Wang Xuenan, Yu Cheng, Li Meiling, Cai Huiling, Yang Yongjian, Lan Cong
Department of Cardiology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Department of Cardiology, General Hospital of Western Theater Command, Chengdu, Sichuan, China.
ESC Heart Fail. 2025 Aug;12(4):2843-2854. doi: 10.1002/ehf2.15292. Epub 2025 Apr 16.
Right ventricular (RV) remodelling, a progressive condition characterized by maladaptive cardiac structural and functional changes, primarily results from prolonged pressure overload in patients with pulmonary hypertension (PH). Accurate, universal and easy-to-use biomarkers for assessing the severity of RV remodelling are lacking. This study aimed to identify serum proteins as potential biomarkers of RV remodelling using high-throughput proteomic analysis-based screening.
Sprague-Dawley rats were subjected to sham surgery (control group) or pulmonary artery banding for 4 weeks with 2.3-mm diameter and 1.8-mm diameter rubber rings to induce mild and severe RV modelling, respectively. Serum proteomic profiling revealed 170 differentially expressed serum proteins (DEPs) among the three groups, and three DEPs gradually increased with worsening RV remodelling. Among the three DEPs, C4b-binding protein alpha chain (C4BPA) exhibited the highest upregulation in the severe group (6.93 vs. 16.5 ng/mL, P < 0.001), and linear regression analysis revealed a negative correlation between serum C4BPA levels and tricuspid annular plane systolic excursion (TAPSE) in rats [beta = -0.78, 95% confidence interval (CI) -14.5 to -7.11, P < 0.001]. The diagnostic power of C4BPA was further validated in 127 patients (34 with adaptive RV pressure overload, 36 with maladaptive RV pressure overload, 32 with left ventricular hypertrophy and 25 controls). Control and left ventricular hypertrophy patients exhibited lower serum C4BPA levels than the two RV groups, and serum C4BPA levels were higher in patients with maladaptive RV than in those with adaptive RV (754 vs. 524 pg/mL, P < 0.001). Linear regression analysis revealed a negative correlation between serum C4BPA levels and TAPSE in PH patients. The predictive power of C4BPA for maladaptive RV function in PH patients, indicated by receiver operating characteristic analysis (cut-off value 573 pg/mL, area under the curve 0.792), was as good as that of B-type natriuretic peptide (BNP). High serum C4BPA levels (≥573 pg/mL) were associated with lower TAPSE/pulmonary arterial systolic pressure ratios (P < 0.001) and higher BNP levels (P < 0.001).
Serum C4BPA may represent a novel diagnostic biomarker for RV pathological remodelling associated with RV maladaptation in PH patients.
右心室（RV）重构是一种以适应性不良的心脏结构和功能改变为特征的进行性病症，主要由肺动脉高压（PH）患者的长期压力超负荷引起。目前缺乏用于评估RV重构严重程度的准确、通用且易于使用的生物标志物。本研究旨在通过基于高通量蛋白质组学分析的筛选来鉴定血清蛋白作为RV重构的潜在生物标志物。
将Sprague-Dawley大鼠进行假手术（对照组）或分别用直径2.3毫米和1.8毫米的橡胶环进行4周的肺动脉环扎，以分别诱导轻度和重度RV建模。血清蛋白质组分析显示三组之间有170种差异表达的血清蛋白（DEP），其中三种DEP随着RV重构的恶化而逐渐增加。在这三种DEP中，C4b结合蛋白α链（C4BPA）在重度组中上调最为明显（6.93对16.5 ng/mL，P < 0.001），线性回归分析显示大鼠血清C4BPA水平与三尖瓣环平面收缩期位移（TAPSE）之间呈负相关[β = -0.78，95%置信区间（CI）-14.5至-7.11，P < 0.001]。在127例患者（34例适应性RV压力超负荷、36例适应性不良RV压力超负荷、32例左心室肥厚和25例对照）中进一步验证了C4BPA的诊断能力。对照组和左心室肥厚患者的血清C4BPA水平低于两个RV组，适应性不良RV患者的血清C4BPA水平高于适应性RV患者（754对524 pg/mL，P < 0.001）。线性回归分析显示PH患者血清C4BPA水平与TAPSE之间呈负相关。通过受试者工作特征分析（截断值573 pg/mL，曲线下面积0.792）表明，C4BPA对PH患者适应性不良RV功能的预测能力与B型利钠肽（BNP）相当。血清C4BPA水平高（≥573 pg/mL）与较低的TAPSE/肺动脉收缩压比值（P < 0.001）和较高的BNP水平（P < 0.001）相关。
血清C4BPA可能是PH患者中与RV适应性不良相关的RV病理重构的一种新型诊断生物标志物。
