2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647627摘要：背景心房中隔缺損是常見成人先天性心臟病，若超過25 歲未手術治療，死亡率及併發症會明顯增加，而之前研究顯示超過四十歲心房心律不整會達到13%。對於此病治療過去以手術為主，最近二十年以心導管關閉器證實有相同甚至更好的療效，所以目前為首選治療方法，我們已累積超過900 個病例。然而即使以心導管關閉長期追蹤，心房撲動及顫動仍為常見併發症。風險因子包括術前即有心房心律不整，手術年紀較大，及肺高壓。然而對於心房中隔缺損合併心房撲動及顫動的機轉及預防治療目前仍無定論。心房顫動為老年人常見問題，目前許多研究顯示腎素-血管張力素基因扮演一定角色，第二型血管張力素活化會造成纖維母細胞增生及心肌細胞纖維化。另外本院之前研究顯示血管張力素轉化酵素的基因變異與心房撲動及顫動有重要相關，然而此相關在心房中隔缺損病人仍未知。對於心房撲動及顫動，藥物治療仍是主流，由於腎素-血管張力素基因扮演重要角色，腎素-血管張力素抑制可能對於此病人有幫助。目前國外報告認為腎素-血管張力素抑制對於心房顫動病人有幫助，特別是在初級預防上，然而在治療上及對於這些合併有心房中隔缺損病人情形仍未知。目標我們嘗試找出這些心房中隔關閉器關閉病人持續心房撲動顫動的危險因子，並研究與腎素血管張力素基因關係。我們另外研究以藥物抑制腎素血管張力素對於這些心房中隔缺損病人預防心房顫動的幫助。方法臨床從1998 到2010 年所有大於十八歲在台大醫院接受心房中隔缺損關閉病人列入研究，病人的病歷資料將會被紀錄，我們並會安排心電圖及廿四小時心電圖來觀察長期追蹤心房撲動及顫動情形。這些病人中有心房撲動或顫動者，我們讓病患每天服用Losartan 50mg 一年，之後再以廿四小時心電圖檢測心房顫動情形。基礎對於有心房顫動病人，我們安排基因檢測，包括以定序法檢測血管張力素轉化基因的(T174M, M235T, G-6A, A-20C, G-152A, and G-217A)及第二型血管張力素接受器基因的A1166C，另外我們安排沒有心房顫動作為對照組。我們將觀測此基因變異對於藥物感受性的影響。<br> Abstract: Atrial septal defect (ASD) is the most common congenital heart disease in adult population.Withoutsurgery, the mortality and morbidity rate of hemodynamic significant ASD increase significantly after 25years old, and the prevalence of atrial arrhythmia increased to 13% after the age of 40. In recent two decades,new technology with atrial septal occluder has evolved to become a practical alternative to surgical repairwith comparable or even better outcome. Now we have accumulated the experience of more than 900 casesin our hospital.Long term follow-up in these transcatheter repaired ASD patients showed that atrial flutter and fibrillation(AF/Af) still complicated in some patients. Risk factors of persistent AF/Af reported include preoperativeAF/Af, older age, and high pulmonary pressure. However, the true mechanism and the treatment orprevention of AF/Af are still not known.Af is a common sustained arrhythmia in the elderly, and often associated with underlying heart disease.Recently, several studies showed genetic predisposition especially renin-angiotensin system (RAS) gene inthese AF/Af patients. Serial studies showed that angiotensin II activation can cause proliferation offibroblasts and cardiomyocytes fibrosis. Besides, specific Angiotensin converting enzyme haplotype hasstrong association with AF/Af patients.Whether this association exists in these ASD patients is not known.For the treatment of AF/Af, medical control is still the mainstay of treatment. As the RAS gene hasassociation with AF/Af development, we may speculate that the RAS blocker may be benefit in AF/Afpatients. Although the RAS blocker showed benefit in primary prevention in some meta-analysis studies,their use in the treatment or secondary prevention in these ASD patients is not known.AimWe try to delineate the risk factors of AF/Af in these adult ASD occluder patients and see itsassociation with RAS gene.We will also evaluate if the postoperative RAS blocker treatment have anyimpact on the prevention of Af recurrence.MethodClinical From 1998 to 2010, all patients older than 18 years of age and received ASD occluder in NationalTaiwan University Hospital will be enrolled in our study. The basic clinical characteristics, cardiaccatheterization reports, and follow-up data will be collected through chart review.We will also perform EKGand 24 hours Holter exam for atrial flutter/fibrillation status evaluation.RAS blocker therapy- all patients receiving ASD occluder with concomitant AF/Af will be enrolled.Wewill check 24 hours Holter examination prior to enrollment. The patients will then receive Losartan 50mg perday for 1 year and Holter examination will be checked to see the change of Af burden.Basic For these concomitant Af patients, we will invite them back for genetic study. Previous identifiedpolymorphisms on ACE gene (T174M, M235T, G-6A, A-20C, G-152A, and G-217A) and A1166Cpolymorphism on anigotensin II type I receptor gene will be checked by direct sequencing. Age andsex-matched ASD patients will be served as control. The association of susceptible haplotype (identified inprevious study) with paroxysmal and persistent AF/Af, and the response to RAS blocker will be analyzed.Predicted outcome(1)We can delineate the risk factors of postoperative atrial flutter/fibrillation in ASD receiving occluderimplantation patients through a large cohort. In addition, the late AF/Af status will be analyzed as previousstudies about long term follow-up in such patient group is still very limited. (2)We can know the role ofRAS genes polymorphisms played in the AF/Af of ASD patients. In addition, combining genetic factors,we can construct an algorism for the prediction of early and late AF/Af in ASD patients. (3)We can showthe effectiveness of the angiotensin receptor blockers on the AF/Af in ASD patients.We can also seeprediction power of RAS genes polymorphisms on the response of RAS blockers therapy in these ASDpatients.Preliminary DataFrom Dec 1998 till Dec 2010, we have performed ASD occluder implantation in 923 patients. The meanimplantation age was 24.3±19.7 years-old. Male/Female ratio was 663/260. The total follow-up periodwas 4811 person- years. The mean annual case number is 93.3 patients in these 5 years.Among these patients, 83 patients presented with AF/Af before ASD occluder implantation. Many of thesepatients still have AF/Af after ASD occluder implantation. These patients will then be enrolled for furtherstudy.心房中隔缺損心房撲動顫動腎素血管張力素基因變異atrial septal defectatrial flutter/fibrillationrenin-angiotensin gene polymorphisms