{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T15:11:12Z","timestamp":1779894672015,"version":"3.53.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u201312 weeks. NLRP3 expression, cytokine release, and fibrosis were evaluated via western blot, ELISA, and histology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CFD revealed elevated turbulent kinetic energy (TKE) and TSS in the RVOT compared to inflow and apical regions (<jats:italic>P<\/jats:italic>\u2009=\u20090.001). <jats:italic>in vitro<\/jats:italic>, OF (15\u2005dyn\/cm<jats:sup>2<\/jats:sup>) activated NLRP3 inflammasome in cardiomyocytes, increasing NLRP3 (10-fold, <jats:italic>P<\/jats:italic>\u2009=\u20090.01) and caspase-1 (4-fold, <jats:italic>P<\/jats:italic>\u2009=\u20090.012), and elevating IL-1\u03b2 (775.1\u2009\u00b1\u20099.4 vs. 658.4\u2009\u00b1\u200919.6\u2005pg\/ml, <jats:italic>P<\/jats:italic>\u2009=\u20090.03) and IL-18 (1,264.8\u2009\u00b1\u200910.7 vs. 1,038.6\u2009\u00b1\u200918.8\u2005pg\/ml, <jats:italic>P<\/jats:italic>\u2009=\u20090.022) levels compared to SF. <jats:italic>in vivo<\/jats:italic>, PR induced progressive RV dilation (RVEDVi: 7.4\u2009\u00b1\u20090.4\u201310.8\u2009\u00b1\u20090.6\u2005ml\/m<jats:sup>2<\/jats:sup>, <jats:italic>P<\/jats:italic>\u2009&amp;lt;\u20090.01) and reduced longitudinal strain (45.6\u2009\u00b1\u20092.5\u201319.1\u2009\u00b1\u20090.5\u2005s<jats:sup>\u22121<\/jats:sup>, <jats:italic>P<\/jats:italic>\u2009&amp;lt;\u20090.01), and RVOT-predominant NLRP3 expression (12 weeks: 0.07\u2009\u00b1\u20090.02 vs. 0.005\u2009\u00b1\u20090.001 in controls, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001) and fibrosis (33.9\u2009\u00b1\u20094.8% vs. 12.8\u2009\u00b1\u20093.2% in control, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2025.1546581","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:46:19Z","timestamp":1746186379000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["NLRP3 inflammasome activation by turbulent shear stress drives right ventricular outflow tract fibrosis in pulmonary 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