Division of Cardiothoracic Surgery, Department of Surgery (S.R.E., C.B.L., J.M.O., R.K.P., A.D.R., R.E.S., R.M., J.S.I., J.A.J.) and Division of Cardiology, Department of Medicine (W.B.W.), Medical University of South Carolina, Charleston, SC; Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC (J.A.J.); and Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, and Wm. Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, SC (F.G.S.).
Circulation. 2013 Sep 10;128(11 Suppl 1):S186-93. doi: 10.1161/CIRCULATIONAHA.112.000363.
Thoracic aortic aneurysms (TAAs) develop secondary to abnormal aortic extracellular matrix remodeling, resulting in a weakened and dilated aortic wall that progressed to rupture if left unattended. Currently, no diagnostic/prognostic tests are available for the detection of TAA disease. This is largely driven by the lack of a large animal model, which would permit longitudinal/mechanistic studies. Accordingly, the objective of the present study was to establish a reproducible porcine model of aortic dilatation, which recapitulates the structural and biochemical changes observed during human TAA development.
Descending TAAs were induced in Yorkshire pigs (20-25 kg; n=7) through intra-adventitial injections of collagenase (5 mL, 0.35 mg/mL) and periadventitial application of crystalline CaCl2 (0.5 g). Three weeks after TAA induction, aortas were harvested and tissue was collected for biochemical and histological measurements. A subset of animals underwent MRI preoperatively and at terminal surgery. Results were compared with sham-operated controls (n=6). Three weeks after TAA induction, aortic luminal area increased by 38 ± 13% (P=0.018 versus control). Aortic structural changes included elastic lamellar degradation and decreased collagen content. The protein abundance of matrix metalloproteinases 3, 8, 9, and 12 increased in TAA tissue homogenates, whereas tissue inhibitors of metalloproteinases 1 and 4 decreased.
These data demonstrate aortic dilatation, aortic medial degeneration, and alterations in matrix metalloproteinase/tissue inhibitors of metalloproteinase abundance, consistent with TAA formation. This study establishes for the first time a large animal model of TAA that recapitulates the hallmarks of human disease and provides a reproducible test bed for examining diagnostic, prognostic, and therapeutic strategies.
胸主动脉瘤（TAAs）是由于主动脉细胞外基质重塑异常而发展的，导致主动脉壁变弱和扩张，如果不加以治疗，会进展为破裂。目前，尚无用于检测 TAA 疾病的诊断/预后测试。这主要是由于缺乏大型动物模型，而该模型将允许进行纵向/机制研究。因此，本研究的目的是建立一种可重现的猪主动脉扩张模型，该模型可重现人类 TAA 发展过程中观察到的结构和生化变化。
通过向胶原酶（5 毫升，0.35 毫克/毫升）的内膜下注射和结晶氯化钙（0.5 克）的外膜下应用，在约克夏猪（20-25 公斤；n=7）中诱导降主动脉瘤。TAA 诱导后 3 周，收获主动脉并采集组织进行生化和组织学测量。一部分动物在术前和终末期手术进行 MRI。结果与假手术对照组（n=6）进行比较。TAA 诱导后 3 周，主动脉管腔面积增加了 38±13%（P=0.018 与对照组相比）。主动脉结构变化包括弹性层降解和胶原蛋白含量减少。TAA 组织匀浆中基质金属蛋白酶 3、8、9 和 12 的蛋白丰度增加，而金属蛋白酶组织抑制剂 1 和 4 减少。
这些数据表明，主动脉扩张、主动脉中层退化以及基质金属蛋白酶/金属蛋白酶组织抑制剂丰度的改变与 TAA 的形成一致。本研究首次建立了一种可重现的大型动物 TAA 模型，该模型可重现人类疾病的特征，并为检查诊断、预后和治疗策略提供了一个可重复的测试平台。
