法洛氏四重症術後之心室心律不整-再極化異質性的角色探討

Ventricular arrhythmia in repaired Tetralogy of Fallot-role of repolarization heterogeneity

邱舜南(Shuenn-Nan Chiu)

指導教授 ： 吳美環

共同指導教授 ： 蘇銘嘉(Ming-Jai Su)

國立臺灣大學/醫學院/臨床醫學研究所/博士(2011年)

https://doi.org/10.6342/NTU.2011.03357

摘要

背景 因為開刀技術與術後照顧的進步，法洛氏四重症（Tetralogy of Fallot, TOF）的長期預後在這三十年來有了長足的進步，然而仍有一定比例的病人在術後晚期死亡，心因性猝死是造成這些病人術後晚期的重要死因，大多與心室心律不整及心臟原因引起有關。根據前人的研究，心室心律不整的危險因子包括血行動力方面，如嚴重肺動脈逆流，右心室擴張，左心室舒張末期壓力增加，以及心電氣生理方面如心電圖QRS間距及QTc間距延長。根據上述危險因子，Gatzoulis等人提出了機械電氣生理交互作用（mechanical-electrical interaction）的理論，認為血行動力因素如肺動脈逆流及狹窄，會造成右心室特別是出口處擴大，再加上開刀造成的疤痕，就提供了心室心律不整的重要基質（substrate），然後就會造成病人單型性的心室心搏過速（monomorphic ventricular tachycardia），最後造成心因性死亡。
雖然單型性心室心搏過速是法洛氏四重症術後的重要死因之一，多型性心室心搏過速也相當重要，Khairy等人在心導管誘發心室心律不整的研究中發現，誘發出多型性心室心搏過速，其之後臨床上有心室心搏過速或猝死的風險比高達12.9；而單型性次之，風險比為5.0。由於多型性心室心搏過速產生的主要機轉是再極化異質性（repolarization heterogeneity），因此再極化異質性在法洛氏四重症術後心律不整扮演的角色就格外引人注意。此外，最近的研究也發現再極化異質性也是單型性心室心搏過速的重要基質，當心臟有結構上的障礙（structural barrier）時，有再極化異質性會使電刺激容易誘發出單型性心室心搏過速。因此，再極化異質性在法洛氏四重症術後心室心律不整可能扮演重要角色。
過去再極化異質性臨床上指標包括心電圖上的QTc間距及QT離散度，然而這些參數的敏感度及特異度都偏低，因此新的指標，即微小T波變異(microvolt T wave alternans)已經取而代之成為主要參考指標，並且在臨床上廣泛應用。微小T波變異的分析包括譜分析（spectral method）及時間領域分析（time domain analysis），在時間領域分析中最常使用的是修正移動平均心律分析法（modified moving average beat analysis，MMA），它的作法是將心跳分成奇數及偶數，並將連續心跳型態依奇數及偶數分別加總平均然後相減，而微小T波變異就定義為在十二導程中差別最大者。在許多大規模臨床試驗及綜合分析（meta-analysis），以譜分析或時間領域分析得到的微小T波變異，都被證實在缺氧性或擴張性心肌病變病人，對於死亡或心因性猝死有相當高的預測度，其風險比可高達2.7到5.5倍。然而微小T波變異在法洛氏四重症術後心室心律不整的研究仍有限，因此我們嘗試觀察此參數與法洛氏四重症心室心律不整的關係。
先天性QT過長症候群（long QT syndrome）是一種遺傳疾病，特徵是心電圖上有QT間距延長及容易心因性猝死，而其再極化常會延長並且離散。而先天性QT過長症候群主要致病機轉是基因突變造成離子通道的變異，因而造成再極化延長及異質性。除了先天性QT過長症候群外，在一些有基因易感性病人（亦即有QT過長症候群基因變異），在接觸到一些藥物或電解質不平衡時也會產生QT間距延長及危及生命心室心律不整，這些人通稱為後天性QT過長症候群。而在法洛氏四重症術後病人若有QT過長症候群基因突變或多形性變異（polymorphism）是否會加重既有的再極化異質性，而增加心因性猝死的機率目前仍未有相關研究。
研究主題 我們研究的主題有（1）再極化異質性在法洛氏四重症術後的心室心律不整扮演重要角色；（2）在法洛氏四重症術後的機械與電生理交互作用是雙向的，不只血行動力學變化會加重再極化異質性，電氣生理因素也會加重心室擴大；(3) QT過長症候群基因對於法洛氏四重症術後再極化異質性有加成效果並進而增加心室心律不整及危及生命事件的風險。
方法與結果 我們分析了819位法洛氏四重症在1970至2002年在本院接受完全矯正手術的病人，並以國民健康局資料庫死亡記錄來確定其存活狀態。在13,808人年的追蹤後，30年的存活率為90.5%，與西方國家相近。且死亡率隨追蹤時間的延長而增加，由前15年的0.123%/年增加到15年以後的0.395%/年。在死因的分佈上也與之前資料相類似，心因性死亡佔了51.7%，然而我們有較高的非自然死亡因素（意外及自殺合計佔了27.6%），這也顯示了我們缺乏醫療及社會心理方面的整合照護。
我們接下來建立了動物模式，研究血行動力與電氣生理因素在引發心室心律不整所扮演角色。我們以開刀製造右心室出口跨肺動脈瓣膜補片加上破壞肺動脈瓣膜來模擬血行變化（機械）因素，並以心導管高周波燒灼右側傳導支（right bundle branch）來模擬電氣生理因素。我們將動物分成三組，即血行因素組，電氣生理因素組，及合併血行因素及電氣生理因素組，我們發現（1）血行因素組及合併組都有右心室逐漸擴大情形，然而合併組擴大趨勢較明顯；（2）比較術後一個月及一年的心電圖參數變化，包括QRS，QTc，JTc間距及QT離散度，發現增加的趨勢也是以合併組最為明顯；（3）以心內記錄器（implanted loop recorders）記錄到的心室心律不整事件在合併組最為頻繁（中位數3.3次/月，其他兩組中位數1次/月），根據上述結果，我們認為電氣生理因素及與血行變化因素的交互作用對於法洛氏四重症術後再極化異質性及心室心律不整非常重要，而且電氣生理因素藉由不同步（dyssynchrony）的機轉，對於右心室擴大也有影響。
我們接著分析法洛氏四重症術後病人的微小T波變異情形，我們比較101位病人與103位年齡性別相合的對照組，我們發現法洛氏四重症比起正常人有較高的微小T波變異值(25.1±14.0 比 17.6±9.2 μV, p<0.001)。而在一些風險較高的病人，如QRS間距較長，嚴重肺動脈逆流，及有接受右心出口跨瓣膜補片的病人，微小T波變異值也較高。此外，在之前有心室心律不整事件者，其微小T波變異數值更高(34.0±16.5比 24.2±13.5 μV, p=0.053)。然而，以微小T波變異來預測心室心律不整其預測度較單純用QRS間距來得低。總結來說，這個結果顯示了再極化異質性在法洛氏四重症術後病人相當常見，且會因為肺動脈逆流及QRS間距延長而加重，另外也支持我們假說中再極化異質性對於法洛氏四重症術後心室心律不整的重要性。
最後，我們嘗試釐清QT過長症候群基因在法洛氏四重症病人是否會加重再極化異質性而增加心室心律不整機會。我們檢驗84位法洛氏四重症病人三個最常見的QT過長症候群基因（KVLQT1，hERG及SCN5A），這些病人中有5位有危及生命事件或需要裝置體內去顫器（implantable cardioverter defibrillator），我們發現在這些有危及生命事件者基因變異的比率較高（5/5 比 35/79, p=0.021），特別是hERG及SCN5A基因變異，而有複合式QT過長症候群基因變異（compound long QT syndrome gene variants）者危及生命事件機率也是比較高（3/13 比 2/71, p=0.025）。由以上結果，我們認為QT過長症候群基因變異對於術後因為血行動力及電氣生理因素造成的再極化異質性會有加成效果，而增加法洛氏四重症心室心律不整機率。
結論 藉由動物實驗，我們確定了電氣生理因素與血行因素個別與交互作用在法洛氏四重症病人再極化異質性與心室心律不整的重要性，而藉由臨床微小T波變異研究，我們發現再極化異質性在法洛氏四重症術後病人相當常見，且與心室心律不整高度相關，而QT過長症候群基因會進一步加重原有法洛氏四重症術後的再極化異質性，而增加心室心律不整危險性。

關鍵字

法洛氏四重症 ； 心室心律不整 ； 心因性猝死 ； 再極化異質性 ； 肺動脈逆流 ； 右側支傳導障礙 ； 微小T波變異 ； QT過長症候群基因 ； 變異或多型性變異

並列摘要

Background With advances in operative techniques and perioperative support, surgical outcome of Tetralogy of Fallot (TOF) has been greatly improved in recent three decades. However, patients are still at risk of cardiac death late after total repair. Sudden cardiac death (SCD), mostly due to ventricular tachyarrhythmia, are the major causes of late death. From previous reports, risk factors for ventricular arrhythmia include hemodynamic factors such as severe pulmonary regurgitation (PR), right ventricular dilatation, and increased left ventricle end-diastolic pressure, and electrophysiologic factors such as prolonged QRS duration and QTc interval. Gatzoulis et al had proposed mechanoelectrical interaction as the mechanism for the ventricular arrhythmia in repaired TOF. They proposed that the hemodynamic factors, including pulmonary regurgitation and peripheral pulmonary stenosis, caused right ventricle dilatation especially the outflow tract. Such ventricular dilatation and right ventricular outflow tract surgical scar would then provide the substrate of ventricular arrhythmia and increase susceptibility to monomorphic ventricular tachycardia (VT).
In repaired TOF, not only the monomorphic VT, but also the polymorphic VT is important cause of cardiac death. In the electrophysiological studies of repaired TOF patients, Khairy et al found that those with inducible polymorphic VT has highest risk developing clinical VT or SCD at follow-up (odds ratio of 12.9), followed by those with inducible monomorphic VT (odds ratio 5.0). As polymorphic VT often associates with repolarization heterogeneity, the role played by repolarization heterogeneity in the genesis of ventricular arrhythmia in repaired TOF patients is crucial. In addition, repolarization heterogeneity is also an important substrate for monomorphic VT. In the previous animal studies using optical mapping method, for the myocardium with structural barrier, electrical stimulation often induces monomorphic VT in the presence of repolarization heterogeneity. Therefore, repolarization heterogeneity may be in the central pivot of the pathogenesis of ventricular arrhythmia in these repaired TOF patients.
The indicators of repolarization heterogeneity include QTc interval or QT dispersion detected by surface EKG. However, the sensitivity and specificity were both low. Microvolt T wave alternans (MTWA), had recently been recognized as a new indicator of repolarization heterogeneity. It can be analyzed either by spectral method or time domain analysis. The method used in time domain analysis is modified moving average beat analysis (MMA), which averaged the morphologies of odd and even beats of continuing heart beats and subtracted the amplitude of them. MTWA value was then defined as the maximal difference in twelve leads. In several large-scale long-term follow up studies and meta-analysis, MTWA by either spectral or MMA methods has been documented as a useful predictor for mortality and SCD in patients with ischemic heart disease and dilated cardiomyopathy. However, the data of MTWA in repaired TOF patients is still limited.
Congenital long QT syndrome (LQTS) is a familial disorder characterized by prolonged QT interval in surface EKG and sudden cardiac death. The exact pathogenesis of congenital LQTS is mutation of ion channel genes which induces repolarization prolongation and repolarization heterogeneity. In addition to congenital LQTS, QT prolongation and life threatening events can be acquired after exposure to drugs or electrolyte imbalance in those with genetic susceptibility i.e., patients with long QT gene polymorphisms. They are categorized as acquired LQTS. Whether the long QT genes mutations or polymorphisms will further aggravate the repolarization heterogeneity caused by surgery, hemodynamic and electrophysiological factors in repaired TOF patients and increase the risk of sudden death, it has never been studied.
Thesis We hypothesized that (1) repolarization heterogeneity plays a central role in the genesis of ventricular arrhythmia in repaired TOF patients; (2) The interactions between mechanical and electrical factors are two-way: the hemodynamic factors may accentuate the repolarization heterogeneity, and the electrophysiologic factors may cause progression of ventricular dilatation; (3) long QT gene mutation/polymorphisms may have additive effects on the repolarization heterogeneity in repaired TOF patients and thereby increase the risk of ventricular arrhythmia and life threatening events.
Methods and Results
Epidemiology study
The patient cohort constituted consecutive 819 TOF patients who received total repair in our hospital from 1970 to 2002. The survival status was confirmed by data check using National Health Bureau death records. After 13,808 patient-years follow-up, the 30 year survival rate was 90.5%. The mortality rate increased significantly at late follow-up period and the annual mortality increased from 0.123% in the first 15 years to 0.395% after 15 years follow-up. Cardiac cause of deaths accounted for 51.7% of the total death in our patient cohorts. Besides, we also noticed a relatively high unnatural death rate (accident and suicide joining, 27.6%) in our patient cohort. Such observation suggested that integrated care of medical and psychosocial support for these patients is still inadequate in our country.
Animal model creation and finding
We created an animal model to assure the effects and the interaction of mechanical and electrophysiological factors on the genesis of ventricular arrhythmia. We performed surgical right ventricular outflow tract (RVOT) transannular patch plus pulmonary valve destruction to simulate mechanical factors of repaired TOF patients. We performed right bundle branch (RBB) ablation and sham operation to simulate electrophysiological factors. Among the three groups of dogs, mechanical factors, electrophysiological factors, and combined mechanical and electrophysiological factors groups, we found (1) progressive RVOT dilatation was found in both mechanical factors group and combined group, but it was most significant in combined group, (2) the increments of QRS duration, QTc interval, JTc interval, and QT dispersion between 1 month and 1 year were all greatest in combined group, and (3) ventricular arrhythmia events recorded by implanted loop recorders were also most frequent in combined group (median 3.3/month in combined group and 1/month in the other two groups). Based on these results, we suggest that the electrophysiological factors and its interaction with mechanical factors are important determinants of the repolarization heterogeneity and genesis of ventricular arrhythmia in repaired TOF. Besides, electrophysiological factors may contribute to the progression of right ventricular dilatation via the mechanism of right ventricle dyssynchrony.

Clinical repolarization heterogeneity significance
We analyzed the microvolt T wave alternans (MTWA) through Treadmill EKG examination on the repaired TOF patients. By comparison of 101 repaired TOF patients to 103 age- and sex-matched controls, we found higher MTWA values in the repaired TOF patients (25.1±14.0 versus 17.6±9.2 μV, p<0.001). The MTWA values are also higher in those with high risk patients including longer QRS duration, severe degree of pulmonary regurgitation, and those receiving transannular RVOT patch repair. In addition, for those with previous ventricular arrhythmia events, their MTWA values are even higher (34.0±16.5 vs. 24.2±13.5 μV, p=0.053). However, the predictive value of MTWA was less than QRS duration alone. Nevertheless, these results showed that the repolarization heterogeneity is common in repaired TOF patients and aggravated by pulmonary regurgitation and longer QRS duration. It also supported the importance of repolarization heterogeneity on ventricular arrhythmia in repaired TOF patients.
Genetic study of LQT gene
Finally, we investigated the effects of long QT syndrome (LQTS) gene mutations/polymorphisms on the aggravation of the repolarization heterogeneity in repaired TOF patients. We checked the three common LQTS gene (KVLQT1, hERG, SCN5A) on the 84 repaired TOF patients. Five of them had life-threatening events and received implantable cardioverter defibrillator implantation. We found the life-threatening events were more often found in those with genetic variants (5/5 vs. 35/79, p=0.021), particularly the presence of hERG or SCN5A gene. Presence of compound long QT gene variants further increased the risk of life-threatening events (3/13 vs. 2/71, p=0.025). Therefore, multiple hits from LQTS gene mutation/polymorphisms and repolarization heterogeneity after cardiac repair increase the risk of ventricular arrhythmia in repaired TOF.
Conclusion From animal study, we addressed the importance of interaction of electrophysiological factors with mechanical factors on the repolarization heterogeneity and ventricular arrhythmia. From the clinical study of MTWA in repaired TOF patients, we found the repolarization heterogeneity is common and is highly associated with the risk of ventricular arrhythmia in these patients. The presence of LQT gene mutation/polymorphisms may further aggravate the repolarization heterogeneity and therefore increased the risk of ventricular arrhythmia in repaired TOF patients.

並列關鍵字

Tetralogy of Fallot ； ventricular arrhythmia ； sudden cardiac death ； repolarization heterogeneity ； pulmonary regurgitation ； right bundle branch block ； microvolt T wave alternans ； long QT syndrome gene ； variants or polymorphisms

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