摘要:由歐美報告,Wolff-Parkinson-White(WPW)症候群之罹病率在千人中大約占1-4.8人。我們的研究顯示臺灣罹病率是每千人有0.67人,略低於西方國家報告,但與日本相近。WPW症候群病兒因附隨導線可導致正向或逆向房室迴轉頻脈,或與心房顫動有關之猝死。在WPW症候群病兒心房顫動產生之機轉仍有許多未明之處,一般認為與頻脈或附隨導線造成心房電生理特性改變有關。在電燒灼術去除後,病人之電生理檢查顯示,其心房之電生理特性仍偏異常。由過去研究顯示,WPW病人發生心因性猝死之機率大約1.5/1000病人年。在兒童方面曾有一篇184位病兒之報告,估計產生有危及生命之心頻脈大約為0.9/1000病人年。這些猝死資料的確非常有限。此外,近年之研究也發現WPW症候群病人因附隨導線導致不同序之心室收縮啟動,可能造成心臟電性心肌收縮不協調,繼而造成心室功能受損,其臨床表現甚而與擴張性心肌症。然而大規模系統性之分析仍屬闕如。反觀成人之心房顫動,雖然這些非家族性心房顫動多合併於其他心血管疾病,但近年之研究強烈指出有些基因變異(SNP)與心房顫動發生有關。這些基因變異在病人心房因其他心血管疾病有病變時,會再加強其變化並誘發心房顫動發生。這些基因變異大致位於,離子通道相關基因,renin-angiotensin系統基因,connexin-40基因,發炎基因與目前功能尚不清楚的基因段。在WPW症候群病人是否也若有些基因變異(SNP)與其心房顫動發生有關,目前資料完成闕如。倘若有些基因變異也會誘發WPW症候群病人發生心房顫動,是否可以用藥物避免,甚或這樣病人應提早接受心導管心燒灼術治療。而這樣之病人接受心導管心燒灼術治療後,若有這些基因變異是否病人年長後是心房顫動之風險也較高。目前的確沒有答案。因此,本計劃擬探討:1) 以學校篩檢出之病兒及醫院資料庫之病人來釐清台灣WPW病兒之自然病史,包括其心頻脈與危及生命之心頻脈,甚或猝死之概率。2) WPW症候群病兒之心電收縮不協調之臨床表徵與其對預後的影響。3) 心房顫動病人是否有基因變異點與心房顫動發生有關。本計劃若能完成,對於WPW症候群病人治療策略會有極大影響,例如,治療性心導管檢查的時間點選擇,運動準則,內科治療方式等。若能找到誘因基因 其影響面將是極廣的。
Abstract: As described in the western reports, the prevalence of Wolff–Parkinson–White (WPW) syndrome ranged from 1 to 4.8/1000. From our previous study, the prevalence in Taipei City population is a bit lower and is 0.67/1000 in school children, being quite close to that from Japan. Patients with WPW syndrome may encounter orthodromic and antidromic atrioventricular (AV) reentrant tachycardia, as well as atrial fibrillation (AF) related sudden collapse. The mechanisms responsible the AF initiation are still unclear, though several mechanisms had been proposed, such as spontaneous degeneration of the AV reciprocating tachycardia into AF, effects of accessory pathway on atrial architecture, electrical properties of the accessory pathway, and intrinsic atrial vulnerability. In patients with accessory pathway with an antegrade effective refractory period shorter than 250 ms, rapid AF cycle lengths may conduct to the ventricles causing a rapid ventricular response. This in turn can degenerate into a ventricular fibrillation and lead to sudden cardiac death (SCD), that had been estimated at 1.5/1,000 WPW patient-years. In pediatric population, the risk of SCD is unclear; only one cohort of 184 children reported a risk of the risk of life-threatening tachycardia at 0.9% per patient-year. However, such data are still limited and not any for the Asia population had been reported.Our previous studies also showed that the prevalence of WPW syndrome in Taiwan was much higher in school children after puberty. The accessory pathways were less likely to be manifest. Manifest accessory pathways account for only 40-50% of the whole accessory pathways in our patient cohort. Whether such racial related difference will influence the antegrade conduction properties of the accessory pathway and the subsequent risk of cardiac events remain unclear.Other than tachyarrhythmias, recent studies disclosed the potential of ventricular dysfunction caused by the elctromechanical dyssynchrony from the accessory pathway. We have such clinical experience, in which the cardiomyopathy in patients with WPW syndromewas resolved only after successful ablation of the accessory pathway. However, the incidence and clinical implication of such electromechanical dyssynchrony remain ill-defined.Recent studies in adults with nonfamiliar AF strongly suggested the presence of genetic susceptibility to AF. The reported genes include 1) genes of potassium channel subunits and regulatory proteins, genes controlling the renin-angiotensin system, Connexin-40 gene and inflammatory genes that were identified from candidate gene approach, as well as 2) function-defined loci identified from genome-wide approach. Whether genetic basis also underlay the susceptibility to develop AF in WPW syndrome or not is still unknown.Aims: The specific aims of this study are 1) by using the population and extended follow-up, to have an estimate for the risk of SCD and cardiac events in symptomatic and asymptomatic WPW syndrome, 2) by using institutional approach, to correlate the clinical presentation, including the evidence of ventricular dysfunction, to the natural history established from the population study, 3) by targeting on WPW patients being called back, to conduct a large scale cohort study to further elucidate the incidence of electromechanical dyssynchrony and its clinical implication, and 4) by targeting the specific patient population, who have spontaneous and induced AF and aborted sudden death, to determine if any genetic susceptibility to AF.Study design:Part I. We will invite the children with WPW syndrome identified from Taipei school survey to have their long-term (average 10 years) outcome data to delineate the natural history of WPW syndrome in the young. The institutional cohort will be retrospectively studied to provide the outcome data after treatments.Part II. While the incidence of ventricular dysfunction may be elucidated by institutional cohort review, the electromechanical dyssynchrony will be systemically assessed by echocardiography evaluation, including TDI, and determination of B-type natriuretic peptidePart III. Genetic susceptibility to the development of AF in patients with WPW syndrome will be examined by genotyping each individual using the Affymetrix Genome-Wide Human SNP Array 6.0, which features 1.8 million genetic markers, including more than 906,600 singlenucleotide polymorphisms (SNPs) and more than 946,000 probes for the detection of copy number variation.Predictive outcome: After the completion of the study, the results will provide us the information regarding 1) the incidence of cardiac events in asymptomatic WPW children, which is very important data for us to establish the therapeutic guideline; 2) if any genetic loci may be identified as the susceptibility gene for AF in WPW syndrome, the information will be extremely important for us to make risk stratification for WPW patients; and 3) the clinical implication of electromyocardial dyssynchrony is also critical for us to refine the medical treatment in such patients.Preliminary data1.There are 290 children (151 male and 139 female) with WPW syndrome who were identified from School Survey of 432,166 students. The surveys were conducted between 1999 and 2001. If 80% of them are enrolled into the current study, the follow-up duration will be amounted to 2320 patient-year, which will be effective for us to estimate the cardiac events.2.There are around 1200 patients who were diagnosed to have WPW syndrome at their age younger than 30 years in our institution. The medical record will be reviewed and the follow-up will be updated. The estimated total follow up duration will be effective to assess the outcomes of natural and unnatural history.