肺动脉高压联合治疗的荟萃分析

目的 对现已完成的肺动脉高压联合治疗的随机对照试验进行荟萃分析,评价肺动脉高压联合治疗的有效性和安全性.方法 检索Cochrane图书馆、MEDLINE、EMBASE、PubMed、Elsevier数据库、中国生物医学文献数据库和ClinicalTrials.gov等中2001～2012年已完成的有关肺动脉高压联合治疗的随机对照试验,按纳入排除标准收集相关资料.按Cochrane系统评价方法,由2名评价者独立评价所纳入研究的文献质量,提取有效数据后,采用RevMan 5.1软件进行荟萃分析.结果 纳入9个随机对照研究,包括979例肺动脉高压患者.荟萃分析结果显示:与单药治疗组相比,联合用药组能改善患者6分钟步行距离,加权标准差(WMD)=24.37 m,95％CI=11.24～37.50(P＜0.01)、降低临床恶化率(RR =0.50,95％ CI =0.31～0.83,P＜0.01),但不能降低患者病死率(RR=0.55,95％CI=0.21～1.44,P＞0.05).联合用药组与单药治疗组间药物相关的严重不良事件率和研究中断率(RR=0.86,95％ CI =0.52～1.44,P＞0.05)差异无统计学意义.结论 与单药治疗相比,联合用药可提高肺动脉高压患者运动耐量,减少临床恶化,而且联合用药是安全的、易耐受的;但对患者病死率无影响.尚需更多大型的随机对照试验来进一步评价联合治疗的有效性和安全性.     

Genetic aspect of pulmonary arterial hypertension

This paper concentrates on the genetic aspects of pulmonary arterial hypertension (PAH), a diagnostically based subclass of pulmonary hypertension that includes primary pulmonary hypertension (PPH). During the past year, patients with familial and sporadic PPH were found to have germline heterozygous missense, nonsense and frameshift mutations in bone morphogenetic protein receptor II (BMPRZ). Mutations in BMPR2, a member of the transforming growth factor-β (TGF-β) receptor superfamily, are predicted to interrupt the bone morphogenetic protein (BMP) signalling pathway, resulting in proliferation, rather than apoptosis of cells within small arterioles. Mechanistically, haploinsufficiency was found by using in vitro gene expression experiments, but a dominant-negative mechanism has not been excluded. The failure to find BMPR2 mutations in all families with familial PPH and in all patients with sporadic PPH suggests that other genes remain to be identified. Mutations in ALK1, a TGF-β type 1 receptor, previously known to cause type 2 hereditary haemorrhagic telangiectasia (HHT), have also been reported in a few HHT families with clinical and histological features of PPH. The clinical development of PPH, as in neoplasia, appears to require ‘two hits’. The two hits can be provided either by genetic or environmental factors.     

Diagnosis and treatment of pediatric pulmonary arterial hypertension

Introduction: Pediatric pulmonary arterial hypertension (PAH) remains a rare and severe disease with a poor prognosis. PAH may be idiopathic, heritable or associated with systemic conditions in particular associated with congenital heart disease.

Areas covered: A thorough and extensive diagnostic approach is required for a correct diagnosis. The outcome has improved over the last decade with a better diagnostic approach and with the initiation of new targeted therapies. However, there is still significant progress to achieve as there is still no cure for this devastating disease.

Expert opinion: Adapted clinical studies to define the best therapeutic approach are needed. Even if the treatment approach is still mainly derived from adult data and expert consensus, several studies and registries are currently underway and should deliver important information in the next future.

This review aims to give an overview of the current diagnosis and treatment strategies of PAH.     

Computed tomography angiographic parameters of pulmonary artery as prognostic factors of residual pulmonary hypertension after pulmonary endarterectomy

ObjectivesThis study aimed to retrospectively assess using computed tomography pulmonary angiography (CTPA) for predicting residual pulmonary hypertension (RPH) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy (PEA).MethodsWe retrospectively analyzed data of 131 patients with CTEPH who underwent PEA in our center (2008–2015). We measured several diameters of the pulmonary artery and thoracic aorta preoperatively. We evaluated the relationship between these measurements (and their indices) and signs of RPH represented by pulmonary artery systolic pressure (PASP) estimated by echocardiography.ResultsSignificant correlations were observed between the aortopulmonary index and prediction of any residual hypertension and moderate/severe hypertension 1 year after PEA, and any residual hypertension and severe hypertension 2 years after PEA. The aortopulmonary index was significantly related to a reduction in PASP 1 year after the operation. A lower aortopulmonary index (≤0.88 for the ascending aorta and ≤0.64 for the descending aorta) predicted lower RPH.ConclusionsPreoperative CTPA parameters can be used to assess the risk of RPH after PEA. The aortopulmonary index has significant predictive value for RPH and a reduction in PASP after PEA. Lower values of the aortopulmonary index suggest a better outcome after PEA.     

硫化氢可通过改善肺动脉内皮间质转化减轻野百合碱诱导的大鼠肺动脉高压

目的：探讨硫化氢（H2S）对野百合碱（MCT）诱导的大鼠肺动脉高压（PAH）的影响，以及内皮间质转化（EndMT）在其中发挥的作用。方法：选择40只雄性SD大鼠，将其随机分为对照组、模型组、硫氢化钠（NaHS）组和炔丙基甘氨（PAG，H2S合成抑制剂）组。模型组、NaHS组和PAG组大鼠予以一次性腹腔注射MCT（60mg/kg）制备PAH模型，7d后，分别给予腹腔注射0.9%氯化钠溶液、NaHS（1mg·kg-1·d-1）、PAG（10mg·kg-1·d-1）干预14d。MCT注射21d后，通过右心导管检测各组大鼠肺动脉压力，随后处死大鼠，评估肺动脉重构和肺动脉EndMT情况。另将人肺动脉内皮细胞（HPAECs）予以0.9%氯化钠溶液或NaHS（50、100、200μmol/L）预处理2h，然后予以转化生长因子-β1（TGF-β1，10ng/mL）刺激1h、3d、10d，分别观察Snail的表达、EndMT情况及细胞形态学变化。结果：与对照组相比较，模型组大鼠的肺动脉收缩压（PASP）、平均肺动脉压（mPAP）、右心室肥厚指数（RVHI）、肺小动脉管壁厚度、肺组织α平滑肌肌动蛋白（α-SMA）、肺组织Snail水平均升高（P<0.05），血管内皮钙黏蛋白（VE-cadherin）表达水平降低（P<0.05）。予以NaHS干预后，这一趋势被逆转；而予以PAG干预后，相关指标则进一步恶化（P<0.05）。体外实验结果显示，TGF-β1刺激后，HPAECs梭形细胞增加，α-SMA、Snail表达升高（P<0.05），VE-cadherin表达减少（P<0.05）；NaHS预处理可剂量依赖性地抑制TGF-β1诱导的HPAECs形态学变化及α-SMA、VE-cadherin和Snail表达水平变化。结论：H2S可减轻MCT诱导的PAH，其机制可能与其抑制肺动脉EndMT有关。     

Cardiovascular magnetic resonance in pulmonary hypertension

Background

To assess changes in right heart flow and pulmonary artery hemodynamics in patients with repaired Tetralogy of Fallot (rTOF) we used whole heart, four dimensional (4D) velocity mapping (VM) cardiovascular magnetic resonance (CMR).

Methods

CMR studies were performed in 11 subjects with rTOF (5M/6F; 20.1 ± 12.4 years) and 10 normal volunteers (6M/4F; 34.2 ± 13.4 years) on clinical 1.5T and 3.0T MR scanners. 4D VM-CMR was performed using PC VIPR (Phase Contrast Vastly undersampled Isotropic Projection Reconstruction). Interactive streamline and particle trace visualizations of the superior and inferior vena cava (IVC and SVC, respectively), right atrium (RA), right ventricle (RV), and pulmonary artery (PA) were generated and reviewed by three experienced readers. Main PA net flow, retrograde flow, peak flow, time-to-peak flow, peak acceleration, resistance index and mean wall shear stress were quantified. Differences in flow patterns between the two groups were tested using Fisher's exact test. Differences in quantitative parameters were analyzed with the Kruskal-Wallis rank sum test.

Results

4D VM-CMR was successfully performed in all volunteers and subjects with TOF. Right heart flow patterns in rTOF subjects were characterized by (a) greater SVC/IVC flow during diastole than systole, (b) increased vortical flow patterns in the RA and in the RV during diastole, and (c) increased helical or vortical flow features in the PA's. Differences in main PA retrograde flow, resistance index, peak flow, time-to-peak flow, peak acceleration and mean wall shear stress were statistically significant.

Conclusions

Whole heart 4D VM-CMR with PC VIPR enables detection of both normal and abnormal right heart flow patterns, which may allow for comprehensive studies to evaluate interdependencies of post-surgically altered geometries and hemodynamics.     

When cure is care: diagnosis and management of pulmonary arterial hypertension

PURPOSE: The purpose of this article is to provide nurse practitioners with an understanding of the pathophysiology of pulmonary arterial hypertension (PAH) disease, clinical manifestations, diagnostic evaluation, drug therapy, strategies for health promotion, and relevant care issues for patients and families. DATA SOURCES: Selected clinical and research articles, as well as current government guidelines. CONCLUSIONS: Symptoms expressed are more apparent as PAH disease progresses, leaving fewer treatment options in advanced disease stages. New drugs are currently being tested for the treatment of PAH; however, the costs of many of the currently approved treatments may be prohibitive. IMPLICATIONS FOR PRACTICE: Earlier recognition of disease symptoms leads to prompt initiation of diagnostic evaluation and referral to specializing medical centers. Upon referral, specialty centers may begin appropriate treatment regimens earlier in the disease process, which could improve clinical outcomes and quality of life.     

基于单中心的波生坦治疗先天性心脏病相关肺动脉高压有效性及安全性分析

目的：回顾性观察波生坦治疗先天性心脏病相关肺动脉高压的远期有效性与安全性。 方法：经临床诊断后,纳入先天性心脏病相关肺动脉高压患者33例,其中2例为外科手术后患者,3例为介入封堵后患者,28例为临床诊断重度肺动脉高压存在手术禁忌症患者,我们对这些患者进行了5年左右的随访,波生坦的用量从62.5mg bid开始,4周后若无明显的副反应则加量至125mg bid。服药前分别进行6分钟步行试验（6MWD）,心超估测肺动脉压,评定心功能等级,肝功能检查,6个月后复查上述指标,之后每半年随访一次。平均随访年限为4.7±0.5年。 研究结果：33例患者（其中女性患者26例,平均年龄31岁,心功能II-IV级,5例接受封堵或修补手术）,死亡1例,接受波生坦口服治疗平均长达4.6年。随访至第三年时,患者6分钟步行试验距离从基线从303.0±88.1m增加至3年时的370.1±68m（P<0.001）;肺动脉收缩压（SPAP）从基线时的113.7±26.7mmHg降至92.9±31.8mmHg（P<0.001）;NYHA心功能分级从基线2.5±0.6降至2.2±0.6（P＝0.018）。肝功能指标：谷丙转氨酶（ALT）在随访期间均无显著性差异。但在3年随访之后,肺动脉收缩压,6分钟步行试验和心功能分级的改善情况开始明显减缓,甚至呈现“逆升高”趋势,服药五年后随访肺动脉收缩压、6分钟步行距离分别为101.0±32.8mmHg, 332±86m,较服药前基线数据仍有明显统计学差异（P=0.018,P=0.02）,患者心功能分级升至2.4±0.6,较服药前无明显统计学差异（P=0.43）。 结论：波生坦可以降低先天性心脏病相关重度肺动脉高压的肺动脉压力,有效控制其进行性升高趋势,改善心功能分级,提高患者的活动耐量,且对肝功能无明显影响。但在长期随访中,波生坦的作用逐步趋向下降,其长期效用仍待更多临床试验证实。     

Extended-release oral treprostinil for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance ultimately resulting in progressive right heart failure. Although new specific treatments have demonstrated improvements in various end points including morbidity/mortality, prognosis remains unfavorable with an on-treatment yearly mortality rate of 10%. Due to complex delivery systems, the use of parenteral prostanoids has been limited to patients with advanced disease. While inhaled prostanoids have had little effect, an oral prostacyclin analog is a desired initial treatment for PAH patients. To that end, UT-15C was synthesized as a sustained-release tablet. FREEDOM-M in treatment-naïve PAH patients resulted in significant improvements of 6-min walk distance supporting the use of oral treprostinil as initial monotherapy in PAH patients with class II or III symptoms. A further study targeting patients on combination treatments is currently exploring a morbidity/mortality end point in a large patient population.     

Sitaxsentan: an endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension

Endothelin (ET-1) is a potent vasoconstrictor and smooth muscle mitogen that mediates its effects through activation of ET-A and ET-B receptors. Pulmonary arterial hypertension (PAH) encompasses a heterogeneous group of disorders characterised by inappropriate overactivation of the ET system. There is clear evidence that strategies that block both ET receptors are associated with clinical improvement in PAH. However, there are theoretical physiological advantages to treatments that specifically inhibit only the ET-A receptor. Sitaxsentan is an orally active selective ET-A receptor antagonist that in recent clinical trials has demonstrated improvements in exercise capacity, functional class and haemodynamics in PAH patients with modified New York Heart Association class II, III and IV symptoms.     

前列地尔治疗小儿重度高原性肺动脉高压的临床疗效

目的观察小儿高原性重度肺动脉高压(HPAH)患者接受静脉注射前列地尔治疗的临床疗效。方法 33例重度HPAH患者接受静脉注射前列地尔,用量5～7ng/(kg.h)持续静脉注射,治疗时间7～10d,观察其对心功能和非侵入性血流动力学参数的影响。结果纽约心脏病协会(NYHA)心功能级别改善,非侵入性血流动力学参数明显改善:肺动脉收缩压从(69.9±18.3)mm Hg下降至(35.8±13.0)mm Hg,每搏输出量治疗前(36.2±16.7)mL,治疗后(37.7±18.4)mL,动脉血气氧分压和二氧化碳分压轻微增加。血浆B型利钠肽浓度治疗前(7 799.2±6 451.6)pg/mL,治疗后(1 887.7±1 263.7)pg/mL,治疗后明显下降,差异有统计学意义(P<0.01)。结论静脉注射前列地尔治疗能明显降低重度HPAH患者肺动脉压力,改善心功能。     

Pulmonary arterial hypertension

Pulmonary arterial hypertension is a disease of the small pulmonary arteries characterized by vascular narrowing and increased pulmonary vascular resistance, which eventually leads to right ventricular failure. Vasoconstriction, vascular proliferation, remodeling of the pulmonary vessels, and thrombosis are all contributing factors to the increased vascular resistance seen in this disease. Pulmonary arterial hypertension develops as a sporadic disease (idiopathic), as an inherited disorder (familial), or in association with certain conditions (collagen vascular diseases, portal hypertension, human immunodeficiency virus infection, congenital systemic‐to‐pulmonary shunts, ingestion of drugs or dietary products, or persistent fetal circulation). The pathogenesis of pulmonary arterial hypertension is a complicated, multifactorial process. It seems doubtful that any one factor alone is sufficient to activate the necessary pathways leading to the development of this disease. Rather, clinically apparent pulmonary arterial hypertension most likely develops after a second insult occurs in an individual who is already susceptible owing to genetic factors, environmental exposures, or acquired disorders. Currently, there is no cure for pulmonary arterial hypertension but several novel therapeutic options are now available that can improve symptoms and increase survival.     

Sitaxsentan: a novel endothelin-A receptor antagonist for pulmonary arterial hypertension

Sitaxsentan is an orally active, selective endothelin-A receptor antagonist that may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictive effects of endothelin-A receptors, while maintaining the vasodilator and endothelin-1 clearance functions of the endothelin-B receptors. In its first randomized, placebo-controlled study, sitaxsentan improved exercise capacity assessed by the 6-min walk test, New York Heart Association functional class, cardiac index and pulmonary vascular resistance in New York Heart Association Class II, III and IV patients with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension related to connective tissue disease or congenital heart disease. Although doses of 100 and 300 mg once daily demonstrated equivalent efficacy, the lower dose had a better safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg once-daily dosing. The most common side effects include rhinitis, headache, peripheral edema, chest pain, nausea, constipation, increased prothrombin time/international normalized ratio (in patients on warfarin), flushing and insomnia. As with other endothelin receptor antagonists, increases in hepatic transaminases have been observed with sitaxsentan. Initial studies using the selective oral endothelin-A receptor antagonist sitaxsentan in pulmonary arterial hypertension patients have revealed a favorable risk–benefit therapeutic profile with the 100 mg once-daily dose.     

HIV‐associated pulmonary arterial hypertension: from bedside to the future

Pulmonary arterial hypertension (PAH) is a life‐threatening complication of HIV infection. The prevalence of HIV‐associated PAH (HIV‐PAH) seems not to be changed over time, regardless of the introduction of highly active antiretroviral therapy (HAART). In comparison with the incidence of idiopathic PAH in the general population (1–2 per million), HIV‐infected patients have a 2500‐fold increased risk of developing PAH. HIV‐PAH treatment is similar to that for all PAH conditions and includes lifestyle changes, general treatments and specific treatments.     

肺动脉高压诊断和治疗进展

慢性阻塞性肺疾病（COPD）引起的肺动脉高压（PAH）是影响患者生存的主要原因。本文重点介绍COPD合并PAH的诊断和治疗进展。