模型有较高的可行性.     

肺脏内皮功能障碍与慢性血栓栓塞性肺动脉高压

慢性血栓栓塞性肺动脉高压（chronic thromboembolic pulmonary hypertension,CTEPH）是继急性肺栓塞发生后,血栓未能完全溶解或发生血栓扩展,进而机化,造成受累血管狭窄或闭塞而引起解剖学肺血管床的减少以及神经体液因素和低氧血症所致肺血管痉挛、功能性的肺血管床面积减少,导致血管阻力增大而引起肺动脉高压.有统计资料表明,临床确诊为急性肺栓塞的患者中约有0.1%～4.0%患者可能发生CTEPH,然而大多数患者在诊断为慢性血栓性疾病前并未发现急性肺栓塞性疾病,因此CTEPH的真正发病率可能更高.据尸检诊断,目前在美国多于10万人患有CTEPH.……     

肺灌注断层显像评价肺动脉血栓内膜剥脱术对慢性血栓栓塞性肺动脉高压的疗效

目的 采用⁹⁹Tc^m-人体大颗粒聚合白蛋白（⁹⁹Tc^m-MAA）肺灌注断层显像评价肺动脉血栓内膜剥脱术（PTE）对慢性血栓栓塞性肺动脉高压（CTEPH）的疗效。方法 对16例CTEPH患者分别于术前、术后6~12个月行肺灌注断层显像,观察术前、术后肺叶、肺段灌注病变及改善情况,计算全肺灌注缺损百分比（PPDs%）,并采用超声心动图观察术前、术后肺动脉收缩压（SPAP）的变化。结果 16例患者术后SPAP[（36.56±8.47） mmHg]较术前[（90.52±14.55） mmHg]明显减低（t=14.14,P<0.001）。PTE术前16例患者的96个肺叶中有86个（86/96,89.58%）存在灌注异常,术后完全改善、部分改善的肺叶分别为21个（21/86,24.42%）、65个（65/86,75.58%）;术前16例患者的304个肺段中,230个（230/304,75.66%）肺段灌注异常,术后完全改善、部分改善和未改善的肺段分别为73个（73/230,31.74%）、74个（74/230,32.17%）和83个（83/230,36.09%）。术前PPDs%为（56.79±14.54）%,术后6~12个月降低为（28.20±15.24）%（t=8.13,P<0.001）。PPDs%与同期SPAP呈正相关（r=0.68,P<0.001）。结论 PTE可使CTEPH患者的SPAP明显降低,肺血流灌注明显改善,肺灌注显像可有效评价PTE疗效。     

慢性血栓栓塞性肺动脉高压的误诊分析

1　研究对象和方法1. 1　研究对象　本院收治的慢性血栓栓塞性肺动脉高压(CTEPH)患者共 7例,其中男性 2例,女性 5例。年龄最小 40岁,最大 66岁[(52±9. 52)岁]。均经螺旋CT肺血管造影(CTPA)和肺通气灌注扫描证实至少有一个肺段以上的肺栓塞,超声多普勒检测肺动脉收缩压力>30mmHg以上。1. 2　研究方法　分析被入选CTEPH的临床资料,计算其误诊率,统计其误诊病程、病种和误诊的次数。2　结果2. 1　症状体征　气短 7例,心悸 6例,乏力 6例,咳嗽 4例,胸闷 5例,咯血 1例,胸痛 1例。阳性体征有低血压 1例,紫绀 4例,肺部血管杂音 2例,心前区收…     

超声引导下犬自体血栓栓塞性急性肺动脉高压模型的建立及意义

目的 探讨超声引导下建立肺动脉血栓栓塞所致犬急性肺动脉高压模型的可行性.方法 模拟人体急性肺动脉血栓栓塞的病理生理过程,建立肺动脉血栓栓塞所致的犬急性肺动脉高压模型.超声引导下经股静脉穿刺,放置右心导管监测肺动脉压力,同时对侧股静脉推注自体血栓,以肺动脉收缩压超过30 mmHg为模型建立成功的标准.结果 超声可以准确引导右心导管的放置.实验用犬27只,成功建立急性肺动脉高压模型24只,成功率88.9%.结论 超声引导下建立肺动脉血栓栓塞所致犬急性肺动脉高压模型的方法具有良好的可行性和可重复性.     

慢性血栓栓塞性肺动脉高压的现状与进展

慢性血栓栓塞性肺动脉高压( chronic throm boem bolic pulm onaryhypertension,CTEPH)是急性肺栓塞或肺动脉原位血栓形成的长期后果,由于种种原因血栓未溶解而持续存在,通过机化、纤维化形成。CTEPH发生率虽然较低,但预后很差,最终进展至右心衰竭而死亡。近年来,肺动脉内膜剥脱术的成功实施以及新药物的出现使CTEPH预后大为改观。因此,充分认识其自然病程,及时诊断并采取正确的干预措施,对降低病死率、延长生存期、提高患者生活质量有重要意义。1　自然史CTEPH与急性肺血栓栓塞密切相关,临床观察显示,1次急性栓塞事件或反复血栓栓…     

慢性肺动脉血栓栓塞动物模型的建立

背景:目前国内外接近人体生理学的慢性肺动脉血栓栓塞的动物模型较少见。目的:采用自体血栓反复注射法建立慢性肺动脉血栓栓塞的动物模型。方法:将家兔随机分为栓塞组和假栓塞组,栓塞组家兔肺动脉多次注入自体血栓,假栓塞组用生理盐水替代血栓。结果与结论:栓塞组干预4周后解剖肺动脉并经病理检测可发现有血栓机化,肺动脉CT造影均可见局部肺动脉截断征,以及炎症、梗死、胸膜增厚等间接征象,肺动脉解剖及病理均可发现实验兔肺动脉血栓形成机化及慢性炎症改变。结果证实,采用兔自体血栓反复注射法可成功建立慢性肺血栓栓塞动物模型。     

慢性肺动脉栓塞实验动物模型构建的技术进展

目的:综述国内外关于慢性血栓栓塞性肺动脉高压(chronic thromboembolism pulmonary hypertension,CTEPH)实验动物模型构建技术的研究概况.方法:应用计算机检索PubMed数据库2006/2009相关文章,检索词为"model of pulmonary thromboembolism".同时计算机检索中国期刊全文数据库2003/2009相关文章,检索词为"肺动脉栓塞,实验".此外还手工查阅相关专著数部.纳入标准:①文章所述内容应与CTEPH实验研究相关,包括慢性血栓栓塞性肺动脉高压流行病学,不同实验动物及不同制备方式.②同一领域选择近期发表或在权威杂志上发表的文章.排除标准:①重复研究.②Meta分析.结果与结论:目前用于CTEPH模型制备的实验动物主要有犬、猪和鼠等.很多研究者都尝试模仿深静脉血栓形成后,多次急性肺栓塞事件所导致的CTEPH形成机制,建立CTEPH验动物模型.建立犬CTEPH模型主要有反复自体血凝块注入法及陶瓷念珠输入法,可用于CTEPH病理生理特点、数字剪影检查、解剖研究以及肺动脉内膜剥脱手术和介入治疗等干预治疗血栓栓塞性肺动脉高压的研究与影像学诊断技术的研究.建立猪CTEPH模型主要采用体外注入栓子法,可用于影像技术诊断CTEPH研究.建立鼠CTEPH模型主要采用反复自体血凝块注入法与肺动脉结扎法,可用于CTEPH病理生理及诊断方面研究.目前对CTEPH的研究主要是使用犬、猪和鼠实验动物模型,各有优缺点,在具体的实验研究中需根据实验目的和设计选择适当的实验动物及制作方法,以便取得最佳的实验结果.     

慢性血栓栓塞性肺动脉高压的诊断

肺栓塞是由于内源性或外源性栓子阻塞肺动脉或其分支引起肺循环障碍的临床和病理生理综合征。肺栓塞临床表现复杂多样,慢性血栓栓塞性肺动脉高压（ＣＴＰＨ）是肺栓塞一种较特殊的临床类型,易误诊和漏诊,现介绍如下。１发病机制大多数急性肺栓塞随着治疗或通过正常的血...     

超声评价慢性血栓栓塞性肺动脉高压患者肺动脉球囊成形术后右房功能

目的:应用超声诊断技术评价慢性血栓栓塞性肺动脉高压(Chronic thromboembolic pulmonary hypertension,CTEPH)患者肺动脉球囊成形术(Ballon angioplasty of pulmonary artery,BPA)术后右房功能的变化,结合血流动力学,对手术效果做出评价,...     

Bosentan for chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe and underdiagnosed disease characterized by progressive hypertension secondary to organized thrombi in pulmonary vessels. The arteriolar lesions of CTEPH are similar to those seen in idiopathic pulmonary arterial hypertension (PAH). Surgical disobliteration of the vessels by pulmonary endarterectomy is the therapy of choice but this is not suitable for all cases. To date, there is no licensed specific drug for CTEPH. Endothelin-1, a vasoconstrictor and promoter of cell proliferation, is involved in the pathogenesis of both CTEPH and PAH. Bosentan, the first oral dual endothelin receptor antagonist, has been shown to be effective in PAH. Preliminary uncontrolled and/or unblinded studies reported efficacy of bosentan in CTEPH, and the only randomized, controlled trials showed a positive hemodynamic effect but failed its other co-primary end point, namely the improvement of 6-min walking distance. Nevertheless, bosentan has been shown to be safe and the data from most literature encourage its use for inoperable CTEPH. However, further randomized controlled trials are needed to definitively establish bosentan as a standard drug for CTEPH.     

Pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension

INTRODUCTION: Pulmonary thromboendarterectomy (PTE) is a surgical procedure which is considered the only effective and potentially curative treatment for chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is a rare outcome from pulmonary emboli and, when left untreated, will result in right ventricular failure and death. METHODS: From June 1999 to November 2003, 40 of these procedures were performed in our institution. Emphasis is placed on multidisciplinarity and cooperation between different medical and surgical disciplines. Perfusion management consists of myocardial and cerebral protection, deep hypothermia with multiple periods of circulatory arrest, reperfusion at hypothermia, hemofiltration and cellsaving techniques. RESULTS: Hemodynamic improvement occurs immediately post operation. Mean pulmonary artery pressure decreased from 50 +/- 11 to 38 +/- 10 mmHg, pulmonary vascular resistance from 1246+482 to 515 +/- 294 dynes s/cm5 and cardiac index increased from 1.54 +/- 0.54 to 2.63 +/- 0.75 L/min per m2. Pump runs had an average duration of 187 +/- 29 min, circulatory arrest time was 29 +/- 11 min and crossclamp time 36 +/- 14 min. Extracorporeal membrane oxygenation can be an ultimate treatment for specific postoperative problems like persistent pulmonary hypertension and/or reperfusion pulmonary edema.     

Treprostinil for severe inoperable chronic thromboembolic pulmonary hypertension

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) results from non‐resolving pulmonary thromboemboli that are resistant to plasmatic anticoagulation. Because of a secondary pulmonary arteriopathy accompanying major vessel obstruction, the disorder may be a target for vasodilator therapy. Objectives: In an open‐label uncontrolled study, we investigated the prostacyclin analog treprostinil given s.c. in patients with severe inoperable CTEPH. Methods: Between September 1999 and September 2005, 25 patients were included if their World Health Organization (WHO) functional class was III or IV, if their six‐minute walking distance (6‐MWD) ≤ 380 m, and if they had undergone at least one hospitalization for right heart decompensation within the prior six months, albeit not within one month before treatment start. Right heart catheterization was performed at baseline and after a minimum of 12 months (range: 12–33 months) of treatment. Treprostinil plasma concentrations were determined after at least six months of treatment. A historical group of 31 patients at our center with inoperable CTEPH matched for disease severity was used for comparative analyses. Results: Treprostinil‐treated patients demonstrated significant improvements in 6‐MWD (P = 0.01), WHO functional class (P = 0.001), B‐type brain natriuretic peptide plasma levels (P = 0.02), cardiac outputs (P = 0.007) and pulmonary vascular resistances (P = 0.01) after 19 ± 6.3 months. Treprostinil plasma concentrations correlated with drug dose (P < 0.001), indicating stable absorption over time. Long‐term survival was significantly better than in controls. Conclusions: Treprostinil improves exercise capacity, hemodynamics and survival in patients with severe inoperable CTEPH. We speculate that the effects may be explained by a combined vasodilatatory, platelet‐antagonistic and potential antiproliferative action of the drug.     

Endovascular treatment for chronic pulmonary hypertension: a focus on angioplasty for chronic thromboembolic pulmonary hypertension

Introduction: Percutaneous transluminal pulmonary angioplasty (PTPA) was introduced for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) in the late 20^th century, and first attempts in collective patients were made in 2001 with beneficial effects but a moderate amount of complications. It was refined around 2010, and has been recently established as an effective and safe treatment.

Areas covered: The indication was originally inoperable CTEPH with peripheral lesions, but has now widened to symptomatic or hypoxic patients. The lesion is typically a meshwork-like structure of organized thrombi and is sometimes not seen as a stenosis angiographically, necessitating other means of investigation such as measurement of distal pressure. The technique to treat lesions is the same as for coronary angioplasty except in several ways.

Expert commentary: The effects of PTPA are comparable to those of surgical endarterectomy, and the complications of reperfusion pulmonary edema and vascular injury are now controlled by several strategies and based on experience.     

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: State of the art

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complex chronic disease in which pulmonary artery stenosis or obstruction caused by organized thrombus can lead to increased pulmonary artery pressure and pulmonary vascular resistance, ultimately triggering progressive right heart failure and death. Currently, its exact mechanism is not fully understood. Pulmonary endarterectomy (PEA) has immediate effects with low perioperative mortality and satisfactory prognosis in experienced expert centers for CTEPH patients with proximal lesions. Nevertheless, 37% of patients are deemed unsuitable for PEA surgery due to comorbidities and other factors, and nearly half of the operated patients have residual or recurrent pulmonary hypertension. Riociguat is the only approved drug for CTEPH, although its effect is limited. Balloon pulmonary angioplasty (BPA) is a promising alternative treatment for patients with CTEPH. After more than 30 years of development and refinements, emerging evidence has confirmed its role in patients with inoperable CTEPH or residual/recurrent pulmonary hypertension, with acceptable complications and comparable long-term prognosis to PEA. This review summarizes the pathophysiology of CTEPH, BPA history and development, therapeutic principles, indications and contraindications, interventional procedures, imaging modalities, efficacy and prognosis, complications and management, bridging and hybrid therapies, ongoing clinical trials and future prospects.     

Pulmonary capillary endothelial metabolic function in chronic thromboembolic pulmonary hypertension

Summary.  Background:  Chronic thromboembolic pulmonary hypertension (CTEPH) causes physical plugging of large pulmonary arteries as well as a distal micro-vasculopathy. Pulmonary endothelium is an active metabolic tissue in normal humans. The effects of CTEPH on pulmonary endothelial metabolism are unknown. Objectives:  We studied pulmonary capillary endothelium-bound angiotensin converting enzyme (ACE) activity as an index of endothelial metabolism in patients with CTEPH. Patients/methods:  We measured single-pass transpulmonary per cent metabolism (%M) and hydrolysis of an ACE synthetic substrate and calculated functional capillary surface area (FCSA), normalized to body surface area (BSA), in 13 patients with CTEPH and 23 controls. Results:  Mean %M for CTEPH (71.6 ± 4.0% SE) was similar to controls (74.7 ± 2.7%). Substrate hydrolysis ( v ) was similar for CTEPH (1.47 ± 0.22) and controls (1.51 ± 0.11). However, FCSA/BSA was reduced ( P  < 0.01) for CTEPH (1530 ± 218 mL min⁻¹*m⁻²) as compared with controls (2948 ± 245). Conclusions:  The metabolically functional pulmonary capillary bed is reduced in CTEPH. However, because %M and hydrolysis are preserved, this points to a reduction in functional capillary surface area rather than reduced ACE activity on the pulmonary capillary endothelial cell. The reduction in functional capillary surface area may just be a result of decreased capillary recruitment because of upstream vascular plugging by chronic organized thrombus.