Current Therapy of Pulmonary Hypertension

Abstract Pulmonary arterial hypertension (PAH) affects vascular proliferation and remodeling in small pulmonary arteries and results in right ventricular failure and death due to a progressive increase in pulmonary vascular resistance. Recent advances in understanding of the molecular mechanisms involved in PAH suggest that endothelial dysfunction plays a major role. Impaired production of vasoactive mediators, such as prostacyclin and nitric oxide, accompanied with prolonged overexpression of vasoconstrictors such as endothelin-1, affects vascular tone and reinforces vascular remodeling. As the latter substances represent logical pharmacological targets, new drugs affecting these mechanisms have evolved during the past 2 decades and led to umpteen placebo-controlled trials in bygone years. Prognosis and quality of life of patients suffering from PAH seem to improve due to these new treatment strategies resulting in a reduction of mortality and morbidity, but there is still a substantial need for further long-term and head-to-head trials.     

交感神经系统在肺动脉高压发生发展过程中的作用

肺动脉高压（pulmonary arterial hypertension,PAH）是各种原因所致的一种慢性肺血管性疾病,主要表现为肺动脉重构和肺血管阻力进行性增加,最后导致右心室功能衰竭和死亡,预后极差。PAH时交感神经表现为过度激活,交感激活后可以通过多种机制参与肺动脉重构及加重右心室功能紊乱。干预交感神经可以改善PAH的预后,其原因与改善PAH的右心室功能和肺动脉重构密切相关,但是不良反应也较多,交感神经系统参与PAH发生发展的确切机制尚不完全知道,仍需进一步研究。     

肺动脉平滑肌细胞:肺动脉高压的关键治疗靶点

肺动脉高压(PAH)是一种进展快、预后欠佳、死亡率高的心血管疾病。研究表明,肺血管重构是PAH发生发展的重要病理基础,而肺动脉平滑肌细胞的增殖和肥大是PAH肺血管重构的主要病理改变。在PAH时,肺血管平滑肌细胞由收缩表型向增殖状态的合成表型转化,主要表现为肺血管平滑肌细胞的增殖和肥大。上述病理改变最终导致肺血管管腔狭窄,管壁僵硬,进而促进PAH的发生发展。本文对肺动脉平滑肌细胞在PAH中的关键作用及作用机制进行阐述,为临床防治PAH提供新靶点和新策略。     

电压依赖性钾离子通道在肺动脉高压发病过程中的作用

肺动脉高压是一种肺血流受限引起肺血管阻力和压力持续性增高,最终导致右心衰竭甚至死亡的综合征.病理生理学改变主要为肺血管收缩、重塑及原位血栓形成.研究表明,钾离子通道尤其电压依赖性钾离子通道功能与表达水平的降低是引起肺血管平滑肌细胞增殖和凋亡异常、肺血管重塑的关键因素.本文着重论述近年来有关电压依赖性钾离子通道与肺动脉高...     

Intermedin modulates hypoxic pulmonary vascular remodeling by inhibiting pulmonary artery smooth muscle cell proliferation

BackgroundHypoxic pulmonary arterial hypertension (PAH) is a disabling disease with limited treatment options. Hypoxic pulmonary vascular remodeling is a major cause of hypoxic PAH. Pharmacological agents that can inhibit the remodeling process may have great therapeutic value.ObjectiveTo examine the effect of intermedin (IMD), a new calcitonin gene-related peptide family of peptide, on hypoxic pulmonary vascular remodeling.MethodsRats were exposed to normoxia or hypoxia (∼10% O₂), or exposed to hypoxia and treated with IMD, administered by an implanted mini-osmotic pump (6.5 μg/rat/day), for 4 weeks. The effects of IMD infusion on the development of hypoxic PAH and right ventricle (RV) hypertrophy, on pulmonary vascular remodeling, on pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, and on the activations of l-arginine nitric oxide (NO) pathway and endoplasmic reticulum stress apoptotic pathway were examined.ResultsRats exposed to hypoxia developed PAH and RV hypertrophy. IMD treatment alleviated PAH and prevented RV hypertrophy. IMD inhibited hypoxic pulmonary vascular remodeling as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-exposed rats. IMD treatment inhibited PASMC proliferation and promoted PASMC apoptosis. IMD treatment increased tissue level of constitutive NO synthase activity and tissue NO content in lungs, and enhanced l-arginine uptake into pulmonary vascular tissues. IMD treatment increased cellular levels of glucose-regulated protein (GRP) 78 and GRP94, two major markers of endoplasmic reticulum (ER) stress, and increased caspase-12 expression, the ER stress-specific caspase, in lungs and cultured PASMCs.ConclusionsThese results demonstrate that IMD treatment attenuates hypoxic pulmonary vascular remodeling, and thereby hypoxic PAH mainly by inhibiting PASMC proliferation. Promotion of PASMC apoptosis may also contribute to the inhibitory effect of IMD. Activations l-arginine–NO pathway and of ER stress-specific apoptosis pathway could be the mechanisms mediating the anti-proliferative and pro-apoptotic effects of IMD.     

血吸虫病相关性肺动脉高压研究进展

血吸虫病相关性肺动脉高压因其临床表现、实验室检查和血流动力学特征与特发性、遗传性、HIV和自身免疫性疾病所致肺动脉高压类似而被归为WHO 定义的第I类肺动脉高压,通常是肝脾型血吸虫病的一种危及生命的并发症。以血管壁改变、重构、血管收缩为特征,病变主要位于肺血管的毛细血管前段,可导致肺血管阻力显著和持续增加、右心室衰竭乃至死亡。尽管虫卵沉积到肺部和随后的炎症级联反应是血吸虫病相关性肺动脉高压发生的关键因素,但其确切发病机制、病程和治疗仍有很大不确定性。本文主要探讨血吸虫病相关性肺动脉高压的病理生理学和免疫学机制,以期为临床诊断和治疗提供帮助。     

Mediators involved in HIV-related pulmonary arterial hypertension

HIV-related pulmonary arterial hypertension (PAH) is one of the long-term complications of HIV infection that has become increasingly apparent in recent years. The clinical presentation and underlying pathology of PAH in HIV is similar to that in other forms of the disease, although there are data to suggest subtle differences, such as a greater inflammatory component in the HIV-related form. Advances continue to be made in defining the underlying pathogenesis of PAH, but the overall processes leading to vascular dysfunction and remodeling remain unclear. It would appear that PAH has a multifactorial etiology, with various risk factors--probably acting on an underlying genetic predisposition--that lead to the pulmonary vascular dysfunction that characterizes the disease. A range of growth factors, chemokines, cytokines and other inflammatory mediators, together with mediators involved in vasoconstriction and dilation, have been implicated in the pulmonary vascular remodeling resulting from this dysfunction. An increased understanding of the processes and factors involved in PAH has led to the development of new therapeutic strategies that have improved the management of various forms of PAH, including PAH associated with HIV (HIV-PAH). Recent results from studies into other potential mediators of PAH offer the possibility of new targets for therapy in this progressive and serious condition.     

Endothelin antagonism in pulmonary arterial hypertension

The pathobiology of pulmonary arterial hypertension (PAH) reflects a multifactorial process and complex evolution that involves dysfunction of underlying cellular pathways and mediators. Among these, the endothelin system has been shown to be important in the pathogenesis of PAH. Endothelin-1 (ET-1), which is found in high levels in PAH, is a known potent vasoconstrictor with proliferative vascular remodeling properties. Left unchecked, endothelin excess, along with other derangements, may contribute to the development and perpetuation of PAH. There is now substantial evidence from clinical trials and long-term data that monotherapy with an endothelin receptor antagonist (ERA) is a beneficial, therapeutic approach in PAH. Combination therapy of an ERA with a prostanoid or phosphodiesterase-5 inhibitor, two drug classes that have different mechanisms of action, is conceptually appealing, but the evidence for its efficacy and safety are still being investigated. This review provides an overview of endothelin biology and the clinical use of ERAs for the treatment of PAH. The use of ERAs for other forms of pulmonary hypertension will not be reviewed here.     

Medical therapies for pulmonary arterial hypertension

Pulmonary Arterial hypertension (PAH) is a chronic and progressive disease characterized by an increase in pulmonary vascular resistance due to severe remodeling of the small pulmonary arteries. In PAH, the endothelial cells fail to maintain their homeostatic balance, with the consequent impaired production of vasodilators and over-expression of vasoconstrictors and proliferators. Current treatment of PAH is based on the discovery of three main pathways of endothelial dysfunction (prostacyclin, nitric oxide and endothelin-1), and includes drugs such as prostacyclin analogs, phosphodiesterase-5 inhibitors and endothelin receptor antagonists (ERAs). Recently approved drugs that act through these classic pathways include riociguat (cyclic GMP stimulator) and macitentan (a tissue specific dual ERA). However, several new drugs and new pathways are under study. New targeted therapies include tyrosine kinase inhibitors, Rho kinase inhibitors and serotonin receptor blockers. There are now ten drugs approved for the treatment of PAH that, alone or in combination, have changed the natural history of this disease. The new drugs will allow us to further modified the patients’ life expectancy and move towards a cure.     

Exercise physiology and pulmonary arterial hypertension

The lungs are the only organ that receives the entire cardiac output with every stroke. The pulmonary circulation is normally a high-flow, low-resistance, low-pressure system that carries blood into the pulmonary microcirculation. In pulmonary artery hypertension (PAH)vascular remodeling contributes to a sustained elevation of pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) as a result of vascular remodeling characterized largely by vascular smooth muscle cell proliferation and medial hypertrophy, and endothelial cell proliferation resulting in lumen obliteration. The loss of pulmonary arterial compliance and development of elevated PVR puts an excessive burden on the right ventricle due to the increased workload necessary to overcome the downstream pressure, ultimately leading to right-sided heart failure. The functional status of the pulmonary circulation and the levels of PVR and PAP ultimately determine the outcome of patients with PAH. Study of the pressure–flow relationships in the pulmonary vascular bed will provide an improved appreciation of the pathophysiology of pulmonary hypertension.     

微小RNA在肺动脉高压发病机制中的研究进展

肺动脉高压是一种致命性疾病,缺氧、炎症、遗传等各种病因导致肺血管重塑、肺动脉压力升高,最终导致右心衰竭,甚至死亡.但目前对肺动脉高压的发病机制并不清楚,尚无治愈肺动脉高压的药物.近年来,微小RNA在许多疾病病理和生理过程中发挥的作用引起了人们的关注,许多研究表明微小RNA有逆转肺血管重塑,从而治愈肺动脉高压的可能.本文就研究较多的微小RNA在肺动脉高压的发病机制,尤其是参与血管重塑的几条通路的研究进展作一综述.     

肺动脉高压的药物治疗进展

肺动脉高压是以肺小动脉的血管痉挛、内膜增生、重构为主要特征的一种疾病。肺小动脉的血管增生、重构导致肺血管阻力进行性增加,最终导致右心衰竭和死亡。在过去的20多年,随着我们对肺动脉高压病理机制的认识增加,该病的治疗也获得了很大的进步。除了传统的吸氧、利尿、强心、钙离子拮抗剂、抗凝等治疗,靶向药物治疗的研发与推广使用使肺动脉高压患者的预后得到了明显的改善,目前主要的靶向药物治疗包括：前列环素类似物、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂,且一些新型的药物及联合治疗方案也在研究中。现就肺动脉高压的药物治疗进展简要地做一综述。     

Inflammation in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. Although the exact pathophysiology remains unknown, there is increasing evidence to suggest an important role for inflammation. Firstly, pathologic specimens from patients with PAH reveal an accumulation of perivascular inflammatory cells, including macrophages, dendritic cells, T and B lymphocytes, and mast cells. Secondly, circulating levels of certain cytokines and chemokines are elevated, and these may correlate with a worse clinical outcome. Thirdly, certain inflammatory conditions such as connective tissue diseases are associated with an increased incidence of PAH. Finally, treatment of the underlying inflammatory condition may alleviate the associated PAH. Underlying pathologic mechanisms are likely to be "multihit" and complex. For instance, the inflammatory response may be regulated by bone morphogenetic protein receptor type 2 (BMPR II) status, and, in turn, BMPR II expression can be altered by certain cytokines. Although antiinflammatory therapies have been effective in certain connective-tissue-disease-associated PAH, this approach is untested in idiopathic PAH (iPAH). The potential benefit of antiinflammatory therapies in iPAH is of importance and requires further study.     

Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension

Objective: To investigate the effects of angiotensin-converting enzyme 2 (ACE2) activation on pulmonary arterial cell apoptosis during pulmonary vascular remodeling associated with pulmonary arterial hypertension (PAH) and to elucidate potential mechanisms related to Hippo signaling. Methods: PAH model was developed by injecting monocrotaline combined with left pneumonectomy using Sprague-Dawley rat. Then, resorcinolnaphthalein (Res; ACE2 activator), MLN-4760 (ACE2 inhibitor), A-779 (Mas inhibitor), and 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino) benzenesulfonamide (XMU-MP-1; MST1/2 inhibitor) were administered via continuous subcutaneous or intraperitoneal injection for 3 weeks. Animals were randomly divided into six groups: control, PAH, PAH+Res, PAH+Res+MLN-4760, PAH+Res+A-779, and PAH+Res+XMU-MP-1. On 21 day, hemodynamics and pathologic lesions were evaluated. Apoptosis and apoptosis-associated proteins were detected by TUNEL and western blotting. ACE2 activity and Hippo pathway components including large tumor suppressor 1 (LATS1), Yes-associated protein (Yap), and phosphorylated Yap (p-Yap) were investigated by fluorogenic peptide assays and western blotting. Results: In the PAH models, the mean pulmonary arterial pressure, right ventricular hypertrophy index, pulmonary vascular remodeling, anti-apoptotic protein Bcl-2 and Yap were all increased but the pulmonary arterial cell apoptosis, pro-apoptotic proteins caspase-3 and Bax were lower. ACE2 activation significantly ameliorated pulmonary arterial remodeling, this action was related to increased apoptosis and up-regulation of LATS1 and p-Yap. These protective effects were mitigated by the co-administration of A779 or MLN-4760. Moreover, inhibiting the Hippo/LATS1/Yap pathway with XMU-MP-1 blocked apoptosis in pulmonary vascular cells induced by ACE2 activation during the prevention of PAH. Conclusions: Our findings suggest that ACE2 activation attenuates pulmonary vascular remodeling by inducing pulmonary arterial cell apoptosis via Hippo/Yap signaling during the development of PAH.     

白细胞介素-6与低氧性肺动脉高压关系的探究

肺动脉高压（PAH）是一种常见的临床症状,凡是能引起血管阻力增大、血流量增多的因素都可成为其诱因。低氧性肺动脉高压（HPH）则是以低氧性肺动脉收缩和低氧性肺血管重构引起的肺动脉压持续升高为特征的病症。急、慢性低氧均可引起白细胞介素-6（IL-6）的分泌,导致炎症细胞浸润,继而通过对动脉内膜的改建引起PAH。     

血管重构在动脉型肺动脉高压中的研究进展

动脉型肺动脉高压（PAH）是以肺动脉压力持续升高、肺小动脉结构持续改变为特征的致命性疾病,肺动脉重构是其主要的病理学特点。许多研究发现PAH中血管重构的病理机制主要包括各种细胞的病理学改变和多种分子信号通路的参与,最新的研究指出表观遗传学也参与血管重构,从而导致疾病的发生发展。目前针对PAH发病机制的各种新型药物及新疗法正在被开发,其副作用更小、疗效更佳。本文重点阐述PAH中血管重构的病理机制包括病理学改变、新分子信号通路及表观遗传学内容,以及治疗的新进展。     

What’s new in the treatment of portopulmonary hypertension?

Portopulmonary hypertension (POPH) is a complication of portal hypertension characterized by pulmonary vasoconstriction and vascular remodeling that can lead to right heart failure and death. Differentiation of POPH from other causes of pulmonary hypertension, such as volume overload or a hyperdynamic high flow state, is critical because a diagnosis of POPH has significant implications for liver transplant risk stratification, Model for End Stage Liver Disease exception points, and the use of pulmonary arterial hypertension-(PAH) specific therapy. Currently, there are 12 approved medications for the treatment of PAH in the US, and three of these were approved in 2013. This review will discuss the diagnosis, evaluation and management of POPH and the role of recently approved PAH therapies in the treatment of POPH.