右旋大動脈轉位病人接受大動脈轉置術後長期追蹤: 著重於主動脈根部擴張與藥物之研究

Abstract

從西元2000年到西元2006年由國家數據庫中，發現右旋大動脈轉位（d-Transposition of great arteries）在臺灣的發生率是0.36/1000，是臺灣第二常見的發紺型先天性心臟疾病。從西元1989年臺大醫院成功地進行了第一例新生兒時期大動脈轉置術（Arterial switch operation）以來；這些右旋大動脈轉位病患經長期術後追蹤，有可能出現轉換後的主動脈狹窄、主動脈瓣閉鎖不全、轉換後的肺動脈狹窄、冠狀動脈病變等變化。其中主動脈根部擴大（Aortic root dilatation）是近年發現早期易被忽略的問題。其病變之頻率、及其病變與馬凡氏症(Marfan syndrome)之主動脈根部擴大是否有部分類似之致病機轉等問題，目前並無研究報告。依據最新研究，馬凡氏症(Marfan syndrome)的小鼠模型表明主動脈根的擴大是由於β-轉化生長因子（TGF-β）信號過度的增加而導致，治安方面使用β-轉化生長因子受體拮抗劑治療包括血管緊張素Ⅱ受體阻斷劑（angiotensin II-receptor blockers）可以減少β-轉化生長因子（TGF-β）信號的增加。我們最近的研究顯示，有主動脈根擴大的馬凡氏症病人使用血管緊張素Ⅱ受體阻斷劑可減緩主動脈根擴大的速度。 因此，我們收集臺大醫院右旋大動脈轉位接受大動脈轉置術患者的長期追蹤資料，我們記錄術後的長期追蹤結果，主動脈根部擴大（Aortic root dilatation）的頻率和分析臨床相關的危險因素。 在西元1990年到西元2006年之間，臺大醫院有103例右旋大動脈轉位病人術後存活（男有79例，女有24例），他們接受大動脈轉置術的年齡中位數為12天。其中有10個病人接受手術年齡超過6個月。在大動脈轉置術完全矯正之前，有16例先接受階段性手術治療。整體追蹤為1284年人和(patient-years)，追蹤時間平均為13.02年。追蹤過程只有一個病人死亡。 主動脈根部的大小和主動脈瓣閉鎖不全之診斷以一連串心臟超音波的測量為根據。在研究期間，其中60例（58％）有嚴重的主動脈根部擴大，嚴重的主動脈根部擴大是指主動脈根部Z分數(Z-score) > 3。無嚴重的主動脈根部擴大之概率分別在1，2，5，10和15年的概率為71.8％，62.9％，55％，44％和37％。從術後發展嚴重的動脈根部擴大的病人時間為中位數為1.09年（術後16天到術後17.11年）。嚴重的主動脈根部擴大的危險因素為合併Taussig-Bing異常(P = 0.02）、左心室出口阻塞（P = 0.01），手術時體重大於7公斤（P = 0.02）、手術時年齡大於 6個月（P = 0.01）和中度以上主動脈瓣膜閉鎖不全(P=0.001)； 多變數分析顯示，只有中度以上主動脈瓣膜閉鎖不全是獨立預測的主動脈根部擴大相關的風險 (P=0.005；勝算比 odds ratio=2.2)。主動脈瓣膜閉鎖不全共有73例（70.8％）：其中中度有9例（8.73％）、重度有4例（3.8％）。當主動脈根部擴大程度越厲害的時候, 主動脈瓣閉鎖不全的機率越增加（P <0.001; r=0.321），主動脈狹窄則與主動脈根部擴大的機率無關（P = 0.77; r=0.029）。 在這些主動脈根部擴大病人中，目前只有一例病人受主動脈根部擴大手術，21例患者接受藥物治療，年齡介於3.59歲至18.76歲：以血管緊張素Ⅱ受體阻斷劑來治療共13例，有6例使用血管收縮素反轉脢抑制劑 (Angiotensin-converting enzyme inhibitors)來治療和β-腎上腺素受體阻斷劑(beta-blockers)用在2例。血管緊張素Ⅱ受體阻斷劑治療開始前，患者主動脈根部直徑的變化率平均每年為2.2±0.12毫米。治療後這個變化率下降到每年0.4±0.55毫米（P = 0.009）。同樣，治療前在主動脈根直徑的Z分數的平均變化率分別每年為0.53±0.58，和治療後每年減少至-0.16±0.59（P = 0.009），則可見臨床與統計上有顯著差異。另外有8位患者接受β-腎上腺素受體阻斷劑或血管收縮素反轉脢抑制劑治療，治療開始前在主動脈根部直徑的變化率平均每年為1.54±0.74毫米，而治療後這個變化率下降至每年0.86±1.24毫米（P = 0.208）。Z分數在此藥物治療前主動脈根直徑的平均變化率分別每年為0.12±0.49，治療後每年下降至-0.11±0.67（P = 0.16），則可見臨床與統計上沒有顯著差異。全部患者在長期追蹤中，共有47例患者進行了心導管手術或心臟外科手術。所有右旋大動脈轉置術術後併發症中，肺動脈狹窄是最常見進行了心導管手術或心臟外科手術的原因，周邊肺動脈狹窄是第二常見的原因，7例患者周邊肺動脈狹窄接受支架植入術於左或右周邊肺動脈；只發現3例有冠狀動脈後遺症。 總之，由這個右旋大動脈轉位接受大動脈轉置術患者之縱向研究，我們發現嚴重的主動脈根部擴大主動脈根部(Z分數> 3）是非常常見的。大動脈轉置術5年後無主動脈根部擴大之概率為55％。尤其好發於較大年齡才接受大動脈轉置術之患者。血管緊張素Ⅱ受體阻斷劑來治療有助於降低主動脈根部直徑擴大的進展之速度，這對右旋大動脈轉位接受大動脈轉置術患者，產生主動脈根部擴大併發症將是一種很有前途的治療方案。 關鍵詞：血管緊張素Ⅱ受體阻斷劑；主動脈根部擴大；主動脈瓣膜閉鎖不全；大動脈轉置術；右旋大動脈轉位

The incidence of d-transposition of great arteries (d-TGA) in Taiwan was 0.36/1000 from the national database 2000-2006, and was the second common cyanotic congenital heart disease in Taiwan. The first arterial switch operation (ASO) for the neonate in our institution was successfully performed in 1990. Based on the long-term follow up data of these TGA patients after ASO, we sought to follow up the long-term result, investigate the chance of aortic root dilatation (ARD) and the clinical correlates as the risk factors. Recent data from mouse models of Marfan syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor β (TGF-β) that can be mitigated by treatment with TGF-β antagonists, including angiotensin II–receptor blockers (ARBs).We evaluated the clinical response to ARBs in our patients who had severe aortic-root enlargement. There were 103 hospital survivors (79 males and 24 females) with d-TGA who received an ASO between 1990 and 2006 who constituted the study cohort. The ASO was performed at a median age of 12 days. Ten of them received the ASO at ages older than 6 months of the age. Prior to the ASO, palliative surgery had been performed in 16 patients. The total follow up amounted to 1284 patient-years and the mean follow up was 13.02 years. There was only one late death. Serial echocardiograms were reviewed for the size of neo-aortic root and neo-aortic regurgitation (AR). Among them, aortic root dilatation (ARD, an aortic root z score >3) was noted in 60 (58%) patients during the study period. The probability free from ARD was 71.8 %, 62.9%,55%, 44% and 37%,at 1, 2, 5, 10 and 15 years, respectively. The median time from ASO to ARD for the patients in whom it developed was 1.09 years (range, 16 days to 17.11 years). The risk factors associated with ARD were Taussig–Bing abnormality (p =0.02), body weight >7 kilograms at ASO (p=0.02), age > 6 months at ASO (P=0.01) as well as the coexisting at least moderate AR(p=0.001) and left ventricular outflow tract obstruction(p=0.01).Multivariate analysis revealed only at the least moderate AR was the only independent predictor associated with the risk of developing ARD(p=0.005, Odds ratio=2.2). AR was noted in 73 patients (70.8%); moderate in 9 (8.73%) and severe in 4 (3.8%). While AR tended to be higher with increasing degree of neo-aortic root dilatation. (P<0.001; r= 0.321), the neo-aortic root dilatation was not related with aortic stenosis (P=0.77; r=0.029). Among those with ARD, only one patient received ARD operation during follow up and 21 patients received drug therapy at age 3.59 to 18.76 years: ARB in 13, Angiotensin-converting enzyme inhibitors (ACEI) in 6 and β-blockers in 2. The mean rate of change in aortic-root diameter in patients before the initiation of ARB therapy was 2.2±0.12 mm per year. After therapy, this rate decreased to 0.4±0.55 mm per year (P=0.009). Similarly, the mean rate of change in aortic-root-diameter z scores was 0.53±0.58 per year before ARB therapy and decreased to −0.16±0.59 per year after therapy (P=0.009). Of the 8 patients with d-TGA who received beta-blocker or ACEI therapy, the mean rate of change in aortic-root diameter before the initiation of beta-blocker or ACEI therapy was 1.54±0.74 mm per year and this rate decreased to 0.86±1.24 mm per year (P=0.208). Likewise, the mean rate of change in aortic-root-diameter z scores before therapy (0.12±0.49 per year) was not statistically different from that after therapy (-0.11±0.67 per year) (P=0.16). Reintervention in 47 patients were performed during the follow up. Pulmonary stenosis was the most frequent cause of reintervention after ASO. Branch pulmonary arteries stenosis was second common cause and 7 patients received stent implantation on branch pulmonary arteries. Coronary sequelae were only found in 3 patients. In conclusion, from this longitudinal study on d-TGA after ASO, we found that severe neo-aortic root enlargement (an aortic root z score >3) was common and the probability free from ARD was only 55% 5 years after ASO, particularly in those repaired at older age. ARB seems helpful to reduce the progression rate of ARD and will be a promising therapeutic regimen in repaired TGA patients. Running title: arterial switch operation, transposition of great arteries, aortic root dilatation, angiotensin II–receptor blockers, Angiotensin-converting enzyme inhibitors Keywords：Angiotensin II–receptor blockers；Aortic root dilatation；Aortic valve regurgitation；Arterial switch operation；D-transposition of great arteries