第一部分：肺动脉顺应性在先天性心脏病相关肺动脉高压患者中的预后预测价值研究

摘要

研究背景：目前已有研究揭示了肺动脉顺应性（pulmonary arterial compliance，PAC）在动脉性肺动脉高压（pulmonary arterial hypertension, PAH）及其不同亚组患者中的长期预后预测具有潜在的价值。然而，既往研究对象多为PAH患者总体而非先天性心脏病相关肺动脉高压（pulmonary arterial hypertension associated with congenital heart disease, PAH-CHD）患者；而现有针对于PAH-CHD患者的研究主要聚焦于儿童和婴儿患者，以及特定的PAH-CHD临床分类或缺损类型的患者，且普遍存在样本量较小、多为回顾性单中心研究等局限性。目前尚缺乏针对PAC在PAH-CHD患者总体人群中的预后预测价值的研究，PAC在PAH-CHD总体患者中的长期预后预测价值仍有待阐明。

研究目的：本研究旨在探讨PAC对PAH-CHD患者预后的预测价值。

研究方法：从2009年8月至2019年12月，本研究前瞻性地纳入了434名成年PAH-CHD患者。主要终点为全因死亡。通过多因素Cox比例风险回归模型和限制性立方样条分析评估PAC与主要终点之间的关联。通过计算C指数、连续净重新分类指数和综合判别改善指数来评估PAC预测主要终点的的预测增量效应。

研究结果：低PAC组患者表现出更差的心功能状态、运动耐量、四分层危险分层、动脉血气分析和超声心动图参数以及血流动力学参数。多因素Cox回归分析表明，在调整基线PAH预后因素后，无论PAC作为连续变量（风险比[HR]: 0.660, 95%置信区间[95%CI]: 0.455-0.957, P=0.034）还是分类变量（HR: 0.229, 95% CI: 0.098-0.535, P=0.002），均与全因死亡显著相关。此外，限制性立方样条分析显示PAC与主要终点之间存在线性剂量-反应关系（P for nonlinear = 0.210，P for overall = 0.038）。亚组分析中PAC对主要终点的影响在不同的预先定义的亚组中是一致的（P for interaction＞0.05）。进一步将PAC纳入基线PAH预后因素和2022年ESC/ERS危险分层评估模型中，可以显著提高基线变量对全因死亡的预测性能。

研究结论：PAC对PAH-CHD患者的长期预后有较好的预测价值，是PAH-CHD患者长期生存的独立预后因素。

第二部分：遗传性出血性毛细血管扩张症相关动脉性肺动脉高压的10年生存研究

摘要

研究背景：遗传性出血性毛细血管扩张症（hereditary hemorrhagic telangiectasia，HHT）是一种以血管结构发育异常为特征的罕见常染色体遗传性疾病，合并肺动脉高压（pulmonary hypertension，PH）会显著影响此类患者的长期生存和预后。HHT患者中合并PH仅占约10%，而动脉性肺动脉高压（pulmonary arterial hypertension，PAH）作为PH中的一种临床分类，合并PAH的情况更为罕见，仅占HHT患者的1%。目前世界范围内仅有两项研究分别报道了HHT-PAH患者的3年和5年生存率，尚无研究报道HHT-PAH患者的10年远期生存情况的预后影响因素，中国HHT-PAH患者的10年远期生存情况和预后影响因素有待阐明。

研究目的：本研究旨在阐明中国HHT-PAH的10年远期生存情况和预后因素。

研究方法：基于中国全国多中心前瞻性PAH登记注册研究，本研究连续纳入了2009年8月至2019年12月在中国医学科学院阜外医院和广东省人民医院两家中心通过右心导管检查诊断的HHT-PAH患者，采集患者的基线资料，每6个月±2周对患者进行随访，研究终点为全因死亡，分析其生存和预后因素。

研究结果：本研究共纳入18例HHT-PAH患者，女性14例（77.8%），中位年龄为39（32,45）岁。本队列中位随访时间为129（51,156）个月，随访期间12例（66.7%）患者死亡。本队列患者的中位生存时间为70（32,123）个月，1年、3年、5年、10年生存率分别为100%、70.8%、53.1%、26.6%。多因素Cox比例风险回归模型分析显示存在肝动静脉畸形与HHT-PAH患者死亡风险增加相关（HR=4.493，95% CI：1.064-18.978，P = 0.041）。在双因素Cox比例风险回归模型中分别调整了年龄、性别和既往公认的PAH预后因素（包括6分钟步行距离、WHO功能分级、NT-proBNP、肺动脉平均压、肺血管阻力、混合静脉血氧饱和度）后，发现存在肝动静脉畸形仍是HHT-PAH患者死亡风险增加的独立危险因素。

研究结论：本研究在国际上首次报道了HHT-PAH患者的10年生存率，HHT-PAH患者的10年生存情况极差，存在肝动静脉畸形是HHT-PAH患者死亡的独立危险因素。

Part I: Prognostic value of pulmonary artery compliance in patients with pulmonary arterial hypertension associated with congenital heart disease

Abstract

Background: Previous studies have revealed the potential value of pulmonary arterial compliance (PAC) in predicting long-term prognosis in patients with pulmonary arterial hypertension (PAH) and its various subgroups. However, previous studies mostly focused on the overall PAH patients rather than patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). Research on the long-term prognostic value of PAC in patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) has primarily focused on pediatric and infant patients, as well as specific clinical classifications of PAH-CHD, with common limitations including small sample sizes and retrospective single-center studies. Currently, there is a lack of research on the prognostic value of PAC in the entire population of PAH-CHD patients, and the long-term prognostic value of PAC in the entire PAH-CHD population remains to be elucidated.

Objective: This study aims to investigate the predictive value of PAC on the prognosis of PAH-CHD patients.

Methods: From August 2009 to December 2019, this study prospectively enrolled 434 adult PAH-CHD patients. The primary endpoint was all-cause mortality. The association between PAC and the primary endpoint was assessed by multivariable Cox regression and restricted cubic spline analysis. Incremental predictive effects of PAC on the primary endpoint were evaluated by calculating the C-index, continuous net reclassification improvement, and integrated discrimination improvement.

Results: Patients with lower PAC exhibited significantly worse cardiac function status, exercise tolerance, risk stratification, arterial blood gas analysis, echocardiographic parameters, and hemodynamic parameters. Multivariable Cox regression analysis demonstrated that after adjusting for baseline PAH prognostic factors, PAC, whether treated as a continuous variable (hazard ratio [HR]: 0.660, 95% confidence interval [CI]: 0.455-0.957, P=0.034) or a categorical variable (HR: 0.229, 95% CI: 0.098-0.535, P=0.002), was significantly associated with all-cause mortality. Additionally, restricted cubic spline analysis revealed a linear dose-response relationship between PAC and the primary endpoint (P for nonlinearity = 0.210, P for overall <0.05). Subgroup analyses showed consistent effects of PAC on the primary endpoint across different predefined subgroups (P for interaction >0.05). Incorporating PAC into baseline PAH prognostic factors and the 2022 ESC/ERS risk stratification model significantly improved the predictive performance for all-cause mortality.

Conclusion: PAC has good prognostic value for long-term outcomes in patients with PAH-CHD and is an independent prognostic factor for long-term survival in these patients.

Part II: 10-year survival study of hereditary hemorrhagic telangiectasia-associated pulmonary arterial hypertension

Abstract

Background：Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disease characterized by abnormal vascular development. The presence of pulmonary hypertension (PH) significantly impacts the long-term survival and prognosis of these patients. In patients with HHT, the incidence of PH is approximately 10%, while pulmonary arterial hypertension (PAH), a clinical classification of PH, is even rarer, affecting only about 1% of HHT patients. To date, only two studies worldwide have reported the 3-year and 5-year survival rates of HHT-PAH patients, respectively. There is a lack of research on the 10-year long-term survival and prognostic factors in HHT-PAH patients. The 10-year long-term survival and prognostic factors of HHT-PAH patients in China remain to be elucidated.

Objective：This study aims to investigate the 10-year survival and prognostic factors of HHT-PAH in Chinese patients.

Methods：Based on a national multicenter prospective PAH registry, this study consecutively enrolled HHT-PAH patients diagnosed by right heart catheterization between August 2009 and December 2019 at Fuwai Hospital and Guangdong Provincial People's Hospital. Baseline data were collected, and patients were followed up every six months ± two weeks. The primary endpoint was all-cause mortality, and survival and prognostic factors were analyzed.

Results：A total of 18 HHT-PAH patients were included in this study, with 14 (77.8%) being female and a median age of 39 (32, 45) years. The median follow-up duration was 129 (51, 156) months, during the period 12 (66.7%) patients died. The median survival time for this cohort was 70 (32, 123) months, with 1-, 3-, 5-, and 10-year survival rates of 100%, 70.8%, 53.1%, and 26.6%, respectively. Multivariate Cox proportional hazards regression analysis revealed that the presence of hepatic arteriovenous malformations (HR = 4.493, 95% CI: 1.064-18.978, P = 0.041) was associated with an increased risk of death in HHT-PAH patients. After adjusting for age, sex and previously recognized prognostic factors for PAH, including 6-minute walking distance, WHO functional class, NT-proBNP, mean pulmonary arterial pressure, pulmonary vascular resistance, and mixed venous oxygen saturation, the presence of hepatic arteriovenous malformations remained an independent risk factor for mortality in HHT-PAH patients.

Conclusion：This study is the first to report the 10-year survival rate of HHT-PAH patients internationally. The 10-year survival outcome for HHT-PAH patients is poor, and the presence of hepatic arteriovenous malformations is an independent risk factor for mortality in HHT-PAH patients.