Raaz Uwe, Zöllner Alexander M, Schellinger Isabel N, Toh Ryuji, Nakagami Futoshi, Brandt Moritz, Emrich Fabian C, Kayama Yosuke, Eken Suzanne, Adam Matti, Maegdefessel Lars, Hertel Thomas, Deng Alicia, Jagger Ann, Buerke Michael, Dalman Ronald L, Spin Joshua M, Kuhl Ellen, Tsao Philip S
From Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (U.R., I.N.S., R.T., F.N., Y.K., M.A., A.D., A.J., J.MS., P.S.T.); Cardiovascular Institute, Stanford University School of Medicine, CA (U.R., A.M.Z., F.N., M.B., F.C.E., Y.K., M.A., R.L.D., J.M.S., P.S.T.); VA Palo Alto Health Care System, CA (U.R., I.N.S., Y.K., M.A., A.D., A.J., J.M.S., P.S.T.); Department of Mechanical Engineering, Stanford University School of Medicine, CA (A.M.Z., E.K.); Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA (F.C.E., E.K.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (S.E., L.M.); Center for Vascular Medicine, Zwickau, Germany (T.H.); Division of Cardiovascular Medicine and Intensive Care Medicine, Saint Mary's Hospital, Siegen, Germany (M.B.); Division of Vascular Surgery, Stanford University School of Medicine, CA (R.L.D.); and Department of Bioengineering, Stanford University School of Medicine, CA (E.K.).
Circulation. 2015 May 19;131(20):1783-95. doi: 10.1161/CIRCULATIONAHA.114.012377. Epub 2015 Apr 22.
Stiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined.
Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening precedes aneurysm growth. Finite-element analysis reveals that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) wall stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent aortic segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with the reduced segmental stiffness of the AAA-prone aorta (attributable to equalized stiffness in adjacent segments), reduced axial wall stress, decreased production of reactive oxygen species, attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, and attenuated apoptosis within the aortic wall, as well. Cyclic pressurization of segmentally stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening.
The present study introduces the novel concept of segmental aortic stiffening as an early pathomechanism generating aortic wall stress and triggering aneurysmal growth, thereby delineating potential underlying molecular mechanisms and therapeutic targets. In addition, monitoring segmental aortic stiffening may aid the identification of patients at risk for AAA.
主动脉壁硬化是在衰老过程以及腹主动脉瘤（AAA）中一直观察到的现象。然而，其在AAA病理生理学中的作用在很大程度上尚不清楚。
使用已建立的小鼠弹性蛋白酶诱导的AAA模型，我们证明节段性主动脉硬化先于动脉瘤生长。有限元分析表明，易发生动脉瘤的主动脉节段的早期硬化会导致由相邻更顺应性的壁节段的周期性（收缩期）束缚产生的轴向（纵向）壁应力。对AAA相邻主动脉节段进行介入性硬化（通过外部应用手术粘合剂）可显著减少动脉瘤生长。这些变化与易发生AAA的主动脉节段的节段性硬度降低（归因于相邻节段的硬度均衡）、轴向壁应力降低、活性氧产生减少、弹性蛋白分解减弱、炎性细胞因子表达降低和巨噬细胞浸润减少以及主动脉壁内凋亡减弱相关。离体对节段性硬化的主动脉节段进行周期性加压会增加与炎症和细胞外基质重塑相关的基因表达。最后，人体超声研究表明，衰老作为AAA的一个重要危险因素，伴有肾下腹主动脉节段性硬化。
本研究引入了节段性主动脉硬化这一新概念，作为产生主动脉壁应力并触发动脉瘤生长的早期发病机制，从而阐明了潜在的分子机制和治疗靶点。此外，监测节段性主动脉硬化可能有助于识别有AAA风险的患者。
