肺动脉高压的研究进展

肺动脉高压(PAH)是由不同致病机制导致的、以肺循环压力和肺血管阻力升高为主要特点,主要病理表现是血管收缩、血管重构和原位血栓的形成,最终导致右心负荷增大或心功能不全、肺血流量明显减少,严重影响患者生活质量和预后效果。近年来,PAH的研究在包括分类、致病机制、诊断和治疗等方面均有重大突破.为临床指导治疗肺动脉高压奠定了坚实的基础。     

小儿肺动脉高压治疗进展

肺动脉高压(pulmonary artery hypertension,PAH)是肺血管和肺实质发生病变的主要表现,是由于肺大小动脉、肺微血管和肺静脉受损害而引起的临床常见病征。正常肺动脉压力为15～30mmHg/5-10mmHg,平均压(MPA)为10～20mmHg,肺血管阻     

肺动脉高压与钙通道的相关性

肺动脉高压 (pulmonaryarteryhypertension ,PAH )是慢性阻塞性肺疾患 (chronicobstructivepulmonarydiseases ,COPD)发展成为肺源性心脏病 (肺心病 )的关键环节 ,PAH的形成及其严重程度直接影响着COPD和肺心病的病程及预后。PAH的发病机制相当复杂 ,如各种致病因素造成肺血管内皮细胞功能不全 ,使一些调节血管平滑肌舒缩和增生的体液因子的代谢、生成、释放、转运和分泌过程处于紊乱状态 ,从而增加了肺血管的阻力 ;另外 ,致病因素引起的肺血管平滑肌细胞的异常收缩和增生、肺血管胶原合成增加及弹性蛋白等细胞外基质沉积过多均可以…     

小儿肺动脉高压的内科治疗进展

肺动脉高压(pulmonary arterial hypertension,PAH)是儿科常见的一种难治性疾病,以肺血管床的进行性狭窄为主要特征,分原发性(IPAH)和继发性PAH.无论是IPAH还是继发性PAH,它们的共同病理生理特点是致病因素造成直接肺血管床的损伤.肺血管收缩和重塑、原位血栓形成和血管内皮损伤是可能的病因,血管内皮细胞功能紊乱导致血管收缩和舒张障碍,上皮细胞一氧化氮(NO)及前列环素(PGI2)的合成下降及内皮素(ET)表达的增加引起肺血管收缩反应增强和血管结构重塑,是形成PAH的关键因素.     

肺动脉高压分类及影像学诊断研究进展

肺动脉高压 （pulmonary artefia hypertension,PAH）是以肺血管阻力增加为本质的血流动力学概念,以肺循环高血压为特征的慢性疾病。肺血管阻力进行性增加导致右心衰竭,引起过早死亡．目。肺动脉高压的一般定义：海平面状态下,安静状态时动脉收缩压大于30mmHg或肺动脉平均压大于25mmHg或在活动状态下肺动脉平均压大于30mmHg。     

肺动脉高压发生机制与药物治疗的现状和进展

肺动脉高压（PAH）是一种以肺血管阻力增加、肺动脉压（PAP）升高为主要特征的疾病。患者出现PAH压后可以诱发进行性右心衰竭和肺血管疾病,大部分患者诊断PAH后预期寿命仅有2～3年。近年来随着对PAH发病机制的认识不断深入,治疗水平不断提高,大大改善了患者的生存质量。以下就近年来对PAH的治疗进展作一综述。     

新型磷酸二酯酶5抑制剂CPD1对肺动脉高压大鼠血管收缩的影响

目的探讨新型磷酸二酯酶5抑制剂CPD1对肺动脉高压(pulmonary arterial hypertension,PAH)大鼠肺动脉和主动脉收缩效应的影响。方法一次性腹腔注射野百合碱(monocrotaline,MCT,50 mg·kg^-1),制备PAH大鼠模型,造模7 d后给予CPD1(10 mg·kg^-1·d^-1)灌胃治疗,持续14 d。通过血管环张力检测技术观察CPD1对MCT致PAH大鼠血管收缩效应的作用。结果成功制备PAH大鼠模型;CPD1治疗可显著降低PAH大鼠右心室收缩压和右心质量指数,改善肺小动脉内膜增生情况,抑制苯肾上腺素(phenylephrine,Phen)和内皮素-1(endothelin-1,ET-1)诱导的PAH大鼠肺动脉和主动脉的收缩效应,而对KCl诱导的血管收缩效应无影响。结论磷酸二酯酶5抑制剂CPD1干预能抑制PAH大鼠模型,其机制可能是CPD1抑制PAH大鼠非电压依赖性钙通道功能,引起血管收缩力降低、血管平滑肌增殖减弱和血管重塑减轻。     

肺动脉高压药物治疗新靶点及免疫调节治疗策略

肺动脉高压(PAH)是一种慢性的严重心肺功能障碍性疾病,其病理机制尚不明确,特征是肺血管重构和肺血管阻力增加,病因复杂,病死率高.在过去的几十年中,一氧化氮通路激活剂、内皮素受体拮抗剂和前列环素类似物等靶向药物的出现显著改善了患者结局,但仍难以阻止或逆转PAH的病程进展,因此开发新的药物治疗靶点显得尤为重要.近年来,许...     

瑞司瓜特临床应用进展

瑞司瓜特为首创可溶性鸟苷酸环化酶(s GC)激动剂,获批用于治疗肺动脉高压(PAH)和慢性血栓栓塞性肺动脉高压(CTEPH)。本文综述了口服瑞司瓜特的作用机理及其对成人PAH或CTEPH的临床效果与耐受性。结果表明,瑞司瓜特对PAH和不能手术或做过肺动脉内膜切除术后顽固、复发的CTEPH患者有效,且耐受性良好,可以改善患者运动能力、肺血液动力学参数、WHO功能分级。     

波生坦联合西地那非在先天性心脏病合并肺动脉高压患者中的应用进展

肺动脉高压（PAH）是指一种罕见且预后不良的疾病,当肺动脉平均压>25 mm Hg(1 mm Hg=0.133 k Pa),或者运动时m PAP>30 mm Hg,肺毛细血管嵌压≤15 mm Hg,肺血管阻力>3 Wood(1 Wood=80 dyne s/cm5)诊断为PAH。先天性体肺分流性心脏病（先天性心脏病）是由于缺损部位大量左向右分流导致肺循环容量明显增加,肺血管处于高流量高压力状态,导致肺动脉压力阻力增加,从而导致PAH的发生。对先天性心脏病早期动力性PAH患者,手术治疗可以阻断肺血流量异常增加,阻断PAH进展。但对于肺血管不可逆性改变的患者,即使手术后缺损仍存在。如果不及时治疗,右心房的负担会随着病情的恶化而加重,严重影响患者的生存质量和生存率。因此,对于先天性心脏病合并PAH患者,应用有效药物进行术前、术后短期或长期服用,是治疗PAH的重要手段。近年来,靶向性药物控制肺血管压成为临床研究的热点。波生坦是一类非选择性内皮素受体阻滞剂,而西地那非作为PAP-5抑制剂具有很高的选择性,本文就波生坦联合西地那非治疗先天性心脏病相关性PAH的进展进行综述。     

Hypoxic pulmonary vasoconstriction and vascular contractility in monocrotaline-induced pulmonary arterial hypertensive rats

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodeling of pulmonary arteries (PAs) and increased vascular resistance in the lung. Monocrotaline (MCT), a toxic alkaloid, is widely used for developing rat models of PAH caused by injury to pulmonary endothelial cells; however, characteristics of vascular functions in MCT-induced PAH vary and are not fully understood. Here, we investigated hypoxic pulmonary vasoconstriction (HPV) responses and effects of various vasoconstrictors with isolated/perfused lungs of MCT-induced PAH (PAH-MCT) rats. Using hematoxylin and eosin staining, we confirmed vascular remodeling (i.e., medial thickening of PA) and right ventricle hypertrophy in PAH-MCT rats. The basal pulmonary arterial pressure (PAP) and PAP increase by a raised flow rate (40 mL/min) were higher in the PAH-MCT than in the control rats. In addition, both high K⁺ (40 mM KCl)- and angiotensin II-induced PAP increases were higher in the PAH-MCT than in the control rats. Surprisingly, application of a nitric oxide synthase inhibitor, L-N^G-Nitroarginine methyl ester (L-NAME), induced a marked PAP increase in the PAH-MCT rats, suggesting that endothelial functions were recovered in the three-week PAH-MCT rats. In addition, the medial thickening of the PA was similar to that in chronic hypoxia-induced PAH (PAH-CH) rats. However, the HPV response (i.e., PAP increased by acute hypoxia) was not affected in the MCT rats, whereas HPV disappeared in the PAH-CH rats. These results showed that vascular contractility and HPV remain robust in the MCT-induced PAH rat model with vascular remodeling.     

Endothelial cell dysfunction and cross talk between endothelium and smooth muscle cells in pulmonary arterial hypertension

The pathogenesis of pulmonary arterial hypertension (PAH) involves a complex and multifactorial process in which endothelial cell dysfunction appears to play an integral role in mediating the structural changes in the pulmonary vasculature. Disordered endothelial cell proliferation along with concurrent neoangiogenesis, when exuberant, results in the formation of glomeruloid structures known as the plexiform lesions, which are common pathological features of the pulmonary vessels of patients with PAH. In addition, an altered production of various endothelial vasoactive mediators, such as nitric oxide, prostacyclin, endothelin-1, serotonin, chemokines and thromboxane, has been increasingly recognized in patients with PAH. Because most of these mediators affect the growth of the smooth muscle cells, an alteration in their production may facilitate the development of pulmonary vascular hypertrophy and structural remodeling characteristic of PAH. It is conceivable that the beneficial effects of many of the treatments currently available for PAH, such as the use of prostacyclin, nitric oxide, and endothelin receptor antagonists, result at least in part from restoring the balance between these mediators. A greater understanding of the role of the endothelium in PAH will presumably facilitate the evolution of newer, targeted therapies.     

Iloprost inhalation solution for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a condition that is characterised by increased pulmonary arterial pressure and vascular resistance that can lead to right ventricular failure and death. A variety of disturbances in pulmonary vascular endothelial and smooth muscle function are present in PAH, including reduced production of vasodilator and antiproliferative substances, such as nitric oxide and prostacyclin, and an overproduction of mitogens, such as endothelin. As a result of these observations, therapies have been developed for PAH that specifically target these pathogenic processes, including prostacyclin analogues and endothelin receptor antagonists. This article reviews iloprost inhalation solution, the most recently approved form of prostacyclin therapy that is delivered directly to the lungs by inhalation.     

Endothelin receptor antagonism in pulmonary arterial hypertension – a role for selective ETA inhibition?

ABSTRACT

Background: Pulmonary arterial hypertension (PAH) develops from an abnormal interaction between the endothelium and smooth muscle cells in the pulmonary arteries and is characterized by a progressive increase in pulmonary vascular resistance resulting from vascular remodeling, vasoconstriction, and cellular proliferation. A rapidly progressive disease with limited therapeutic options, PAH may progress to right ventricular failure and death. Endothelin (ET-1), a potent vasoconstrictor, has vascular remodeling properties that contribute to the acceleration of the disease. ET-1 predominantly binds to two receptors, endothelin-A (ET_A) and endothelin-B (ET_B) receptors. ET_A receptors are found on smooth muscle cells only and, when activated, induce vasoconstriction and cellular proliferation. ET_B receptors on smooth muscle cells, when activated, cause vasoconstriction, whereas those on endothelial cells produce vasodilation and clear circulating ET-1. Therefore, a clinically important question arises as to whether selective ET_A receptor antagonism is superior to nonselective dual-receptor antagonism in the treatment of PAH.

Scope: To review clinical trials that studied safety and efficacy of various endothelin receptor antagonists (ETRAs) for the treatment of PAH and address the rationale for the use of either a nonselective or a selective ETRA.

Findings: Nonselective blockade of both ET receptors with the ETRA bosentan has demonstrated benefit in PAH, as have sitaxsentan and ambrisentan, two investigational agents with more selectivity for the ET_A receptor. Data from placebo-controlled studies and long-term, openlabel studies suggest that all ETRAs have similar efficacy, though there is some evidence suggesting that selective ETRAs may have a safer profile.

Conclusion: Both selective and nonselective ETRAs have proven to be efficacious in treatment of PAH patients, and selective ETRAs may have a slightly safer profile. However, because PAH is a rare disease and trials have relatively small numbers of patients, it is difficult to quantify the magnitude of the difference between the different agents.     

Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2

Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6 months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.     

The effect of bosentan on matrix metalloproteinase-9 levels in patients with systemic sclerosis-induced pulmonary hypertension

Summary

Objective: Systemic sclerosis (SSc) is an autoimmune disease that can potentially involve all tissues and organs of the human body. Based on the extent of the disease and organ involvement, different subsets of patients and organ involvement, different subsets of patients have been identified and several classifications proposed have been identified and several classifications proposed aiming to better stratify affected patients. The occurrence aiming to better stratify affected patients. The occurrence of pulmonary arterial hypertension (PAH), characterized of pulmonary arterial hypertension (PAH), characterized by altered tissue remodelling of the entire vessel wall, is the most severe complication that influences prognosis and survival. The molecular basis underlying the vascular damage is not yet known, but a family of enzymes named matrix metalloproteinases (MMPs), with a proteolytic activity towards several extra-cellular matrix (ECM) components, is likely to be involved. Recently, a dual inhibitor of endothelin-1, bosentan, has been successfully evaluated in clinical trials in PAH patients.

Research design and method: The aim of this study is to investigate the expression of MMP-2 and MMP-9 in the serum of different subsets of SSc patients, and in patients treated with bosentan. Thirty-five Caucasian patients with SSc were enrolled in the study, 12 of whom were found to have isolated PAH assessed by Doppler echocardiography. Eight patients fully met the inclusion criteria and were eligible for therapy with bosentan given at the dosage of 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily for 50 weeks¹⁵. The remaining patients (4/12) initiated bosentan therapy for a few weeks and, therefore, were considered at the baseline level only. Serum samples were analysed by gelatine zymography.

Results: The results suggest that MMP-9 but not MMP-2 is differently expressed according to the degree of organ involvement. In particular, MMP-9 serum levels are significantly decreased in PAH with respect to other subsets of SSc patients. Moreover, in bosentan-treated patients, after 12 months of therapy MMP-9 significantly (p < 0.05) increased and correlated with an improved clinical outcome, as measured by the '6-minutes walking' test.

Conclusions: This is the first time that MMP-9 serum levels are reported to be down-regulated in PAH patients and up-regulated following bosentan treatment. Whether MMP-9 has a pathogenetic role in the vascular damage observed in PAH patients or it is a marker of bosentan effectiveness is not yet known. However, MMP-9 may be an important molecule that needs further investigation in SSc patients to better define its role.     

Dissecting histone deacetylase role in pulmonary arterial smooth muscle cell proliferation and migration

Pulmonary Arterial Hypertension (PAH) is a rare and devasting condition characterized by elevated pulmonary vascular resistance and pulmonary artery pressure leading to right-heart failure and premature death.     

辛伐他汀对慢性阻塞性肺疾病合并肺动脉高压患者血管内皮功能及肺动脉压的影响

目的探讨辛伐他汀对慢性阻塞性肺疾病（COPD）合并肺动脉高压患者血管内皮功能及肺动脉压的影响。方法将60例COPD合并肺动脉高压患者随机分为治疗组和对照组各30例。对照组给予吸氧、抗感染、化痰、平喘等常规治疗,治疗组在对照组治疗基础上加用辛伐他汀治疗。利用彩色多普勒超声心动图检测2组治疗前后肺动脉压的变化,并比较2组肺功能变化及血浆一氧化氮（NO）和内皮素-1（ET-1）水平。结果治疗后,2组肺动脉压均低于治疗前,且治疗组低于对照组,差异均有统计学意义（P〈0.05或P〈0.01）。治疗后2组FEV1和FVC均改善,且治疗组肺功能的改善情况优于对照组,差异均有统计学意义（P〈0.05或P〈0.01）。治疗后,治疗组NO水平较治疗前升高,ET-1水平较治疗前降低,差异均有统计学意义（P〈0.05）;且治疗组NO水平高于对照组,ET-1水平低于对照组,差异均有统计学意义（P〈0.05）。结论在常规吸氧、抗感染等治疗的基础上,联合应用辛伐他汀可显著改善COPD合并肺动脉高压患者的血管内皮功能,降低肺动脉高压。     

阻塞型睡眠呼吸暂停综合征与肺高血压研究进展

阻塞型睡眠呼吸暂停综合征是由于患者在睡眠时上呼吸道的阻塞从而导致机体长期反复的间断性缺氧，可引起肺高血压，最终可发展成肺心病。其发生机制可能是由于肺动脉平滑肌细胞钙、钾通道功能失常，血管内皮功能紊乱、免疫炎症反应、凝血功能障碍、肺血管的重塑等因素相互作用的结果。     

Pharmacokinetic drug evaluation of selexipag for the treatment of pulmonary arterial hypertension

Introduction: Management of pulmonary arterial hypertension (PAH) remains challenging even in the contemporary era. Intravenous prostacyclin therapy, while associated with decreased mortality, has practical limitations and requires significant lifestyle modifications. The recently approved long-acting oral IP prostacyclin receptor agonist for treatment of PAH, selexipag, is a non-prostanoid agent that vasodilates, impacts remodeling (anti-proliferative), reduces endothelial cell dysfunction, inhibits platelet aggregation (anti-thrombotic), and increases right heart inotropy.

Areas covered: This review discusses the limitations of non-oral prostacyclin therapy for PAH and describes the factors which led to successful development of selexipag in in vitro and preclinical studies. We review the pharmacokinetics and pharmacodynamics of selexipag. We further discuss the methodology and results of phase II and III trials, which led to approval of selexipag for PAH management.

Expert opinion: As compared to previously developed oral prostacyclins, selexipag has limited adverse effects despite similar or better efficacy. Its final place in the treatment paradigm is not yet clear but it does represent a significant advance in the area of oral PAH therapy.