研究背景：遗传性出血性毛细血管扩张症 （HHT）是一种常染色体显性遗传病，该病通常临床表现包括反复鼻衄、口鼻唇等部位的毛细血管扩张以及内脏器官内动静脉畸形形成。目前发现 ENG 基因和 ALK1 基因是遗传性出血性毛细血管扩张症最为重要的致病基因。近十几年来，肺动脉高压（PAH）作为 HHT 的相关疾病越来越受到关注。 HHT相关 PAH 的临床特征、血流动力学特点与病理特点均与 IPAH 十分相似。HHT 相关PAH 会显著增加 HHT 患者死亡风险，且患者预后情况似乎也差于特发性肺动脉高压患者（IPAH）。目前 ALK1 基因突变，特别是位于蛋白激酶域的突变与 HHT 相关 PAH有着密切关系。但目前这些结论均缺乏较大样本的研究支持，且对于不同基因突变导致的 HHT 相关 PAH 也缺乏相关对比研究。研究目的：1. 探究 HHT 相关 PAH 患者的临床特征和预后情况.2. 探究 HHT 相关 PAH 患者的遗传学特征.研究方法：本研究计划纳入从 2006 年 1 月至 2018 年 12 月就诊于上海市肺科医院和中国医学科学院阜外医院并符合纳入排除标准的 HHT 相关 PAH 患者。本研究收集了入选患者的既往病史资料、临床实验和检查数据、右心导管检查数据以及随访结果，同时对入选患者进行了全外显子或全基因组测序。另外以 1： 1 比例按照性别、年龄匹配原则纳入了既往本中心确诊的 IPAH 患者进行对比研究。本研究还总结了既往文献中对 HHT 相关 PAH 患者 ALK1 突变情况，并与本研究结果进行对比。本文利用独立样本 t 检验、Mann-Whitney U test、卡方检验、Fisher 精确检验进行组间数据比较。利用 Kaplan-Merier 生存分析、 log-rank 检验比较了组间预后差异。利用单因素和多因素 COX 风险比例模型寻找 HHT 相关 PAH 患者预后预测因子。P 值小于0.05 被认为存在显著性。研究结果：共纳入 77 名 HHT 相关 PAH 患者，平均诊断时间为 24 个月。诊断时 NYHA 功能分级为 I 级 0%、II 级 42.9%，III 级 49.3%、IV 7.8%。58%的患者存在反复鼻衄、75%的患者存在毛细血管扩张、 27.3%和 27.9%的患者存在肺动静脉畸形和肝动静脉畸形。这些患者的平均肺动脉压力（mPAP）均值为 63.49±18.8mmHg、中位肺动脉楔压(PAWP)为 10 mmHg(8-11)、中位肺血管阻力（PVR）为 13.53 Wood units。急性肺血管舒张试验阳性率为 6%。与特发性肺动脉高压患者相比， HHT 相关 PAH 患者诊断时 NYHA 功能分级更差，mPAP 和心指数（CI）显著更高，同时与既往 IPAH 患者的研究相比，急性肺血管舒张试验阳性率显著更低。患者整体 1 年、3 年、5 年生存率为 90.4%、73.8%、60.2%。在控制 NYHA 功能分级、NT-proBNP、平均右心房压力 mRAP、心指数CI、肺血管阻力 PVR、 SvO2 等多个变量后， 6 分钟步行距离 6MWD 仍是患者预后的显著预测因素。全部 HHT 相关 PAH 患者中 75.3%的患者携带有 ALK1 基因突变患者、10.4%携带 ENG 基因突变、 14.3%未发现相关基因突变。携带 ENG 突变的患者其 6MWD要显著长于其他两组患者，且其 NT-proBNP 水平更低。生存分析显示 ENG 突变患者其生存率显著高于其他两组。对于突变的研究发现，引起 HHT 相关 PAH 的 ALK1 主要存在于胞内蛋白激酶域，且主要分布在外显子 7、 8 和 10。与 HHT 中 ALK1 突变的双峰分布存在明显差别（外显子 3，外显子 7 和 8）。研究结论：1． 遗传性出血性毛细血管扩张症相关肺动脉高压患者的整体预后不佳。2． ALK1 是遗传性出血性毛细血管扩张症相关肺动脉高压最重要的基因，占比约75%。携带 AKL1 突变的患者其临床功能指标和临床预后劣于携带 ENG 突变的患者。3． 位于 ALK-1 蛋白胞内激酶域的 ALK1 基因突变与 HHT 相关 PAH 关系更为密切。

Background:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease that usually manifests as repeated nose bleeding, telangiectasia and the formation of arteriovenous malformations in the internal organs. It has been found that the ENG gene and the ALK1 gene are the most important pathogenic genes of hereditary hemorrhagic telangiectasia. Pulmonary hypertension (PAH) has received increasing attention as a disease associated with HHT in the past 10 years. The clinical features, hemodynamic characteristics and pathological features of HHT-associated PAH are very similar to IPAH. HHT-associated PAH significantly increased the risk of death in patients with HHT, and the prognosis of patients also appeared to be worse than patients with idiopathic pulmonary hypertension (IPAH). The current known ALK1gene mutations, especially in the protein kinase domain, is closely related to HHT-related PAH. However, at present, these conclusions lack the support of large sample research, and there is no relevant comparative study on HHT-related PAH caused by different gene mutations.Aim :1.Explore the clinical features and prognosis of patients with HHTrelated PAH.2. Explore the genetic characteristics of patients with HHT-associated .PAH.Method:This study included patients NYHA fulfilled the inclusion and exclusion criteria and diagnosed as HHT-related PAH in the Shanghai Pulmonary Hospital and the Chinese Academy of Medical Sciences Fuwai Hospital from January 2006 to December 2018. The study collected previous medical history, clinical examination data, right heart catheterization data, and follow-up results. All patients were enrolled in a whole exon or whole genome sequencing. In addition, the IPAH patients diagnosed in the same center were included in the 1:1 ratio according to the principle of gender and age matching for comparative study. This study also summarizes the ALK1 mutations in patients with HHT-associated PAH in previous literature and compared them with the results of this study.This study used independent sample t-test, Mann-Whitney U test, chisquare test, Fisher exact test to compare component data. Differences in prognosis between the groups were compared using Kaplan-Merier survival analysis and log-rank test. The single-factor and multi-factor COX risk ratio models were used to find prognostic factors for patients with HHT-associated PAH. A P value of less than 0.05 is considered to be significant.Result:A total of 77 patients with HHT-related PAH were enrolled, with an average diagnosis interval duration of 24 months. The NYHA function grade of these patients was 0% for grade I, 42.9% for grade II, 49.3% for grade III, and 7.8% for grade IV. 58% of patients had recurrent nasal discharge, 75% had telangiectasia, 27.3% and 27.9% had pulmonary arteriovenous malformations and hepatic arteriovenous malformations.The mean pulmonary artery pressure (mPAP) for these patients was 63.49 ± 18.8 mm Hg, the median pulmonary wedge pressure (PAWP) was 10 mm Hg (8-11), and the median pulmonary vascular resistance (PVR) was 13.53 Wood units. The positive rate of acute pulmonary vasodilation test was 6%. Compared with patients with idiopathic pulmonary hypertension, patients with HHT-related PAH had a worse grade of NYHA, a significantly higher mPAP and heart index (CI), and a significantly lower positive rate of acute pulmonary vasodilation. The overall 1-, 3-, and 5-year survival rates of patients were 90.4%, 73.8%, and 60.2%. After controlling NYHA functional grading, NT-proBNP, mean right atrial pressure mRAP, cardiac index CI, pulmonary vascular resistance PVR, SvO2 and other variables, 6-minute walking distance 6MWD is still a significant predictor of patient prognosis. 75.3% of all HHT-related PAH patients had ALK1 gene mutations, 10.4% carried ENG gene mutations, and 14.3% did not find related gene mutations. Patients with ENG mutations had significantly longer 6MWD than the other two groups and had lower levels of NT-proBNP. Survival analysis showed that patients with ENG mutations had significantly higher survival rates than the other two groups. Studies on mutations have found that ALK1, which causes HHT-associated PAH, is mainly present in the intracellular protein kinase domain and is mainly distributed in exons 7, 8, and 10. There is a significant difference from the bimodal distribution of the ALK1 mutation in HHT (exon 3, exons 7 and 8).Conclusion:1.The overall prognosis of patients with hereditary hemorrhagic telangiectasia-associated pulmonary hypertension is poor.2.ALK1 is the most important gene for hereditary hemorrhagic telangiectasia associated pulmonary artery hypertension, accounting for about 75%. Patients with AKL1 mutations have clinical function indicators and clinical prognosis that are inferior to those with ENG mutations.3.The ALK1 gene mutations located in the intracellular kinase domain of ALK-1 protein are more closely related to HHT-related PAH.