Role of the endothelium in pulmonary arterial hypertension

Pulmonary hypertension represents a significant disease burden in both the developed and developing worlds. Certain forms of pulmonary hypertension are more common in some countries than others but people of all races, all ages and both sexes are affected. Treatment options are limited and expensive. The development of new therapies will be determined by improved understanding of endothelial cell biology.     

Role of the serotonin transporter in pulmonary arterial hypertension

Pulmonary arterial hypertension is a disease in which pulmonary arterial pressure is raised, leading to right heart failure. Survival is poor despite current therapeutic strategies. The ‘serotonin hypothesis of pulmonary arterial hypertension’ arose in the 1960s following an ‘epidemic’ of pulmonary arterial hypertension in women taking the indirect serotinergic agonist aminorex as an anorexigen. In the 1980s, the hypothesis was revisited following the occurrence of pulmonary arterial hypertension associated with the use of fenfluramines as anorexigens; these are also indirect serotinergic agents. Research has identified changes in serotonin synthesis, serotonin receptor activation and serotonin uptake via the serotonin transporter in experimental and clinical pulmonary arterial hypertension. This review will discuss our current understanding of this serotonin hypothesis with particular reference to the role of the serotonin transporter.     

Sitaxentan: in pulmonary arterial hypertension

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

泛素羧基末端水解酶L1在氟西汀抑制大鼠肺动脉高压中的作用

目的研究泛素羧基末端水解酶L1(UCH-L1)在氟西汀抑制野百合碱诱导的大鼠肺动脉高压中的作用。方法用野百合碱(60 mg·kg-1)建立肺动脉高压大鼠模型,用低剂量(2 mg·kg-1·d-1)或高剂量(10 mg·kg-1·d-1)的氟西汀进行干预,观察各组大鼠血流动力学,肺组织与肺小动脉形态,以及UCH-L1蛋白表达与核因子κB(NF-κB)核转位的变化。结果野百合碱诱导大鼠肺动脉压力升高、肺动脉重构、肺组织炎症反应、肺组织UCH-L1表达减少以及NF-κB活性增加。氟西汀剂量依赖地抑制这些变化。但是各组之间大鼠肺动脉UCH-L1蛋白表达差异无显著性。结论氟西汀抑制野百合碱诱导的大鼠肺组织炎症反应,与上调的UCH-L1蛋白抑制NF-κB活性有关。     

西他生坦治疗肺动脉高压

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

Bosentan for pulmonary arterial hypertension

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

急性肺血管扩张试验筛查在肺动脉高压中的应用

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

Targeting PDGF pathway in pulmonary arterial hypertension

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

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

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

Biomarkers in systemic sclerosis-related pulmonary arterial hypertension

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

Bosentan预防大鼠低氧性肺动脉高压形成的作用

目的研究Bosentan预防低氧诱导的肺动脉高压发生的药效作用,探讨内皮素-1(ET-1)在慢性高原病发病中的作用。方法30只Wistar大鼠随机均分为常氧对照组、低氧对照组和Bosentan组,将低氧对照组和Bosentan组放入模拟海拔为5.5 km的低氧、低压环境中。常氧对照组和低氧对照组ig 0.9%生理盐水,Bosentan组ig 100 mg.ml-1Bosentan水剂,每天2次。饲养15 d后,测量大鼠平均肺动脉高压(PAP)、左右心室比重[RV/(LV S)]比值。结果Bosentan组大鼠血红蛋白(Hb)、红细胞压积(Hct),ET-1与低氧对照组相比无差异,而PAP、RV/(LV S)均显著低于低氧对照组(P<0.01)。结论Bosentan可显著预防低氧性肺动脉压的升高,缓解低氧对心肌细胞和血管平滑肌细胞的损伤,但不能抑制红细胞的过度增生。     

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.     

Emerging therapies for pulmonary arterial hypertension

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

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。     

Emerging treatments for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980s, prior to the current treatment era, idiopathic PAH carried a very poor prognosis, with a median survival of 2.8 years from the time of diagnosis. Since then, continuous intravenous epoprostenol has been used for the treatment of severe PAH with tremendous success, improving haemodynamics, quality of life, exercise capacity, functional class and even survival. In addition, in the past 5 years there have been several new advances in the treatment of PAH; however, there is still no cure. A better understanding of how the currently available agents work together is essential to optimise the long-term care of patients with PAH. Ultimately, additional agents that target the underlying pulmonary vasculopathy and endothelial abnormalities are necessary to cure this fatal disease. This comprehensive review of the currently available and emerging novel therapies provides insight into future management of PAH patients.     

Emerging therapies for pulmonary arterial hypertension

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

肺动脉高压的药物治疗进展

肺动脉高压是一种严重的疾病，本文收集了近年来肺动脉高压药物治疗进展的国内外文献，重点介绍其药理特点，供临床医生参考。     

Modulation of ion channels in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular hypertrophy, right heart failure and ultimately to death. PAH is a disease of small pulmonary arteries inducing vascular narrowing leading to a progressive increase in pulmonary vascular resistance. The therapeutic means that improve PAH are still very limited and are too often restricted to heart/lungs transplantation. Numerous forms of pulmonary hypertension exist. Although it is still unclear as to all types of PAH share a common pathogenesis, it is generally admitted that pulmonary vasoconstriction and remodelling of the arterial wall are key events. In this review, we discuss pulmonary artery smooth muscle cells (PASMC) ion channels implication in both phenomena and we examine whether variations in expression and/or the activity of these channels can contribute to the development of PAH with special attention to K(+), Cl(-) and voltage- and non voltage-activated Ca(2+) channels. For each family of ion channels, we describe their implication in the control of both membrane potential and resting cytosolic calcium concentration which are key parameters of PASMC in PAH. We also provide evidence for an implication of these channels in not only vasoconstriction but also proliferation and/or decreased apoptosis of PASMC, phenomena which contribute to remodelling of pulmonary arterial wall. In this respect, PAH may be considered as form of vascular "channelopathy". Finally, we present examples of some substances acting on ion channels and thus potentially constituting innovative therapeutic approaches of PAH.     

Prevalence of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the United States

Abstract

Background:

The prevalence of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in the US is largely unknown. Prior research has estimated PAH prevalence in Europe at ～15–52 per million.