结缔组织病相关肺动脉高压的治疗进展

肺动脉高压(PAH)是结缔组织病(CTD)的严重并发症,也是当前CTD死亡的重要因素之一。重视针对PAH治疗的同时,还应通过糖皮质激素联合免疫抑制剂积极控制CTD,从而实现双重达标治疗目标,以期改善预后,提高患者生活质量。     

Inhibition of endocan attenuates monocrotaline-induced connective tissue disease related pulmonary arterial hypertension

Connective tissue disease related pulmonary arterial hypertension (CTD-PAH) is characterized by vascular remodeling, endothelial dysfunction and inflammation. Endocan is a novel endothelial dysfunction marker. The aim of the present study was to investigate the role of endocan in CTD-PAH. Monocrotaline (MCT)-induced PAH rats were used as the CTD-PAH model. Short hairpin RNA packed in a lentiviral vector used to inhibit endocan expression was intratracheally instilled in rats prior to the MCT injection. Endocan was found to be increased in the serum and lung of MCT-induced PAH rats. Short hairpin RNA mediated knockdown of endocan significantly decreased right ventricular systolic pressure, attenuated pulmonary remodeling and inflammatory responses in the lung. In the in vitro study, tumor necrosis factor-α (TNF-α) exposure caused increased endocan expression in the primary cultured rat pulmonary microvascular endothelial cells (RPMECs). Endocan knockdown inhibited the permeability increase and adhesion molecules secretion in RPMECs induced by TNF-α. In addition, TNF-α induced MAPK activation was blocked when endocan gene was knocked down. These data demonstrate that endocan may play an important role in the development of CTD-PAH. This study provides novel evidence to better understand the pathogenesis of CTD-PAH, which may be beneficial for the treatment of this disease.     

波生坦治疗结缔组织病相关肺动脉高压临床疗效观察及安全性分析

目的观察波生坦治疗结缔组织病相关肺动脉高压(CTD-PAH)的有效性及安全性。方法分析和比较42例经波生坦治疗的CTD-PAH患者4周的6 min步行距离(6MWD),Borg呼吸困难评分,生活质量调查表评分(SF-36),肺动脉高压心功能分级及超声心动图指标较基线变化情况。结果与基线时相比,波生坦治疗4周6MWD从(328±68)m增加至(402±62)m(P<0.05)。Borg评分由(3.1±1.3)减少至(2.5±1.4)(P<0.05)。SF-36量表中除社会功能外其他7项维度评分均有改善(P<0.05)。肺动脉高压心功能分级较前改善(P<0.05)。并发心包积液由基线19例(45%)减少至8例(19%)(P<0.05)。超声心动图中左房内径、左室舒张末期内径、三尖瓣反流速率和肺动脉压力分别由基线状态时的(35±7)mm、(41±9)mm、(4.4±0.6)m/s和(63±23)mmHg减少至治疗4周后的(37±7)mm、(40±7)mm、(4.2±0.5)和(54±12)(P<0.05)。治疗组无药物不良反应发生。结论波生坦有效改善CTD-PAH患者心脏功能,是治疗CTD-PAH安全有效靶向药物。     

汉防己甲素 川芎嗪对结缔组织病合并肺动脉高压对照研究

目的观察汉防已甲素(TET)和川芎嗪(TMP)注射液对结缔组织病(CTD)合并肺动脉高压(PAH)的影响。方法采用开放随机对照方法,将37例CTD合并PAH患者随机分为4组:A组(一般治疗组)9例;B组(一般治疗+TET)9例;C组(一般治疗+TMP)10例;D组(一般治疗+TET+TMP)9例。一般治疗包括口服利尿剂、洋地黄制剂、抗凝剂和氧疗;观察项目包括治疗前和治疗后1个月末、3个月末的运动耐量(6min步行距离),PAH的心功能分级(NYHA),肺动脉压力测试(多普勒测定),同时观察药物不良事件和不良反应。结果观察的37例患者中死亡、失访各2例,因不良反应退出3例,共有30例患者完成3个月的观察期;观察项目结果:运动耐量测试3个月末D组和A组比较差异有统计学意义;肺动脉压力测试4组间的比较差异均无统计学意义;心功能分级测试3个月末D组和A组比较差异有统计学意义(P<0.05)。结论CTD合并PAH一般治疗与一般治疗单独加用TET注射液或TMP注射液比较疗效无明显提高;而一般治疗联合应用TET和TMP,对提高运动耐量和改善心功能有益;本研究结果可为临床治疗提供新的思路和方法。     

肺动脉高压治疗进展

肺动脉高压（Pulmonary Arterial Hypertension,PAH）是以肺小动脉的血管痉挛、内膜增生及重构和微血栓病灶形成为主要特征的一种疾病[1]。患者最终往往死于右心衰竭。PAH是一种进展性疾病,预后较差,目前缺乏有效的治疗方案。近年来,一些新的药物和治疗方法开始应用于临床,使患者的生活质量和临床预后不断改善,现将最近的治疗进展综述如下。     

肺动脉高压的免疫调节治疗

肺动脉高压是临床上常见的疾病,其发病机制尚未完全清楚。免疫因素在肺动脉高压的发病机制中起重要作用。免疫抑制疗法为肺动脉高压治疗提供了新的途径。本文就机体免疫紊乱对肺动脉高压的影响机制及其免疫调节治疗的临床应用及研究现状进行综述。     

Treatment approach to connective tissue disease-associated interstitial lung disease

Interstitial lung disease (ILD) is a common manifestation in connective tissue diseases (CTD), such as rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory myositis (IM). ILD is associated with significant morbidity and mortality in nearly all CTD highlighting the critical need for effective treatment strategies in this patient population. In this review, we will summarize the approach to treatment when there is concern for CTD-ILD and highlight recent advancements in therapeutics within various forms of CTD-ILD.     

Sitaxentan: in pulmonary arterial hypertension

Sitaxentan is a highly selective endothelin (ET)(A) receptor antagonist, with an approximately 6500 higher affinity for ET(A) than ET(B) receptors. In pulmonary arterial hypertension (PAH), elevated ET-1 levels are strongly correlated with disease severity and prognosis. Sitaxentan 100 mg once daily was efficacious in the management of moderate to severe PAH in the pivotal, 12-18 week, large (n > or = 98), well designed, placebo-controlled STRIDE-1, -2 and -4 trials. In the STRIDE-1 and -2 trials (the majority of patients had New York Heart Association [NYHA]/WHO functional class III PAH), sitaxentan-treated patients experienced significantly greater improvements from baseline in distance walked over 6 minutes (6MWD; primary endpoint in STRIDE-2) and in NYHA/WHO functional class than placebo recipients. In STRIDE-4, although there was no between-group difference in terms of improvements in 6MWD in the primary analysis of patients across all WHO functional classes (61% were functional class II) [primary endpoint], improvements in 6MWD significantly favoured sitaxentan versus placebo-treated patients in a post hoc subgroup analysis of those with WHO functional class III or IV disease. The beneficial effects of sitaxentan therapy on exercise capacity and NYHA/WHO functional class were maintained after up to 2 years' treatment. Treatment with sitaxentan for up to 2 years was generally well tolerated in clinical trials.     

西他生坦治疗肺动脉高压

肺动脉高压是一种以肺小动脉痉挛、内膜增生和重构为特征的恶性血管疾病。近年来随着对肺动脉高压发病机制深入研究和选择性肺血管舒张药物的研发,肺动脉高压的治疗已经取得极大进步。西他生坦作为一个新型的高选择性内皮素受体拮抗药也因此备受临床关注。西他生坦通过阻断A型内皮素受体,抑制内皮素-1的缩血管效应,舒张血管。本文综述了西他生坦的药理学特点、相关基础及临床研究进展。     

Bosentan for pulmonary arterial hypertension

Pulmonary arterial hypertension is an uncommon but disabling and often fatal condition, in which there is a sustained rise in pulmonary arterial pressure due to progressive obliteration of the pulmonary vascular bed. [symbol: see text] Bosentan (Tracleer-Actelion), which belongs to a new class of drugs called endothelin receptor antagonists, is now available for treating patients with pulmonary arterial hypertension. Here we assess whether bosentan offers worthwhile benefits in the management of patients with this condition.     

先天性心脏病合并肺动脉高压患儿57例临床分析

目的分析先天性心脏病合并肺动脉高压患儿的临床资料,以提高对该病的临床诊治水平。方法 57例患儿均予以吸氧、抗感染以及强心、利尿、扩血管治疗。11例左向右分流型先天性心脏病以及5例复杂型先天性心脏病经内科治疗后肺部感染、心力衰竭难以控制,转我院心外科予以手术。术后8例患儿用前列地尔,6例患儿用西地那非降肺动脉压力。患儿于内科治疗前后、手术后药物治疗前后测肺动脉压力(PAP)、左室射血分数(LVEF)及血浆N端-脑钠肽前体(NT-proBNP)。结果 38例左向右分流型先天性心脏病患儿经内科治疗后PAP、血浆NT-proBNP水平均较治疗前下降(P<0.05),LVEF较治疗前升高(P<0.05)。11例左向右分流型先天性心脏病以及5例复杂型先天性心脏病患儿PAP、血浆NT-proBNP水平均高于前述38例患儿(P<0.05),LVEF低于前述38例患儿(P<0.05)。8例患儿术后予以前列地尔,6例予以西地那非治疗后,PAP、血浆NT-proBNP水平较用药前下降(P<0.05),LVEF较用药前升高(P<0.05)。结论先天性心脏病合并肺动脉高压需早治疗,可改善预后。前列地尔、西地那非在治疗肺动脉高压方面是有效的。     

Clinical study on congenital heart disease with pulmonary arterial hypertension in children

目的 分析先天性心脏病合并肺动脉高压患儿的临床资料,以提高对该病的临床诊治水平.方法 57例患儿均予以吸氧、抗感染以及强心、利尿、扩血管治疗.11例左向右分流型先天性心脏病以及5例复杂型先天性心脏病经内科治疗后肺部感染、心力衰竭难以控制,转我院心外科予以手术.术后8例患儿用前列地尔,6例患儿用西地那非降肺动脉压力.患儿于内科治疗前后、手术后药物治疗前后测肺动脉压力(PAP)、左室射血分数(LVEF)及血浆N端脑钠肽前体(NT-proBNP).结果 38例左向右分流型先天性心脏病患儿经内科治疗后PAP、血浆NT-proBNP水平均较治疗前下降(P<0.05),LVEF较治疗前升高(P<0.05).11例左向右分流型先天性心脏病以及5例复杂型先天性心脏病患儿PAP、血浆NT-proBNP水平均高于前述38例患儿(P<0.05),LVEF低于前述38例患儿(P<0.05).8例患儿术后予以前列地尔,6例予以西地那非治疗后,PAP、血浆NT-proBNP水平较用药前下降(P<0.05),LVEF较用药前升高(P<0.05).结论 先天性心脏病合并肺动脉高压需早治疗,可改善预后.前列地尔、西地那非在治疗肺动脉高压方面是有效的.     

急性肺血管扩张试验筛查在肺动脉高压中的应用

钙拮抗剂(CCB)长程治疗仅对急性肺血管扩张试验(AVT)筛查阳性患者有效,因此AVT筛查对肺动脉高压患者的治疗策略具有关键作用,本文综述AVT筛查在肺动脉高压诊治中的应用.     

Biomarkers in systemic sclerosis-related pulmonary arterial hypertension

Systemic sclerosis (SSc) is a complex multisystem disease characterized by vascular involvement and generalized disturbance of the microcirculation. Pulmonary vascular disease leads to systemic sclerosis-related pulmonary arterial hypertension (SScPAH). SScPAH is a devastating complication with a considerable impact on prognosis, being a common cause of disease-related death. The ability to detect this process at an early stage by simple means would be of great value, since effective treatment is now available. There is increasing evidence that several biomarkers increase in proportion to the extent of right ventricular dysfunction and correlate with hemodynamic, echocardiographic and functional measurements of pulmonary vascular disease. Biomarkers may be used to identify high-risk patients for more invasive procedures, provide prognostic information, and guide vasodilator therapy. In this article, we review potential biomarkers in SScPAH as tools for screening, diagnostic evaluation, risk stratification, prediction of disease severity and indicators of treatment efficacy.     

Targeting PDGF pathway in pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) encompasses a rare potentially lethal group of diseases characterized by vasoconstriction, in situ thrombosis and vascular remodeling. Most of the existing therapies including endothelin receptor antagonists, prostacyclin and derivatives, or phsophodiesterase-5 inhibitors tackle mainly the endothelial dysfunction, leaving the remodeling suboptimally inhibited. This explains the disease progression that occurs even with combined therapies and the need for other therapies able to adequately inhibit the vascular remodeling.

Areas covered: Platelet-derived growth factor (PDGF) signaling pathway was demonstrated to be involved in the vascular remodeling in PAH, and therefore, it might be a desirable therapeutic target in this setting. This review discusses the pathogenic role of this pathway in PAH and its potential inhibitory approaches, focusing on imatinib as well as on the existing preclinical data on this compound.

Expert opinion: Preclinical studies demonstrated that PDGF inhibition with receptor antagonists such as imatinib reduces vascular remodeling. Therefore, PDGF might represent a plausible therapeutic target in this disease. However, compounds able to block this pathway via different mechanisms might also become potential PAH therapies.     

混合性结缔组织病的肺部损害

目的了解混合性结缔组织病的肺部损害.方法选择26例混合性结缔组织病患者,进行临床、放射学及肺功能的观察.结果26例患者中有呼吸系统症状者7例,X线检查有肺间质病变10例伴肺动脉高压者2例,X线仅有肺动脉高压者1例;16例行CT检查有肺间质病变14例,其中8例X线检查无异常者CT检查发现有肺间质炎症6例;肺功能检查有限制性通气功能障碍者21例,血气分析示低氧血症11例,肺泡-动脉氧分压差增宽9例.结论混合性结缔组织病的肺部损害主要表现为肺间质病变及肺动脉高压.肺功能损害表现为限制性通气功能障碍及弥散功能障碍.肺功能损害早于临床及放射学表现.     

Elevated serum HMGB1 in pulmonary arterial hypertension secondary to congenital heart disease

AimsThis study investigated the potential value of serum high mobility group box-1 (HMGB1) level in the diagnosis, staging and treatment response of patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD).Methods and resultsThis was a single-center prospective study in 106 CHD patients. Serum HMGB1 levels were measured by enzymelinked immunosorbent assay. HMGB1 levels were significantly increased in patients with PAH compared to patients without PAH (P < 0.01) and healthy controls (P < 0.001). HMGB1 levels significantly correlated with pulmonary arterial pressure (P < 0.001) and pulmonary vascular resistance (PVR) (P < 0.001). In patients with severe PAH, HMGB1 levels were significantly higher in patients with Eisenmenger syndrome (ES) than in patients exhibiting low PVR (P < 0.001). Severe PAH and ES was identified by serum HMGB1 with a cutoff value of 13.62 ng/mL (P < 0.001) with a specificity of 82.8% and a sensitivity of 90%, and a cutoff value of 21.62 ng/mL (P = 0.001) with a specificity of 85.2% and a sensitivity of 64.3%, respectively. HMGB1 levels were significantly decreased after sildenafil therapy for 6 months (P < 0.01).ConclusionsOur study suggests that serum HMGB1 level may be used as a biomarker to identify PAH in CHD patients, assess pulmonary vascular remodeling, and evaluate the treatment response to sildenafil.     

Emerging therapies for pulmonary arterial hypertension

Pulmonary arterial hypertension is characterised by increased pulmonary vascular resistance due to increased vascular tone and structural remodelling of pulmonary vessels. The therapies that are in use so far have been developed to correct endothelial dysfunction and reduce vasomotor tone. These treatments have a limited effect on the remodelling process and, increasingly, the focus is turning to potent strategies for inhibiting vascular proliferation and promoting vascular apoptosis. Multiple novel targets have been uncovered over the last 5 years and several are now in early clinical trials. At present, it is clear that there is no single treatment for the condition. Although this is the case, studies are investigating the role of combining therapies that are already established.