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  • 學位論文

使用血管張力素轉化酶抑制劑是否助於慢性心房纖維顫動心律不整復整術後維持正常竇性心律之研究

Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation

指導教授 : 林中生

摘要


本研究主要目的在於評估血管張力素轉化酶抑制劑 enalapril是否能減少慢性心房纖維顫動(atrial fibrillation, AF)給予心律復整術(electrical cardioversion)後心房纖維顫動之復發。近來的流行病學及大型臨床研究亦顯示心房顫動增高病患的住院醫療費用及死亡率,尤其中風的危險性達一般人的5至6倍,這已凸顯心房顫動並非 ”良性的不整脈”。目前,心房纖維顫動的治療可分為較積極性的維持正常竇性脈 (rhythm control)及較消極的心速控制 (rate control) 。雖然最近在新英格蘭雜誌刊登的AFFIRM研究顯示心房纖維顫動治療策略,心律控制並未優於心速控制的結果; 然而心律控制組大都使用第一及第三類對抗心律不整藥(Class I and Class III antiarrhythmic agents),如 propafenone, flecanide, quinidine及sotalol,這些藥物的減少心臟收縮能力(negative inotropic effects)及又常誘發更惡性心律不整(proarrhythmia),遠較控制心速的藥物如digitalis、beta-blockers及calcium channel blockers來得多,因此限制其臨床之使用。然而研究中並未針對可能防止心房組織再塑造作用(atrial remodeling) 藥物如血管張力素轉化酶抑制劑或血管張力素-II 阻斷劑作探討。 最近的研究發現,在心房壓力上升時,會活化心房局部腎素-血管張力素系統(local renin-angiotensin system),使血管張力素-II(angiotensin II)濃度上升。血管張力素-II 會活化分裂原蛋白激脢訊息傳導系統 (mitogen-activated protein kinase pathway; MAPK),造成心房解剖學上的再塑造(structural remodeling)作用,使心房產生纖維化並導致心房擴大。血管張力素-II 也可造成心房電生理再塑造 (electrical remodeling),使得心房有效不反應期(atrial refractory period)縮短,且靜注血管張力素-II 阻斷劑(如 candesartan)或血管張力素轉化酶抑制劑(如 enalapril),可避免心房有效不反應期在短期心房快速刺激(rapid atrial pacing)時縮短及心房電生理再塑造作用。因此,心房纖維顫動的發生和腎素-血管張力素系統有重大關連,血管張力素-II 上升可使得心房纖維顫動更容易發生及維持。 吾等共收集180位具有慢性心房纖維顫動達三個月以上之病患隨機分派為兩組,第一組接受amiodarone 200毫克一天三次(n=75),第二組則除amiodarone之外加上enalapril 10毫克1天二次(n=70)。經至少4星期之藥物治療並維持Prothrombin time (PT) INR 2.0-3.0之後所有患者接受心律不整復整術並分析之後心電圖變化及心房纖維顫動之復發。在各項臨床基本資料及由心臟超音波所測量到的關於心臟腔室大小及心臟收縮功能,兩組都沒有顯著的差別。心律不整復整術後,Amiodarone則僅給予維持劑量每天200毫克,Enalapril則維持10毫克每天二次,或者根據血壓之需求調整為20毫克一天二次,抗凝血劑則繼續給予至少四週。在患者出院前,吾等教導患者如何使用Event recorder,在清晨睡醒後,做一個90秒鐘之心律記錄,出院後第一個月,每週接受門診之檢查,第二個月後則維持每月一次門診檢查。24小時心律記錄器則在心律不整復整術後一個月、半年、一年及病人有任何懷疑心律不整復發時做完整之記錄。 結果發現接受amiodarone加enalapril合併治療之患者有較少之心房纖維顫動立即復發傾向(4.3% vs 14.7%, P=0.067)。Kaplan–Meier存活分析更證實接受enalapril治療之患者在第四週及270天之追蹤發現有統計學上意義更高之比例能維持正常之竇性心律。針對慢性心房纖維顫動之治療於傳統之amiodarone 再加上enalapril可以有效降低心房纖維顫動之立即及亞急性復發並有助於長期之正常竇性心律之維持。 本研究證實血管張力素轉化酶抑制劑在傳統觀念而言並非抗心律不整藥物,卻能有效降低心房纖維顫動之復發,其作用點可能在於防止心房組織之結構塑造作用(Structure remodeling)減少心房之纖維化(atrial fibrosis)此乃心房纖維顫動治療觀念上之ㄧ大突破。 本研究的結果間接提供腎素血管張力素系統在心房纖維顫動病理生理機轉上扮演重要的角色,在臨床上,更提供血管張力素轉化酶抑制劑可治療心房纖維顫動效用的另一個佐證。

並列摘要


Atrial fibrillation (AF), the most common sustained arrhythmia in the elderly, increases the risk of stroke and it also is an independent predictor of mortality. Transthoracic electrical cardioversion of AF is one of the most widely used and effective treatments for restoration of sinus rhythm. However, it has a limited success rate and a high recurrence rate, which is only partially affected by anti-arrhythmic treatment. Clinical observations have demonstrated that the recurrence of AF is frequently clustered within the first month after cardioversion. Most of the recurrences are probably due to electrical and structural remodeling caused by changes in the refractory period of atrial muscle and atrial fibrosis with intra-atrial conduction disturbances. Recently, several studies have demonstrated that the atrial angiotensin system may play an important role as a mediator of atrial remodeling in AF. A recent study supporting this notion showed that there was a lower recurrence rate of AF and a longer time to first arrhythmia recurrence in patients with AF lasting more than 7 days who were treated with amiodarone and irbesartan. However, the effect of angiotensin converting enzyme (ACE) inhibitor on cardioversion outcome and subsequent maintenance of sinus rhythm in patients with persistent AF lasting more than 3 months is not known. Therefore, the aim of the current study was to investigate in a prospective, controlled fashion whether the ACE inhibitor enalapril facilitates maintenance of sinus rhythm in patients receiving electrical cardioversion of chronic AF. Patients with chronic AF for more than 3 months were assigned to receive either amiodarone (200 mg orally 3 times a day; group I: n=75) or the same dosage of amiodarone plus enalapril (10 mg twice a day; group II: n=70) 4 weeks before scheduled external cardioversion. The end point was the time to first recurrence of AF. In 125 patients (86.2%), AF was converted to sinus rhythm. Group II had a trend to a lower rate of immediate recurrence of AF than group I (4.3% vs. 14.7%, p=0.067). Kaplan-Meier analysis demonstrated a higher probability of group II remaining in sinus rhythm at 4 weeks (84.3% vs. 61.3%, p=0.002) and at the median follow-up period of 270 days (74.3% vs. 57.3%, p=0.021) than group I. We concluded that the addition of enalapril to amiodarone decreased the rate of immediate and subacute arrhythmia recurrences and facilitated subsequent long-term maintenance of sinus rhythm after cardioversion of persistent AF.

參考文獻


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