兒童與成人期先天性心臟病患者之頻脈與猝死: 解剖構造與電生理學之影響研究

Abstract

背景 頻脈對兒童與成人期先天性心臟病族群的健康影響甚劇，其最嚴重的表現是猝死，雖然不常見，卻會造成家庭深遠的影響與社會的損失。因此頻脈與猝死的研究為至關重要的健康議題。隨著醫療的進步，兒童與成人期先天性心臟患者頻脈的治療逐漸地進步，猝死發生亦可能隨之而降低。然而針對此族群的流行病學資料仍稀缺，新發展導管技術治療頻脈的安全性、可行性，以及基因變異對此族群頻脈與猝死的影響，尚待進一步的研究。 研究方法 為探究兒童猝死的樣貌並瞭解先天性心臟病於其中之重要性，需要完善的兒童猝死背景値資料，我們進行臺灣與美國國家型資料庫猝死流行病學的比較研究。為了瞭解解剖構造與頻脈和猝死的關連，我們以先天性矯正型大動脈轉位這個解剖構造具雙重連接不一致(double discordance)的先天性心臟病族群，進行研究；為了將頻脈治療進行最佳化，我們發展了無輻射心導管治療心律不整技術與電磁解剖標測技術，並藉由病例對照研究了解這個新頻脈治療技術的安全性、可行性與成效。最後，為了探究基因變異對於不良心血管事件(包括: 心律不整、猝死等)的影響，以兒童左心室緻密不全這個心肌病變的世代資料進行研究。 研究結果 於全國性資料庫3,097,277位活產個案中，總計共1,661位發生猝死，男性佔56.8%。出生後累積猝死率，依年齡0、5、11、14歲，每1000活產中有0.35、0.49、0.56與0.59人次。這些猝死的兒童病患中，合併心臟疾患者有347名(20.9%)，其中先天性心臟患者有228名(65.7%)，具有非心臟之其他共病者則有300名(18.1%)。依年齡0、5、11、14歲的累積全因死亡率則為每1000活產中5.3、6.78、7.63與 8.06人。猝死之風險與全因死亡率皆隨出生年而逐步下降，其中猝死風險之下降，於2008年後尤其明顯。依地域分析，猝死風險與全因死亡率於臺灣東部最高，猝死佔全因死亡率之比例，則為北臺灣較高。與美國資料相比，其年齡逾14歲之猝死風險與全因死亡率分別為0.54與9.06人，其數據與我國資料相當，且長期趨勢觀之，亦隨出生年份有逐年降低。這些流行病學資料，對我國猝死之研究與相關之預防政策推動，相當有幫助。我們亦可以從全國流行病學資料，了解到具先天性心臟病病患，猝死的比率實是相當地高。 先天性矯正型大動脈轉位之研究顯示，追蹤20年與30年累積無發生心室上頻脈的比率分別為68%與54%。頻脈機轉與位於右心的副傳導路徑相關者最為常見(55.6%)，另外亦有相當高的比例是具有特殊的雙重房室結迴繞頻脈的狀況(33.3%)。以心導管進行頻脈燒灼者，成功率高且復發率低，以無輻射心導管技術進行燒灼成績亦相當。族群中有4位病患發生猝死(3.85%)。此部分研究結果顯示，先天性心臟結構異常與心律不整之特性與猝死之發生，具高度相關性。 推廣無輻射心導管到所有兒童頻脈治療後，我們發現可以在無輻射三維定位指引下成功燒灼去除右心與左心之頻脈病灶，不僅安全而且成功率高。於右心燒灼，68次傳統輻射導引燒灼的輻射線使用時間，平均為 30.9±23.9分鐘；41次的新式無輻射燒灼，無人使用輻射線(P < 0.001)。兩組間成功率以及復發率皆無差異。左心燒灼，雖然逆行性經主動脈進行燒灼困難度較高，於轉換前期仍須輻射線輔助導引，但整體仍有與傳統方式相同的高成功率與低復發率。對兒童以及輻射累積劑量較高的成人期先天性心臟病患，此一新技術相當重要。 至於基因變異於心肌病變族群之影響，我們蒐集了33位兒童期左心室緻密不全患者，有4例合併頻脈(2例猝死)。24位接受基因測試。其中肌小節基因變異有5名，離子通道基因變異2名，其他單一變異有4名，複合性基因變異則有6名。部分基因變異與頻脈有相關。顯示於兒童左心室緻密不全患者中，基因的調節對成長中兒童之重要性。而基因的調節對主要不良心血管事件，如心律不整與猝死的影響，對先天性心臟病患，亦可能佔有類似之重要角色。 結論 為了估量猝死與先天性心臟疾病之間的關連，我們建立了臺灣出生後的累積猝死與全因死亡率之基礎數據，並藉臺美對照，可見猝死率隨時間逐降。先天性矯正型大動脈轉位病患具雙重連接不一致之解剖學異常，其頻脈與猝死發生率，皆較一般人高。新科技發展帶來的無輻射心導管技術，有效而安全的地降低病患的輻射線暴露。基因資訊對成長中的兒童尤其重要，基因多型性帶來的基因調節效果，可能影響臨床表現，而多重基因變異，更可能增加頻脈或猝死之風險。 頻脈與猝死在兒童與成人期先天性心臟病患者族群中，有特殊的機制，其反映了個體於持續發展時期的影響。對於這類病患，相應治療的發展應考量其持續成長的需求，更需考慮多樣的基因變異與非基因因子可能造成的影響。

Background Tachyarrhythmia disorders in pediatric population and adults with congenital heart diseases (ACHD) carry significant morbidity and mortality. One of the most serious manifestations of tachyarrhythmia disorders is sudden cardiac arrest and ensuing sudden death (SD). Although SD is not common, the drastic presentation leads the issue the top-priority health issue. With medical advances, the management of tachyarrhythmia may be improved and the occurrence and outcome of SD may be reduced. However, relative studies are scarce and further investigation is of paramount importance. Methods We examined the epidemiological profile of pediatric SD as background reference and to know the importance of congenital heart disease (CHD) in SD by using nationwide databases from Taiwan and US. To elucidate the anatomical correlation, we investigated the mechanisms underlying the major adverse cardiovascular events (MACE), including tachyarrhythmia and SD in patients with congenitally corrected transposition of great arteries (ccTGA), a unique CHD with anatomical double discordance. To optimize treatment for tachyarrhythmias and prevent SD, we developed zero-fluoroscopy transcatheter ablation in children and ACHD, along with confirmation of safety, feasibility and effectiveness. Finally, we explored association and impact from genetic causes of left ventricular non-compaction (LVNC) and MACE in pediatric population. Results Our nationwide analysis for SD revealed 1661 children out of 3,097,277 live births with SD (56.8% male). The postnatal cumulative risk of SD was 0.35, 0.49, 0.56 and 0.59/1000 by age 0, 5, 11 and 14 years, respectively. Coexisting cardiac diagnosis was noted in 347 (20.9%), CHD in 228 (65.7%), and non-cardiac diagnosis in 300 (18.1%) patients. Cumulative all-cause mortality was 5.3, 6.78, 7.63 and 8.06/1000 by age 0, 5, 11 and 14 years. Risks of SD and all-cause death decreased over birthyear. SD risk decreased particularly after the 2008 birthyear. Risks of SD and all-cause death were the highest in Eastern Taiwan, but SD/all-cause death ratio was high in Taipei metropolitan and Northern Taiwan. Cumulative risk of SD (0.54/1000 by age 14) and all-cause mortality (9.06/1000 by age 14) in the US also decreased over time. These data are extremely helpful for us to have strategic planning for SD prevention. As compared with the general pediatric population, the risk was surprisingly higher in CHD patients. In patients with ccTGA, the 20-year and 30-year freedom from supraventricular tachycardia (SVT) was 68% and 54%, respectively. Tachyarrhythmias were associated with right-sided accessory pathways (5/9, 55.6%) and a unique twin atrioventricular nodal reentry (3/9, 33.3%). Catheter ablation was highly effective with low recurrence rate. There was four SD (3.85%). To optimize the ablation on the radiation reduction in children with or without CHD, we established a novel systematic non-fluoroscopic mapping/ablation. In the right sided substrates, the mean fluoroscopy time was 30.9±23.9 minutes in control group (68 procedures) while all 41 procedures in study group were performed without fluoroscopy (p < .001). The acute procedural success rates were similarly high in both groups and the recurrence rate was comparable at mid-term follow-up. As to the left-sided substrates, including SVT and ventricular tachycardia, which us more frequently associated with SD. In spite of the technology difficulty in retrograde transaortic approach under non-fluoroscopy guidance, the acute procedural success rates were high and the recurrence rate was low, without significant difference between the fluoroscopic and non-fluoroscopic guidance. The novel technology is particularly important for growing children who are relatively vulnerable to radiation. In analysis of 33 pediatric LVNC patients, 4 had tachyarrhythmia and 2 SD. Among the 24 patients who received genetic testing, isolated sarcomere gene variants were found in 5 patients, isolated channelopathy gene variants in 2, neuromuscular, mitochondria and other gene variants in 4. In addition, compound gene variants or chromosomal anomalies were found in 6. The yield of genetic findings in pediatric LVNC suggest important roles of genetic modification in growing children and may indicate the potential impact as a coexisting factor in children with CHD. Conclusions To estimate the risk of SD and the association with cardiac disease, especially CHD, we derived the postnatal cumulative risks of SD and all-cause mortality in Taiwan and US. The time trend underlined the impact from medical advance and education on SD prevention. With unique anatomical double discordance, patients with ccTGA are at high risk of not only tachyarrhythmia but also SD. Novel non-fluoroscopic guidance transcatheter ablation is effective and safe, and could reduce the radiation exposure hazard significantly. Genetic information is import particularly for growing children, including the genetic causes per se, genetic modification from single nucleotide polymorphism to influence the phenotype, the double or multiple hits to increase the risk of tachyarrhythmia or even SD. Tachyarrhythmia and SD in children and ACHD are distinct in the underlying mechanisms and reflect the developmental influence. Treatment needs to consider the growing potential and the various genetic and non-genetic modification.