内皮素受体拮抗剂在肺动脉高压中的应用

肺动脉高压是指静息时肺动脉平均压>25 mm Hg(1 mm Hg=0.133 3 kPa)或者运动时肺动脉平均压≥30 mm Hg。随着肺动脉高压发病机制的研究进展,针对细胞增生和血管重塑的治疗大大改善了肺动脉高压的预后。现就内皮素受体拮抗剂在肺动脉高压中的应用进行综述。     

肺动脉高压的治疗进展

肺动脉高压以肺血管床的进行性闭塞为主要特征，是临床上一个常见却治疗困难的疾病，针对细胞增生、血管重塑的治疗——前列环素和内皮素受体拮抗剂的应用改善了原发和继发性肺动脉高压的预后。一些临床试验证实了它们的疗效。     

内皮素受体拮抗剂治疗肺动脉高压进展

肺动脉高压是一种以肺血管阻力升高最终导致右心衰竭的严重的症候群.内皮素在其发生、发展过程中起着重要作用,目前已经认识到内皮素受体拈抗剂对治疗肺动脉高压具有一定疗效.但仍需对其疗效和安全性进行进一步研究.本文将对近年内皮素受体拮抗剂治疗肺动脉高压的研究进展作一综述.     

吸入伊洛前列素治疗重症肺动脉高压三例

肺动脉高压是临床上的常见疾病，一直以来缺乏有效的治疗措施，其致残率和致死率较高。近年来，国外已应用前列环素及其类似物、内皮素受体拮抗剂和磷酸二酯酶抑制剂等药物治疗肺动脉高压，取得较为满意的效果，改善了肺动脉高压患者的预后。我院观察了3例重症肺动脉高压患者吸入伊洛前列素的临床效果，现报道如下。     

肺动脉高压药物治疗进展

肺动脉高压(pulmonary artery hypertension,PAH)是指静息时平均肺动脉压>25 mm Hg,且肺毛细血管压或左房压<15 mm Hg [1].血管扩张剂是治疗肺动脉高压的一类重要药物,能降低肺动脉压力,改善患者血流动力学及肺通气/灌注比值,提高肺动脉高压患者的生活质量,运动耐力以及存活率.其理论基础是肺动脉高压时存在肺动脉的痉挛.当前主要的肺血管扩张剂主要有钙离子拮抗剂、前列环素类药物、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂和一氧化氮.现就肺动脉高压治疗中肺血管扩张剂的应用及部分药物治疗进展进行综述.     

用伊洛前列素吸入治疗心脏病患者围术期肺动脉高压

目前肺动脉高压的治疗仍然是一个棘手的问题,前列环素类似物伊洛前列素是近年来应用较多的肺动脉高压治疗药物,由于其具有高度肺血管选择性、能调节肺血管内皮功能、抑制血管重塑和微血栓形成等药物学特点,因此可明显改善血流动力学和临床症状。本文主要综述吸入伊洛前列素在成人心脏手术围术期肺动脉高压的应用。     

肺动脉高压常规治疗效果及其局限性

肺动脉高压的常规治疗如吸氧、强心、利尿、钙离子拮抗剂和抗凝是肺动脉高压的基本治疗措施,这些方法对少数患者可产生较好的效果,但对多数患者来说疗效并不理想,因此在临床上应把握好应用指征.     

内皮素受体及其拮抗剂与肺动脉高压

内皮素及其受体在左向右分流先天性心脏病肺动脉高压的发生与发展过程中起重要的作用,因此内皮素受体拮抗剂可能是一种新的治疗肺动脉高压的有效方法.     

洛沙坦对大鼠缺氧性肺动脉高压的治疗效应

血管紧张素Ⅱ(AngⅡ)可引起肺血管收缩和肺血管重建而参与肺动脉高压的形成，应用血管紧张素转换酶抑制剂(ACEI)或血管紧张素Ⅱ受体拮抗剂能阻断AngⅡ的合成或作用的发挥，可减轻和延缓肺动脉高压及右室肥厚。洛沙坦(商品名：科素亚)是一种AngⅡ受体拮抗剂，我们采用缺氧复制肺动脉高压模型，以洛沙坦对缺氧大鼠进行治疗，     

内皮素受体及其拮抗剂与肺动脉高压

内皮素及其受体在左向右分流先天性心脏病肺动脉高压的发生与发展过程中起重要的作用,因此内皮素受体拮抗剂可能是一种新的治疗肺动脉高压的有效方法.     

肺动脉高压的诊断和治疗进展

肺动脉高压是一种病死率很高的严重疾病,它以肺血管阻力不断升高为主要特征并最终引起右心衰竭和死亡。近年来,在肺动脉高压的诊断、治疗的研究中取得了长足的进步。规范的诊断和治疗将有助于改善肺动脉高压患者的生活质量和预后。     

肺动脉高压发生的细胞及分子机制

肺动脉高压是由肺动脉张力增加和肺血管重塑联合引起的以肺动脉阻力病理性增加为特征的临床综合征。由于发病机制的不同,且病程各异,这导致了血管表型损伤也种类各异。但比较明确的是随病情的不断加重,由肺动脉高压所导致的血管重塑将发展为固定的、不可逆的病变。现有研究发现,血管壁的三种主要细胞(内皮细胞、平滑肌细胞及成纤维细胞)通过增殖、迁移和细胞外基质沉积共同介导了血管病变。现有的治疗仅着眼于直接舒张肺血管这一层面,而近年来不断累积的实验证据提示,通过降解血管壁内沉积的细胞外基质和调控血管细胞凋亡为靶点的逆转肺血管重塑可望成为肺动脉高压治疗领域全新的理念,这些研究为肺动脉高压治疗提供了新的思路,现就近年来对肺动脉高压的最新研究进行介绍。     

Tumour necrosis factor-related apoptosis-inducing ligand is a novel therapeutic target in pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension is a fatal disease characterised by progressive narrowing of pulmonary arterioles, driven by aberrant cellular proliferation. Identification of key pathways in disease pathogenesis is required for the development of new-targeted therapies. We have previously reported tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic pulmonary arterial hypertension and animal models. Since TRAIL induces endothelial cell apoptosis and smooth muscle cell proliferation, we hypothesised that TRAIL is an important driver of disease in pulmonary arterial hypertension.MethodsWe characterised the expression of TRAIL in human and rodent pulmonary arterial hypertension and determined the effects of TRAIL on pulmonary artery smooth muscle cells (PASMCs) in vitro. Using genetic deletion, pharmacological overexpression, antibody blockade, and bone marrow transplant (BMT) chimera experiments we determined the direct pathogenic role of TRAIL in three independent rodent models of pulmonary arterial hypertension. We then tested the efficacy of inhibiting TRAIL in halting or regressing established disease in two preclinical models. Terminal phenotyping included cardiac catheterisation, echocardiography, and pulmonary vascular immunohistochemistry.FindingsTRAIL mRNA and protein expression was upregulated in PASMCs from patients with pulmonary arterial hypertension. In vitro, TRAIL was a mitogen for PASMCs. TRAIL-deficient mice were protected from both hypoxia-induced and diet-induced pulmonary arterial hypertension. Antibody blockade prevented rats from developing toxin-induced disease. In BMT chimeras, only mice with expression of TRAIL restricted to tissue developed pulmonary arterial hypertension. In rodents with established pulmonary arterial hypertension, an anti-TRAIL antibody reversed pulmonary vascular remodelling, through reducing proliferation and inducing apoptosis, improved pulmonary haemodynamics, and significantly improved survival.InterpretationOur studies are the first to determine the importance of TRAIL in the pathogenesis of pulmonary arterial hypertension and demonstrate its potential for translation into a novel therapeutic targetFundingBritish Heart Foundation.     

Congenital heart disease and pulmonary hypertension: pharmacology and feasibility of late surgery

Pulmonary arterial hypertension (PAH) with increased pulmonary vascular resistance (PVR), previously termed pulmonary vascular obstructive disease or pulmonary vascular disease is a frequent complication of congenital heart disease (CHD).While there have been advances in the medical treatments available for classic Eisenmenger syndrome patients who are not suitable for repair, the sub-group of patients with moderate sized congenital systemic to pulmonary shunts and mild to moderately elevated PVR remains challenging. With the development of targeted medical treatments for pulmonary arterial hypertension (PAH), the concept of a combined medical and interventional/surgical approach for patients with PAH associated with CHD (APAH-CHD) has emerged. Careful evaluation and an understanding of the predominant physiologic features will help guide the management of these complex patients and whether late surgical repair is feasible.     

Genetics of pulmonary hypertension: from bench to bedside.

Primary pulmonary hypertension has been described as either sporadic or clustered in families. Familial primary pulmonary hypertension segregates as an autosomal dominant trait with markedly reduced disease gene penetrance. Defects within bone morphogenetic protein receptor type II gene, coding for a receptor member of the transforming growth factor-beta family, underlie familial primary pulmonary hypertension. Several lines of evidence point to the potential requirement of additional factors, either environmental or genetic, in the pathogenesis of the disease. In addition, a proportion of so-called sporadic primary pulmonary hypertension turns out to have an inherited basis, as demonstrated by germline bone morphogenetic protein receptor type II gene mutations. Analysis of cases in association with hereditary haemorrhagic telangiectasia led to the demonstration that pulmonary arterial hypertension can involve activin-receptor-like kinase 1 mutations, a type I transforming growth factor-beta receptor. These findings emphasise the critical role of the transforming growth factor-beta signalling pathway in pulmonary arterial hypertension. While this achievement has generated extreme interest, the pathobiology of severe pulmonary arterial hypertension remains unclear and genomic approaches to pulmonary hypertension research may identify additional molecular determinants for this disorder. Finally, there is an urgent need to develop relevant guidelines for genetic counselling to assist patients, their relatives and pulmonary vascular specialists to utilise these recent observations.     

肺动脉高压患者的预后评估

肺动脉高压是发病率较低、预后较差的肺血管疾病.近10余年来,随着靶向治疗药物的应用,肺动脉高压的生存率较前有明显的改善;多个登记注册研究和一些临床研究结果的发布,促使对肺动脉高压预后相关的因素有了更加全面的认识.现简要综述各预测因素在肺动脉高压预后评估中的作用,以及肺动脉高压预后模型的建立.     

Evaluating operability in adults with congenital heart disease and the role of pretreatment with targeted pulmonary arterial hypertension therapy

Pulmonary arterial hypertension (PAH) associated with congenital heart disease remains a major problem despite advances in cardiac surgery. Recently, advanced therapies for PAH have become available and have been effective in reducing pulmonary vascular resistance and symptoms in patients with near-systemic pulmonary arterial pressures, previously thought to have irreversible pulmonary vascular disease. This has led to a new dilemma, namely could intracardiac communications previously considered inoperable due to severe pulmonary vascular disease become amenable to surgery after successful treatment with advanced therapy? We address, hereby, the potential merits and hazards of a "treat-and-repair" approach using advanced therapies in patients with PAH associated with congenital heart disease.     

Use of the Prostacyclin Receptor Agonist Selexipag in Patients With Pulmonary Arterial Hypertension Associated With Eisenmenger Syndrome

Eisenmenger syndrome is a multisystem disorder and the most severe form of pulmonary arterial hypertension in adult congenital heart disease. Pulmonary arterial hypertension represents a fatal disease, characterized by increased pulmonary vascular resistance, right heart failure, and death. Although therapeutic management has rapidly advanced in recent years, these patients were not included in randomized controlled trials for specific pulmonary arterial hypertension drugs, except for bosentan. However, in clinical practice we apply treatment strategies combining drugs targeting multiple pathobiological pathways. We present 3 patients with Eisenmenger syndrome and their improvement after starting treatment with selexipag, an oral selective IP prostacyclin receptor agonist.     

The pressure-flow response of the pulmonary circulation in patients with heart failure and pulmonary vascular disease

Although it is well known that the pulmonary circulation is altered in patients with pulmonary arterial or venous hypertension, the resultant hemodynamic behavior has not been systematically studied. We undertook to do so in a group of patients with pulmonary hypertension of diverse etiology. We measured pulmonary arterial (PAP) and occlusive wedge pressures and cardiac output at rest (i.e., standing) and during progressive upright treadmill exercise in 51 patients. Forty-two had chronic, stable, cardiac failure secondary to ischemic, myopathic or valvular heart disease and were grouped according to whether their mean PAP was less than (normotensive) or greater than (hypertensive) 19 mm Hg, and nine had pulmonary vascular disease of diverse etiology and were considered separately. In the majority of patients, we found that irrespective of whether the hypertension was arterial or venous in origin or etiology: the mean PAP-flow relationship was linear; pulmonary capillary wedge pressure was greater than or equal to the average closure pressure of the pulmonary vascular bed and could therefore be used as the downstream pressure in calculating pulmonary vascular resistance; and pulmonary vascular resistance declined with exercise. Notable exceptions to the third observation were patients with valvular heart disease or a resting pulmonary vascular resistance greater than 800 dyne-sec-cm-5.     

前列环素治疗肺动脉高压的临床应用进展

本文综述了近年来前列环素治疗肺动脉高压的临床应用进展。目前已有多种前列环素制剂可以应用于临床：静脉、皮下、口服或吸入;临床治疗范围包括特发性肺动脉高压及结缔结组织性疾病、门脉高压、HIV感染、食欲抑制剂伴肺动脉高压。临床研究结果显示前列腺素制剂可以延长患者寿命、改善心功能、改善运动耐量、改善血液动力学指标（增加心输出量、降低肺动脉压和肺血管阻力）。