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系統識別號 U0026-1505201217511700
論文名稱(中文) 以窄化誘發腹主動脈瘤的豬隻動物模式
論文名稱(英文) Coarctation-induced Abdominal Aortic Aneurysm in a Porcine Model
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 100
學期 2
出版年 101
研究生(中文) 林寶彥
研究生(英文) Pao-Yen Lin
學號 S98911055
學位類別 博士
語文別 英文
論文頁數 119頁
口試委員 指導教授-楊友任
指導教授-吳華林
召集委員-江美治
口試委員-羅傳堯
口試委員-王水深
口試委員-陳英富
口試委員-陳玉怜
口試委員-王玠能
中文關鍵字 腹主動脈瘤  窄化  猪模式  脈動指數  血行動力壓力 
英文關鍵字 abdominal aortic aneurysm  coarctation  porcine model  pulsatility index  hemodynamic stress 
學科別分類
中文摘要 腹主動脈瘤好發於超過65 歲以上的老年人口,盛行率大約在百分之6到9之間,而該疾病潛在的危險就是破裂,一旦發生破裂,九成的病人將不治死亡。現今主動脈瘤的臨床治療,主要以外科手術或血管支架來防範及搶救巨型動脈瘤(﹥5.0公分)的破裂,因此主動脈瘤的徑度便成為為破裂風險的指標,通常大於5.5公分的主動脈瘤即被視為瀕破狀態而建議介入治療,然而介入治療並非真正有效的療法,統計顯示介入治療既不能降低主動脈瘤的死亡率,也無法減少相關之併發症,而欲發展有效的治療方式和策略,必先全盤了解腹主動脈瘤的致病機轉,但由手術中取得的檢體多屬末期動脈瘤,從而收集的資料並無法建構完整的疾病原貌,尤其是疾病前期的病態生理,所以建立一個擬似人類腹主動脈瘤的動物模式,當有助於病因的探討,也可供作新式療法研發的平台。
循環即是血液在血管內的動力表現,因此血流與血管會不斷的交互作用以維持循環的運轉和穩定的血行動力,若改變某一區段的血流型態,則該區段及下游的血管管壁會因亂流產生的血流應力而出現構造性代償反應,特別是主動脈中層的彈性纖維、膠原纖維甚至平滑肌細胞,因為血流應力作用的方向是多變而雜亂的,管壁因代償反應而形成的構造重整區域也隨之零散且分佈不均,但無論管壁幾何構造如何變異重整,最終目的都是要維護正常的血行動力,如果血流型態持續不正常,管壁的局部代償反應終究會演變成全面結構之不可逆性的崩解與中層的弱化,最後膨大成為動脈瘤。基此理論,我們提出了一個假說: 將腎動脈下方的腹主動脈長期窄化會誘導動脈瘤的形成,並利用蘭嶼迷你猪來建立以血管窄化誘導腹主動脈瘤的動物模式。我們將臨床上使用的人工血管(ePTFE Teflon),裁成0.8公分寬的長條帶,環繞包覆在介於腎動脈與總腸股動脈分叉處之間的腹主動脈以進行漏斗狀窄化,我們也同時建立了動脈窄化的量化指標-脈動指數pulsatility index (PI)來確認窄化的程度,脈動指數(PI)的計算是將最大流量減去最小流量所得的值再除以平均流量而得,當窄化後的PI值降至原先的三分之一時,我們定義為適中窄化(moderate coarctation) ,腹主動脈適中窄化四週、八週與十二週後,將之取下,並觀察血管形態、管壁組成和細胞激素等變化之情形。
在窄化手術後四週,窄化末端的主動脈即呈現外徑膨大現象,相較窄化前端腹主動脈之外徑,膨大比例均超過1.5倍,已達動脈瘤之定義,其後8週、12週外徑雖無明顯增大,但管壁變薄、彈性喪失,且相較於腎動脈上端的對照組,窄化後端動脈的內徑膨大更行顯著,絕大部分8週及12週窄化末端主動脈的內徑均超過腎動脈上端的主動脈內徑50%以上,證明8週後腹主動脈瘤確實已然發生。窄化8週後末端主動脈的組織染色結果也顯示典型的腹主動脈瘤特徵,包括血管內膜局部增厚、彈性膜密度降低、內彈性膜斷裂、血管中層平滑肌細胞數量減少、細胞肥厚及排列失序、血管中層細胞外基質以及外層彈性纖維與膠原纖維的再重塑等情形。當檢驗動脈瘤的管壁中公認與動脈壁彈性纖維代謝最有關的間質性金屬蛋白酶(MMP-9)和調控管壁構造重塑的細胞激素(Rho kinase)及其下游作用酶(ROCK)的表現與活性時,亦偵測到這些蛋白酶在管壁中都有明顯上升且伴隨主動脈瘤的進展更行升高,此外,因窄化而造成立即性的前後動脈段明顯壓力差、末端血流量及脈壓減少、PI值下降等異常血行動力現象,在經過四到八週的持續窄化後,除了末端血流量未恢復外,其餘血行動力參數都幾乎回歸到原先的基本值,血行動力的變化更進一步提供了吾人可利用流相改變誘發主動脈瘤的支持證據,所以由上述實驗的結果顯示,血管窄化確實可誘發腹主動脈瘤的發生。
英文摘要 Abdominal aortic aneurysm (AAA) occurs in 6~9% of the population over 65 years of age and is a life-threatening disease with the propensity of rupture. Once AAA ruptures, the mortality is up to 90%. To resolve this clinical problem, comprehensive understanding of the AAA pathophysiology is needed to facilitate the development of optimal therapeutic modalities and strategies. Up to date, the pathogenesis of AAA is not clearly understood. Moreover, the specimen obtained from end-stage AAAs during operation cannot provide a panoramic insight of aneurysmal degeneration. We, therefore, attempted to establish a large animal model simulating human degenerative AAA. Such an animal model is expected to be a versatile platform for both basic and translational researches.
Hemodynamics, presented as flow and pressure, evolve from the interaction between pulsatile blood flow and elastic vascular wall. Aorta functions as a modulator to maintain constant or stable hemodynamics. When flow pattern is changed by curving or branching, local aortic wall engages in structural reorganization to restore normal hemodynamics. If flow disturbance can not be lessened by the physiological compensation, prolonged regional hemodynamic stresses may induce aortic remodeling, either inward hyperplasia or outward dilatation, at the affected region and segment downstream. We hypothesized that prolonged coarctation of an infrarenal abdominal aorta segment leads to AAA formation. Taiwanese Lanyu mini pigs were used to establish such a coarctation-induced AAA animal model. Using an 8 mm-width ePTFE Teflon strip, funnel-shaped aortic coarctation was made by wrapping the infrarenal AA segment at apporximately 2 cm above the terminal aortic bifurcation. We have established decreases in pulsatility index (PI), which is calculated by dividing the difference between maximal and minimal flow rate with mean flow rate, to one third the inherent levels as a quantitative index of moderate aortic coarctation. Aorta was harvested at 4 weeks (4w), 8 weeks (8w), and 12 weeks (12w) post-coarctation to examine the changes of vascular morphology, medial composition and protease activity.
Between 4w and 12w post-coarctation, AAA was detected at the distal AA. The maximal outer diameter of distal AA segment was 1.5 times that of proximal AA segment. While the distal-to-proximal ratio of outer diameter didn’t increase further at 8w and 12w post-coarctation, true aneurysm formation was validated by the enlargement of inner lumen at the distal AA with over 50% dilatation compared to the lumen of the suprarenal AA. In addition, a thinner and less elastic wall characterized the dilated distal AA segment to be a degenerative AAA at 8w and 12w post-coarctation. Histological examination supported evolutionary medial degeneration during AAA formation. These features included intimal thickening, elastic lamellae fragmentation and loss, smooth muscle cell (SMC) decrease, hypertrophy and disarray, and collagen redistribution in the media after prolonged coarctation. Activation of MMP-9 markedly increased in the distal AA of the coarctation groups, particularly at 4w post-coarctation. The expression and activity of Rho-associated kinase, which was shown to be associated with AAA formation, in the aneurysm wall also markedly increased as AAA progressed. Hemodynamic changes strongly supported such a flow-mediated AAA model as a degenerative aneurysm.
Immediately after the coarctation, the amplitudes of pressure and flow pulse waves were diminished and significant proximal-to-distal AA pressure gradient was created with concomitant decrease in PI. However, pulse pressure and PI, but not flow rate, were restored to basal levels during AAA formation. These results indicated that we have successfully induced AAA formation through aortic coarctation.
論文目次 Chinese abstract…………………………………………………………………….1
English abstract…………………………………………………………………….4
Chapter One: Introduction..….………………………………………………………..7
1-1
Terminology and definition..….………………………………………………7
1-2
Impact of AAA on primary health care .….…………………………………..8
1-3
Risk factors related to AAA pathogenesis.….……………….….…………...11
1-4
Putative pathobiology of AAA.….……………….….………………………13
1-5
Significance of experimental animal models.….……………….….………..16
1-6
Rationale and hypothesis of the thesis.….……………….….………………18
1-7
Specific aims of this study.….……………….….…………………………...19
Chapter Two: Materials & Methods…………………………………….…………...20
2-1
Experimental animals.…………………….….……...………………………20
2-2
Anesthesia and aortic coarctation…………………….….……...…………...21
2-3
Quantitative characterization of aortic coarctation……………….…………24
2-4
Sacrifice and tissue collection and processing.………….…………………..27
2-5
Histological examination of the abdominal aorta……………….…………..28
2-6
Detecting smooth muscle density with immunohistochemistry……….…….34
2-7
Quantification.…………………….….……...………………………………35
2-8
Gelatin zymography.…………………….….……...………………………..35
2-9
Immunoblotting.…………………….….……...…………………………….39
2-10
Statistical analysis.…………………….….……...………………………….47
Chapter Three: Results……...….……………………………………………………48
3-1
Resistive hemodynamics appeared at the distal AA following moderate coarctation……...….………………………………………………………...48
3-2
Pulsatility index is superior to pressure changes for quantitative characterization of moderate coarctation…………………...……………….49
3-3
Moderate coarctation induced AAA formation in mini pigs.……………….50
3-4
Changes in elastic lamellae and collagen fibers during AAA formation……52
3-5
Smooth muscle cell density decreased during AAA formation.…………….53
3-6
MMP-2 and MMP-9 activities increased in coarctation-induced AAA……..54
3-7
Expression and activity of ROCK 1 & 2 increased during AAA formation...55
3-8
Reverse of pressure gradient and pulse pressure reflect aneurysmal remodeling in the distal AA……...….………………………………………56
Chapter Four: Discussion……………………………………………………………58
4-1
Coarctation induces a true degenerative aneurysm……...….……………….58
4-2
Decreased number of VSMCs with cellular hypertrophy indicates early stage aneurysmal degeneration…………………………………………………….60
4-3
Significant upregulation of MMP-9 activity at 4w post-coarctation suggests that MMP-9 may mediate the early progression of AAA….………..………62
4-4
Expression and activity of Rho kinase might be related to the remodeling of AA segments. ………………………………………………………...……..64
4-5
Flow-mediated hemodynamic stresses participate in AAA development.…..66
4-6
Pulsatility index provides a valid index for moderate coarctation of the abdominal aorta……………………………………………………………...69
4-7
Asymmetric inflow entry may promote AAA formation……………………71
Chapter Five: Conclusion……………………………………………………………73
Chapter Six: References…………………………………………………………...74
Chapter Seven: Figures & Tables……………………………………………………86
Figure 1…………………………..…………………………………………………86
Figure 2…………………………..…………………………………………………87
Figure 3…………………………..…………………………………………………88
Figure 4…………………………..…………………………………………………89
Figure 5…………………………..…………………………………………………90
Figure 6…………………………..…………………………………………………91
Figure 7…………………………..…………………………………………………92
Figure 8…………………………..…………………………………………………95
Figure 9…………………………..…………………………………………………96
Figure 10……………………………………………………………………….…...97
Figure 11……………………………………………………………………….…...98
Figure 12……………………………………………………………………….…...99
Figure 13……………………………………………………………………….….100
Figure 14……………………………………………………………………….….101
Figure 15……………………………………………………………………….….102
Figure 16……………………………………………………………………….….104
Figure 17……………………………………………………………………….….105
Figure 18……………………………………………………………………….….106
Figure 19……………………………………………………………………….….107
Table І...............…...................................................................................................108
Table П……………………………………………………………………….…...109
Table Ш...........…....................................................................................................110
Chapter Eight: Appendix…………………………………………………………...111
Appendix 1...............................................................................................…...........111
Appendix 2...............................................................................................…...........112
Appendix 3...............................................................................................…...........113
Appendix 4...............................................................................................…...........114
Appendix 5...............................................................................................…...........115
Appendix 6...............................................................................................…...........116
Appendix 7...............................................................................................…...........117
Appendix 8...............................................................................................…...........118
Publication.................................................................................................119
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