中文摘要

 中国可遗传性肺动脉高压成人患者的长期生存与预后因素：

来自一项全国多中心、前瞻性登记注册研究的发现

研究背景：可遗传性肺动脉高压（heritable pulmonary arterial hypertension, HPAH）是一种罕见的进展性疾病，作为动脉型肺动脉高压（pulmonary arterial hypertension, PAH）的亚类，其包括家族性PAH和散发性PAH。目前，对于HPAH的长期生存和预后因素等方面的认识非常有限。在既往的研究报道中，HPAH和IPAH患者通常被合并为同一队列进行生存分析，而针对HPAH成人患者生存情况的独立研究报告较为少见，特别是在长期随访方面，且中国目前尚无关于HPAH成人患者生存预后的报道。

研究目的：本研究旨在阐明中国HPAH成人患者的长期生存情况及预后预测因素，并与特发性肺动脉高压（idiopathic pulmonary arterial hypertension, IPAH）成人患者的长期生存情况进行对比分析。

研究方法：本研究基于一项全国多中心、前瞻性PAH登记注册研究，自2009年8月至2019年12月连续入组经右心导管检查确诊且具有PAH阳性家族史的成人HPAH患者。收集所有纳入患者的基线数据，包含人口学资料、临床特征、血流动力学指标及治疗情况，并通过定期随访收集患者的生存状态信息。研究的主要终点为全因死亡。为平衡组间基线特征，采用倾向性评分匹配法，将HPAH队列与同一登记注册研究中的IPAH队列按1:2进行匹配，并比较HPAH与IPAH两组患者的生存差异。

研究结果：本研究共纳入38例HPAH患者（年龄≥18岁），其中有18例（47.37%）被诊断为遗传性出血性毛细血管扩张症（hereditary haemorrhagic telangiectasia, HHT）相关PAH，并将整个HPAH队列分为HHT-HPAH和nonHHT-HPAH两组。本研究的中位随访时间为110个月。HPAH总体队列在1年、3年、5年和10年的Kaplan-Meier生存率分别为97.3%、80.7%、66.6%和46.2%。亚组生存分析显示，入组后早期连续≥1年靶向治疗患者的长期生存率有高于无或间断靶向治疗患者的趋势（log-rank 检验, p=0.050；Cox回归分析风险比=0.406，95%置信区间：0.160-1.031，p=0.058；Bootstrap法p=0.056）。采用REVEAL肺动脉高压疾病早期及长期管理评估注册研究（Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management, REVEAL）2.0风险评分进行HPAH基线时危险分层，三组患者的组间生存率存在显著差异（log-rank检验，p=0.021），基线时处于高危状态的HPAH成人患者的10年生存率极差。HHT-HPAH组患者的长期生存率显著低于nonHHT-HPAH组（10年：28.5% vs. 62.8%；log-rank 检验，p=0.032）。经倾向性评分匹配后，HPAH与IPAH两组患者的基线特征平衡，Kaplan-Meier生存曲线显示匹配后HPAH组患者的长期生存率显著低于IPAH组（10年：41.7% vs. 60.8%；log-rank 检验，p=0.048）。多因素Cox回归分析结果表明，世界卫生组织功能分级（World Health Organization functional class, WHO-FC）Ⅲ/IV和心率增快是HPAH总体队列患者死亡的独立预测因素。存在肝动静脉畸形和心率增快是HHT-HPAH组患者死亡的独立预测因素，而6分钟步行距离（6-minute walking distance, 6MWD）减少是nonHHT-HPAH组患者死亡的独立预测因素。

研究结论：本研究首次报告了中国可遗传性肺动脉高压（HPAH）成人患者的10年生存率，其长期生存状况极差。本研究发现HPAH患者的长期生存率显著低于IPAH患者。此外，对比nonHHT-HPAH患者，HHT-HPAH患者的长期预后更差。基线时WHO-FC Ⅲ/IV和心率增快是HPAH患者死亡的独立预测因素。本研究数据来源于真实世界的研究，为临床实践提供了重要的参考依据。

Abstract

 Long-term survival and prognostic factors of adult patients with heritable pulmonary arterial hypertension in China: Insights from a national multicenter prospective registry

Background: Heritable pulmonary arterial hypertension (HPAH) is a rare progressive disease, as well as a devastating disorder. As a subclass of pulmonary arterial hypertension (PAH), it includes both familial PAH and sporadic PAH. Currently, there is extremely limited knowledge of the long-term survival and prognostic factors of HPAH. In previous studies, HPAH and idiopathic pulmonary arterial hypertension (IPAH) patients have often been combined into a single cohort for survival analysis. However, independent studies focusing on the survival of adult HPAH patients are relatively rare, particularly for long-term follow-up. Moreover, the long-term survival of adult patients with HPAH has not yet been reported in China.

Objectives: This study aims to elucidate the long-term survival of adult patients with HPAH in China and identify prognostic factors for survival, as well as to compare the long-term survival with that of patients with IPAH.

Methods: Based on a national multicenter prospective PAH registry of China, adult patients with HPAH diagnosed by right heart catheterization (RHC) and with a positive family history of PAH were consecutively enrolled from August 2009 to December 2019. Baseline data of the enrolled patients were collected, including demographic information, clinical characteristics, hemodynamic parameters, and treatment. Survival status information was collected through regular follow-up. The primary endpoint of this study was all-cause death. Propensity score matching (PSM) was used to match the HPAH cohort with the IPAH cohort from the same registry study in a 1:2 ratio to balance the baseline characteristics, and survival differences between the HPAH and IPAH groups were compared.

Results: A total of 38 adult patients with HPAH were enrolled in this study, 18 of whom were diagnosed with hereditary haemorrhagic telangiectasia-associated pulmonary arterial hypertension (HHT-PAH). The median follow-up time was 110 months. The Kaplan-Meier survival estimates for the overall HPAH cohort at 1, 3, 5, and 10 years were 97.3%, 80.7%, 66.6%, and 46.2%, respectively. Subgroup analysis showed that HPAH patients who received early continuous targeted therapy for ≥1-year after enrollment exhibited a trend toward higher long-term survival rates compared to those with no or intermittent targeted therapy (log-rank test; p = 0.050). Cox regression analysis further indicated a trend toward reduced mortality risk in HPAH patients with early continuous ≥1-year targeted drug therapy (hazard ratio = 0.406, 95% confidence interval: 0.160-1.031, p = 0.058; Bootstrap test, p = 0.056). The REVEAL 2.0 risk score (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management, REVEAL) was used for baseline risk stratification in HPAH patients. Significant differences in survival rates were observed among the three groups (log-rank test, p = 0.021). Adult patients with HPAH classified as high-risk at baseline demonstrated extremely poor 10-year survival rates. The estimated 10-year survival of patients with hereditary haemorrhagic telangiectasia (HHT) was significantly worse than that of patients without HHT (28.5% vs. 62.8%; log-rank test, p = 0.032). After propensity score matching, the baseline characteristics of patients in the HPAH and IPAH groups were well-balanced. The Kaplan-Meier survival curve showed that the 10-year survival rate of patients in the HPAH group was significantly lower than that in the IPAH group (41.7% vs. 60.8%; log-rank test, p = 0.048). Multivariate Cox regression analysis indicated that World Health Organization functional class (WHO-FC) III/IV and higher heart rate were independent predictors of increased mortality in the overall cohort of HPAH patients. Hepatic arteriovenous malformations (AVMs) and higher heart rate were found to be independent predictors of mortality in patients with HHT. The 6-minute walking distance (6MWD) was a unique predictor of survival in patients without HHT.

Conclusions: The present study is the first to report the 10-year survival rate of adult patients with HPAH in China, revealing an extremely poor long-term survival status. This study identifies that the long-term survival rate of HPAH patients was significantly lower than that of IPAH patients. Furthermore, compared with patients without HHT, those with HHT have worse long-term prognosis. Mortality is most closely associated with baseline WHO-FC Ⅲ/IV and higher heart rate in adult HPAH patients. The data from this study, derived from real-world research, provide valuable insights and reference for clinical practice.