Freiholtz David, Reyes-Goya Claudia, Lång Karin, Bergman Otto, Olsson Christian, Granbom Koski Malin, Dismorr Michael, Österholm Cecilia, Caidahl Kenneth, Franco-Cereceda Anders, Eriksson Per, Gisterå Anton, Björck Hanna M
Division of Cardiology, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital, Solna, Sweden (D.F., C.R.-G., K.L., O.B., P.E., H.M.B.).
Section of Cardiothoracic Surgery, Department of Molecular Medicine and Surgery , Karolinska Institutet, Stockholm, Karolinska University Hospital, Solna, Sweden (C.O., M.G.K., M.D., A.F.-C.).
Arterioscler Thromb Vasc Biol. 2025 Sep;45(9):1636-1647. doi: 10.1161/ATVBAHA.125.323112. Epub 2025 Jul 31.
An abnormal accumulation of immune cells and inflammation has been described in ascending aortic aneurysm, but the factor driving disease initiation remains elusive. Interestingly, ascending aortic dilatation often occurs alongside aortic regurgitation but rarely with aortic stenosis. We sought to investigate ascending aortic aneurysm initiation by assessing the relation between aortic regurgitation and vascular activation and inflammation.
In this prospective cohort study, patients with tricuspid aortic valves undergoing elective open-heart surgery were included. Aortic specimens from organ donors were obtained through the University of Miami Tissue Bank. Spatial transcriptomics measured gene expression in nondilated aortic endothelium, intima, and subintima. Immunohistochemistry determined protein expression. Aortic dimensions were recorded preoperatively and 10 years after surgery using echocardiography. Aortic gene expression affected by physiological blood flow was previously measured in Wistar rats.
We show a mesenchymal activation of endothelial cells, possibly mediated by bidirectional flow, in the nondilated ascending aorta of patients with aortic regurgitation, accompanied by intimal infiltration, retention, and oxidation of apoB-containing lipoproteins. We further observed intimal upregulation of genes coding for core proteins of lipoprotein-binding proteoglycans and the (oxidized low-density lipoprotein receptor 1), the latter by infiltrating macrophages and in association with progressive inflammation and dilatation. None of the above was observed in patients with aortic stenosis. Notably, surgical replacement of regurgitant valves, but not stenotic valves, mitigated 10-year aortic growth.
Our results highlight a distinct pathological role of aortic regurgitation in ascending aortic aneurysm formation by promoting mesenchymal activation of endothelial cells and lipoprotein-related immune cell infiltration and inflammation in patients with tricuspid aortic valves. We also provide novel insights into the long-term impact of surgical aortic valve replacement on ascending aortic growth and suggest a diagnostic or therapeutic target in oxidized low-density lipoprotein cholesterol.
升主动脉瘤中存在免疫细胞异常聚集和炎症反应，但疾病起始的驱动因素仍不明确。有趣的是，升主动脉扩张常与主动脉反流同时发生，但很少与主动脉狭窄同时出现。我们试图通过评估主动脉反流与血管激活及炎症之间的关系来研究升主动脉瘤的起始。
在这项前瞻性队列研究中，纳入了接受择期心脏直视手术的三尖瓣主动脉瓣患者。通过迈阿密大学组织库获取器官捐献者的主动脉标本。空间转录组学测量非扩张主动脉内皮、内膜和内膜下的基因表达。免疫组织化学测定蛋白质表达。术前和术后10年使用超声心动图记录主动脉尺寸。先前在Wistar大鼠中测量了受生理血流影响的主动脉基因表达。
我们发现，在主动脉反流患者的非扩张升主动脉中，内皮细胞存在间充质激活，可能由双向血流介导，同时伴有内膜浸润、含载脂蛋白B的脂蛋白滞留和氧化。我们进一步观察到，编码脂蛋白结合蛋白聚糖核心蛋白的基因以及（氧化低密度脂蛋白受体1）在内膜上调，后者由浸润的巨噬细胞引起，并与进行性炎症和扩张相关。在主动脉狭窄患者中未观察到上述任何情况。值得注意的是，手术置换反流瓣膜而非狭窄瓣膜可减轻10年的主动脉生长。
我们的结果突出了主动脉反流在升主动脉瘤形成中的独特病理作用，即通过促进三尖瓣主动脉瓣患者内皮细胞的间充质激活以及脂蛋白相关免疫细胞浸润和炎症反应。我们还为外科主动脉瓣置换对升主动脉生长的长期影响提供了新见解，并提出了氧化低密度脂蛋白胆固醇的诊断或治疗靶点。
