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標題: 病竇症候群相關疾病的基因學及臨床預測因子: 腎素血管收縮素系統在心血管疾病的影響
Genetic and clinical predictors of sick sinus syndrome associated diseases: impact of renin-angiotensin system on cardiovascular disorders
作者: 陳建佑
Chen, Jan-Yow
關鍵字: 病竇症候群
sick sinus syndrome
atrial flutter
aotic dissection
renin-angiotensin system
出版社: 生命科學系所
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摘要: 病竇症候群是一群因為竇房節功能異常引起的心律疾病,約占心臟節律器置放病人的50%;病理學上呈現的是竇房節及心房纖維化。家族性病竇症候群的產生被認為與離子通道的突變有關; 然而,有關非家族性病竇症候群的研究機轉卻很少。非家族性病竇症候群經常伴隨著心房撲動以及表現頻-緩脈症候群。右心房的下腔靜脈三尖瓣峽是一個位於心房產生迴旋迴路重要的緩慢傳導區;心房纖維化及肌纖維特別的排列方式被認為是和此區域傳導緩慢的機轉有關。相關的研究發現指出:心臟組織的纖維化可能與腎素–血管收縮素系統上升調控有關。因此,腎素–血管收縮素系統在心房撲動機轉上可能扮演著重要角色。心導管高頻燒灼手術阻斷下腔靜脈三尖瓣峽區的手術被認為是處理心房撲動的優先選擇方法,下腔靜脈三尖瓣峽區結構的變異被報告與高頻燒灼手術的困難有關。然而,與高頻燒灼手術的困難有關的詳細的結構變異預測因子尚未被明確的報告。我們使用經胸心臟超音波儀以評估下腔靜脈三尖瓣峽區的結構變異,發現峽區上歐氏脊的結構變異是心房撲動高頻燒灼手術困難的獨立預後因子。 本論文旨在利用基因學的研究方法來探討“非家族性病竇症候群的可能致病基因和病理機轉”。主要的研究發現為“血管收縮素原啟動子基因的多形性性狀可以調控血管收縮素原的表現,以及影響非家族性病竇症候群疾病的易感性”。 依據基因與疾病的關聯研究,我們發現腎素–血管收縮素系統和非家族性病竇症候群的疾病易感性有關。 除此之外,腎素–血管收縮素系統也曾被報告和其它的心血管疾病相關。 主動脈剝離是一種因主動脈內皮裂傷引起的可致命的心血管疾病。腎素–血管收縮素系統的上升調控曾被報告和主動脈剝離產生的機轉有關,另外主動脈剝離的臨床預後的預測因子也是非常重要的,然而,很少研究報告提出結論。我們運用電腦斷層影像來尋求主動脈剝離預後的解剖學預測因子, 發現主動脈剝離偽腔大小是主動脈剝離預後的獨立預後因子。 總而言之,非家族性病竇症候群的疾病易感性和腎素–血管收縮素系統的基因表現密切相關。我們的研究報告提供了非家族性病竇症候群疾病易感性的生物學預測因子,也提出了和非家族性病竇症候群及腎素–血管收縮素系統相關的心房撲動和主動脈剝離的預後的臨床預測因子。我們認為腎素–血管收縮素系統和非家族性病竇症候群及其相關的心血管疾病的病生理基轉密切相關。
Sick sinus syndrome (SSS) is a group of abnormal heart rhythm disorders that result from sinus node malfunction. The syndrome accounts for approximately 50% of pacemaker implantations for bradyarrhythmia. The pathologic findings of SSS have revealed fibrotic change over the sinus node and atrium. Evidences suggest genetic mutations in ion channels may lead to familial SSS. However, limited study is available regarding the mechanism of age-related non-familial SSS. Non-familial SSS is frequently associated with an atrial flutter and presents as tachycardia-bradycardia syndrome. The cavotricuspid isthmus (CTI) is a critical and slow conduction zone of the reentry circuit. Atrial fibrosis and the architecture of the atrial musculature have been suggested to be associated with the underlying mechanism of the slow conduction zone. Myocardial fibrosis is related to up-regulation of rennin-angiotensin system (RAS). These findings indicate the role of RAS in the underlying mechanism of atrial flutter. Radiofrequency catheter ablation therapy to block the CTI has been suggested as the method of choice for atrial flutter management. Anatomical variants of CTI have been related to the difficulty of ablation therapy. However, the detailed anatomical predictors of the CTI for the difficult procedure of radiofrequency catheter ablation have not been well described. We utilized transthoracic echocardiography to evaluate the anatomy of the CTI and found that a Eustachian valve variation of the CTI is an independent predictor for the difficult procedure of AFL ablation. The primary objective of the present study is utilizing gene study methods to investigate the possible candidate gene and underlying pathologic mechanism for non-familial SSS. We found that angiotensinogen promoter polymorphisms are associated with susceptibility to non-familial SSS through the modulation of angiotensinogen expression. In a gene association study, we found that the RAS system was associated with susceptibility to non-familial SSS. In addition, the RAS has also been reported to be associated with other cardiovascular disorders. Aortic dissection is a lethal cardiovascular disorder due to intimal tearing. The up-regulation in the RAS has been reported to be related to the underlying mechanism of aortic dissection. Besides, the clinical predictors for the outcome of aortic dissection are important. However, few reports have addressed this issue. We utilized computed tomography imaging to identify the anatomical predictors of the outcomes of aortic dissection. The false lumen size of an aortic dissection was found to be an independent predictor for the outcomes of aortic dissection. In conclusion, susceptibility to non-familial SSS is associated with RAS gene expression. This study identifies a biological predictor for susceptibility to non-familial SSS and clinical predictors for the outcomes of atrial flutter and aortic dissection, which are linked to non-familial SSS and RAS. The RAS is suggested to be closely linked to the pathophysiologic mechanisms of non-familial SSS and related cardiovascular diseases.
其他識別: U0005-2201201318410600
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