Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation.

AIMS: To directly compare the differential effects of oxygen, prostacyclin and iloprost (aerosolized and intravenous) in primary pulmonary hypertension. METHODS AND RESULTS: Twenty-one patients with severe primary pulmonary hypertension underwent right heart catheterization following oxygen inhalation, inhalation of aerosolized iloprost, intravenous prostacyclin or intravenous iloprost. The stability of the iloprost solution was tested for up to 4 weeks. Oxygen slightly decreased pulmonary vascular resistance. Intravenous prostacyclin (7.2+/-3.4 ng kg(-1) min(-1)) reduced pulmonary (1772+/-844 vs 1325+/-615 dyn s cm(-5), P<0.001) and systemic vascular resistance, and arterial and right atrial pressure, while cardiac output increased. Iloprost inhalation diminished pulmonary (1813+/-827 vs 1323+/-614 dyn s cm(-5), P<0.001) and systemic vascular resistance, and pulmonary artery (58+/-12 vs 50+/-12 mmHg,P<0.001) and right atrial pressure, while cardiac output increased. With intravenous iloprost (1.2+/-0.5 ng kg(-1) min(-1), n=8) a decrease in pulmonary (2202+/-529 vs 1515+/-356 dyn s cm(-5), P<0.05) and systemic vascular resistance and right a trial pressure occurred while cardiac output increased. Iloprost solution remained stable for 33 days while losing <10% (4 degrees C) of its active drug concentration.Conclusions Intravenous iloprost and prostacyclin have very similar haemodynamic profiles. In contrast, only inhaled iloprost exerted selective pulmonary vasodilation, reducing pulmonary vascular resistance and pulmonary artery pressure without systemic vasodilation. The longer half-life and extended stability despite lower costs render iloprost an attractive alternative to chronic prostacyclin treatment in primary pulmonary hypertension.     

肺动脉高压的抗炎治疗

由各种因素引起的肺动脉高压的根本问题是肺血管重构,但其发病机制尚未完全清楚.炎症反应在肺动脉高压的发病机制中扮演了重要角色已成为共识.近年来,应用多种抗炎药物疗法干预肺动脉高压取得了许多关键进展,为临床治疗提供了新的途径.本文拟就肺动脉高压发病过程中的免疫紊乱及抗炎药物治疗的临床应用及研究现状进行综述.     

肺动脉高压对心脏再同步治疗术后生存的预测价值

目的：分析肺动脉高压（ PAH ）对心脏再同步治疗（ CRT ）临床获益的预测价值。方法2007年3月至2012年6月在上海复旦大学附属中山医院植入CRT的165例患者回顾性分析,根据术前肺动脉收缩压（SPAP）将其分为SPAP〈50 mmHg（1 mmHg=0．133 kPa,n=107）与SPAP≥50 mmHg （n=58）两组。以全因死亡为主要终点事件,心力衰竭再住院为次要终点事件,分析两组生存函数差异,并通过Cox回归模型分析终点事件的预测因子。结果 SPAP≥50 mmHg组与SPAP〈50 mmHg组死亡例数分别为13例（22．4%）和8例（7．5%）,心力衰竭再住院例数分别为25例（43．1%）和21例（19．6%）,两者差异有统计学意义（P〈0．01）。 Kaplan-Meier生存分析显示,与SPAP〈50 mmHg组比较, SPAP≥50 mmHg者累积生存率较低（ P〈0．05）,累积再住院率则较高（ P〈0．01）。多因素回归分析显示,SPAP≥50 mmHg者主要终点事件风险比3．089（95%CI 1．117-8．543,P=0．03）,次要终点事件风险比2．465（95%CI 1．318－4．611,P=0．005）。结论中-重度PAH患者CRT后临床获益不佳,且是全因死亡和心力衰竭再住院的独立预测因子。     

Long-term survival in idiopathic pulmonary arterial hypertension associated with massive pulmonary artery dilation

The present report describes two patients with long-term survival after being diagnosed with idiopathic pulmonary arterial hypertension more than 20 years earlier. Both patients were treated with calcium channel blockers for several years and are currently maintained on bosentan, an oral endothelin receptor antagonist. Severe dilation of the main pulmonary arteries is present in both patients and may be related to long-term survival with idiopathic pulmonary arterial hypertension.     

Clinical aspects of pulmonary hypertension in patients with systemic lupus erythematosus and in patients with idiopathic pulmonary arterial hypertension

Clinical aspects and pathology of pulmonary hypertension (PH) in patients with systemic lupus erythematosus (SLE) have been reported to be similar to those in patients with idiopathic pulmonary arterial hypertension (IPAH). To determine whether PH in these patients is similar, we compared the clinical characteristics, hemodynamics at diagnosis, and survival in groups of patients with SLE–PH and IPAH. We reviewed the case records of 20 patients with SLE–PH and 34 patients with IPAH, who had been assessed by echocardiography or right cardiac catheterization at Asan Medical Center, Seoul, Korea, from January 1995 to October 2003. Clinical features, laboratory data, chest X-rays, electrocardiogram results, pulmonary function tests, pulmonary perfusion scans, echocardiographic findings, serologic profiles, and survival were compared in the two groups of patients. The mean follow-up period was 18.1±20.6 months for patients with SLE–PH and 33.0±23.4 months for patients with IPAH. During follow-up, 12 SLE–PH (60%) and 11 IPAH (32%) patients died. For SLE–PH, the 3-year survival rate was 44.9% and the 5-year survival rate was 16.8%. For IPAH, the 3-year survival rate was 73.4% and the 5-year survival rate was 68.2% (p=0.02). There were no other significant differences in clinical characteristics and laboratory data between the two groups. In contrast to previous reports that the prognosis of patients with pulmonary arterial hypertension associated with collagen vascular disease was better than that of patients with IPAH, we found that the prognosis of patients with SLE–PH was much worse than that of patients with IPAH.     

Current epoprostenol use in patients with severe idiopathic,heritable or anorexigen-associated pulmonary arterial hypertension: Data from the French pulmonary hypertension registry

Objectives

The current use of intravenous epoprostenol in patients with severe idiopathic, heritable or anorexigen-use associated pulmonary arterial hypertension (IHA-PAH) was investigated.

Methods

This observational study evaluated newly diagnosed (≤ 1 year) patients with IHA-PAH, enrolled in the French pulmonary hypertension (PH) registry between 2006 and 2010 and treated with epoprostenol. Among 209 consecutive patients receiving epoprostenol for the treatment of severe PH, 78 had IHA-PAH, including 43 patients naïve of previous PAH-specific treatment.

Results

After 4 months of epoprostenol therapy, improvement was observed for treatment naïve patients (n = 43) and for patients who had received previous PAH-specific therapy (n = 35): NYHA functional class improved in 79% and 44% of these patients, respectively, 6-minute walk distance increased by 146 (p < 0.0001) and 41 m (p = 0.03), cardiac index increased by 1.2 (p < 0.0001) and 0.5 L·min^− 1·m^− 2 (p = 0.006), and pulmonary vascular resistance decreased by 700 (p < 0.0001) and 299 dyn·s·cm^− 5 (p = 0.009). In the treatment-naïve patient group, upfront combination of epoprostenol and oral PAH therapy tended to be more beneficial compared with epoprostenol monotherapy and was associated with improvement in cardiac index (p = 0.03).The observed 1- and 3-year survival estimates from epoprostenol initiation were 84% and 69%, respectively. The highest survival rates were observed for treatment-naïve patients receiving upfront combination of epoprostenol and oral PAH therapy (92% and 88% at 1 and 3 years, respectively).

Conclusions

First-line therapy with epoprostenol, especially when combined with oral PAH treatment, was associated with a substantial improvement in clinical and hemodynamic status and favorable survival estimates in patients with severe IHA-PAH.     

Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension.

Addition of inhaled iloprost to bosentan may have beneficial effects in patients with idiopathic pulmonary arterial hypertension (IPAH). A multicentre, open, randomised, controlled trial was performed to assess the safety and efficacy of inhaled iloprost in patients with IPAH who had already been treated with bosentan. The trial was terminated early after a futility analysis predicted failure with respect to the predetermined sample size. At that time, 40 patients were randomised to receive either bosentan alone (control group) or bosentan plus inhaled iloprost (combination group) for a 12-week period. The primary end-point, change in 6-min walking distance, was not met (mean changes +1 m and -9 m in the control and combination group, respectively). These results may have been skewed by three outliers in the iloprost group who presented with severe clinical worsening. None of the secondary end-points including functional class, peak oxygen uptake, and time to clinical worsening differed significantly between groups. The current study failed to show a positive effect of adding inhaled iloprost to bosentan in idiopathic pulmonary arterial hypertension patients. Further studies involving larger sample sizes and long-term follow-up are needed to determine the efficacy of adding inhaled iloprost to bosentan in patients with idiopathic pulmonary arterial hypertension.     

肺动脉高压联合治疗方案效价研究

目的：探讨吸入型伊洛前列素和西地那非2种药物联合应用及单独用药在治疗重度肺动脉高压患者中的效价。方法：29例肺动脉高压患者随机分为单独应用伊洛前列素组（I组）、西地那非组（S组）和伊洛前列素续减合并西地那非递增的联合治疗组（I＋S组）,观察治疗4、12、24周时3组的临床疗效和经费。结果：治疗12周时,I组及I＋S组较S组在心排出量、6min步行距离和心功能WHO分级的改善方面均有明显差异（P〈0．05）;但I组与I＋S组相比疗效无显著差异：治疗24周时,3组疗效均无显著差异（P〉0．05）。12周及24周时I＋S组治疗费用较I组明显减少,分别节省32％及64％,S组治疗费用最低。结论：吸入伊洛前列素合并口服西地那非的续减递增联合治疗是重度肺动脉高压患者高效价的治疗方案。     

Differences in pulmonary function and exercise capacity in patients with idiopathic dilated cardiomyopathy and idiopathic pulmonary arterial hypertension

Objectives

We observed the pulmonary function and exercise capacity of idiopathic dilated cardiomyopathy (IDCM) and idiopathic pulmonary arterial hypertension (IPAH) patients using cardiopulmonary exercise testing (CPX). We evaluated and compared the two groups.

Background

Pulmonary abnormalities and decreased exercise capacity are common in IDCM and IPAH. Little is known about the differences in these two syndromes.

Methods

Sixty-three patients were involved the study, 23 with IDCM and 40 with IPAH. All patients underwent pulmonary function testing at rest and CPX.

Results

Patients with IPAH had a higher peak respiratory frequency (32.40 ± 7.88 vs 29.60 ± 6.50 b/min), peak dead space volume/tidal volume (29.33 ± 4.55 vs 26.30  ± 3.31%), peak end-tidal partial pressure of O₂ (125.18 ± 5.88 vs 115.17 ± 6.06 mm Hg), peak minute ventilation/CO₂ production (50.14 ± 13.26 vs 33.50 ± 6.80 L/min/L/min), and a lower peak oxygen uptake (1262.70 ± 333.34 vs 742.76 ± 194.72 ml/min), peak minute ventilation (38.20 ± 13.07 vs 45.33 ± 12.31 L), peak oxygen uptake/heart rate (5.11 ± 1.47 vs 9.43 ± 2.79 ml/b) and peak end-tidal partial pressure of CO₂ (23.73 ± 5.39 vs 35.30 ± 5.45 mm Hg) during exercise.

Conclusions

Compared to IDCM, patients with IPAH had worse pulmonary function and exercise capacity resulting from severe ventilation/perfusion mismatching and gas exchange abnormalities.     

特发性肺动脉高压患者血清骨保护素及其受体的变化及临床意义

目的探讨特发性肺动脉高压（idiopathic pulmonary arterial hypertension,IPAH）患者肺动脉压力和血清骨保护素（osteoprotegerin,OPG）及其受体（核因子-κβ受体活化因子配体,RANKL）水平的关系及临床意义。方法纳入IPAH患者28例,同期纳入性别和年龄匹配的健康体检者28例作为对照组。采用酶联免疫吸附法（ELISA）检测所有入组人员血清OPG/RANKL水平、N末端脑钠肽前体（NT-proBNP）水平;对IPAH组患者采用右心漂浮导管测定肺动脉压力的水平,并对肺动脉压和OPG/RANKL水平进行相关性分析。结果与正常对照组相比,IPAH患者血清中OPG、RANKL和NT-proBNP水平均更高[OPG：（190.91±43.39）pg/mL vs.（122.59±41.20）pg/mL;RANKL：（194.05±50.31）pg/mL vs.（117.73±39.89）pg/mL;NT-proBNP：（1894.78±591.97）pg/mL vs.（224.18±60.11）pg/mL],差异均有统计学意义（P＜0.05）。直线相关分析显示血清中OPG/RANKL水平和肺动脉压力呈正相关,相关系数分别为r=0.525（P＜0.05）和r=0.419（P＜0.05）。结论骨保护素及其受体轴（OPG/RANKL）可能参与肺动脉高压的形成,且与肺动脉压力有一定的相关性。     

先天性心脏病并重度肺动脉高压患者雾化吸入伊诺前列素的即刻效应

目的 评价雾化吸入伊洛前列素对重度成人先天性心脏病相关性肺动脉高压血液动力学的影响.方法 对165例经超声心动图诊断先天性心脏病合并重度肺动脉高压患者进行左右心导管检查获得基线血液动力学参数后雾化吸入伊洛前列素20 μg,10 min时再记录相关血液动力学资料,对比吸入伊诺前列素前后血液动力学的变化.结果 伊洛前列素吸入结束后即刻和吸入前比较,患者主动脉和肺动脉的压力略有下降(P＜0.05),但心率、主动脉平均压、肺动脉收缩压与主动脉收缩压的比值(Pp/Ps)差异均无统计学意义(P＞0.05).肺循环血量(Qp)明显增加[(7.2±4.8)L/min比(9.9±7.2)L/min,P＜0.01],肺血管阻力(PVR)明显下降[(13.4±8.7)Wood单位比(9.5±6.6)Wood单位,P＜0.01],左向右分流量明显增加[(3.2±4.4)L/min比(5.5±7.0)L/min,P＜0.01]及右向左分流量明显减少[(1.0±1. 0)L/min比(0.7±0.7)L/min,P＜0.01].亚组分析结果提示,不是所有先天性心脏病合并重度肺动脉高压患者血液动力学均呈相同的变换趋势,存在动脉导管未闭和(或)心室间隔缺损患者的肺动脉压力明显高于继发于心房间隔缺损患者,而且更易出现艾森曼格综合征(P＜0.05).结论 伊洛前列素雾化吸入可快速降低先天性心脏病相关性肺动脉高压的压力、肺血管阻力,明显增加右心排血量,对体循环压力及心率影响较小,可以作为评估急性肺血管反应的肺血管扩张剂.

Abstract：

Objective To investigate the immediately effects of inhaled aerosolized iloprost in adult patients with severe pulmonary arterial hypertension(PAH)secondary to congenital heart diseases(CHD).Methods Adult patients with severe PAH secondary to CHD(n = 165)were included in this study. Right heart catheterization was performed, Pulmonary and systemic blood flow, the oxygen consumption VO2(ml/min)were calculated using Fick's principle. Pulmonary vascular resistances(PVR)were calculated with standard formulas and indexed to body surface area. Hemodynamic parameters were measured before and after iloprost inhalation(20 μg). Results Post iloprost inhalation, heart rate, mean aortic pressure, pulmonary systolic pressure to aortic systolic pressure ratio all remained unchanged(P ＞ 0. 05), while pulmonary artery pressure(PAP)were significantly reduced and Qp significantly increased from(7. 2 ±4. 8)L/min to(9. 9 ±7.2)L/min(P＜0.01), PVR was also significantly reduced from(13.4 ±8.7)Wood units to(9.5 ±6. 6)Wood units(P ＜0. 01),and left-to-right shunt volume increased from(3.2 ±4. 4)L/min to(5. 5 ±7.0)L/min(P ＜ 0. 01)and right -to-left shunt volume decreased from(1.0 ± 1.0)L/min to(0. 7 ± 0. 7)L/min(P ＜ 0. 01). Subgroup analysis showed that adult patients with patent ductus arteriosus and/or ventricular septal defects are more likely to develop severe pulmonary arterial hypertension or Eisenmenger syndrome than patients with atrial septal defects. Conclusions Inhaled Aerosolised iloprost use is effective and safe for adult patients with severe pulmonary arterial hypertension secondary to congenital heart diseases.     

结缔组织病并发肺动脉高压110例临床分析

目的：评估结缔组织病并发肺动脉高压的发生率、临床特点、诊断及治疗方法。方法：1278例结缔组织病患者中110例伴有肺动脉高压,对其进行回顾性分析。结果：结缔组织病合并肺动脉高压的发生率约为8.6%（110/1278）。110例患者中,女性95例,男性15例,年龄11～79岁,平均（46±17）岁;病程0.5～20年,平均（7±6）年。系统性硬化症（SSc）和混合性结缔组织病（MCTD）合并肺动脉高压发生率最高,分别为40.0%和25.0%,显著高于其他结缔组织病（P〈0.01）。有雷诺现象或雷诺现象合并肺间质病变者肺动脉压力显著升高（P〈0.01和P〈0.05）。且雷诺现象与肺动脉压力呈正相关（r=0.531,P〈0.01）。肺功能异常发生率较高,以弥散量降低最为多见。轻度肺动脉高压患者临床表现少,治疗可逆转;重度肺动脉高压治疗反应差,病死率高。结论：结缔组织病合并肺动脉高压较为常见,其中以SSc和MCTD合并肺动脉高压发生率最高。雷诺现象与肺动脉压力呈正相关,是预测肺动脉高压的良好指标。早期诊断和治疗,可以改善患者预后。     

吸入伊洛前列素在儿童先天性心脏病肺血管扩张试验中的应用

目的:该研究在心导管检查中通过对先天性心脏病(CHD)合并肺动脉高压(PAH)儿童,吸入伊洛前列素前后的血流动力学参数的测定,评价吸入伊洛前列素在CHD相关性PAH儿童急性肺血管扩张试验的安全性、有效性。方法:研究选择2007年6月至2010年5月,于北京安贞医院小儿心脏科住院的左向右分流型CHD合并重度PAH患儿,所有患儿行左、右心导管检查,并采用雾化吸入伊洛前列素,监测吸药前后血流动力学参数改变及不良反应。结果:该研究入选43例左向右分流型CHD合并重度PAH患儿,年龄(8.52±4.76)岁。吸入伊洛前列素后肺动脉平均压由(77.14±12.14)mmHg(1 mmHg=0.133 kPa)降至(69.35±12.14)mmHg(P<0.05);肺体循环血流量比值(Qp/Qs)由1.80±1.26升至3.06±2.90(P<0.05);肺血管阻力指数(PVRI)下降约5 Wood unit.m2〔吸入前(14.51±8.46)Wood unit.m2,吸入后(9.58±7.43)Wood unit.m2,P<0.05),体循环血压无明显变化〔吸入前(83.16±13.69)mmHg,吸入后(83.09±11.03)mmHg,P>0.05〕。以吸入伊洛前列素后PVRI较基础水平下降至少20%以上作为急性肺血管扩张试验阳性标准。肺血管反应阳性患儿31例,占72%,阴性反应患儿(PVRI下降<20%)12例,占28%。结论:对左向右分流型CHD合并重度PAH儿童在心导管检查中吸入伊洛前列素可明显降低肺血管阻力,体循环血压无明显变化,无明显不良反应发生,可作为安全有效的急性肺血管扩张试验的用药。     

特发性肺动脉高压一例临床分析

特发性肺动脉高压（idiopathic pulmonary arterial hypertension,IPAH）是一种罕见的、进行性加重、原因不明的肺动脉血管硬化病变,诊断往往比较困难,预后险恶。至今全世界约有1000多例报道,我国尚无精确统计,但也有散在报道。2010年我院收治1名患者,现将其临床资料进行回顾性分析。     

结缔组织病相关肺动脉高压79例临床分析

目的探讨结缔组织病相关肺动脉高压的发生率、临床特点及预后,提高对该病的认识。方法收集2005年1月～2008年8月我科收治的1876例弥漫性结缔组织病（CTD）中合并肺动脉高压的79例患者的临床资料及部分患者的随访资料。结果①混合性结缔组织病（MCTD）与系统性硬化症（SSc）肺动脉高压发生率最高（40．0％,30．2％）;②主要的临床表现为雷诺现象（62．0％）,抗SSA抗体与抗U1RNP抗体阳性率最高（51．9％）;③雷诺征发生率、血尿酸水平在轻、中重度肺动脉高压组间比较有统计学差异（P〈0．05）,肺动脉收缩压与雷诺征、心包炎、呼吸困难、血尿酸水平呈正相关（P〈0．05）,与关节炎呈负相关（P〈0．05）;④死亡3例,均为系统性红斑狼疮合并重度肺动脉高压者。结论CTD合并肺动脉高压并不少见,雷诺征与血尿酸水平可作为预测肺动脉高压严重程度的指标。     

Addition of sildenafil in patients with pulmonary arterial hypertension with inadequate response to bosentan monotherapy

BACKGROUND:

Pulmonary arterial hypertension (PAH) remains a progressive disease despite improvement when using one of three medication classes: prostanoids, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Combination therapy has been proposed for patients with unsatisfactory response to monotherapy.

OBJECTIVES:

To examine the effect of adding sildenafil to bosentan on 6 min walk distance (6MWD) and New York Heart Association (NYHA) classification in patients with PAH who achieved inadequate improvement with bosentan monotherapy.

METHODS:

Patients with idiopathic PAH or connective tissue disease-associated PAH, and who had either self-reported inadequate improvement in exercise tolerance or a decline in 6MWD after initial improvement, were included in the study (n=10). Data on 6MWD and NYHA class at baseline (before initiation of bosentan), three and six months after baseline, second baseline (before initiation of combination therapy with sildenafil), and three and six months after second baseline were analyzed for any changes.

RESULTS:

Mean time from initiation of bosentan monotherapy to initiation of combination therapy was 558 days (range 150 to 900 days). Six months after initiation of bosentan, 6MWD increased by 57.2 m above the baseline of 314.4 m. Six months after combination therapy, 6MWD was 62.80 m higher than the baseline before initiation of combination therapy of 339 m (P<0.02). The overall increase in 6MWD six months after combination therapy was higher than the first baseline by 87.4 m (P not significant). NYHA functional class did not improve with combination therapy in all patients.

DISCUSSION:

Initiating combination therapy in patients who achieve an inadequate improvement in exercise tolerance with mono-therapy may result in further improvement in exercise tolerance.