Fan Qiang, Wang Yabo, Zhu Dongyong, An Qi, Ling Yunfei
Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Front Cardiovasc Med. 2025 May 2;12:1546581. doi: 10.3389/fcvm.2025.1546581. eCollection 2025.
This study aimed to investigate the role of turbulent shear stress (TSS) induced by pulmonary regurgitation (PR) in driving right ventricular (RV) dysfunction, with a focus on NLRP3 inflammasome activation, inflammation, and fibrosis, particularly in the RV outflow tract (RVOT).
Clinical data from 6 repaired tetralogy of Fallot (rTOF) patients with PR were analyzed using cardiac magnetic resonance (CMR) and computational fluid dynamics (CFD) to quantify TSS distribution. Human cardiomyocytes were cultured under static (SF), unidirectional (UF), or oscillatory flow (OF) conditions to simulate TSS. A rat PR model was established to assess RV remodeling over 4-12 weeks. NLRP3 expression, cytokine release, and fibrosis were evaluated via western blot, ELISA, and histology.
CFD revealed elevated turbulent kinetic energy (TKE) and TSS in the RVOT compared to inflow and apical regions ( = 0.001). , OF (15 dyn/cm) activated NLRP3 inflammasome in cardiomyocytes, increasing NLRP3 (10-fold, = 0.01) and caspase-1 (4-fold, = 0.012), and elevating IL-1β (775.1 ± 9.4 vs. 658.4 ± 19.6 pg/ml, = 0.03) and IL-18 (1,264.8 ± 10.7 vs. 1,038.6 ± 18.8 pg/ml, = 0.022) levels compared to SF. , PR induced progressive RV dilation (RVEDVi: 7.4 ± 0.4-10.8 ± 0.6 ml/m, < 0.01) and reduced longitudinal strain (45.6 ± 2.5-19.1 ± 0.5 s, < 0.01), and RVOT-predominant NLRP3 expression (12 weeks: 0.07 ± 0.02 vs. 0.005 ± 0.001 in controls, < 0.001) and fibrosis (33.9 ± 4.8% vs. 12.8 ± 3.2% in control, < 0.01).
PR-induced TSS in the RVOT activates the NLRP3 inflammasome in cardiomyocytes, triggering inflammation and fibrosis that drive regional RV dysfunction. Quantifying TSS may serve as an early biomarker for subclinical RV injury, while targeting NLRP3 signaling could offer a therapeutic strategy to mitigate fibrosis in PR patients.
本研究旨在探讨肺动脉反流（PR）诱导的湍流切应力（TSS）在导致右心室（RV）功能障碍中的作用，重点关注NLRP3炎性小体激活、炎症和纤维化，尤其是在右心室流出道（RVOT）中的情况。
对6例接受修复的法洛四联症（rTOF）合并PR患者的临床资料进行分析，采用心脏磁共振成像（CMR）和计算流体动力学（CFD）来量化TSS分布。将人心肌细胞置于静态（SF）、单向流（UF）或振荡流（OF）条件下培养以模拟TSS。建立大鼠PR模型以评估4至12周内右心室重构情况。通过蛋白质印迹法、酶联免疫吸附测定法（ELISA）和组织学评估NLRP3表达、细胞因子释放和纤维化情况。
CFD显示，与流入区域和心尖区域相比，RVOT中的湍流动能（TKE）和TSS升高（P = 0.001）。OF（15 dyn/cm）激活心肌细胞中的NLRP3炎性小体，使NLRP3增加（10倍，P = 0.01）和半胱天冬酶 - 1增加（4倍，P = 0.012），与SF相比，IL - 1β水平升高（775.1±9.4对658.4±19.6 pg/ml，P = 0.03）和IL - 18水平升高（1264.8±10.7对1038.6±18.8 pg/ml，P = 0.022）。PR诱导右心室逐渐扩张（右心室舒张末期容积指数：7.4±0.4 - 10.8±0.6 ml/m²，P < 0.01）并降低纵向应变（45.6±2.5 - 19.1±0.5 s，P < 0.01），且RVOT中NLRP3表达占主导（12周时：0.07±0.02对对照组的0.005±0.001，P < 0.001）和纤维化（33.9±4.8%对对照组的12.8±3.2%，P < 0.01）。
PR在RVOT中诱导的TSS激活心肌细胞中的NLRP3炎性小体，引发炎症和纤维化，导致局部右心室功能障碍。量化TSS可作为亚临床右心室损伤的早期生物标志物，而靶向NLRP3信号通路可为减轻PR患者的纤维化提供治疗策略。
