西地那非治疗肺动脉高压疗效和安全性的初步观察

目的 探讨西地那非治疗对肺动脉高压患者的临床疗效及耐受性,为西地那非治疗肺动脉高压提供依据.方法 连续入选2007年5月至2009年4月阜外心血管病医院收治的肺动脉高压患者56例,其中男11例,女45例,年龄(31±11)岁.给予西地那非25 mg口服,3次/d,记录治疗前和治疗12周后患者心功能和肺动脉高压功能分级、6 min步行距离、Borg呼吸困难指数、血流动力学改变及临床症状,同时监测患者血液循环及实验室检测指标及不良反应.结果 治疗12周后,患者心功能和肺动脉高压功能分级有明显改善(P<0.01),其中2例Ⅳ级升高至Ⅲ级;8例Ⅲ级改善为Ⅱ级,2例升高至Ⅰ级;5例Ⅱ级升高至Ⅰ级.无纽约心功能分级及世界卫生组织肺动脉高压功能分级恶化病例;6 min步行距离由(352±80)m增加至(396±78)m;差值为(44±70)m(P<0.01);肺动脉平均压降低(6±14)mm Hg(1 mm Hg=0.133 kPa)、肺血管阻力降低(490±832) Dys·s·cm-5(均P<0.01)心输出量增加(1.1±2.0) L/min,P<0.01;心指数增加(0.7±1.1) L·min-1·m-2(均P<0.01).患者无临床恶化情况,耐受性良好,无严重不良事件.结论 西地那非治疗可显著改善肺动脉高压患者功能分级,活动耐力及血流动力学.

Abstract：

Objective To explore the safety and efficacy of oral sildenafil therapy for pulmonary arterial hypertension(PAH), and to provide evidence for sildenafil treatment for Chinese patients with PAH. Methods In this 12-week, prospective, open-label, uncontrolled study, 56 patients with PAH were given oral sildenafil (25 mg, tid). The primary end point was change from baseline to 12 weeks in exercise capacity assessed by 6 min walk (6MW) test. Secondary end points included changes in WHO class and cardiopulmonary hemodynamics. Clinical worsening was defined as death, transplantation, hospitalization for PAH, or initiation of additional therapies for PAH, such as intravenous epoprostenol or oral bosentan. Results After 12 weeks, the compliance was good in 56 patients. Significant improvement was seen in NYHA heart function class and WHO class as compared to baseline(P<0.01): from class Ⅳ to class Ⅲ in 2, from class Ⅲ to class Ⅱ in 8 and to class Ⅰ in 2 cases, and from class Ⅱ to class Ⅰ in 5 cases. No NYHA heart function class and WHO PAH function class deterioration were observed. Oral sidenafil increased 6MW distance, from (352±80) m to (396±78) m, with a change of (44±70) m(P<0.01). Significant improvement was seen in hemodynamics (mean pulmonary artery pressure, P<0.01; cardiac index, P<0.01; pulmonary vascular resistance, P<0.01) at week 12 as compared with baseline. Mean right atrial pressure decreased (3±11)mm Hg (1 mm Hg=0.133 kPa), mean pulmonary arterial pressure decreased (6±14) mm Hg, cardiac output increased (1.1±2.0)L/min, cardiac index increased (0.7±1.1)L·min-1·m-2, and total pulmonary resistance decreased (490±831) Dys·s·cm-5. Side effects were mild and consistent with those reported with sildenafil treatment. No statistically significant clinical worsening was observed with sildenafil therapy for PAH patients. Conclusions Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with pulmonary arterial hypertension.     

瑞舒伐他汀干预野百合碱诱导大鼠肺动脉高压的实验研究

目的 探讨他汀类药物改善内皮细胞功能、抗增殖等降脂外作用在防治肺动脉高压中的作用及可能机制.方法 雄性SD大鼠,体重(255.7±12.5)g,皮下注射野百合碱诱导大鼠形成肺动脉高压,肺动脉高压形成前后分别接受瑞舒伐他汀预防和治疗.预防实验:32只SD大鼠随机分为4组,分别为瑞舒伐他汀低剂量(2 mg·kg-1·d-1)预防组(n=8)、瑞舒伐他汀高剂量(10 mg·kg-1·d-1)预防组(n=8)、肺动脉高压4周组(n=8)和正常对照4周组(n=8),野百合碱注射当日起预防组每日予瑞舒伐他汀灌胃至第4周末,正常对照组、肺动脉高压4周组仅予生理盐水灌胃.治疗实验:52只SD大鼠随机分为4组,分别为瑞舒伐他汀低剂量(2 mg·kg-1·d-1)治疗组(n=12)、瑞舒伐他汀高剂量(10 mg·kg-1·d-1)治疗组(n=12)、肺动脉高压8周组(n=20)和正常对照8周组(n=8),野百合碱注射4周后治疗组每日予瑞舒伐他汀灌胃至第8周末,正常对照组、肺动脉高压8周组仅予生理盐水灌胃.比较各组生存率、平均肺动脉压(mPAP)、肺小动脉管壁厚度、右心室肥厚程度,比较肺小动脉增殖细胞核抗原(PCNA)、内皮型一氧化氮合酶(eNOS)蛋白表达水平,比较肺组织Rho激酶1(ROCK-1)、eNOS mRNA表达水平.结果 预防实验大鼠均存活,肺动脉高压形成之后瑞舒伐他汀治疗能改善生存率(瑞舒伐他汀低剂量治疗组、瑞舒伐他汀高剂量治疗组与肺动脉高压8周组比较为58%、75%比30%,P均＜0.05);肺动脉高压形成之前和之后瑞舒伐他汀预防和治疗均能降低mPAP[预防实验:瑞舒伐他汀低剂量预防组、瑞舒伐他汀高剂量预防组与肺动脉高压4周组比较为(27.53±3.43)mm Hg(1 mm Hg=0.133 kPa)、(25.72±1.76)mm Hg比(36.05±2.45)mm Hg,P均＜0.01;治疗实验:瑞舒伐他汀低剂量治疗组、瑞舒伐他汀高剂量治疗组与肺动脉高压8周组比较为(30.39±3.17)mm Hg、(27.59±1.99)mmHg比(40.68±1.39)mm Hg,P均＜0.01],减轻肺小动脉管壁增厚、右心室肥厚程度(P均＜0.01),下调肺小动脉平滑肌细胞PCNA表达(P均＜0.01),上调内皮细胞eNOS表达(P均＜0.05),抑制ROCK-1基因表达(P均＜0.05),有一定的剂量依赖性(P均＜0.05).结论 瑞舒伐他汀防治肺动脉高压可能是通过抑制ROCK-1基因表达,抑制肺动脉平滑肌增殖和恢复内皮细胞功能等机制来实现的.

Abstract：

Objective To investigate the effects of rosuvastatin on monocrotaline (MCT)-induced pulmonary artery hypertension in rats. Methods Pulmonary arterial hypertension was induced by a single subcutaneous injection of monocrotaline (50 mg/kg) in rats. In the prevention protocol, 32 male SpragueDawley rats were randomly divided into four groups ( n = 8 each): low-dose rosuvastatin prevention group (2 mg · kg-1 · d-1 ), high-dose rosuvastatin prevention group ( 10 mg· kg-1 · d-1 ), pulmonary arterial hypertension group, normal control group. Beginning on the MCT injection day, rats were treated with rosuvastatin by daily gavage for 4 weeks. Normal control group and pulmonary arterial hypertension group received vehicle by garage. In the treatment protocol, 52 male Sprague-Dawley rats were randomly dividedinto four groups (n = 13 each): low-dose rosuvastatin treatment group (2 mg · kg-1 · d-1), high-dose rosuvastatin treatment group( 10 mg · kg-1 · d-1), pulmonary arterial hypertension group, normal control group. Four weeks after MCT injection, rats were treated with rnsuvastatin by daily gavage for 4 weeks.Normal control group and pulmonary arterial hypertension group received vehicle by gavage. At the end of study, survival rates, mean pulmonary arterial pressure (mPAP), wall thickness of small pulmonary artery and right ventricular hypertrophy among groups were compared. The expression levels of proliferating cell nuclear antigen (P CNA) and endothelial nitricoxide synthase (eNOS) protein in small pulmonary artery,the expression levels of Rho kinase 1 ( ROCK-1 ) and eNOS mRNA in lung tissue were also detected. Results All rats in the prevention protocol survived. Rosuvastatin treatment improved survival in the treatment protocol (58%, 75% vs. 30%, P ＜0. 05 ). Rosuvastatin therapy in both preventment or treatment protocols significantly lowered mPAP [prevention protocol: ( 27.53 ± 3.43 ), ( 25.72 ± 1.76 ) vs. ( 36. 05 ± 2. 45 )mm Hg(1 mm Hg =0. 133 kPa), P ＜0.01; treatment protocol: (30. 39 ±3. 17), (27.59 ±1.99) vs.(40. 68 ± 1.39) mm Hg, P ＜0. 01], reduced thickening of small pulmonary artery wall (P ＜0. 01 ) and right ventricular hypertrophy ( P ＜ 0. 01 ). Rosuvastatin also inhibited PCNA expression of SMC ( P ＜0. 01 ), restored eNOS expression of EC ( P ＜ 0. 05) and inhibited ROCK-1 mRNA expressions in lung tissue (P ＜ 0. 05 ). Conclusions Rosuvastatin therapy reduced mPAP in monocrotaline-induced pulmonary arterial hypertension rat model and this effect is linked with inhibition of ROCK-I expression, inhibition of smooth muscle cell proliferation and restoration of endothelial cell functions.     

Carvedilol therapy for patients with Eisenmenger syndrome

Background: Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with resultant intracardiac right-to-left shunt and hypoxemia in patients with congenital heart defects. In clinical practice, we found that these patients might benefit from carvedilol therapy. Thus, we designed this prospective, open label, observational study to evaluate the efficacy of carvedilol for patients with Eisenmenger syndrome. Methods Twenty patients(17.5 ± 4.8 years) with Eisenmenger syndrome were treated with carvedilol for 6 weeks. The efficacy of carvedilol on 6-minute walking distance, World Health Organization(WHO) functional class, arterial oxygen saturation and right ventricle systolic pressure were assessed.Results At the end of observation, change from baseline in 6-minute walking distance increased 36.35 meters(95% confidence intervals [CI] 25.43 to 47.27 m, P 0.01). WHO functional class was also significantly improved(P 0.05). Change from baseline in right ventricular systolic pressure assessed by echo was reduced by 8.11 mm Hg(95% confidence intervals [CI],-10.78 to-5.44 mm Hg, P 0.05). However, arterial oxygen saturation remained unchanged(87.5 ± 3.02 % at baseline versus 87.80 ± 7.29 % at the end of observation). Conclusions Carvedilol can improve clinical function, symptoms as well as exercise capacity in patients with Eisenmenger syndrome. These findings need to be confirmed in further randomized clinical trials.     

室间隔缺损和动脉导管未闭合并中重度肺动脉高压的分期复合治疗

目的 评价经导管介入封堵加择期外科手术的分期复合治疗应用于室间隔缺损和动脉导管未闭合并中重度肺动脉高压患者的安全性及有效性.方法 自2004年7月至2009年7月,对22例室间隔缺损和动脉导管未闭合并中重度肺动脉高压患者进行了先经导管介入封堵动脉导管未闭,随后择期行开胸室间隔缺损修补术的分期复合治疗.术后进行随访,观察心律改变、残余分流、封堵器形态、有无瓣膜反流及主动脉狭窄等情况,测量肺动脉压变化,评价治疗效果.结果 经导管介入封堵治疗后,患者肺动脉收缩压由(76.2±25.8)mm Hg(1 mm Hg=0.133 kPa)降至(55.4±20.6)mm Hg(P=0.005),肺动脉平均压由(53.5±23.5)mm Hg降至(36.2±17.8)mm Hg(P=0.049),全肺动脉阻力由(8.2±4.9)wood单位降至(6.9±4.3)wood单位(P=0.037),肺循环血流量与体循环血流量的比值(Qp/Qs)由2.8±2.3升至3.4±1.7(P=0.045).外科手术后,肺动脉收缩压由(64.5±22.3)mm Hg降至(43.1±18.9)mm Hg(P=0.001),肺动脉平均压由(40.2±18.7)mm Hg降至(29.5±15.8)mm Hg(P=0.040).随访中所有患者均未出现右心衰竭和死亡.结论 室间隔缺损和动脉导管未闭合并中重度肺动脉高压的经导管介入封堵加择期外科手术的分期复合治疗安全、有效.

Abstract：

Objective To evaluate the safety and efficacy of staged hybrid approach in treating ventricular septal defect (VSD) patients combined with patent ductus arteriosus (PDA) and pulmonary artery hypertension (PAH). Methods From July 2004 to July 2009, 22 VSD patients with PDA and PAH were enrolled and received staged hybrid approach treatment( transcatheter PDA occlusion and elective open surgery for VSD several lays after PDA occlusion). All patients were followed up to examine rhythm change,residual shunt, shape of occlude, possible valve regurgitation, and aortic stenosis by echocardiography. Results After transcatheter PDA occlusion, pulmonary arterial systolic pressure decreased from (76. 2 ± 25. 8 ) mm Hg ( 1 mm Hg = 0. 133 kPa) to ( 55.4 ± 20. 6 ) mm Hg ( P = 0. 005 ),mean pulmonary artery pressure decreased from ( 53.5 ± 23.5 ) mm Hg to ( 36. 2 ± 17. 8 ) mm Hg ( P=0. 049), total pulmonary resistance decreased from (8. 2 ±4.9)wood units to (6.9 ±4. 3)wood units (P =0. 037), and pulmonary-to-systemic flow ratio (Qp/Qs) increased from 2. 8 ± 2. 3 to 3.4 ± 1.7 ( P = 0. 045 )post transcatheter interventional PDA occlusion. After VSD repair, pulmonary arterial systolic pressure decreased from (64. 5 ± 22. 3 ) mm Hg to (43. 1 ± 18. 9) mm Hg ( P = 0. 001 ) and mean pulmonary artery pressure decreased from (40. 2 ± 18. 7 ) mm Hg to (29. 5 ± 15. 8) mm Hg ( P = 0. 040). There was no death or right heart failure during the follow-up. Conclusion Staged hybrid approach is an effective and safe strategy for treating VSD patients with PDA and PAH.     

Prognostic value of the echocardiographic right/left ventricular end-diastolic diameter ratio in patients with idiopathic pulmonary arterial hypertension

Background Previous studies have shown that an echocardiographic right/left ventricular end-diastolic diameter ratio(RV/LV ratio)≥0.9 is an independent predictor of poor prognosis in patients with acute pulmonary embolism. The prognostic value of the RV/LV ratio in patients with idiopathic pulmonary arterial hypertension(IPAH) is still unknown. Methods We retrospectively enrolled 95 consecutive patients with newly diagnosed IPAH and 16 of them were reevaluated by echocardiography at 3-12 months following targeted therapy.Follow-up data were obtained by telephone interviews and review of the patients’ records.Results The RV/LV ratio was in parallel with the severity of World Health Orgnization(WHO) functional class and mean right atrial pressure.The RV/LV ratio was positively correlated with total pulmonary resistance(P P P 2 saturation(P P = 0.001),weight and absence of targeted therapy were independent predictors of death.No significant changes in the RV/LV ratio before and after targeted therapy were observed. A baseline RV/LV ratio≥0.84 or a further increase in the RV/LV ratio during targeted therapy indicated a poor prognosis. Conclusions The RV/LV ratio helps to assess the severity of IPAH and serves as an independent predictor of prognosis in patients with IPAH.     

Hybrid方法建立肺血减少型先天性心脏病幼猪动物模型

目的 研究肺血减少型先天性心脏病(先心病)肺血管发育的病理生理过程及其相关调节机制,探讨肺血减少型先心病幼猪动物模型构建的可行性方法.方法 采用出生1～2个月的幼猪共20只,按照购入时的编号顺序(1～20),随机分为3组:(1)对照组(C组,n=6),右胸前外侧切口造成一过性肺血减少;(2)轻中度狭窄组(T1组,n=7),右胸前外侧切口经右心房表面送入球囊扩张器行人工房间隔造口+肺动脉Banding环缩术,术中收缩期肺动脉环缩处压差(systolic trans pulmonary artery banding pressure,Trans-PABP)20～30 mm Hg(1 mm Hg=0.133 kPa);(3)重度狭窄组(T2组,n=7),术中Trans-PABP≥30～50 mm Hg.术后1个月行64排CT扫描评估,2个月二次开胸手术测定动脉血气分析及血常规,测量各组血管直径及Trans-PABP,处死动物切取心肺组织测量房间隔缺损(ASD)和Banding环直径.结果 C组动物因麻醉意外,术后10 h死于呼吸衰竭1例.T1组术后21 d死于肠梗阻、肠坏死1例.T2组死亡2例,分别于术后24 b和39 d因急性和慢性右心功能衰竭死亡.T1和T2组存活动物房间隔造口+肺动脉环缩术均获得成功.术后超声测定T1和T2组房缺大小分别为(8.0±0.5)mm、(8.9±1.4)mm(P＞0.05),Trans-PABP术后至2个月持续显著增加,T1组由(19.1±5.6)mm Hg增加至(24.1±3.0)mm Hg(P＜0.01),T2组由(34.2±3.9)mm Hg增加至(43.6±6.4)mm Hg(P＜0.01).术前三组间氧分压(PaO2)和血细胞比容(Hct)差异均无统计学意义.术后2个月T1、T2组PaO2显著低于C组,且T2组低于T1,T1、T2组Hct显著高于C组,且T2组高于T1组(P＜0.05).64排CT扫描示T1组主动脉直径(AOD)明显低于C组,T1、T2组肺动脉环缩处直径显著低于各自的AOD(P＜0.01).结论 采用球囊扩张房间隔造口+肺动脉环缩的方法成功的建立了理想的肺血减少型先心病模型,该模型简单可靠、经济实用,十分接近临床的病理生理状态,为该类疾病的临床研究奠定了坚实的实验基础.

Abstract：

Objective To establish an animal model of congenital heart defect with decreased pulmonary blood flow for better understanding the pathophysiology of pulmonary vascular development and related regulatory mechanisms of congenital heart defect with decreased pulmonary blood flow. Method One to two months old pigs were randomly divided into three groups: control group(group C, n = 6)with right chest small incisions induced transient pulmonary blood reduction;light-moderate stenosis groups (group T1, n = 7):artificial atrial septum defect(ASD)plus controlled pulmonary artery banding to generate a systolic pressure gradient of 20-30 mm Hg(1 mm Hg = 0. 133 kPa);severe stenosis groups (group T2, n = 7): similar surgical procedures as group T1, and controlled pulmonary artery banding to generate a systolic pressure gradient ≥ 30 ～50 mm Hg. 64-slice computed tomography scanning was performed at one month post operation. Arterial blood gas analysis, hemoglobin value, pulmonary vessel,ASD and banding ring diameters and trans-pulmonary artery banding pressure(Trans-PABP)were determined at two months post operation. Results One pig died due to tracheal intubation accident in the C group, one pig died due to bowel obstruction in the T, group and two pigs died due to acute right heart failure and chronic heart failure respectively in T2 group. 64-slice CT angiography results showed that aortic diameter of T1 group was significantly lower than that of C group and banding diameter was significantly lower than aortic diameter in the T1 and T2 groups at one month post operation. Two months after operation, the size of ASD were(8.0 ± 0. 5)mm and(8.9 ± 1.4)mm(P ＞ 0. 05)respectively in the T1 and T2 groups after operation. The Trans-PABP was significantly higher in the T1 and T2 groups than in C group(P ＜0. 01), and the Trans-PABP was significantly higher in the T2 group than in T1 group(P ＜0. 01). PaO2 and SaO2 in the T1 and T2 groups were significantly lower than those in C group. Conclusion Artificial atrial septum defect combined pulmonary artery banding procedures could be successfully used to establish model of congenital heart defect with decreased pulmonary blood flow and this model could help to understand the pathophysiology and monitor therapy efficacy for patients with congenital heart defect with decreased pulmonary blood flow.     

经导管封堵心脏人工瓣膜置换术后周围漏

目的 探讨经导管堵闭器封堵外科瓣膜置换术后人工瓣膜周围漏(PVL)的可行性、有效性和安全性.方法 回顾性分析外科瓣膜置换术后诊断为PVL的5例患者,其中主动脉瓣机械瓣置换术后PVL 2例,二尖瓣生物瓣置换术后PVL 2例,主动脉瓣和二尖瓣机械瓣置换术后二尖瓣PVL1例.封堵前后检查超声心动图以评价疗效.结果 患者均采用国产封堵器进行堵闭.2例主动脉瓣PVL封堵术后无残余;3例二尖瓣PVL堵闭术后残存微量至少量反流.其中1例主动脉瓣PVL患者介入术中出现心脏穿孔、心包填塞,经穿刺引流后痊愈.3例二尖瓣PVL患者出现术后早期溶血,于术后1～3周恢复.与术前比较,3个月随访期间左心室舒张末期内径减小[(52.2±6.8)mm比(61.1±7.2)mm,P＜0.05],肺动脉收缩压下降[(40.0±5.4)mm Hg(1 mm Hg=0.133 kPa)比(57.0±3.6)mm Hg,P＜0.05],二尖瓣PVL患者左心房内径减小[(49.0±4.3)mm比(56.0±6.3)mm,P＜0.05].结论 经导管封堵人工瓣置换术后PVL可行而且安全、有效,在具备适应证患者中可作为治疗选择.

Abstract：

Objective To evaluate the feasibility and efficacy of transcatheter closure of paravalvular leak (PVL) with Chinese-made occlder. Methods Five PVL patients were involved in this study, 2 out of the 5 patients underwent aortic mechanical valve replacements, 2 underwent mitral bioprosthetic valve replacements, and the remaining 1 underwent double mechanical valve replacement. Left ventricular end diastolic diameter, left atrial diameter and the systolic pulmonary artery pressure were assessed by echocardiography before and post the procedure. Results Complete occlusion without residual regurgitation was achieved in 2 patients with aortic PVL, for the 3 patients with mitral PVL, there was only tiny or mild mitral paraprosthetic leak remained post closure procedure. Cardiac perforation and pericardium tampenade occurred in 1 patient with aortic PVL during interventional closure and the patient recovered post emergent pericardiocentesis. Transient severe hemolysis and hemoglobinuria occurred in 3 patients with mitral PVL post closure procedure and they recovered after 1 to 3 weeks concervative therapy. During 3 months follow up, left ventricular end diastolic diameter [( 52. 2 ± 6. 8 ) mm vs. ( 61.1 ± 7.2 ) mm, P ＜0. 05], the systolic pulmonary artery pressure [(40. 0 ±5.4) mm Hg( 1 mm Hg =0. 133 kPa) vs. (57. 0 ±3.6) mm Hg, P ＜ 0. 05] and left atrial diameter of mitral PVL patient [( 49. 0 ± 4. 3 ) mm vs. ( 56. 0 ±6. 3) mm, P ＜ 0. 05] were significantly reduced compared to before closure procedure. Conclusion Percutaneous or transapical left ventricular access closure of PVL is feasible, effective and relative safe in selected patients.     

特发性肺动脉高压发病机制研究进展

正1概述近年来,特发性肺动脉高压(idiopathic pulmonary arterial hypertension,IPAH)越来越受到人们的关注。IPAH属于毛细血管肺高血压(pulmonary hypertension,PH),既没有家族病史,也没有一个确定的危险因素,被定义为海平面、静息状态下,右心导管测得平均肺动脉压力≥25mm Hg(1mm Hg=0.133kPa)     

贝那普利/氨氯地平复方制剂与贝那普利单药治疗轻中度高血压的多中心随机双盲平行对照研究

目的 评价贝那普利/氨氯地平复方片剂与贝那普利片单药治疗轻、中度高血压患者的有效性和安全性.方法 本研究为多中心、随机、双盲、平行对照研究.356例原发性高血压患者经2周洗脱期后,再给予4周贝那普利片10 mg单药治疗,220例平均坐位舒张压(SeDBP)仍≥90 mm Hg(1 mm Hg=0.133 kPa)的患者随机分为贝那普利(10 mg)/氨氯地平(5 mg)固定剂量复方片剂组(复方制剂组,1片/d,n=113)和贝那普利片单药组(单药治疗组,20 mg/d,n=107),治疗4周末两组诊室SeDBP≥90 mmHg者剂量加倍.SeDBP＜90 mm Hg者续服原剂量,共随机双盲治疗8周.以总有效率和SeDBP下降差值作为主要疗效指标.其中74例患者(复方片剂组38例,单药组36例)完成了24 h动态血压监测,并作为降压疗效的评价指标.结果 随机、双盲治疗8周末,复方片剂组SeDBP下降值为(11.7±6.8)mm Hg、达目的 血压占65.7%、总有效率为88.5%;单药治疗组SeDBP下降值为(7.7±6.9)mm Hg、达目的 血压占35.5%、总有效率为65.5%.两组组间比较差异均有统计学意义(P＜0.001).24 h动态血压监测结果,复方制剂组和单药组的舒张压/收缩压(DBP/SBP)的谷/峰比率(T/P)分别为83.1%/76.0%和85.8%/79.5%(P＜0.05).复方制剂组与单药治疗组的不良反应发生率分别为16.8%和35.5%(P＜0.01).结论 贝那普利/氨氯地平复方制剂治疗原发性高血压患者的降压疗效明显优于贝那普利单药治疗,且有良好的耐受性.

Abstract：

Objective To evaluate the efficacy and tolerability of the fixed combination of amlodipine 5 mg/benazepril 10 mg once-daily therapy, compared with benazepril, 10 mg, monotherapy in patients with mild and moderate hypertension, and to evaluate the 24 h antihypertensive efficacy and the duration of action by ambulatory blood pressure monitoring Methods In a multicenter, randomized,double-blind, parallel controlled trial, 356 cases of hypertensive patients after 2 weeks wash-out, and then given 4 weeks of benazepril 10 mg monotherapy, 220 patients with mean seated diastolic blood pressure (SeDBP)remained ≥90 mm Hg(1 mm Hg = 0. 133 kPa)were randomly divided into benazepril 10 mg/amlodipine 5 mg(BZ10/AML5)fixed-dose combination therapy group(once a day, n = 113), and benazepril monotherapy group(daily 20 mg, n = 107). In the two groups the patients with SeDBP≥90 mm Hg were doubled the dosage of the initial regimen at the end of 4-week treatment for additional 4 weeks , and the patients with SeDBP ＜ 90 mm Hg remained the initial regimen for additional 4 weeks. The primary endpoint was to evaluate the improvement of SeDBP at the end of 8-week treatment. There were 74 patients(the combination therapy group n = 38, monotherapy therapy group n = 36)completed the 24 h ambulatory blood pressure monitoring which was included in the final efficacy analysis. Results The randomized, doubleblind treatment for 8 weeks, the mean value of SeDBP reduction, the reaching target blood pressure rate and total successful response rate to the treatment(a SeDBP ＜ 90 mm Hg or a decrease of 10 mm Hg or more from baseline)were(11.7 ± 6.8)mm Hg, 65.7% and 88.5% in the combination therapy group,respectively, and were(7.7 ±6. 9)mm Hg, 35.5% and 65.5% in the monotherapy group, respectively.There were statistically significant difference between the combination therapy and the monotherapy groups in all the 3 indexs(P ＜ 0. 001). The fixed combination significantly reduced systolic blood pressure(SBP)and diastolic blood pressure(DBP)values throughout the 24 h. The trough to peak ratios of DBP/SBP in the fixed compound of benazepril/amlodipine(10 mg/5 mg)and benazepril(20 mg)alone were 83. 1%/76. 0% and 85.8%/79. 5%, respectively. Adverse events rates were 16. 8% in the combination therapy group and 35.5% in the monotherapy group(P ＜ 0. 001). Conclusions The combination therapy with benazepril/amlodipine was superior to benazepril monotherapy and was well tolerated in patients with essential hypertension and allowing a satisfactory BP control for 24 hours.     

Cardiac catheterization and comprehensive clinical evaluation after bidirectional Glenn shunt surgery in 60 patients with complex congenital heart disease

Background The bidirectional Glenn shunt surgery is a palliative procedure for patients with complex congenital heart disease(CHD) who are not suitable for biventricular repair in early life. There is limited evidence of successful strategies for long-term hemodynamic stabilization. Furthermore, there have been no data on optimal hemodynamics that could be used as a reference for patients' follow-on management. Methods Sixty CHD patients, 44 male and 16 female, with bidirectional Glenn shunt surgery and cardiac catheterization were enrolled at our hospital between January 2014 and December 2016. Pre-and post Glenn shunt percutaneous oxygen saturation(SpO_2), 6-minute walk test(6 MWT), superior vena cava pressure(SVCP), pulmonary arterial pressure(PAP), pulmonary capillary wedge pressure(PCWP), pulmonary vascular resistance(PVR), small pulmonary vascular resistance(s PVR) were measured. Pre-and post-total cavopulmonary connection(TCPC) SpO_2, and in-hospital complications were monitored. The optimal hemodynamic cutoff values for TCPC patient selection were estimated by receive operating characteristic(ROC) curve analysis. Results SpO_2 was significantly increased by bidirectional Glenn shunt surgery(75.42 ± 9.62% to 86.98 ± 7.63%, P 0.001) from 82.70 ± 5.99% to 95.00 ±4.07% in the 47 patients with TCPC. Forty-two patients completed the 6 MWT with a mean distance of 362.7 ±75.0 m and a SpO_2 decrease from 81.80 ± 7.84% to 67.59 ± 1.82%(P 0.001). The △SpO_2 and 6-minute walk distance(6 MWD) in the 32 who underwent TCPC and ten of them did not reach statistical significance(17.22 ±13.82% vs. 13.87 ± 8.74%, P = 0.08 and 358.88 ± 78.97 m vs. 374.80 ± 62.55 m, P = 0.564]. After cardiac catheterization, 47 patients were selected for TCPC. The right pulmonary artery systolic pressure(s RPAP), mean right pulmonary artery pressure(m RPAP), mean left pulmonary artery pressure(m LPAP), PVR, and s PVR were significantly lower in the TCPC group than in the non-TCPC group. The differences in superior vena cava systolic blood pressure(s SVCP), mean superior vena cava pressure(m SVCP), and left pulmonary artery systolic pressure(s LPAP) were not significant. The optimal cutoff values for TCPC were s SVCP ≤ 20 mm Hg(P = 0.025),s RPAP ≤ 22 mm Hg(P = 0.0001, mRPAP ≤ 13 mm Hg(P =0.003), s LPAP ≤ 27 mm Hg(P =0.03), m LPAP ≤ 11 mm Hg(P = 0.01), PVR ≤ 4.3 Wood U/m~2(P 0.0001) and were significantly associated with TCPC selection,except for m SVCP ≤ 19 mm Hg(P = 0.06) and s PVR ≤ 2.0 wood U/m~2(P = 0.0531). One patient died because of low cardiac output after TCPC. In-hospital mortality was 2.1%. Conclusion The SpO_2 can be significantly improved after bidirectional Glenn shunt and TCPC surgery. The 6 MWT is an index of activity tolerance prior toTCPC. Hemodynamic values of s SVCP ≤ 20 mm Hg, s RPAP ≤ 22 mm Hg, m RPAP ≤ 13 mm Hg, s LPAP ≤ 27 mm Hg, m LPAP ≤ 11 mm Hg, and PVR ≤ 4.3 Wood U/m~2 can help identify post Glenn-shunt patients indicated for TCPC.     

Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension.

AIMS: Data on long-term efficacy of bosentan in unselected idiopathic pulmonary arterial hypertension (IPAH) patients are lacking. We aimed to describe the long-term outcome of consecutive IPAH patients treated first-line with bosentan. METHODS AND RESULTS: A retrospective analysis of 103 consecutive New York Heart Association functional class III/IV IPAH patients treated with bosentan at our centre between November 1999 and May 2004 was performed. The 6-minute walk distance (6MWD) and haemodynamics were assessed at baseline and after 4 and 12 months. Mean follow-up was 24+/-15 months. At 4 months, significant improvements in exercise capacity and haemodynamics were observed and persisted up to 1 year. Overall survival estimates were 90 and 87% and event-free status (survival without transplantation, prostanoid initiation, or hospitalization for right heart failure) estimates were 61 and 44% at 1 and 2 years, respectively. Forty-five (44%) patients required prostanoid therapy during follow-up. The 6MWD and the right atrial pressure at baseline and the 6MWD, the increase in 6MWD, and the decrease in pulmonary resistance after 4 months of treatment were associated with long-term outcomes. CONCLUSION: In our series of consecutive IPAH patients treated with bosentan, improvements in exercise capacity and haemodynamics were similar to those observed in previous randomized trials. However, on the basis of local criteria, many patients required the addition of prostanoid therapy during follow-up.     

静脉注射左卡尼汀治疗肺动脉高压并右心功能障碍疗效观察

目的 观察静脉注射左卡尼汀治疗肺动脉高压导致右心功能障碍的疗效.方法 入选66例WHO心功能分级Ⅲ～Ⅳ级的特发性肺动脉高压14例、先天性心脏病相关性肺动脉高压36例及结缔组织病相关性肺动脉高压16例患者,分为左卡尼汀治疗组40例和对照组26例.左卡尼汀治疗组在常规治疗基础上给予左卡尼汀5 g/d,静脉滴注,连用7 d.分别于研究开始及7 d后进行6min步行距离、WHO心功能分级、体格检查及血清标记物检查,评价两组疗效和记录不良反应.结果 治疗前后比较,左卡尼汀组患者的6 min步行距离增加75 m,对照组增加45 m(P=0.04).左卡尼汀组16例心功能改善2级,13例改善1级,6例无变化,5例恶化一级以上;对照则分别为心功能改善2级3例,改善1级8例,无变化9例和恶化一级以上6例(P=0.04).左卡尼汀组B型利钠肽水平下降58.16 ng/L,而对照组下降33.29 ng/L(P=0.01).左卡尼汀组收缩压升高8.1 mm Hg(1 mm Hg=0.133 kPa),对照组升高2.4 mm Hg(P=0.03).无患者因严重不良反应退出研究.结论 常规治疗的基础上联合应用左卡尼汀,可改善肺动脉高压所导致的右心功能障碍患者的运动耐量和心功能分级,并且安全性、耐受性良好.     

Conversion to bosentan from prostacyclin infusion therapy in pulmonary arterial hypertension: a pilot study

STUDY OBJECTIVES: We assessed the efficacy of bosentan in transitioning from prostacyclin infusions in patients with pulmonary arterial hypertension (PAH). METHODS: Twenty-two PAH patients were recruited from five PAH centers if they had been clinically stable while receiving therapy with IV epoprostenol or subcutaneous treprostinil for at least 3 months. Patients were observed in an open-label prospective trial while bosentan was added to therapy, and then epoprostenol or treprostinil were tapered after 2 months. RESULTS: Ten of the 22 patients were transitioned off prostacyclin infusion therapy after a mean (+/- SEM) duration of 6.1 +/- 1.2 months. Of those patients, seven patients have continued not receiving prostacyclin infusion therapy for a mean duration of 17.7 +/- 5.3 months, with no significant changes in pulmonary artery (PA) pressure estimated by echocardiography, World Health Organization (WHO)/New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD), or Borg dyspnea score. The conditions of three patients deteriorated, necessitating the resumption of prostacyclin therapy, and two patients subsequently died. Twelve patients failed to transition or even lower the prostacylin infusion rate and had worsening of their WHO/NYHA functional class and estimated systolic PA pressures, and had a trend toward deterioration in their mean 6MWD (294 +/- 41 to 198 +/- 34 m, respectively; p = 0.2). Of these, two patients subsequently died. The baseline characteristics of those who transitioned successfully vs those who transitioned unsuccessfully were a lower prostacyclin infusion rate, and less severe elevations in the mean and estimated systolic PA pressures. CONCLUSION: Transitioning from therapy with prostacyclin to bosentan is possible in some PAH patients, mainly in those receiving lower prostacyclin doses and having less pulmonary hypertension at baseline. Careful patient selection and close interim monitoring is needed because the conditions of patients can deteriorate, and they may not respond to the resumption of therapy with prostacyclin.     

Long-term outcome and effects of oral bosentan therapy in Taiwanese patients with advanced idiopathic pulmonary arterial hypertension

STUDY DESIGN: We report on the long-term outcome and effects of bosentan treatment in Taiwanese patients with advanced (functional class III or IV) idiopathic pulmonary arterial hypertension (IPAH). MATERIALS AND METHODS: IPAH patients on stable bosentan therapy for more than 12 months and regularly monitored were eligible for this prospective uncontrolled study. Patients were evaluated for several clinical parameters, both measured at the time of initiation of bosentan therapy and after 12 months on therapy: New York Heart Association functional class (NYHA FC), change in 6-min walk distance (6MWD), right ventricle ejection fraction (RVEF), cardiothoracic ratio (CTR), and pulmonary functional status. RESULTS: Twelve of 15 patients met eligibility requirements and were enrolled. Their mean age was 37.6+/-12.9 years and 92% were female. Six (50%) patients were in NYHA FC IV and the others were in NYHA FC III at baseline. Three (25%) patients were chronic hepatitis C virus (HCV) carriers, with normal liver function. After 12 months of bosentan treatment, 6-MWD, RVEF, and pulmonary function all increased significantly. CTR and NYHA FC both decreased significantly. Oral bosentan was well tolerated and there was no episode of liver dysfunction that required adjustment of the bosentan dosage or discontinuance of therapy. CONCLUSION: Long-term treatment with oral bosentan appears to have beneficial effects on functional status, exercise capacity, right heart function, and pulmonary function in Taiwanese patients with advanced IPAH, regardless of whether or not they presented with chronic HCV infection.     

Initial Riociguat Monotherapy and Transition from Sildenafil to Riociguat in Patients with Idiopathic Pulmonary Arterial Hypertension: Influence on Right Heart Remodeling and Right Ventricular–Pulmonary Arterial Coupling

Purpose

To evaluate the influence of riociguat on World Health Organization functional class (WHO FC), 6-min walk distance (6MWD), right heart remodeling, and right ventricular–pulmonary arterial (RV–PA) coupling in patients with idiopathic pulmonary arterial hypertension (IPAH) who are treatment-naïve or who have failed to achieve treatment goals with sildenafil therapy.

Methods

Twenty patients with IPAH were enrolled: 12 had not previously received PAH-targeted therapy (treatment-naïve subgroup) and 8 had been receiving sildenafil therapy but failed to achieve treatment goals; on entering this pilot study these 8 patients were switched from sildenafil to riociguat therapy (treatment-switch subgroup). Patients received riociguat individually dose-adjusted up to a maximum of 2.5 mg three times daily. After 12 weeks, patients were assessed for WHO FC, 6MWD, right heart remodeling, and RV–PA coupling.

Results

Riociguat significantly improved WHO FC in treatment-naïve patients (from 0/4/8/0 patients in WHO I/II/III/IV at baseline to 1/6/5/0 at week 12) and in treatment-switch patients (from 0/4/4/0 patients in WHO I/II/III/IV at baseline to 1/4/3/0 at week 12). Additionally, treatment-naïve and treatment-switch patients showed significant improvements at week 12 versus baseline in 6MWD (increases of +?76.8 m and +?71.6 m, respectively), RV systolic function, and RV–PA coupling.

Conclusion

These results support the proven efficacy of riociguat in patients with IPAH, including treatment-naïve patients and those switching to riociguat following failure to achieve treatment goals with sildenafil, and suggest that it may be possible to delay disease progression in this patient group.

     

Bosentan therapy for chronic thromboembolic pulmonary hypertension. A national open label study assessing the effect of Bosentan on haemodynamics, exercise capacity, quality of life, safety and tolerability in patients with chronic thromboembolic pulmonary hypertension (BOCTEPH-Study)

STUDY OBJECTIVES: we performed an open-label national study to evaluate the effects of Bosentan on haemodynamics, exercise capacity, quality of life, safety and tolerability in patients with chronic thromboembolic pulmonary hypertension (CTEPH). PATIENTS AND METHODS: fifteen patients with CTEPH not eligible or waiting for surgery were enrolled. The primary endpoint was the change in pulmonary vascular resistance (PVR). Secondary endpoints included quality of life (measured by the Minnesota living with heart failure questionnaire, MLHF), 6 minute walk distance (6MWD), World Health Organization (WHO) functional class, Borg dyspnoea scale, plasma endothelin, serum values of disease severity such as uric acid, N-terminal-pro brain natriuretic peptide (NTproBNP), C-reactive protein measured by a highly sensitive method (CRPs) and other serum and haemodynamic parameters. RESULTS: after six months of treatment with bosentan, the PVR decreased from 852 (319) to 657(249) dyn*s*m-5 (p = 0.02). Quality of life considerably improved from a mean total score of 48(14) to 35(17) (p = 0.003) with improvements in the physical (from 25(5) to 17(7)) and emotional (from 11(6) to 6(5)) subscores (p = 0.005 and 0.011), respectively. The 6MWD improved from 389(78) to 443(79) meters (p = 0.005). 4 patients (27%) improved and 11 patients (73%) maintained their WHO class with no deterioration during the six months of bosentan treatment (p = 0.02). Uric acid serum levels declined from 525(145) to 453(151) micromol/l (p = 0.006), NTproBNP and CRPs declined insignificantly. Endothelin serum levels increased from 4.3(1.5) to 5.9(2.2) pg/ml (p = 0.025). Patients tolerated the treatment well, and there were no severe adverse events or deaths. CONCLUSION: this open-label study suggests a beneficial effect of bosentan therapy not only on pulmonary haemodynamics, but also on quality of life and exercise capacity for patients with severe CTEPH.     

Bosentan in pulmonary arterial hypertension secondary to scleroderma

OBJECTIVE:. To assess the efficacy and tolerability of bosentan in pulmonary arterial hypertension secondary to systemic sclerosis (SSc-PAH) including patients with restrictive lung disease. METHODS: We retrospectively reviewed 23 SSc-PAH patients with PAH at baseline [PA systolic pressure (PASP) >or= 45 mm Hg by echocardiogram or mean PA pressure > 25 mm Hg at rest by cardiac catheterization], World Health Organization (WHO) functional classes II-IV, and with data available for 18 months. Bosentan dose was 62.5 mg twice daily for 1 month then 125 mg twice daily. Outcomes were WHO functional class, PASP, and pulmonary function tests (PFT) at 3-month intervals for 18 months. RESULTS: WHO class at baseline 3.1 +/- 0.1 (mean +/- SE); 3 months, 2.5 +/- 0.2*; 6 months, 2.4 +/- 0.2*; 9 months, 2.5 +/- 0.2* (*p < 0.02 vs baseline, n = 21 to 23), indicating clinical improvement at 9 months. After 9 months, results were not significant versus baseline. Reduction in WHO class by at least one rank was 57% at 3 months; none worsened. After 9 months, WHO class tended to worsen compared to baseline. Baseline PASP was 54 +/- 2 mm Hg (n = 23) and did not change significantly with therapy. Restriction (total lung capacity 76% +/- 4% of predicted) and reduced diffusing capacity (39% +/- 3% of predicted) were unchanged during therapy. Abnormal transaminases in 2 patients (9%) necessitated discontinuing drug in both. CONCLUSION: Bosentan is clinically beneficial in patients with SSc-PAH including patients with restrictive lung disease, but pulmonary hemodynamics and PFT results remained stable during treatment.     

经皮腔内肺动脉成形术治疗慢性血栓栓塞性肺动脉高压的有效性及安全性评估

目的评估经皮腔内肺动脉成形术(PTPA)治疗慢性血栓栓塞性肺动脉高压(CTEPH)患者的有效性和安全性。方法该研究为前瞻性单臂试验。纳入2017年1月至2019年6月武汉亚洲心脏病医院心外科确诊的CTEPH患者。以明确诊断CTEPH的时间为基线, 收集入选患者的基线临床资料, 包括年龄、性别、世界卫生组织(WHO)功能分级、6 min步行距离、N末端B型利钠肽原(NT-proBNP)水平以及右心导管测定的血流动力学指标等。患者分次行PTPA, 统计每位患者扩张血管数, 术后24周随访并复查右心导管。记录手术安全性指标, 包括全因死亡、围术期并发症、再灌注肺水肿等。结果共入选患者19例, 年龄(56.3±12.5)岁, 男性7例。入选患者分别进行了1～7次PTPA, 总计56次, 累计扩张肺动脉260支, 每次扩张血管(5.14±2.36)支。共13例患者测定了6 min步行距离, 为(307±130)m。入选患者PTPA术后均自述体力明显改善, 尤其以第一次手术后为著。PTPA术后24周, 入选患者平均肺动脉压由基线的(40.11±7.55)mmHg(1 mmHg=0.133 kPa)...     

Ambrisentan therapy for pulmonary arterial hypertension

OBJECTIVES: The purpose of this study was to examine the efficacy and safety of four doses of ambrisentan, an oral endothelin type A receptor-selective antagonist, in patients with pulmonary arterial hypertension (PAH). BACKGROUND: Pulmonary arterial hypertension is a life-threatening and progressive disease with limited treatment options. Endothelin is a vasoconstrictor and smooth muscle cell mitogen that plays a critical role in the pathogenesis and progression of PAH. METHODS: In this double-blind, dose-ranging study, 64 patients with idiopathic PAH or PAH associated with collagen vascular disease, anorexigen use, or human immunodeficiency virus infection were randomized to receive 1, 2.5, 5, or 10 mg of ambrisentan once daily for 12 weeks followed by 12 weeks of open-label ambrisentan. The primary end point was an improvement from baseline in 6-min walk distance (6MWD); secondary end points included Borg dyspnea index, World Health Organization (WHO) functional class, a subject global assessment, and cardiopulmonary hemodynamics. RESULTS: At 12 weeks, ambrisentan increased 6MWD (+36.1 m, p < 0.0001) with similar and statistically significant increases for each dose group (range, +33.9 to +38.1 m). Improvements were also observed in Borg dyspnea index, WHO functional class, subject global assessment, mean pulmonary arterial pressure (-5.2 mm Hg, p < 0.0001), and cardiac index (+0.33 l/min/m2, p < 0.0008). Adverse events were mild and unrelated to dose, including the incidence of elevated serum aminotransferase concentrations >3 times the upper limit of normal (3.1%). CONCLUSIONS: Ambrisentan appears to improve exercise capacity, symptoms, and hemodynamics in patients with PAH. The incidence and severity of liver enzyme abnormalities appear to be low.