前列环素及其类似物在肺动脉高压中的应用

肺动脉高压（PAH）是一类以小肺动脉血管重构为特征的恶性肺血管疾病,往往由于肺血管阻力进行性升高而最终导致患者右心衰竭甚至死亡。内源性前列环素缺乏在PAH形成中占有相当重要的作用。前列环素及其类似物是有效的血管扩张剂,并具有抗血小板形成、抗增殖和抗炎作用。本文从4种前列环素类似物的药动学、临床研究、临床应用及整体联合治疗4个方面,阐述前列环素及其类似物在临床治疗PAH中的应用。     

组织多普勒Tei指数在评价肺动脉高压患者右心功能中的应用价值

目的应用组织多普勒技术,测量并计算肺动脉高压患者的右室Tei指数,探讨其在评价肺动脉高压患者右室整体功能方面的价值,并探讨Tei指数与肺动脉压、右室舒张末内径之间的关系。方法对48例肺动脉高压患者和40例健康对照者的右心常规超声指标进行测量,应用组织多普勒技术方法测量三尖瓣环的运动频谱,测量其右室Tei指数,进行分析比较。结果肺动脉高压轻、中、重组患者右室Tei指数均明显高于正常对照组(P<0.05),而肺动脉高压患者各组间比较差异无统计学意义;肺动脉高压患者伴右室扩大与不伴右室扩大者与对照组比较,右室Tei指数差异有统计学意义(P<0.05),而两组间差异无统计学意义。结论 (1)Tei指数是评价肺动脉高压患者右室整体功能的新指标,准确、便捷、稳定。(2)右室Tei指数不受右室压力负荷及右室形态影响。     

Effects of purple grape juice in the redox-sensitive modulation of right ventricular remodeling in a pulmonary arterial hypertension model

The effects of purple grape juice (PGJ) pretreatment in signaling proteins involved in cardiac remodeling in rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) were investigated. Male Wistar rats (control, MCT, PGJ, and MCT + PGJ groups) were treated for 6 weeks with water or PGJ (10 mL·kg(-1)·d(-1)) by gavage. In the third week, they were administered a single dose of MCT (60 mg/kg i.p.). Pulmonary vascular resistance was determined by echocardiography, and hemodynamic analysis was performed in the right ventricle (RV). Hydrogen peroxide (H2O2) concentration and lipid peroxidation were quantified and thioredoxin-1 (Trx-1), p-ERK1/2/ERK1/2, p-Akt/Akt, p-JNK/JNK, and cleaved caspase-3 were detected at RV by Western blot. Pretreatment with PGJ attenuated pulmonary vascular resistance and improved hemodynamic parameters in MCT-induced PAH. PGJ and MCT groups exhibited increased H2O2 levels, which were reduced to baseline in MCT + PGJ. ERK1/2 phosphorylation showed the same profile of H2O2 changes. No changes in p-JNK/JNK and p-Akt/Akt expressions were found. An enhanced cleaved caspase-3 immunodetection was induced by the model, which was reversed in the MCT + PGJ group and associated with increased Trx-1 and reduced lipid peroxidation. Improvement in functional parameters mediated by PGJ pretreatment may be associated with the induction of Trx-1, influencing the expression of proteins involved in RV remodeling.     

Prostacyclin and its analogues in pulmonary artery hypertension: a meta-analysis

Abstract

Objective:

Individual studies examining the effects of prostacyclin and its analogues on pulmonary artery hypertension (PAH) have reported controversial results. This study aims to evaluate the efficacy of these agents for PAH by a meta-analysis based on randomized controlled trials (RCTs).     

Neuregulin‐1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension

We have previously shown that treatment with recombinant human neuregulin‐1 (rhNRG‐1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)‐induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG‐1 treatment showed direct myocardial anti‐remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG‐1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG‐1 treatment on ventricular passive stiffness in RV and LV samples from MCT‐induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling‐associated genes and calcium handling proteins. Chronic rhNRG‐1 treatment decreased passive tension development in RV and LV isolated from animals with MCT‐induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG‐1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB‐induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac‐specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG‐1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling.     

Salubrinal attenuates right ventricular hypertrophy and dysfunction in hypoxic pulmonary hypertension of rats

The phosphorylation of eukaryotic translation initiation factor 2 alpha (p-eIF2α) is essential for cell survival during hypoxia. The aim of this study was to investigate whether salubrinal, an inhibitor of p-eIF2α dephosphorylation could attenuate pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy in rats exposed to hypobaric hypoxia. PAH of rats was induced by hypobaric hypoxia. Salubrinal supplemented was randomized in either a prevention or a reversal protocol. At the end of the follow-up point, we measured echocardiography, hemodynamics, hematoxylin-eosin and Masson's trichrome stainings. RNA-seq analysis is explored to identify changes in gene expression associated with hypobaric hypoxia with or without salubrinal. Compared with vehicle-treatment rats exposed to hypobaric hypoxia, salubrinal prevented and partly reversed the increase of the mean pulmonary artery pressure and RV hypertrophy. What's more, salubrinal reduced the percentage wall thickness (WT%) of pulmonary artery and RV collagen volume fraction (CVF) in both prevention and reversal protocols. We also found that salubrinal was capable of reducing endoplasmic reticulum stress and oxidative stress. The result of RNA-seq analysis revealed that chronic hypoxia stimulated the differential expression of a series of genes involved in cell cycle regulation and ventricular hypertrophy and so on. Some of these genes could be ameliorated by salubrinal. These results indicate that salubrinal could prevent and reverse well-established RV remodeling, and restore the genes and pathways altered in the right ventricles of rats exposed to hypobaric hypoxia.     

肺动脉高压的药物治疗

肺动脉高压(pulmonary hypertension,PH)是临床上常见的一种致残率和致死率较高的疾病,WHO根据病因将PH分为5类。PH治疗从病情严重程度的基线评估开始,进行基础治疗。基础治疗针对PH的基础病因。部分PH患者会进展至需要针对PH本身而并非基础病因的高等级治疗。对于治疗PH的基础病因后仍持续存在PH且WHO分级为Ⅱ、Ⅲ或Ⅳ级的患者,应转诊至专科医学中心进行高等级治疗的评估。高等治疗包括类前列腺素(prostaglandin,PG)、内皮素受体拮抗剂(endothelin receptor antagonist,ERA)、5型磷酸二酯酶(phosphodiesterase 5,PDE5)抑制剂、可溶性鸟苷酸环化酶(soluble guanylate cyclase,sGC)激动剂和钙通道阻滞剂(calcium channel blocker,CCB)。     

Influence of a single dose of captopril on pulmonary haemodynamics and right ventricular function in mitral stenosis with pulmonary hypertension

Summary The response of the pulmonary circulation to captopril 75 mg has been examined in 21 patients with pulmonary hypertension secondary to mitral stenosis. The effects of captopril were measured every 15 min up to 2 h by recording pressures in the pulmonary and systemic circulations and by measuring cardiac output.Pulmonary artery systolic pressure fell significantly by 21.6% (from to 42.8 mm Hg), pulmonary artery diastolic pressure by 23.3% (from 26.2 to 20.1 mm Hg), and the pulmonary artery mean pressure by 23.2% (from 36.9 to 28.3 mm Hg). Right ventricular end-diastolic pressure also fell significantly by 7% (8.1 to 7.5 mm Hg). Heart rate decreased by 6.5% (from 76.3 to 71.3 beats·min^–1). Cardiac index and stroke volume index did not change. The total and vascular pulmonary resistance dropped significantly by 23.2% (from 721 to 553.7 dyn·s·cm^–5) and 40% (from 287.2 to 172 dyn·s·cm^–5), respectively. The right ventricular stroke work index fell by 33% (from 15.1 to 10.1 g/beat/m²). Systemic systolic pressure decreased by 10.5% (from 124.5 to 111.4 mm Hg). Thus, captopril lowered pulmonary pressures and resistances and no deterioration in right ventricular function was observed.     

基于Markov模型的肺动脉高压靶向治疗药物的成本-效果分析

目的：评价中国医疗环境下肺动脉高压一线靶向治疗药物的成本-效果。方法：从支付者角度,根据肺动脉高压的自然转归和现有的医疗成本构建Markov模型。结果指标包括人均总成本、总质量调整生命年和增量成本-效果比,应用一元敏感度和概率敏感度分析验证模型稳定性。结果：基线分析结果显示：在整个生命周期的模拟过程中安立生坦、马昔腾坦、波生坦、他达拉非、西地那非和姑息治疗的人均医疗成本分别为363 406.14,481 387.69,323 264.71,167 531.23,41 700.08和24 507.12元,人均可获得5.61,6.14,5.23,5.88,4.64和2.33个质量调整生命年,姑息治疗作为对照组的增量成本-效果比分别为103 410.74,120 034.97,103 079.80,40 351.36和7 438.14元/质量调整生命年,小于预设的意愿支付阈值,敏感度分析显示结果稳定。结论：在中国肺动脉高压患者使用安立生坦、马昔腾坦、波生坦、他达拉非和西地那非具有成本-效果性。     

肺动脉高压的药物治疗

肺动脉高压(PAH)是一种由异源性疾病和不同发病机制引起的以肺动脉压力增高为表现的疾病状态。PAH的传统治疗主要集中在支持治疗及非选择性血管扩张药等基础治疗。近年来,针对其发病机制各个环节的靶向治疗逐步开展,FDA已批准6种治疗PAH的药物,分别属于前列环素类似物、内皮素受体拮抗剂和磷酸二酯酶5抑制剂。5-羟色胺受体拮抗剂、Rho激酶抑制剂、PAR-2抑制剂正处于临床前研究阶段。     

Treprostinil therapy for pulmonary artery hypertension

Pulmonary artery hypertension is a life-threatening disease characterised by a pulmonary vasculopathy and progressive right ventricular failure. Major advances were made with the development of continuous intravenous epoprostenol (Flolan trade mark ) as a treatment modality. Nevertheless, it is far from ideal as treatment for this disease. Subcutaneous treprostinil has been FDA approved for the treatment of New York Heart Association Functional Class II - IV pulmonary artery hypertension. It is a longer acting subcutaneous prostacyclin analogue that offers an additional mode of therapy for this disease. A discussion of the pharmacology of this prostacyclin analogue as compared to its related compounds, the clinical studies which led to its approval, a review of some additional basic studies and the practical use of this drug in the treatment modalities for precapillary pulmonary artery hypertension in 2002 in light of other available therapies is discussed.     

Treprostinil therapy for pulmonary artery hypertension

Pulmonary artery hypertension is a life-threatening disease characterised by a pulmonary vasculopathy and progressive right ventricular failure. Major advances were made with the development of continuous intravenous epoprostenol (Flolan?) as a treatment modality. Nevertheless, it is far from ideal as treatment for this disease. Subcutaneous treprostinil has been FDA approved for the treatment of New York Heart Association Functional Class II – IV pulmonary artery hypertension. It is a longer acting subcutaneous prostacyclin analogue that offers an additional mode of therapy for this disease. A discussion of the pharmacology of this prostacyclin analogue as compared to its related compounds, the clinical studies which led to its approval, a review of some additional basic studies and the practical use of this drug in the treatment modalities for precapillary pulmonary artery hypertension in 2002 in light of other available therapies is discussed.     

Medical therapy for pulmonary arterial hypertension

Recent advances in the understanding of pulmonary arterial hypertension have led to new therapeutic options, although the disease remains incurable and continues to cause substantial morbidity and mortality. Disease-specific therapies have been approved for use in the US, including epoprostenol and its various analogs, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors. The use of combination therapy with agents from more than one of these drug classes is becoming increasingly common, although guidelines establishing optimal combinations are lacking. Meanwhile, potential future therapeutic options are actively being pursued.     

Prostacyclin does not inhibit rho-kinase: an implication for the treatment of pulmonary hypertension

Primary pulmonary hypertension continues to be a fatal disease. We have recently demonstrated that long-term inhibition of Rho-kinase, an effector of the small GTPase Rho, is effective for the treatment of pulmonary hypertension (PH) in rats and humans. Prostacyclin has been clinically used for the treatment of PH with moderate success. However, it remains to be examined whether Rho-kinase inhibition is involved in its beneficial effects on PH. In an ELISA assay, neither prostacyclin nor its oral analogue, beraprost sodium, inhibited Rho-kinase even at higher concentrations (10(-7) to 10(-5) M, 100 to 10,000 times higher than their clinical concentrations), whereas specific Rho-kinase inhibitors, fasudil and hydroxyfasudil, markedly (approximately 95%) inhibited the Rho-kinase activity at 10(-5) M (near their clinical concentrations). Beraprost sodium did not significantly suppress serotonin-induced vascular smooth muscle cell (VSMC) contractions or Rho-kinase activity of the rat aorta without endothelium, as evaluated by the extent of phosphorylation of the ERM family, a substrate of Rho-kinase, whereas hydroxyfasudil markedly suppressed the VSMC contractions and Rho-kinase activity. These results indicate that prostacyclin lacks direct inhibitory effect on Rho-kinase and suggest that combination therapy with prostacyclin and a Rho-kinase inhibitor could exert further beneficial effects on PH.     

肾上腺髓质素与肺动脉高压右室功能关系的研究

目的探讨肾上腺髓质素（ADM）在肺动脉高压（PH）右室功能损害、右室重塑病理生理过程中的作用和关系。方法PH组58例,非PH组23例,对照组20例。超声心动图分别测量右房室瓣前向血流及反流频谱、肺动脉前向血流频谱;ADM的测定采用非平衡法。结果PH组与非PH组及健康对照组相比,舒张早期右房室瓣最大流速（E）显著降低,舒张晚期右房室瓣最大流速（A）增加,E／A显著降低,肺动脉最大流速（PV）显著降低,右室等容舒张时间（IRT）、右室等容收缩时间（ICT）显著延长,Tei指数显著增加（P〈0．01）;血浆ADM浓度显著增高,与肺动脉收缩压正相关（r=0.678）;ADM与E、E／A、PV负相关（r=-0．438,-0．546,-0．514,P〈0．01）,与A、IRT、ICT正相关（r=0．4Q9,0．504,0．322,P〈0．01～0．05）。结论ADM参与了肺动脉高压及右室功能减退的病理生理过程。     

Recent advances in pulmonary hypertension therapy

Cardiovascular anesthesiologists have traditionally resorted to using intravenous therapy in the operating room to manipulate hemodynamics and the determinants of cardiac output and systemic vascular resistance during cardiac surgery. General anesthesia involves the administration of both intravenous and inhaled drug therapy to achieve the desired goals, i.e. analgesia, amnesia, muscle relaxation and blockade of autonomic activity. Anesthesiologists are the experts in the use and titration of drugs that are administered through the inhaled route. However, this method of drug delivery presents many challenges, notably timing, dosage accuracy, rapid titratability and consistency of drug delivery. Arguably the most rapid method of treating acute reactive pulmonary vasculature would be by drugs that directly act upon the pulmonary endothelium. In the operating room, pulmonary hypertension and right ventricular failure are high predictors of morbidity and mortality and present significant challenges to the anesthesiologist. In this article, we will focus on advances in inhaled therapy of these conditions, including concerned recent patents. This review will focus on some of the advances in the pharmacology of inhaled drugs that are being used to treat pulmonary hypertension, right and left ventricular failure in the perioperative setting.