肺动脉高压(PAH)是一种恶性肺血管综合征,其特征是肺血管阻力和肺动脉压进行性增加,最终导致右心衰竭甚至死亡.尽管PAH的确切机制尚未完全了解,肺血管收缩,血管重塑,免疫和炎症反应,和血栓形成被认为与PAH的发生和发展有关。在非目标特工时代,PAH的预后非常差,中位生存时间仅为2.8年。随着对PAH病理生理机制的深入了解以及药物研究的进展,在过去的30年中,PAH特异性治疗药物发展迅速,但他们主要关注三种经典的信号通路,即内皮素途径,一氧化氮途径,和前列环素途径。这些药物显著改善了肺血流动力学,心功能,运动耐受力,生活质量,和PAH患者的预后,但只能在有限的程度上降低肺动脉压和右心室后负荷。目前的靶向药物可延缓PAH的进展,但不能从根本上逆转肺血管重塑。通过不懈的努力,新的治疗药物如索特西普已经出现,为这一领域注入新的活力。这篇综述全面总结了PAH的一般治疗方法,包括肌力强化剂和血管加压药,利尿剂,抗凝剂,一般血管扩张剂,和贫血管理。此外,本文综述了针对3条经典信号通路的12种特异性药物的药理特性和最新研究进展,以及双重-,序贯三重-,以及基于上述靶向药物的初始三联疗法策略。更关键的是,寻找新的PAH治疗靶点从未停止,随着近年来的巨大进步,本综述概述了目前处于探索阶段的潜在PAH治疗药物,为PAH的治疗提供新的方向,改善PAH患者的长期预后。
Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular syndrome characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, which eventually leads to right heart failure and even death. Although the exact mechanism of PAH is not fully understood, pulmonary vasoconstriction, vascular remodeling, immune and inflammatory responses, and thrombosis are thought to be involved in the development and progression of PAH. In the era of non-targeted agents, PAH had a very dismal prognosis with a median survival time of only 2.8 years. With the deep understanding of the pathophysiological mechanism of PAH as well as advances in drug research, PAH-specific therapeutic drugs have developed rapidly in the past 30 years, but they primarily focus on the three classical signaling pathways, namely the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. These drugs dramatically improved pulmonary hemodynamics, cardiac function, exercise tolerance, quality of life, and prognosis in PAH patients, but could only reduce pulmonary arterial pressure and right ventricular afterload to a limited extent. Current targeted agents delay the progression of PAH but cannot fundamentally reverse pulmonary vascular remodeling. Through unremitting efforts, new therapeutic drugs such as sotatercept have emerged, injecting new vitality into this field. This review comprehensively summarizes the general treatments for PAH, including inotropes and vasopressors, diuretics, anticoagulants, general vasodilators, and anemia management. Additionally, this review elaborates the pharmacological properties and recent research progress of twelve specific drugs targeting three classical signaling pathways, as well as dual-, sequential triple-, and initial triple-therapy strategies based on the aforementioned targeted agents. More crucially, the search for novel therapeutic targets for PAH has never stopped, with great progress in recent years, and this review outlines the potential PAH therapeutic agents currently in the exploratory stage to provide new directions for the treatment of PAH and improve the long-term prognosis of PAH patients.