請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80427完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林彥宏(Yen-Hung Lin) | |
| dc.contributor.author | Yi-Yao Chang | en |
| dc.contributor.author | 張藝耀 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:06:27Z | - |
| dc.date.available | 2022-01-18 | |
| dc.date.available | 2022-11-24T03:06:27Z | - |
| dc.date.copyright | 2022-01-18 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-12-28 | |
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Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. The lancet. Diabetes endocrinology 2017 5:689-99. Williams TA, Monticone S, Schack VR, Stindl J, Burrello J, Buffolo F, Annaratone L, Castellano I, Beuschlein F, Reincke M, Lucatello B, Ronconi V, Fallo F, Bernini G, Maccario M, Giacchetti G, Veglio F, Warth R, Vilsen B, Mulatero P. Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosterone-producing adenomas. Hypertension 2014 63:188-95. Williams TA, Peitzsch M, Dietz AS, Dekkers T, Bidlingmaier M, Riester A, Treitl M, Rhayem Y, Beuschlein F, Lenders JW, Deinum J, Eisenhofer G, Reincke M. Genotype-Specific S……… | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80427 | - |
| dc.description.abstract | "原發性皮質醛酮症(primary aldosteronism, PA)是次發性高血壓疾病中最常見的，其致病機轉為腎上腺腫瘤或不正常增生而產生過量的皮質醛酮所致，盛行率約佔所有高血壓患者的 5-10%。單側皮質醛酮腺瘤(aldosterone producing adenoma; APA)是原發性皮質醛酮症的兩大主要亞型之一，此類型的病症可藉由切除腎上腺獲得痊癒。這些不正常產生的過量皮質醛酮會造成心臟結構的改變和傷害，包含左心室心肌肥厚、心肌纖維化、左心室舒張功能異常、以及血管硬化。在過去研究中，發現 PA 患者有相較於原發性高血壓(essential hypertension, EH)患者有較嚴重的左心室心肌肥厚、心肌纖維化以及較差的左心室舒張功能。而 APA 的發生在近年研究發現與體細胞突變發生相關，其中又以 KCNJ5 最常見，一旦突變會造成CYP11B2 基因過度活化使皮質醛酮合成酶(aldosterone synthase)的製造增加，進而造成皮質醛酮產出過剩而導致原發性皮質醛酮症。有 KCNJ5 突變的 APA 患者在亞洲(台灣、日本)有高達約 55-75%的 APA 病患有 KCNJ5 基因突變，但在西方國家則僅約 25-50%患者有突變，顯現 KCNJ5 基因突變在東西方族群有不同的臨床表徵。目前發現有 KCNJ5 體細胞突變患者較年輕，術前皮質醛酮濃度較高，術後血壓恢復正常的比例較多，但性別差異和腫瘤大小差異則在歐洲團隊的研究較顯著。 而 KCNJ5 突變對於心臟血管系統的影響過往僅有較零星的研究，對於左心室心肌肥厚的影響結果仍分歧，而對於心臟舒張功能以及開刀治療後血管硬度變化的研究更是稀少或無定論，其中可能的重要原因在於 KCNJ5 體基因有突變的患者年紀較輕且主要為女性，血壓亦有一定的差距，這些因素皆對心肌與血管的結構和功能有相當影響。因此本研究希望藉由較足夠的病患總量，藉由傾向分數匹配(propensity score matching)的統計方式，排除年紀、性別、以及血壓等干擾因子的影響，減少組間個案基本資料的落差，來探討 KCNJ5 突變對於心臟結構(心肌質量指數[LVMI，left ventricular mass index]，及不適當過度增加的左心室質量指數[ieLVMI，inappropriate excess LVMI])、左心室舒張功能(e’與 E/e’)、以及動脈血管硬度(baPWV，brachial-ankle pulse wave velocity)的影響，並追蹤其開刀一年後的變化。 在第一部分心臟結構與功能方面的研究，發現在年紀、性別、血壓嚴重程度作配對後，有 KCNJ5 突變的原發性皮質醛酮患者，其左心室質量指數(LVMI)仍較沒突變的患者高，且其增加的左心室心肌質量的組成中，不適當過度增加的左心室質量指數(ieLVMI，代表除血壓外其他因子所造成的左心室肥厚變化)，有KCNJ5 突變患者的 ieLVMI 仍顯著高於沒有突變的患者，顯示有突變的患者其較高的皮質醛酮濃度可能會造成除卻血壓影響外的左心室增厚，且 LVMI 和ieLVMI 與 KCNJ5 突變顯著相關。開刀後，有 KCNJ5 突變的患者其開刀前後的LVMI 以及 ieLVMI 均顯著下降，而 E/e’亦顯著下降，顯示舒張功能的改善；這些變化在沒有突變的患者均無顯著改變。而 LVMI 和 ieLVMI 的術後的降幅與KCNJ5 突變顯著相關。因此 KCNJ5 突變對皮質醛酮患者心臟結構和舒張功能及其術後恢復均具有顯著的影響。在第二部分血管功能方面的研究，發現在年紀、性別、血壓嚴重程度作配對後，有 KCNJ5 突變的原發性皮質醛酮患者，其baPWV 與沒有突變的患者無明顯差異，但開刀術後 baPWV 的降幅，有突變的患者顯著大於沒有突變的患者，且術後 baPWV 的降幅經年紀、性別、血壓嚴重度的校正後仍與 KCNJ5 突變顯著相關。因此 KCNJ5 突變對術後的血管硬度恢復有顯著影響。 高血壓影響心血管健康甚鉅，而原發性皮質醛酮症本身是一種可治癒的高血壓疾病，KCNJ5 體基因突變為單側皮質醛酮腺瘤在亞洲族群常見且重要的致病機轉，本研究結果有助於了解 KCNJ5 突變在原發性皮質醛酮症患者中對心臟結構、舒張功能、以及血管硬度的影響。 " | zh_TW |
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| dc.description.tableofcontents | 口試委員審定書 i 誌謝 ................................................................................................................................... ii 中文摘要 ......................................................................................................................... iii 英文摘要 .......................................................................................................................... v 目錄 ............................................................................................................................... viii 表目錄 ............................................................................................................................ xii 圖目錄 ........................................................................................................................... xiv 第一章 緒論 ..................................................................................................................... 1 1-1 高血壓對心臟血管系統的影響 ................................................................................ 1 1-2 原發性皮質醛酮症文獻回顧 .................................................................................... 1 1-2.1 原發性皮質醛酮症病態生理機轉及亞型 ......................................................... 1 1-2.2 原發性皮質醛酮症流行病學 ............................................................................. 2 1-2.3 原發性皮質醛酮症診斷定義 ............................................................................. 2 1-2.4 原發性皮質醛酮症治療的發展 ......................................................................... 3 1-2.5 原發性皮質醛酮症對全身重要器官的傷害 ..................................................... 4 1-2.6 台灣原發性皮質醛酮研究團隊 ......................................................................... 4 1-3 原發性皮質醛酮症對心臟結構與功能的影響 ........................................................ 5 1-3.1 原發性皮質醛酮症與心肌肥厚 ......................................................................... 5 1-3.2 原發性皮質醛酮症與心肌纖維化的關係 ......................................................... 7 1-3.3 原發性皮質醛酮症與左心室舒張功能 ............................................................. 9 1-4 原發性皮質醛酮症對血管的影響 .......................................................................... 11 1-4.1 皮質醛酮影響動脈血管硬度 ........................................................................... 11 1-4.2 皮質醛酮影響血管舒張功能 ........................................................................... 13 1-5 體細胞突變在原發性皮質醛酮症的角色 .............................................................. 13 1-5.1 KCNJ5 和其他已知與原發性皮質醛酮症相關的體細胞突變 ...................... 13 1-5.2 KCNJ5 基因之定序與其突變 .......................................................................... 16 1-5.3 KCNJ5 體基因突變在皮質醛酮症病患心臟結構及舒張功能的角色 .......... 17 1-5.4 KCNJ5 體基因突變在皮質醛酮症病患血管彈性的角色 .............................. 19 1-6 研究假說和目的 ...................................................................................................... 19 1-6.1 研究目的 1: KCNJ5 體基因突變與心臟結構改變的關係 ............................. 20 1-6.2 研究目的 2: KCNJ5 體基因突變與心臟舒張功能改變的關係 ..................... 21 1-6.3 研究目的 3: KCNJ5 體基因突變與心臟結構改變的關係 ............................. 21 第二章 研究方法與材料 ............................................................................................... 23 2-1 心臟結構與功能 ...................................................................................................... 23 2-1.1 研究族群 ........................................................................................................... 23 2-1.2 實驗數據 ........................................................................................................... 24 2-1.3 心臟超音波、都普勒組織成像 ....................................................................... 24 2-1.4 單側皮質醛酮腺瘤的確認 ............................................................................... 25 2-1.5 腎上腺切除術 ................................................................................................... 26 2-1.6 組織病理學研究 ............................................................................................... 26 2-1.7 DNA 萃取與 KCNJ5 基因定序 ........................................................................ 26 2-1.8 統計分析 ........................................................................................................... 27 2-2 血管硬度 .................................................................................................................. 29 2-2.1 研究族群 ........................................................................................................... 29 2-2.2 實驗數據 ........................................................................................................... 29 2-2.3 肱-踝脈搏波速度測量...................................................................................... 29 2-2.4 單側皮質醛酮腺瘤的確認 ............................................................................... 30 2-2.5 腎上腺切除術 ................................................................................................... 30 2.2.6 組織病理學研究 ............................................................................................... 30 2-2.7 DNA 萃取與 KCNJ5 基因定序 ........................................................................ 30 2-2.8 統計分析 ........................................................................................................... 30 第三章 結果 ................................................................................................................... 32 3-1 心臟結構與功能 ...................................................................................................... 32 3-1.1 配對前與配對後病患臨床與生化數據 ........................................................... 32 3-1.2 配對前與配對後心臟超音波數據 ................................................................... 32 3-1.3 影響左心室質量指數與不適當過度增加的左心室質量指數的因子 ........... 33 3-1.4 腎上腺切除術後心臟超音波數據的改善 ....................................................... 33 3-1.5 影響術後左心室質量指數改變量與不適當過度增加的左心室質量指數改變 量的因子 .................................................................................................................... 35 3-2 血管硬度 .................................................................................................................. 37 3-2.1 配對前與配對後病患臨床與生化數據 ........................................................... 37 3-2.2 配對前與配對後肱-踝脈搏波速度.................................................................. 37 3-2.3 配對前與配對後，腎上腺切除術後臨床數據與脈搏波速度變化 ............... 38 3-2.4 配對前臨床數據與脈搏波速數據開刀前後成對比較 ................................... 38 3-2.5 配對後臨床數據與脈搏波速數據開刀前後成對比較 ................................... 39 3-2.6 配對前與配對後，KCNJ5 體細胞突變與術前脈搏波速與脈搏波速術後變 化量之關聯性 ............................................................................................................ 39 第四章 討論 ................................................................................................................... 41 4-1 心臟結構與功能 ...................................................................................................... 41 4-1.1 研究結果討論及限制 ....................................................................................... 41 4-1.2 研究結論 ........................................................................................................... 48 4-2 血管硬度 .................................................................................................................. 50 4-2.1 研究結果討論及限制 ....................................................................................... 50 4-1.2 研究結論 ........................................................................................................... 54 第五章 展望 ................................................................................................................... 56 5-1 本研究對於原發性皮質醛酮症預後的重要性 ...................................................... 56 5-1.1 KCNJ5 體基因突變的皮質醛酮症患者心臟結構與功能改變甚鉅 .............. 56 5-1.2 KCNJ5 體基因突變的患者術後心臟結構與功能恢復顯著 .......................... 58 5-1.3 KCNJ5 體基因突變的患者術後血管功能恢復顯著 ...................................... 59 5-2 原發性皮質醛酮症術前體基因突變診斷的限制 .................................................. 61 5-3 未來研究的方向 ...................................................................................................... 63 5-3.1 利用類固醇指紋，提升術前診斷體基因突變可能性 ................................... 63 5-3.2 利用 CYP11B2 免疫組織化學染色與次世代定序法，探討其他體基因突變 之臨床表徵 ................................................................................................................ 64 5-3.3 比較 KCNJ5 與其他體基因突變的差異，進一步以動物模型探究其致病機 轉的不同 .................................................................................................................... 65 5-4 結語 .......................................................................................................................... 66 第六章 論文英文簡述 ................................................................................................... 67 參考文獻 ........................................................................................................................ 80 附表 ................................................................................................................................ 95 附圖 .............................................................................................................................. 130 附錄：博士班修業期間所發表之相關論文 .............................................................. 144 | |
| dc.language.iso | zh-TW | |
| dc.subject | 血管硬度 | zh_TW |
| dc.subject | 原發性皮質醛酮症 | zh_TW |
| dc.subject | 皮質醛酮 | zh_TW |
| dc.subject | KCNJ5 體基因突變 | zh_TW |
| dc.subject | 左心室肥大 | zh_TW |
| dc.subject | 左心室舒張功能 | zh_TW |
| dc.subject | KCNJ5 somatic mutation | en |
| dc.subject | pulse wave velocity | en |
| dc.subject | left ventricular diastolic function | en |
| dc.subject | left ventricular hypertrophy | en |
| dc.subject | primary aldosteronism | en |
| dc.subject | aldosterone | en |
| dc.title | KCNJ5體細胞突變在原發性皮質醛酮症單側腺瘤患者的心臟血管系統結構與功能的角色 | zh_TW |
| dc.title | The association between KCNJ5 somatic mutations and cardiovascular structure and functions in aldosterone-producing adenoma | en |
| dc.date.schoolyear | 110-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.author-orcid | 0000-0002-9148-8667 | |
| dc.contributor.advisor-orcid | 林彥宏(0000-0001-8153-1441) | |
| dc.contributor.coadvisor | 劉力瑜(Li-yu Liu),(Yung-Chih Lien) | |
| dc.contributor.coadvisor-orcid | 劉力瑜(0000-0001-6997-8101) | |
| dc.contributor.oralexamcommittee | 楊偉勛(Hsin-Tsai Liu),吳彥雯(Chih-Yang Tseng),鄭浩民 | |
| dc.subject.keyword | 原發性皮質醛酮症,皮質醛酮,KCNJ5 體基因突變,左心室肥大,左心室舒張功能,血管硬度, | zh_TW |
| dc.subject.keyword | primary aldosteronism,aldosterone,KCNJ5 somatic mutation,left ventricular hypertrophy,left ventricular diastolic function,pulse wave velocity, | en |
| dc.relation.page | 144 | |
| dc.identifier.doi | 10.6342/NTU202104574 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-12-28 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床醫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-2412202116414800.pdf 授權僅限NTU校內IP使用（校園外請利用VPN校外連線服務） | 3.64 MB | Adobe PDF |
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