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系統識別號 U0026-3011201616561300
論文名稱(中文) 肺高壓功能預後及生物指標的建立-關於改良REVEAL預測模型及內皮前體細胞
論文名稱(英文) Developments of functional prognostic and biomolecular markers for pulmonary hypertension: the modified REVEAL score and circulating endothelial progenitor cells
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 105
學期 1
出版年 105
研究生(中文) 許志新
研究生(英文) Chih-Hsin Hsu
學號 S98961026
學位類別 博士
語文別 英文
論文頁數 112頁
口試委員 指導教授-陳志鴻
召集委員-蔡惟全
口試委員-林真福
口試委員-劉秉彥
口試委員-蔡曜聲
口試委員-王主科
口試委員-傅懋洋
中文關鍵字 肺高壓  預測模型  實驗模型 
英文關鍵字 pulmonary hypertension  predictive model  experimental models 
學科別分類
中文摘要 肺高壓是一個持續進展而且會導致右心衰竭及死亡的疾病。即使近年來藥物已有進展,但預後進步仍然有限。面對肺高壓,最大的問題就是不佳的預後及不明的機轉。建立一個預後預測模型更精細的調整治療方針及建立實驗模型以供進一步的研究致病機轉及新治療都是相當重要的。
在實驗模型方面,我們特別聚焦在探討肺循環在減少多餘血流後功能及細胞上的改變。我們以心房中膈缺損造成肺高壓的病人為研究對象探討阻斷左至右分流帶來的改變。我們的研究結果顯示肺血管壓力,右心大小及生活效能在阻斷左至右分流之後都獲得改善。我們也成功的利用老鼠做出了一個左至右分流的肺高壓模型,並以此模型探討在血流恢復正常後肺血管和右心的變化。我們的研究結果顯示已經因肺高壓而重塑的肺血管和右心在血流恢復正常後有恢復的現象。我們同時在肺血管的血管張力上看到同樣的變化,從我們的研究結果發現此逆行可能與血管平滑肌的分化及部分發炎因子有相關。在預測模型方面,我們將現有REVEAL模型中的六分鐘行走距離以更普及的運動心電圖取代,並重新評估其效度。我們的結果發現使用運動心電圖在REVEAL模型能得到很好的預測效果。我們的研究結果使得大部分的醫院都能更普及而準確地使用預測模型。
根據我們的研究結果,我們得知逆轉肺高壓的疾病進展是大有可為的。令人振奮的是,我們也發現內皮前驅細胞的功能性同時增強,並與生活效能呈現正相關。我們認為內皮前體細胞在肺血管的重塑上扮演了重要角色。我們一方面在臨床上積極地依照預測模式調整治療方針並積極控制水分,改善病人的預後。一方面同時運用我們已建立的實驗模型繼續探討讓疾病逆轉的關鍵因子。
英文摘要 Pulmonary hypertension is a progressive disease and leading to right heart failure and death. Although newer treatments for pulmonary arterial hypertension have emerged, only modest functional improvement with minimal change in hemodynamic measurements have been achieved. Based on the current knowledge of PAH, the major problem is the poor prognosis and unclear mechanism. Established an adequate predictive model to adjust treatment strategy and an experimental model for deeper understanding of mechanism and new therapies are important.
In experimental models, I focus on the functional and molecular remodeling in pulmonary circulation following cessation of excessive pulmonary flow. We enrolled patients with pulmonary hypertension related to congenital left to right shunt to evaluate dynamic change following cessation of excessive flow. We demonstrated that hemodynamic, right ventricular function and daily performance improve following volume reduction. I also create an A-V fistula rat model demonstrated that normalization of pulmonary blood flow in subjects with flow-induced pulmonary hypertension reverses the remodeling in the right ventricle and pulmonary arterial circulation, and potentiates the vascular reactivity of pulmonary artery. The remodeling process of flow-induced pulmonary hypertension is most likely reversible and these changes are closely related to differentiation and switching of vascular smooth muscle cells in the pulmonary artery and modulation of tissue inflammatory cytokines. In predictive model, my study reassessed the predictive power of the REVEAL prognostic equation using exercise treadmill test in place of six-minute walk distance. The predictive power of the equation improved and supports exercise treadmill test for predicting survival in PAH using the REVEAL risk calculator. The study allows centers to utilize exercise treadmill test in place of the six-minute walk distance allow better prognostic information for their patients.
From our results, we believe that the regression of remodeling caused by pulmonary hypertension is possible. Another novel finding of this study is that qualitative enhancement of colony formation in the circulating EPCs and simultaneous and positively correlated with the patients’ daily performance. Molecular and functional changes of endothelial progenitor cells may play an important role for pulmonary artery remodeling. We adjust treatment strategy according to predictive model and aggressively control volume status in daily practice and critical care leading to improve patient’s outcome. At the same time, deeper investigation to obtain a deeper understanding of the mechanism of remodeling regression is ongoing with our experimental models.
論文目次 Chapter 1. Introduction 1
1.1 Overview of pulmonary arterial hypertension 1
1.1.1 Definition and classification of pulmonary hypertension 1
1.1.2 Pathophysiology of pulmonary arterial hypertension 3
1.1.3 Epidemiology of pulmonary arterial hypertension 7
1.1.4 Prognosis of pulmonary arterial hypertension 8
1.2 Update on management of pulmonary hypertension 9
1.2.1 Volume status and pulmonary hypertension 9
1.2.2 Current management of pulmonary arterial hypertension 11
1.2.3 Ongoing research of pulmonary arterial hypertension 15
1.3 Thesis Aims 16
1.4 Figures and Tables 18
Chapter 2. Physiological changes following flow reduction in patients with flow-induced pulmonary hypertension 22
2.1Backgrounds and Aims 22
2.2Methods 24
2.3 Results 28
2.4 Discussion 30
2.5 Figures and Tables 34
Chapter 3 Animal model of flow-induce pulmonary hypertension 41
3.1 Backgrounds and Aims 41
3.2 Methods 43
3.3 Results 47
3.4. Discussion 49
3.5 Figures 54
Chapter 4 Predictive model for pulmonary hypertension 61
4.1 Previous predictive equation and the REVEAL score 61
4.2 Modified REVEAL score with exercise treadmill test 63
4.2.1 Backgrouds and Aims 63
4.2.2 Methods 65
4.2.3 Results 68
4.2.4 Discussion 70
4.3 Figures and Tables 71
Chapter 5 Improvement in clinical practice. 75
5.1 Backgrounds and Aims 75
5.2 Method 76
5.2.1 Life modification 76
5.2.2. Treatment guideline 77
5.2.3 Critical care 78
5.3 Results 79
5.4 Figures 80
Chapter 6 General discussion, conclusion and prospects 84
6.1 Experimental findings 86
6.1.1 Changes following flow reduction in patients with flow-induced pulmonary hypertension 86
6.1.2 Animal model 87
6.1.3 Prognostic model 88
6.1.4 Clinical practice 89
6.2 Prospects 90
6.3 Figures 92
Bibliography 93
Publication lists 104
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