Department of Medicine, Imperial College London, London, UK.
J Intern Med. 2017 Aug;282(2):129-141. doi: 10.1111/joim.12623. Epub 2017 May 19.
Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. The diagnosis of PAH in more elderly patients has highlighted the need for careful phenotyping of patients and for further studies to understand how best to manage pulmonary hypertension associated with, for example, left heart disease. The breadth and depth of expertise focused on unravelling the molecular pathology of PAH has yielded novel insights, including the role of growth factors, inflammation and metabolic remodelling. The description of the genetic architecture of PAH is accelerating in parallel, with novel variants, such as those reported in potassium two-pore domain channel subfamily K member 3 (KCNK3), adding to the list of more established mutations in genes associated with bone morphogenetic protein receptor type 2 (BMPR2) signalling. These insights have supported a paradigm shift in treatment strategies away from simply addressing the imbalance of vasoactive mediators observed in PAH towards tackling more directly the structural remodelling of the pulmonary vasculature. Here, we summarize the changing clinical and molecular landscape of PAH. We highlight novel drug therapies that are in various stages of clinical development, targeting for example cell proliferation, metabolic, inflammatory/immune and BMPR2 dysfunction, and the challenges around developing these treatments. We argue that advances in the treatment of PAH will come through deep molecular phenotyping with the integration of clinical, genomic, transcriptomic, proteomic and metabolomic information in large populations of patients through international collaboration. This approach provides the best opportunity for identifying key signalling pathways, both as potential drug targets and as biomarkers for patient selection. The expectation is that together these will enable the prioritization of potential therapies in development and the evolution of personalized medicine for PAH.
肺动脉高压（PAH）曾一度被严重忽视，如今已成为许多学术和生物技术团队研究的重点。新疗法的出现提高了人们对这种疾病的认识。这反过来又改变了 PAH 的人口统计学特征，诊断时的平均年龄有所增加。在年龄较大的患者中诊断出 PAH 突出表明需要仔细对患者进行表型分析，并进一步研究如何最好地管理与左心疾病等相关的肺动脉高压。专注于揭示 PAH 分子病理学的专业知识的广度和深度产生了新的见解，包括生长因子、炎症和代谢重塑的作用。PAH 遗传结构的描述也在加速，新的变体，如钾双孔域通道亚家族 K 成员 3（KCNK3）报告的变体，增加了与骨形态发生蛋白受体 2（BMPR2）信号相关的更确定突变基因列表。这些见解支持了治疗策略的范式转变，从简单地解决 PAH 中观察到的血管活性介质失衡，转向更直接地解决肺血管结构重塑。在这里，我们总结了 PAH 的不断变化的临床和分子景观。我们强调了处于不同临床开发阶段的新型药物疗法，例如针对细胞增殖、代谢、炎症/免疫和 BMPR2 功能障碍的疗法，以及开发这些治疗方法所面临的挑战。我们认为，通过国际合作，在大型患者群体中整合临床、基因组、转录组、蛋白质组和代谢组信息，进行深入的分子表型分析，将为 PAH 的治疗带来进展。这种方法为确定关键信号通路提供了最佳机会，这些信号通路既可以作为潜在的药物靶点，也可以作为患者选择的生物标志物。期望这些将共同为潜在疗法的开发和 PAH 的个体化医学的发展提供优先考虑的机会。
