Elevated plasma Pim‐1 and its clinical significance in patients with pulmonary arterial hypertension

This study was aimed to determine plasma Pim‐1 levels in patients with pulmonary arterial hypertension (PAH) and to estimate the clinical value of Pim‐1 as a biomarker of PAH. This was a single‐centre retrospective study in 111 patients with congenital heart disease (CHD) and idiopathic PAH (IPAH). Those CHD patients were divided into two groups: PAH associated with CHD (PAH‐CHD) and CHD without PAH (nPAH‐CHD). Plasma Pim‐1 levels were measured by enzyme‐linked immunosorbent assay. (a) Plasma Pim‐1 levels were significantly increased in patients with PAH‐CHD and IPAH compared with the healthy control group (27.81 ± 11.34 ng/mL vs 13.02 ± 5.30 ng/mL; 32.81 ± 12.28 ng/mL vs 13.02 ± 5.30 ng/mL, P < 0.05) and nPAH‐CHD (27.81 ± 11.34 ng/mL vs 17.33 ± 7.99 ng/mL; 32.81 ± 12.28 ng/mL vs 17.33 ± 7.99 ng/mL, P < 0.05). Pim‐1 levels were substantially increased in patients with severe PAH‐CHD compared with mild‐to‐moderate PAH‐CHD (19.12 ± 6.70 ng/mL vs 8.54 ± 3.71 ng/mL, P < 0.05). (b) Pim‐1 levels were correlated positively with the mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) (r = 0.582, 0.516; P < 0.001, respectively), while negatively with tricuspid annular plane systolic excursion (TAPSE), tricuspid annular plane systolic velocity (S’) and right ventricular fractional area changes (RVFAC) (r = ?0.375, ?0.354, ?0.507; P < 0.05, respectively). (c) PAH‐CHD and severe PAH‐CHD was identified by plasma Pim‐1 with a cutoff value of 16.8 ng/mL (P < 0.001) with a sensitivity of 87.3% and a specificity of 65%, and a cutoff value of 20.53 ng/mL (P < 0.001) with a sensitivity of 87.3% and a specificity of 52%, respectively. Plasma Pim‐1 levels were significantly higher in patients with PAH‐CHD and IPAH. Plasma Pim‐1 may represent an effectively biomarker in patients with PAH.     

先天性心脏病合并肺动脉高压患者可手术性分析

目的 分析先天性心脏病(CHD)合并重度肺动脉高压(PAH)患者的可手术性.方法 回顾性分析2006年6月至2010年10月接受根治手术的30例患者.所有患者接受术前心导管检查并分别吸入100％氧气和伊洛前列素(Iloprost)行急性肺血管扩张试验.根据患者术后是否残存PAH将患者分为肺动脉压力正常组和PAH组.对2组患者的术前检查项目进行观察,用受试者工作特征(ROC)曲线分析可手术性.结果 患者术后全部存活.2组(肺动脉压力正常组和PAH组)患者的术前检查中,胸部X线片心胸比(CTR),心导管检查中基础状态肺小动脉阻力指数(PVRi),吸入100％氧气行急性肺血管扩张试验后肺体循环血流比(Qp/Qs)和PVRi,吸入Iloprost行急性肺血管扩张试验后Qp/Qs,PVRi和肺体循环阻力比(Rp/Rs)差异均有统计学意义[ CTR:(0.67±0.06)比(0.55±0.06),基础状态PVRi:(7.6±3.2) wood unit/m2比( 13.0 ±4.5)wood unit/m2;吸入100％氧气后Qp/Qs:5.6 ±3.5比2.7±0.8,PVRi:( 3.0±1.8) wood unit/m2比( 6.4±2.2)wood unit/m2;吸入Iloprost后Qp/Qs:4.1 ±2.4比2.0±1.3,PVRi:(4.3±3.0) wood unit/m2比( 8.3±3.1)wood unit/m2,Rp/Rs:0.2 ±0.2比0.4±0.2,均P＜0.05].ROC曲线提示CTR敏感性最高(敏感度0.923),吸入100％氧气后PVRi及Iloprost行急性肺血管扩张试验后PVRi准确性最高(准确度均为0.889);CTR高于0.615,吸入100％氧气后PVRi低于4.22wood unit/m2,吸入Ilprost后PVRi低于4.915wood unit/m2的患者短期手术预后较好.结论 CTR、吸入100％氧气及Iloprost行急性肺血管扩张试验后PVRi这几项检查更适合判断CHD合并重度PAH患者的可手术性.     

Short and long term anti-inflammatory effects of bosentan therapy in patients with pulmonary arterial hypertension: relation to clinical and hemodynamic responses

Objective: We sought to investigate the short- and long- term effects of bosentan therapy on endothelial, inflammatory and fibrotic markers in patients with pulmonary arterial hypertension (PAH) and the relation to clinical and hemodynamic responses.

Methods: We studied 16 patients with moderate-severe idiopathic PAH, in WHO functional class II-IV, despite conventional treatment. Patients received additional treatment with bosentan, 62.5 mg twice daily for 1 month, followed by 125 mg twice daily for 11 months. Study endpoints included 6-min walking distance (6MWD), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and plasma levels of intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), IL-6 and brain natriuretic peptide (BNP). Patients were assessed at baseline, 2 months and 12 months after initiation of bosentan.

Results: At 2 months there was an improvement in 6MWD (p < 0.001) and functional class (p < 0.001) and a marked fall in PVR (p < 0.001), ICAM-1 (p < 0.001), IL-6 (p < 0.001)and BNP (p = 0.001). At 12 months, 6MWD was further improved (p < 0.001), PVR remained significantly improved (p < 0.001), mPAP was significantly decreased (p < 0.001) and ICAM-1, IL-6 and BNP remained significantly lower (p < 0.001). Significant correlations were found between changes in ICAM-1 and cardiac index (r = 0.59, p = 0.01), IL-6 and PVR (r = 0.51, p = 0.04), BNP and 6MWD (r = ?0.53, p = 0.03) and BNP and PAP (r = 0.51, p = 0.04) between 2- and 12-months treatment.

Conclusions: In patients with moderate-severe PAH, the addition of bosentan to therapy, exerts favorable anti-inflammatory effects, which are associated with clinical and hemodynamic improvement.     

CPU0123, a novel endothelin receptor antagonist,relieves hypoxic pulmonary hypertension in rats by suppressing excessive ET‐ROS pathway

Pulmonary artery hypertension (PAH, PH) is a chronic and progressive disease with high morbidity and mortality and is resistant to vasodilative drugs in the clinic due to remodeling of pulmonary arterioles involved in PAH. The endothelin (ET) receptor antagonist bosentan is an effective oral medication in relieving PAH due to its antiproliferative effects. The dual ET_A/ET_B antagonist receptor antagonist, CPU0213, was compared with nifedipine in treating hypoxic PAH in SD rats that were exposed to 28 days of hypoxia (O₂ 10±0.5%). In untreated animals, elevated right ventricular systolic pressure (RVSP), central vein pressure (CVP), and remodeling of pulmonary arterioles were predominant. In the pulmonary tissue of PAH rats, the ET‐ROS pathway was over‐activated in association with a reduced NO level, increased iNOS activity and hydroxyproline contents. Following oral treatment with CPU0213, (50 mg/mg, 100 mg/kg, and 200 mg/kg, p.o.), the hemodynamic indices and pulmonary arteriole remodeling were significantly improved in a dose‐dependent manner. Elevated ET‐1 levels, iNOS activity, and maladjustment of pulmonary redox system were reversed, accompanied by a reduction of hydroxyproline in pulmonary tissue. An antiproliferative effect of CPU0213 was superior to that of nifedipine. The efficacy of 50 mg/kg CPU0213 was reduced. It is concluded that the low‐selective ET_A/ET_B receptor antagonist, CPU0213, is effective in relieving hypoxia‐induced pulmonary hypertension by suppressing an over‐activated ET‐ROS pathway in pulmonary tissue. Drug Dev Res 68:42–50, 2007. © 2007 Wiley‐Liss, Inc.     

Iptakalim prevents rat pulmonary hypertension induced by endothelin‐1 through the activation of KATP channel in vivo

Iptakalim has been previously characterized as a novel, selective ATP‐sensitive potassium channel opener. In the present study, to determine whether iptakalim can prevent the pulmonary hypertension induced by endothelin‐1 (ET‐1) through the activation of K_ATP channel in vivo, the effects of iptakalim and glibenclamide (a selective K_ATP channel blocker) on the mean pulmonary pressure (mPAP) induced by ET‐1 were examined in rats. Treatment of the animals with exogenous ET‐1 (via the pulmonary artery at a dose of 1.5 µg/kg) induced a pulmonary hypertension in vivo, whereas the administration of iptakalim (via the pulmonary artery at doses of either 0.5 mg or 1.0 mg/kg) prior to ET‐1 prevented pulmonary hypertension induced by ET‐1 in vivo. The ability of iptakalim to prevent pulmonary hypertension induced by ET‐1 was abolished by glibenclamide (via the femoral artery at a dose of 20 mg/kg) in vivo. These findings provide strong evidence that iptakalim acts as a specific K_ATP channel opener to antagonize the vasoconstrictor effect of ET‐1 in the pulmonary circulation. Thus, iptakalim may be developed as a therapeutic option for the treatment of pulmonary hypertension. Drug Dev Res 69: 89–94, 2008. © 2008 Wiley‐Liss, Inc.     

血清BNP及二维应变和应变率对小儿左向右分流先心病右室功能的评估价值

目的评价血清脑利钠肽(BNP)和右室长轴二维整体收缩期应变(GLS)及应变率(GLSR)对小儿先天性心脏病(CHD)合并肺动脉高压(PAH)的诊断价值。方法左向右分流型先心患儿65例分为无PAH(B组,17例)和PAH(A组,48例)两组;30例健康体检者作为正常对照(C)组。血清BNP用ELISA法测定,保存二维图像分析右室功能。结果 A组血清BNP浓度明显高于B组和C组(P<0.01),并随着肺动脉高压程度的加重而增高。右室GLS、GLSR在A组明显低于B组和C组(P<0.01),GLS随着肺动脉压力程度升高而下降。血清BNP浓度与肺动脉收缩压(PASP)呈正相关(P<0.01)和左向右分流比率(Qp/Qs)呈正相关(P<0.05)。血清BNP与GLS或GLSR呈负相关(P<0.01或P<0.05)。结论血清BNP可以反映左向右分流先心病的容量和压力负荷,可作为先天性心脏病的辅助诊断及疾病严重性评估的客观指标。二维右心室应变和应变率能恰当地评估右心室整体和局部功能。     

前列地尔在先天性心脏病合并重度肺动脉高压患儿治疗中的作用

目的探讨先天性心脏病(CHD)合并重度肺动脉高压(PH)术前应用前列地尔的意义。方法 56例CHD合并PH的患儿,术前予前列地尔100μg加入氯化钠注射液100mL中静脉微量泵泵入,0.02～0.05μg·kg~(-1)·min~(-1),每日持续用药8～10h,连续用药14～18d。对比分析用药前后的平均肺动脉压(mPAP)、平均体动脉压(mSAP)、周围动脉血氧分压(PaO_2)、血氧饱和度(SaO_2)和左心室射血分数(LVEF),并观察患儿不良反应情况。结果前列地尔治疗后,CHD合并重度PH患儿mPAP显著降低(P<0.01),而LVEF、SaO_2及PaO_2均不同程度提高(P<0.05),无严重不良反应发生。结论术前用前列地尔治疗后可明显改善CHD合并重度PH患儿的心、肺功能,提高手术的安全性。     

波生坦联合伊洛前列素治疗先天性心脏病合并肺动脉高压患儿的临床疗效及对galectins-3、GDF-15和NT-proBNP水平的影响

目的 探讨波生坦联合伊洛前列素治疗先天性心脏病（CHD）合并肺动脉高压（PAH）患儿的临床疗效及其对半乳糖凝集素-3（Gal-3）、生长分化因子-15（GDF-15）及氨基末端脑利钠肽前体（NT-proBNP）水平的影响。方法 前瞻性选择邯郸市妇幼保健院2019年1月-2021年1月期间收治的84例CHD合并PAH患儿为研究对象,遵照随机数字表法将患儿分为对照组（n=42）与试验组（n=42）,对照组给予基础治疗+口腔雾化吸入伊洛前列素溶液,吸入用伊洛前列素溶液10 μg与生理盐水2 mL混合后雾化吸入,每次15 min,每天6次。试验组在对照组基础上加用波生坦分散片口服治疗,起始剂量2 mg·kg^-1,每天2次,持续4周,随后增加至4 mg·kg^-1,每天2次,持续4周。两组均持续治疗8周。比较两组患儿治疗前后心功能分级、肺血流动力学、肺功能、Borg呼吸困难指数（BDI）评分,同时检测患儿血清Gal-3、GDF-15、NTproBNP水平,观察治疗期间两组患儿不良反应发生情况。结果 治疗后对照组、试验组心功能分级均较治疗前均改善（P<0.05）,且试验组心功能分级优于对照组（P<0.05）。治疗后两组肺动脉收缩压（PASP）、肺动脉舒张压（PADP）、平均肺动脉压（MPAP）均低于治疗前（P<0.05）,用力肺活量（FVC）、第1秒用力呼气容积（FEV1）、第1秒用力呼气容积占用力肺活量比值（FEV1/FVC）均高于治疗前（P<0.05）,且试验组PASP、PADP、MPAP均低于对照组（P<0.05）,FVC、FEV1、FEV1/FVC均高于对照组（P<0.05）。治疗后两组BDI评分均低于治疗前（P<0.05）,且试验组BDI评分低于对照组（P<0.05）。治疗后两组血清Gal-3、GDF-15、NT-proBNP水平均低于治疗前（P<0.05）,且试验组血清Gal-3、GDF-15、NT-proBNP水平低于对照组（P<0.05）。试验组药物相关不良反应发生率（11.90%）与对照组（9.52%）比较,差异不具有统计学意义（P> 0.05）。结论 波生坦联合伊洛前列素治疗CHD合并PAH患儿,可以改善心功能、肺血流动力学、肺功能,降低BDI评分,调节血清Gal-3、GDF-15、NT-proBNP水平,且具有较高安全性。     

5-羟基癸酸盐对大鼠低氧性肺动脉高压的抑制作用

目的探讨5-羟基癸酸盐(5-HD)对肺动脉高压形成的影响机制及炎症因子的作用。方法 SD大鼠在常压9.5%～10.5%O2的低氧舱中进行低氧处理,每天8 h,每周6 d。1周后,按照分组每天先sc给予5-HD 5 mg.kg-1,再进低氧舱,连续3周。右心导管法测平均肺动脉压(mPAP),测定心脏右心肥厚指数(RVHI),光镜下观察肺血管形态学改变,并用图像分析法测定肺动脉相对中膜厚度(PAMT)。ELISA法检测血清及肺匀浆中白细胞介素6(IL-6),IL-8,巨噬细胞炎症蛋白(MIP)-1a和单核细胞趋化蛋白(MCP)-1含量,免疫组化法测定肺组织中IL-6及MCP-1的表达。结果与正常对照组相比,低氧模型组大鼠mPAP,RVHI及PAMT明显增加(P<0.05);与低氧模型组相比,给予5-HD组明显降低(P<0.05)。与正常对照组相比,低氧模型组大鼠血清IL-6,IL-8,MIP-1a及MCP-1水平增高(P<0.05);与低氧模型组相比,给予5-HD组大鼠血清IL-8,MIP-1a及MCP-1水平明显降低(P<0.05)。结论 5-HD可能是通过抑制肺动脉高压大鼠血清中的某些炎症细胞因子的表达、下调大鼠炎症细胞因子分泌,达到降低肺动脉高压的作用。     

Inhalational therapy for pulmonary arterial hypertension: current status and future prospects

This review summarizes the pathophysiology and current therapeutic and drug delivery strategies for pulmonary arterial hypertension (PAH), a rare but devastating disorder of the pulmonary circulation affecting 50,000 to 100,000 persons in the United States. Chief clinical features of PAH include increased mean pulmonary arterial pressure (>25 mm Hg) and right ventricular and smooth muscle hypertrophy. A wide variety of agents have been studied for use as anti-PAH drugs, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, to name a few. However, a major shortcoming of anti-PAH medications is their short half-lives, requiring them to be administered via parenteral routes, which lead to undesirable side effects, including systemic vasodilation. Inhalational delivery of anti-PAH drugs provides an attractive alternative to conventional routes, with ease of administration and minimal systemic vasodilation. Recently, the U.S. Food and Drug Administration approved inhalable iloprost (Ventavis?), a prostacyclin analogue, for PAH treatment. Other drugs being studied for their potential in inhalable PAH therapy include PGE1, treprostinil, vasoactive intestinal peptide, and fasudil. Controlled-release inhalable delivery systems for anti-PAH medications have also been proposed to facilitate long-term and selective vasodilation of pulmonary arteries. Extensive studies are warranted to develop safe and effective drug delivery systems that will provide a better quality of life to patients.     

肺动脉高压与脑利钠肽、血管内皮功能和炎性细胞因子的相关性

摘 要：目的 通过观察肺动脉高压（PAH）患者的肺动脉收缩压（PASP）与脑利钠肽（BNP）、血管内皮功能和炎性细胞因子的相关性,进一步探讨PAH发病机制。方法 测定92例PAH患者和50例健康者的肺动脉收缩压（PASP）、血浆BNP、内皮素-1（ET-1）、血清一氧化氮（NO）、超敏C反应蛋白（hs-CRP）和肿瘤坏死因子-α（TNF-α）等指标。结果 PAH患者的血浆BNP、ET-1、血清hs-CRP和TNF-α显著高于对照组（P<0.05）,血清NO显著低于对照组（P<0.05）。PAH患者的PASP与血浆BNP（r=0.574）、hs-CRP（r=0.423）、ET-1（r=0.402）和TNF-α（r=0.366）呈显著正相关;与血清NO水平呈显著负相关（r=-0.378）。结论 PAH的发生发展过程是BNP、内皮系统和炎性反应等多因素综合作用的结果。     

西地那非联合贝前列素或阿托伐他汀治疗肺动脉高压的临床观察

目的比较西地那非联合阿托伐他汀、西地那非联合贝前列素治疗肺动脉高压的疗效及安全性。方法选择54例肺动脉高压患者随机分成2组,分别给予西地那非联合阿托伐他汀(A组)、西地那非联合贝前列素(B组)治疗,治疗前及治疗后6个月观察6 min步行距离(6MWD)、平均肺动脉压(mPAP)、肺血管阻力(PVR)和心脏指数(CI)。结果 2组均能增加6MWD,降低mPAP和PVR,提高CI,且西地那非联合贝前列素疗效更显著。2组间不良反应无明显差异,均未见严重不良反应。结论西地那非联合贝前列素治疗肺动脉高压的疗效优于西地那非联合阿托伐他汀,是一种安全有效的治疗方法。     

内皮素心钠素在左向右分流型先天性心脏病肺动脉高压的相关性研究

目的探讨血浆内皮素(ET)、心钠素(ANP)在左向右分流型先天性心脏病(CHD)肺动脉高压形成中的相互关系及临床意义。方法左向右分流型CHD合并肺动脉高压患者32例,正常对照组14例。采用放射性免疫法测定血浆ET、ANP的浓度,分析上述各指标在病变进展过程中的变化特点及相关性。结果①CHD各组术前肘静脉ET的浓度大于对照组(P<0.05);轻度肺动脉高压组与高肺血流量组之间术前肘静脉ET浓度差异无统计学意义(P>0.05);轻度、中度与重度肺动脉高压组之间的术前肘静脉ET浓度差异有统计学意义(P<0.05);重度>中度>轻度肺动脉高压组。②CHD各组术前肘静脉血浆ANP浓度分别明显高于正常对照组(P<0.05);高肺血流量组、轻度、中度与重度肺动脉高压组之间术前肘静脉血浆ANP浓度差异有统计学意义(P<0.05);重度>中度>轻度>高肺血流量组。③CHD各组肺动脉血浆ET浓度与肺动脉收缩压/主动脉收缩压呈正相关关系(r=0.794,P<0.01);ANP浓度与肺动脉收缩压/主动脉收缩压呈正相关关系(r=0.700,P<0.01)。④CHD各组术前肘静脉血浆ET与ANP浓度之间呈正相关关系(r=0.891,P<0.01)。结论ANP、ET共同参与了肺动脉高压的病理生理过程,ET合成增多,使缩血管物质与舒血管物质间失衡,促进了肺动脉高压的发生发展;ANP的升高则为机体的一种防御性反应,对维持肺循环稳定,减缓肺动脉高压的发生发展有积极作用。本实验将为延缓肺动脉高压形成或逆转失去手术机会的肺动脉高压患者的治疗提供一定的实验根据。     

慢性阻塞性肺疾病患者血浆脑肽钠和内皮素水平的变化

目的 测定慢性阻塞性肺疾病（COPD）急性加重期（AECOPD）和稳定期患者血浆脑肽钠（BNP）和内皮素（ET）水平的变化,以探讨BNP和ET在COPD发病机制中的作用。方法检测28例AECOPD患者,24例COPD稳定期患者和26名健康对照者的血浆脑肽钠和内皮素含量。结果AECOPD组分别与对照组和COPD组比较,血浆BNP和ET水平明显升高（P〈0．01,P〈0．05;P〈0．01,P〈0．05）,COPD患者与对照组比较,血浆BNP和ET水平明显升高（P〈0．05;P〈0．05）。结论COPD患者血浆ET和BNP的变化参与COPD的炎症过程,它们的变化可能与其疾病本身和疾病程度有关。     

Suitability evaluation of new endogenous biomarkers for the identification of nitrite‐based urine adulteration in mass spectrometry methods

Urine adulteration to circumvent positive drug testing is a fundamental challenge for toxicological laboratories all over the world. Untargeted mass spectrometry (MS) methods used in metabolomics had previously revealed uric acid (UA), histidine, methylhistidine, and their oxidation products, for example 5‐hydroxyisourate (HIU) as potential biomarkers for urine adulteration using potassium nitrite (KNO₂). These markers should be further evaluated for their reliability, stability, and routine applicability. Influence of KNO₂ concentration, urinary pH, reaction time, and stability at room temperature, 4°C, and ? 20°C was determined in urine under varying conditions. Analysis was performed after protein precipitation with acetonitrile by liquid chromatography–high resolution mass spectrometry (LC–HRMS). Receiver operating characteristics (ROC) analysis was applied for cut‐off evaluation after biomarker quantification (n = 100 per group). Blinded measurements (n = 50) were performed to check the general applicability to identify adulterated samples under routine conditions. The higher the adulterant concentration, the lower the concentrations of histidine, methylhistidine, and UA. In return, amounts of their oxidation products increased. Highest changes were observed under weak acid conditions (pH 4–5). Storage at ?20°C ensured sufficient stability for all oxidative markers over one month. ROC evaluated biomarker performance and application to unknown samples revealed satisfying results, with HIU as the most suitable biomarker (positive predictive value (PPV) 100%), followed by UA (PPV 93%). HIU and UA proved suitable markers to identify urine adulteration using KNO₂ and are ready for implementation into routine MS procedures.     

Role of phosphodiesterases in adult-onset pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by increased mean pulmonary artery pressure (mPAP) due to vasoconstriction and structural changes in the small pulmonary arteries (PAs); proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the remodeling. The abnormal pathophysiology in the pulmonary vasculature relates to decreased cyclic nucleotide levels in PASMCs. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby PDE inhibitors are effective in vasodilating the PA and decreasing PASMC proliferation. Experimental studies support the use of PDE3, PDE5, and PDE1 inhibitors in PAH. PDE5 inhibitors such as sildenafil are clinically approved to treat different forms of PAH and lower mPAP, increase functional capacity, and decrease right ventricular hypertrophy, without decreasing systemic arterial pressure. New evidence suggests that the combination of PDE inhibitors with other therapies for PAH may be beneficial in treating the disease. Furthermore, inhibiting PDEs in the heart and the inflammatory cells that infiltrate the PA may offer new targets to reduce right ventricular hypertrophy and inhibit inflammation that is associated with and contributes to the development of PAH. This chapter summarizes the advances in the area and the future of PDEs in PAH.     

Sitaxsentan, a selective endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension

Sitaxsentan, a highly selective endothelin-A (ET(A)) receptor antagonist (6500-fold more selective for ET(A) receptors than endothelin-B (ET(B)) receptors), may benefit patients with pulmonary artery hypertension (PAH) by blocking the vasoconstrictor effects of ET(A) receptors while maintaining the vasodilator/clearance functions of ET(B) receptors. In its first randomised, placebo-controlled study, Sitaxsentan to Relieve Impaired Exercise-1 (STRIDE-1), sitaxsentan improved exercise capacity assessed by 6 min walk, 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 PAH, PAH related to connective tissue disease or PAH related to congenital heart disease. In STRIDE-1, doses of 100 and 300 mg/day p.o. were evaluated. Although both doses showed equivalent efficacy, the lower dose had a more tolerable safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg/day doses, both in de novo patients and in patients previously treated with the ET(A)/ET(B) receptor antagonist bosentan. Long-term comparative studies are necessary to determine whether there is a clinically meaningful difference between selective ET(A) receptor antagonism and ET(A)/ET(B) receptor antagonism.     

联合检测血清Hcy和Lp (a)与UA对冠心病患者预后评估的价值探讨

目的 探讨血清同型半胱氨酸(Hcy)、脂蛋白a[Lp(a)]和尿酸(UA)联合检测对冠状动脉粥样硬化性心脏病(CHD)的病情及预后的评估价值.方法 选取CHD患者96例(疾病组)和体检健康者50例(正常组),采集清晨空腹静脉血,检测血清Hcy、Lp(a)和UA.观察组(疾病组)随访1年,91例病情缓解或无进展,5例发展为急性心肌梗死(AMI).采用受试者工作特征曲线分析血清Hcy、Lp(a)和UA单独及联合检测对CHD患者预后的诊断价值.结果 疾病组血清Hcy、Lp(a)和UA水平均高于正常组(均P＜ 0.05);随访发展为AMI患者入院时血清Hcy、Lp(a)和UA水平均高于病情缓解或无进展者(均P＜ 0.01).Hcy、Lp(a)和UA联合检测对CHD患者预后评估的AUC为0.855、敏感性为89.4％、特异性为80.2％、阳性预测值86.4％,均高于3项单独检测.结论 冠状动脉粥样硬化性心脏病患者血清Hcy、Lp (a)和UA水平均升高,其水平变化可反映冠状动脉粥样硬化性心脏病病情,三者联合检测可提高对患者预后的判断价值.     

Treatment of pulmonary arterial hypertension with bosentan: from pathophysiology to clinical evidence

In addition to its potent vasoconstricting effect, endothelin (ET)-1 induces proliferation of pulmonary vascular cells and appears to play a pathogenic role in the development of pulmonary arterial hypertension (PAH). Blockade of the ET receptors has been proposed for the treatment of this condition. Bosentan (Tracleer^®, Actelion Pharmaceuticals), an oral ET_A/ET_B receptor antagonist, has been shown to improve exercise capacity, quality of life, haemodynamics and time to clinical worsening of patients with PAH in short-term placebo-controlled trials. These improvements were sustained, and a long-term observational study on idiopathic PAH patients suggested a favourable effect on survival in this subset. In the present report, the pharmacology, clinical efficacy and safety profile of bosentan are summarised. The place of bosentan among the current therapies available for the treatment of PAH is also discussed.     

Asymmetric and symmetric dimethylarginine in patients presenting with risk factors for coronary heart disease

The aim of the present study was to investigate asymmetric (ADMA) and symmetric dimethylarginine (SDMA) production in patients presenting with one or more risk factor (RF) for coronary heart disease (CHD). Patients and methods: Overall, 113 participants were enrolled in the study, including 45 patients presenting with risk for CHD (27 male and 18 female; aged 55.9 ± 6.4 years), 30 sex and age-matched middle-aged healthy controls (16 male and 14 female; aged 56.3 ± 8.4 years), and 38 young healthy controls (38 male; aged 24.6 ± 3.9 years). Results: No significant differences for ADMA and SDMA were recorded between patients groups presenting with risk for CHD. However, ADMA and SDMA were significantly higher in all examined patient groups (≥3 and 1–2 RF, hypertensive and non-hypertensive, obese and non-obese, diabetics and non-diabetics) compared with both control groups (middle-aged and young controls) (p<0.001). ADMA significantly correlated with SDMA in ≥3 RF (p<0.05), hypertensive (p<0.05), non-obese (p<0.05), non-diabetics (p<0.01), as well in middle-aged (p<0.05) and young controls (p<0.001). Conclusion: Significantly higher ADMA and SDMA were found between patients presenting with risk for CHD (≥3 and 1–2 RF, hypertensive and nonhypertensive, obese and non-obese, diabetics and non-diabetics) and healthy, middle-aged and young controls. ADMA significantly correlated with SDMA in ≥3 RF, hypertensive, non-obese and non-diabetic patients, as well as in middle-aged and young controls.