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研究生:林堯彬
研究生(外文):Yao-Ping Lin
論文名稱:腎功能不全時的心臟血管結構功能變化
論文名稱(外文):Cardiovascular Structure and Functional Changes in Renal Insufficiency
指導教授:陳震寰陳震寰引用關係林照雄林照雄引用關係施俊哲施俊哲引用關係
指導教授(外文):Chen-Huan ChenChao-Hsiung LinChun-Che Shih
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:124
中文關鍵詞:腎臟功能不全心臟血管疾病
外文關鍵詞:renal dysfunctioncardiovascular disease
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台灣的尿毒症接受透析患者高居世界第一,而慢性腎功能不全患者的盛行率也達到11.93%。心臟血管疾病是尿毒症患者的最大死因。根據對於血液透析患者的臨床觀察研究,我們發現尿毒症患者左心室肥厚的決定因子與正常人的左心室肥厚有所不同。我們亦發現即使病患已接受良好的透析治療,達到乾體重而不需再服用抗高血壓藥物,仍存在著全身體液多於正常人以及潛在的左心室功能異常。據此可推斷尿毒症的心臟病變除了一般咸信的血壓與體液容積造成的血流動力刺激外,尚存有不同的致病機轉。根據生理阻抗測量血液透析患者的身體組成,我們發現(細胞外水份/細胞內水分)的比值和動脈血管的結構與功能息息相關。(細胞外水份/細胞內水分)比值增加時,臨床意義可能為體液過多堆積,亦有可能代表營養不良。根據正常人生理阻抗測量,我們作出各年齡層細胞外水份、細胞內水分以及細胞外水份/細胞內水分比值的分布區間,據此可提供血液透析患者調整乾體重的基準。尿毒症患者的心臟血管結構與功能有類似老化現象所產生的變化,即動脈粥樣硬化、動脈內徑變大、左心室變厚、變大以及硬化,收縮及舒張功能異常,我們發現此老化現象增強了血壓對左心室容積的敏感性,減少了對缺氧環境的耐受度。在以血管收縮激素轉化酶 ramipril 進行為期一年的雙盲臨床藥物試驗中,我們意外地發現ramipril並不能改善已達正常血壓透析患者的心臟結構及功能的異常。在針對正常血壓透析患者為期34.8±19.4個月的追蹤研究,我們觀察到5.2%的年死亡率以及2.4%的年心臟血管死亡率;而心臟質量是決定病患預後最重要的因素。
經由研究血液透析患者的血漿蛋白質體表現,我們觀察到相較於短期血液透患者,長期透析患者異常表現的蛋白與下列的生物路徑有關,如動脈粥樣硬化加速、抗過氧化能力不足、發炎反應增加以及器官功能缺乏等。在62位透析患者為期2年的追蹤觀察,我們發現血漿中較低的 Vitamin D binding protein 及較高 Clusterin的患者預後較差。
為確實了解腎功能不全時心臟血管病變的機轉,而不侷限在末期腎臟衰竭的觀察,我們建立了腎臟部份切除 (subtotal nephrectomy) 的老鼠腎臟功能不全模式。利用二維電泳及質譜分析,配合先進生物資訊研究以及心臟血管生理訊號記錄,詳盡地探討在腎臟功能不全時動脈血管蛋白質體的表現。我們發現相較於正常腎臟功能大鼠,腎臟功能不全時動脈有異常表現下列蛋白: 如chaperons, cytoskeleton/contractile apparatus, extracellular matrix, oxidative stress, inorganic ion transport and metabolism, lipid transport and metabolism等。據此資料,將有助於釐清尿毒症心臟血管病變的分子生物致病機轉,而便於進一步進行治療性介入。
There is roaring prevalence of chronic renal dysfunction world widely. The national prevalence of chronic kidney disease already reached 11.93% in Taiwan. Cardiovascular disease is the main culprit of morbidity and mortality in the renal dysfunction patients. We adopted both clinical and bench approaches to explore this phenomenon.
Clinically, we incorporate echocardiography, bioimpedance and vascular function assessment techniques as research tools to study the hemodialysis (HD) patients. We observed effective reduction of pressure and volume overload by optimal HD alone may only partially improve the changes of the cardiac and vascular structure caused by hemodynamic overload. However, there is still persistent flow overload and sub-clinical LV dysfunction in these normotensive HD patients. The ECF/ICF derived from bioimpedance could reflect the extracellular volume and nutritional status and is the major determinant of large artery structure and function in HD patients. We also noted the enhanced volume sensitivity of BP in HD patients is due partly to the coupled systolic-ventricular and vascular stiffening in these patients. In the one year randomized control trial, we showed that in normotensive long-term HD patients, the angiotensin converting enzyme inhibitor ramipril, 1.25 to 2.5 mg three times per week did not render significant regression in LVH. We speculated that the renin-angiotensin system might plays little role in this population and a multi-discipline approach should be adopted to alleviate the cardiovascular phenotypes. In the longitudinal follow up of 34.8±19.4 months in our normotensive HD patients, we observed annual all-cause mortality of 5.2% and cardiovascular mortality of 2.4%, and the cardiac factor-left ventricular mass index is the most important determinant in predicting the prognosis.
By harnessing the power of proteomics, we studied the plasma proteome in the hemodialysis patients. The plasma protein alterations alongside HD duration are related to the signaling moieties of accelerated atherosclerosis, defective anti-oxidative activity, increased inflammation/infection and organ dysfunction. In a two-year prospective study in another group of prevalent HD patients (n=62) further highlights lower DBP and higher clusterin levels in plasma could predict prognosis in HD patients.
We established the subtotal nephrectomy rat animal model to simulate the different stages of chronic renal insufficiency. By combining two-dimensional gel electrophoresis, mass spectroscopy, bioinformatics and comprehensive hemodynamic assessment, we explored the global proteomics profile of aorta in renal insufficiency. We have identified the substantially altered aortic proteins related to chaperons, cytoskeleton/contractile apparatus, extracellular matrix, oxidative stress, inorganic ion transport and metabolism, lipid transport and metabolism, etc. We believe this result study will better facilitate the delineation of pathogenesis of uremic cardiovascular pathology and make possible further interventional therapy.
English Abstract 7
Chinese Abstract 9
List of Abbreviations 11
Introduction 13
Can hemodialysis fully reverse cardiovascular structural and functional derangements in ESRD patients? 13
What is the major determinant of arterial function in ESRD patients? 14
Why ESRD patients have hypertension? 15
Can we modify the cardiovascular derangements in ESRD patients already optimally dialyzed? 17
What is the predictor for cardiovascular mortality in normotensive hemodialysis patients? 17
Why some ESRD patients survived longer? 18
What is the molecular signature of cardiovascular derangement in renal dysfunction? 19
Materials and Methods 21
Human studies 21
Study population 21
Hemodialysis procedures 21
Anthropometric and volume status measurements 22
Vascular structure and function 22
Left ventricular parameters 23
Uremia related modulators and laboratory evaluation 24
Statistical analysis 25
Preparation of plasma samples 26
Animal studies 26
Surgical techniques of subtotal nephrectomy 26
Comprehensive hemodynamic study 26
Measurements of BP and aortic PWV 27
2-DE of rat aorta 27
Mass spectrometry 28
Western blot 30
Functional classification 30
Analysis of the correlated pathways 31
Result 32
Left ventricular mass and hemodynamic overload in normotensive hemodialysis patients 32
The ECF/ICF ratio is associated with large-artery structure and function in hemodialysis patients 36
Volume status and blood pressure during long-term hemodialysis 39
Effect of ramipril on left ventricular mass in normotensive hemodialysis patients 41
Cardiac but not arterial factors are independent predictors for cardiovascular mortality in normotensive hemodialysis patients 43
Plasma proteome analysis in patients under chronic maintenance hemodialysis 44
Comparative proteomic analysis of rat aorta in a subtotal nephrectomy model 47
Discussion 49
Can hemodialysis fully reverse cardiovascular structural and functional derangements in ESRD patients? No 49
What is the major determinant of arterial function in ESRD patients? Extracellular fluid / intracellular fluid ratio 52
Why ESRD patients have hypertension? Cardiovascular stiffening is involved in BP responses to volume changes 52
Is it possible to modify the cardiovascular derangements in ESRD patients already optimally dialyzed? Differential cardiac and arterial effects by the ACEI Ramipril 53
What is the predictor for cardiovascular mortality in normotensive hemodialysis patients? The left ventricular mass index 54
Why some ESRD patients survived longer? Vitamin D and Clusterin might be the potential biomarkers 55
What is the molecular signature of cardiovascular derangement in renal dysfunction? 56
Conclusion 63
References 66
Figures and Tables 80
Figure 1. Relative importance of independent noncardiac structural variable 80
Figure 2. Scatter plots of ECF-ICF ratio versus large-artery structure and function 81
Figure 3. Distribution of the volume sensitivity index (Vinx) 82
Figure 4. Scatterplot showing regression between left ventricular end-systolic elastance (Ees) and volume sensitivity index (Vinx) 82
Figure 5. A representative 2D gel of plasma proteins from a long-term HD patient. 83
Figure 6. Protein alterations related to HD duration. 84
Figure 7. Receiver operating characteristic curves for Vitamin D binding protein/clusterin and mortality in HD patients. 85
Figure 8. Carotid and femoral pressure waveform recordings 86
Figure 9. Representative gels of aortic proteins of subtotal nephrectomized and sham operated rats. 87
Figure 10. Quantitation of aortic HSP27 and 14-3-3�� between SNX and SO rats. 88
Figure 11. Functional classification by KOG analysis of the identified differential proteins between subtotal nephrectomized and sham-operated rats. 89
Figure 12. Ingenuity pathway network 90
Table 1. Characteristics of normal controls and HD subjects 91
Table 2. Univariate relations of LVM with anthropometrical, cardiac and vascular indices in the normal controls and HD subjects 93
Table 3. Multiple regression models of LVM in each category of variables 95
Table 4. BIS-derived body fluid compartments parameters of the normal subjects and HD patients. 96
Table 5. Sex- and age-stratified descriptive values of BIS-derived ECF and ICF from the normal subjects and HD patients. 97
Table 6. Correlation coefficients between the body fluid compartments parameters and anthropometrical and hemodialysis parameters in the normal subjects and HD patients. 99
Table 7. Correlation coefficients between the body fluid compartment parameters and blood pressure and large artery structure and function parameters in the normal subjects and HD patients. 100
Table 8. Blood pressure measurements in patients with low and high observed volume sensitivity 101
Table 9. Cardiovascular structure and function variables in patients with low and high observed volume sensitivity 102
Table 10. Anthropometric and hydration variables in patients with low and high observed volume sensitivity 103
Table 11. Effects of ramipril treatment on cardiovascular structure and function 104
Table 12. Demographics and biochemistry of the studied hemodialysis population 105
Table 13. List of differentially expressed proteins in plasma of patients with different HD durations 106
Table 14. Comparison between the surviving and deceased HD patients in a prospective follow-up 107
Table 15. Characteristics of the subtotal nephrectomized and sham-operated rats 108
Table 16. Identification of differentially regulated proteins in the aorta of subtotal nephrectomized rats. 109
Table 17. Ingenuity pathway analysis of differentially regulated proteins in the aorta of subtotal nephrectomized rats 122
Publications 124
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