室性心律失常的基质标测和预警研究

【作者】 刘霄燕；

【导师】 浦介麟；

【作者基本信息】 北京协和医学院 ， 内科学， 2014， 博士

【摘要】 背景：特发性室性心律失常(Idiopathic ventricular arrhythmia, IVAs)是临床上最常见的室性心律失常,多发生于无器质性心脏病的患者,主要包括流出道起源的室性心律失常(IVAs originating from outflow tract, OT-IVAs)和左室特发性室速(Idiopathic left ventricular tachycardia, ILVT)既往多认为IVAs预后良好,但近期的研究发现IVAs可导致左室心功能受损和可逆性心肌病,甚至引起心源性猝死(Sudden Cardiac death, SCD)。抗心律失常药物治疗是国际公认的一线治疗方案,但对于药物不敏感、依从性差的患者来说,导管射频消融(Radiofrequency catheter ablation, RFCA)可达到理想的根治效果。传统的电生理标测技术(激动标测和起搏标测)常受限于术中心律失常非持续、难诱发和局部心肌的不能夺获,使标测、消融的难度及不确定性增大。已证实基质的结构或功能异常是心律失常发生的本质,要根治IVAs,就需要深入研究其发生／维持基质。近年的研究发现部分异常电位与IVAs的消融靶点相关,并被认为是IVAs的发生／维持基质,使IVAs的致心律失常基质的标测和研究成为临床电生理的研究热点,也使得基于异常电位的基质标测逐渐从器质性心律失常发展至IVAs目的：本研究主要应用三维电解剖标测系统,辅以传统的标测技术,对临床常见的IVAs进行基质标测和研究。目的为：(1)尝试探讨起源于右室流出道(Right ventricular outflow tract, RVOT)起源的IVAs中舒张期电位(Diastolic potential, DP)的电生理特点及其对RFCA的指导意义；(2)分析主动脉窦(Aortic sinus cusp, ASC)起源IVAs消融靶点处前电位(Pre-Potential, PP)和晚电位(Late potential, LP)的电生理特点,并探讨其对消融靶点的预测作用；(3)结合既往的解剖学研究,了解ILVT患者左室传导系统(Left ventricular conduction system, LVCS)和缓慢传导区(Slow Conduction zone, SCZ,表现为心内心电图上的DP)的解剖变异情况,以推测ILVT的发生／维持基质和折返环路。方法：前瞻性选择2009年5月至2012年10月间于我院行导管射频消融治疗的单形性IVAs患者(病例组),术前经超声、心脏CT/造影及部分患者的心脏核磁检查排除器质性心脏病,电生理检查及射频消融治疗在签署知情同意书并停用抗心律失常药物≥5个半衰期后进行。术中常规放置标测电极于右室心尖部(ILVT患者还需放置希氏束标测电极),多导记录仪同时记录体表和心内心电图(滤波50-500Hz)。在三维电解剖标测系统(Carto XP,双极滤波10-400Hz)的指导下建立窦律下RVOT (RVOT-IVAs患者)、ASC和RVOT (ASC-IVAs患者)和左室内膜(ILVT患者)的三维电解剖图,部分患者构建三维激动图。标记异常电位(DP、PP、LP)和代表LVCS的蒲肯野电位的位置,以导管的位置、局部激动时间、心动周期三方面稳定性达最佳后进行采点并校正。RVOT-IVAs和ASC-IVAs的研究中采用传统标测方法(激动标测为主、起搏标测为辅)明确消融靶点：提前于QRS波的最早局部心室激动和／或起搏形态与自身IVAs心电图相似度≥11/12或Template matching score (TM score)≥90%; ILVT患者的理想消融靶点位于蒲肯野电位和SCZ的交汇区,消融前需进行隐匿性拖带刺激进行验证。靶点确定后,采用温控模式放电消融(根据消融部位采用不同的消融参数)。试放电30s内出现明显的IVAs频率加快或减慢时继续巩固放电至120s；否则终止放电,重新标测。成功消融终点为消融后30min内无IVAs复现,重复心室刺激和静滴异丙肾上腺素均不能诱发。分析的参数包括：异常电位的电生理特征及其与消融靶点的关系。对照组人群为：房室结折返性心动过速患者10例(RVOT-IVAs对照)、RVOT-IVAs和左侧旁路参与的房室折返性心动过速(Atrioventricular reentrant tachycardia mediated by a left-side accessory pathway, AVRT-L)患者各10例(ASC-IVAs对照)以及AVRT-L患者26例(ILVT对照)。成功消融临床心律失常后,分别在窦律下建立RVOT、ASC或左室的三维解剖图,标记异常电位的位置,并分析其与病例组的异同。结果：RVOT-IVAs的基质标测研究中,共入选RVOT-IVAs患者30例,对照组10例。病例组及1例对照组患者均于RVOT记录到DP。病例组患者的DP区位于肺动脉瓣环下1.4±0.3cm,面积为1.4±0.3cm。,最大振幅为0.3±0.1mV,三维电压标测显示该区域多位于电压移行带(0.5-1.5mY)。其中,24例患者(80.0%)的消融靶点位于DP区内,其他(6例,20.0%)位于DP区边缘,两组间靶点处局部心室激动时间和TM score无统计学差异(P>0.05)。根据窦律下心室激动与DP(V-DP和DP-V间期)的关系可认为DP具有递减和/或自律性,且窦律下V-DP间期显著长于IVAs时(371±57ms vs.268±64ms,P<0.001).ASC-IVAs异常电位对消融靶点的预测研究中,共入选患者29例,对照组20例。ASC-IVAs患者PP、LP发生率、消融前后LP平均振幅及消融后QRS-LP间期显著大于对照组(P<O.05)。病例组中,与非成功消融点相比,消融靶点处PP的平均振幅较小(0.80±0.53vs.0.24±0.25,P=-0.004),且消融前后LP的发生率显著增高(消融前：79.3%vs.30.0%；消融后：86.2%vs.20%,P<0.05)。与消融前相比,消融后消融靶点处LP振幅显著减小(0.30±0.07mV vs.0.21±0.07mV, P=0.016),且21例患者消融后QRS-LP间期显著延长(117±28ms vs.138±31ms, P=0.026),该现象对ASC-IVAs患者消融靶点的预测敏感度为72%,特异度为100%。ILVT的基质标测研究中,入选ILVT患者20例和对照组26例。病例组中,LVCS的解剖学变异可分为3型：左束支的两分支、三分支和扇形分布；与对照组相比各分支长度差异无统计学差异(P>0.05):SCZ亦存在解剖位置和数量的变异：后下间隔(17/20,85%)、间隔近心尖处(1/20,5%)和中后间隔处各一个SCZ(2/20,10％)。LVSC与SCZ共存的交汇区面积约1.5±0.4cm2,该处拖带和消融可取得成功。对照组中,6例患者于后下间隔出记录到SCZ,长度(16.1±3.3mm vs.20.4±4.7mm,P=0.048)和面积(1.8±0,3cm2vs.2.5±0.5cm2,P=0.006)均显著小于病例组。结论：位于电压移行带的DP及其附近区域与RVOT-IVAs的消融靶点相关,可能是IVAs的起源点或出口,其递减性和／或自律性提示该电位或来源于分化不完全或迁移的原始房室结组织。ASC-IVAs的消融靶点处多可记录到异常电位,与PP相比,LP对消融的指导意义最大,提示其可能是IVAs基质的心电学反应,消融后QRS-LP间期延长是预测消融成功与否的较为敏感和特异的指标。与对照组患者相比,LVCS和SCZ在ILVT患者间存在更大的解剖变异,提示ILVT的发生／维持基质变异较大、折返环路更为复杂,且蒲肯野电位和DP的交汇区是消融的关键区域。尽管未涉及解剖学和组织学研究,尚不能明确基质的组织学构成和病理价值,但本研究证实了基质标测在IVAs中的临床应用价值,为术中难诱发或多次消融失败的患者提供一种新的标测消融方法。背景：慢性心力衰竭(Chronic heart failure, CHF)因其较高的发病率、较差的预后和逐年增加的社会医疗负担等已成为当今世界的公共健康难题。尽管近年来已在研究和治疗方面取得了很大进展,尤其针对慢性收缩性心力衰竭(CHF with reduced ejection fraction, CHF-rEF)患者,但其发病率、再入院率和病死率仍然居高不下：国外报道患者5年死亡率约为50%,但尚缺乏现阶段国人CHF-rEF患者治疗现状及长期预后的前瞻性研究,未能对我国CHF-rEF患者进行综合评估。在CHF-rEF的死亡患者中,约半数死于恶性室性心律失常事件,即心源性猝死(Sudden cardiac death, SCD)。因此,对SCD进行预防和预警成为改善CHF-rEF预后的重要措施。研究发现有多种因素可提示CHF-rEF患者SCD的高发风险(包括心电学指标、血流动力学状态、生物学标记物和炎症因子等),但敏感性和稳定性欠佳,限制了其在临床的应用。随着分子遗传学研究的进展,包括一氧化氮合酶1衔接蛋白(NOS1AP)在内的多个基因的常见变异已确定为多种心血管疾病的遗传学标记物。且人群对SCD的易感性是一种可遗传的性状,连锁分析亦发现NOS1AP与多个独立人群的SCD相关。相关电生理研究证实：通过调节一氧化氮合酶1-一氧化氮信号通路(NOS1-NO)、L-型钙电流(ICa-1.)和延迟整流钾电流(IKr),NOS1AP的表达量与动作电位时程相关。目的：本研究为多中心、大样本的前瞻性研究,目的在于(1)揭示我国CHF-rEF患者的临床特征、治疗现状和长期预后；(2)探索NOS1AP基因的多态性与CHF-rEF患者预后的关系,从而确定CHF-rEF致SCD的遗传学标记物。方法：本课题入选对象为2005年7月至2009年12月期间就诊于阜外医院、北京大学人民医院、南京医科大学第一附属医院等13家合作医院,并经由病史、体格检查、血清学和影像学检查明确诊断的CHF-rEF患者。入选标准为：(1)因缺血性心肌病(Ischemic cardiomyopathy, ICM)或特发性扩张性心肌病(Dilated cardiomyopathy, DCM)导致的CHF-rEF;(2)左室射血分数(Left ventricular ejection fraction, LVEF)≤50%(ICM组)或≤45%(DCM组)；(3)纽约心功能分级(New York Heart Association class, NYHA)为Ⅱ-Ⅳ级。排除标准包括：(1)除ICM和DCM外其他病因引起的CHF-rEF;(2)病历资料缺失的患者；以及(3)恶性肿瘤、严重的全身性疾病、妊娠及不愿意参加本研究者。对照组为不伴有器质性心脏病的人群,分为病房对照和社区对照。病房对照为因阵发性室上性心动过速行射频消融术的患者,社区对照为体检正常且无心脏疾患史的社区居民。通过门诊随诊或电话、信件随访CHF-rEF患者的终点事件,包括全因死亡和SCD。采用单因素、多因素Cox回归和生存分析法确定全因死亡和SCD的独立预测因子,并分析不同病因致CHF-rEF的预后差异。采用候选基因法分析6个已报道与SCD相关的NOS1AP基因多态性位点与CHF-rEF致SCD的关系。该研究除外血标本质检不合格、心电图为持续性心律失常或起搏依赖,以及应用影响QT间期药物的CHF-rEF患者。研究采用聚合酶链式反应技术进行基因分型,分别对显性遗传模型和加性遗传模型进行分析。结合临床资料和随访结果,应用单因素、多因素Cox回归分析和生存分析方法对候选变异进行关联研究,并通过多元线性回归分析候选变异与QTc的关系。结果：共入选CHF-rEF患者2279例,在中位期为52个月的随访期间,成功随访患者2154例(94.52%)。我国CHF-rEF患者的治疗仍以药物治疗为主,其中血管紧张素转化酶抑制剂/血管紧张素受体抑制剂(ACEI/ARB)、β受体阻滞剂、利尿剂和螺内酯为主要治疗药物,处方率分别为65.97%,68.29%,74.37%和74.61%。随访期间,850例患者(39.46%)死于心力衰竭,其中302例(35.53%)为SCD。单因素分析显示DCM组全因死亡和SCD比例明显高于ICM组(P<0.001和P=0.004),而校正后无明显差异。两组患者预后的预测因素不同,但在总人群中,副发病变(如高血压等)、NYHA Ⅲ-Ⅳ、室速室颤、宽QRS时限、LVEF≤30%和血肌酐增加等与患者的预后不良相关,而ACEI/ARB、β受体阻滞剂和他汀类药物应用是CHF-rEF患者的保护性因素。既往存在室速／室颤转复事件是SCD最强的预测指标(HR,4.230;95%CI,2.500-7.157; P<.001)。CHF-rEF致SCD的遗传标记物研究中,共入选1428例CHF-rEF患者和480例对照。在中位期为52个月的随访期间内,467例患者(32.70%)死于心力衰竭,其中169例(36.19%)为SCD。基因分析结果显示携带NOS1AP基因上的rs12567209G>A次要等位基因A可增加CHF-rEF人群全因死亡(HR,1.381;95%CI,1.124-1.698;P=0.002)和SCD (HR,1.645;95%CI,1.184-2.287; P=0.003)的风险。校正风险因素后,A等位基因携带者全因死亡(HR,1.309;95%CI,1.054-1.624; P=0.015)和SCD (HR,1.601;95%CI,1.129-2.271; P=0.008)风险亦增加。同时,总人群中携带该等位基因者QTc间期显著延长(+4.04ms, P=0.026)。结论：即使在诊疗技术不断进步的今天,我国CHF-rEF患者的预后仍较差,尤其是DCM所致的CHF-rEF患者。伴有副发病变、NYHA Ⅲ-Ⅳ、LVEF≤30%、室速室颤史等的风险因素的患者有较高的SCD风险,而部分药物的应用(ACEI/ARB、β受体阻滞剂和他汀类)则是CHF-rEF患者的独立保护因素。准确识别这些预测因素可有助于预测患者预后和进行个体化治疗。NOS1AP基因上rs12567209的A等位基因不仅增加CHF-rEF患者的全因死亡和SCD风险,且与总人群的QTc延长相关。提示rs12567209G>A增加CHF-rEF患者全因死亡和心源性猝死的机制与调节心脏复极无关。更多还原

【Abstract】 Backgrounds:Ventricular arrhythmias, including premature ventricular contractions (PVCs) and ventricular tachycardia (VT), in the absence of structural heart disease were known as idiopathic ventricular arrhythmias (IVAs), and the majority of them were IVAs originating from outflow tract (OT-IVAs) and idiopathic left ventricular tachycardia (ILVT). IVAs were previously considered "benign", however, recent studies have shown that it could result in a left ventricular dilatation or reversible cardiomyopathy in certain advance cases:For medically refractory patients, radiofrequency catheter ablation (RFCA) had become a recommended therapeutic option with high success rate and low complication risk. However, there were inherent limitations in the process of traditional mapping (activation and pace mapping). Recently, the abnormal potentials have been recorded at the target ablation sites in IVAs clinically, which was considered as arrhythmogenic substrate. And the substrate mapping and research have become a hot topic in clinical electrophysiology study.Objectives:The present study was performed under the guidance of three-dimensional electroanatomic mapping system (EAM) and traditional mapping which was to determine the relationship between the IVAs and substrate systemically. The purposes were:(1) to clarify the electrophysiological characteristics of diastolic potential (DP) and its role in guiding ablation in IVAs from the right ventricular outflow tract (RVOT-IVAs);(2) to investigate the significance of pre-potential (PP) and late potential (LP) in predicting the target ablation site of IVAs from the aortic sinus cusp (ASC-IVAs);(3) to demonstrate the variation of the electroanatomic substrate (left ventricular conduction system, LVCS and slow conduction zone, SCZ) in ILVT.Methods:Between May2009and Oct2012, patients undergoing catheter ablation of monomorphic RVOT-IVAs, ASC-IVAs and ILVT in Fuwai hospital were included prospectively. The echocardiogram, thallium scintigraphy and/or coronary angiography as well as magnetic resonance imaging were performed to exclude structural heart disease, and antiarrhythmic drugs were stopped for at least5half-life times before operation. During the process, a quadripolar electrode catheter was placed in the right ventricular apex for pacing (another one was placed in His-bundle area in ILVT patients), and surface electrogram and intracardiac electrograms were displayed on the multichannel oscilloscopic recorder (Filtered at50-500Hz) simultaneously. After the geometry of the RVOT (RVOT-IVAs study), RVOT and ASC (ASC-IVAs study) and left ventricular (ILVT study) during sinus rhythm or during IVAs were reconstructed by systematic sampling, the abnormal potentials (DP, PP, LP and LVCS) were tagged on them. After that, traditional mapping (activation mapping and pace mapping) were performed in RVOT-IVAs and ASC-IVAs patients. When the earliest ventricular activation preceding the onset of QRS and/or an average template-matching score (TM score) was≥90%were obtained, a radiofrequency application was delivered. In ILVT patients, the crossover junction area with LVCS and DP was recognized as the marker of ablation, after performing the entrainment study with a cycle length of10-20ms shorter than ILVT cycle length. Radiofrequency energy was delivered in a temperature-controlled mode with different parameters according to the location of ablation. If IVAs were accelerated or abolished within30seconds, the application was continued for120seconds. If not. the energy application was terminated and the catheter was repositioned for a repeat attempt. Successful ablation criterion was that spontaneous IVAs were abolished and not inducible even under isoproterenol infusion for at least30min.Control groups were included:RVOT-IVAs controls:10subjects with atrioventricular nodal reentrant tachycardia (AVNRT); ASC-IVAs controls:10subjects with RVOT-IVAs and10subjects with atrioventricular reentrant tachycardia mediated by a left-side accessory pathway (AVRT-L); and ILVT controls:26subjects with AVRT-L. After ablated the clinical arrhythmias successfully, EVM was performed focused on different region of the endocardium according to design of study. Abnormal potentials were also tagged and analyzed.Results:In the study of RVOT-IVAs substrate mapping,30consecutive patients with RVOT-IVAs and10controls with AVNRT were studied. DP was recorded in all patients in the vicinity of the target site, with the area of1.4±0.3cm2, the maximal amplitude of0.3±0.1mV and the distance to pulmonary valve of1.4±0.3cm, which could still be recorded after ablation except one. The areas with DP mainly located in the transitional-voltage zone (0.5-1.5mV). The target site was within the DP area in24patients (80.0%) and was on the borderline in the other6patients. There was no difference in the local activation time and TM score at the target site between patients with the target site within or on the border of the DP area (P>0.05). According to the intervals between ventricular activation and DP (V-DP) during sinus rhythm, DPs were characterized by decremental and/or automatic property, and the V-DP intervals during sinus rhythm were longer than those during IVAs (371±t57ms vs.268±64ms, P<0.001).In the predictive study of ASC-IVAs substrate mapping,29patients with ASC-IVAs and20controls (10patients with RVOT-IVAs and10patients with AVRT-L) were included. The incidence of PP and LP, the amplitude of LP before and after ablation and interval between QRS and LP (QRS-LP) after ablation were significantly greater than those of controls (P<0.05). In ASC-IVAs group, compared with unsuccessful ablation sites, the amplitude of PP at the target site was smaller (0.80±0.53mV vs.0.24±0.25mV, P-0.004) and the incidences of LP were higher (before ablation:79.3%vs.30.0%; after ablation:86.2%vs.20%, P<0.05). Besides, compared with before ablation, the amplitude of LP was obviously decreased (0.30±0.07mV vs.0.21±0.07mV, P=0.016) and QRS-LP was longer in21patients (117±28ms vs.138±31ms, P=0.026) at the target site after ablation. The sensitivity and specificity of prolonged QRS-LP for predicting target were72%and100%.In the study of substrate and possible reentrant mechanism in ILVT,20patients with ILVT and26controls AVRT-L were included. In ILVT group, LVCS was distinguished into3types:left bundle branch was divided into two discrete fascicles without interconnections, three separate fascicles and fanlike structure distribution over septum broadly. There was no statistical differences in the length of fascicles between patients and controls (P>0.05). SCZ was located at inferoposterior septum in17patients, at inferior apex in1patient and at posterior and mid-septal with2SCZs in2patients. At the crossover junction area with LVCS and DP, with the size of1.5±0.4cm2, could achieved concealed entertainment and/or ablation successfully. However, in controls, the length (16.1±3.3mm vs.20.4±4.7mm,P=.048) and size (1.8±0.3cm2vs.2.5±0.5cm2, P=0.006) of6subjects were significantly shorter and smaller than those of ILVT group. Conclusions:DP and its border region, located at the transitional-voltage zone, were associated with the target site of RVOT-IVAs, the decremental and/or automatic property suggested that it might originate from tissue with incomplete differentiation or migrate from the original atrioventricular node.Many patterns of abnormal potentials were recorded at the target site during ablation of ASC-IVAs. LP, which might the arrhythmogenic substrate of IVAs, has greater significance for guiding ablation than PP. The prolonged interval between QRS and LP might become a sensitive and specific maker for predicting successful ablation. The anatomy of the LVCS and SCZ is highly variable in ILVT, which made the reentrant mechanism complicated. The crossover junction area with LVCS and SCZ might be a marker of ablation.Although it was not involve the anatomical and histological research, and the clinical significance of arrhythmogenic substrate has not yet clear, the present have demonstrated the clinical value and reliability of substrate mapping in mapping and ablation of IVAs. Substrate mapping might provide a new mapping strategy in IVAs, especially in patients without spontaneous IVAs or patients with multiple failures of ablation. Background:Chronic heart failure (CHF) represented a major public health problem worldwide owing to high prevalence, poor prognosis and extreme expenditure. Despite of advances in understanding and management of patients with CHF, especially in CHF with reduced ejection fraction (CHF-rEF), the morbidity and mortality as well as re-hospitalization rates were still high. The5-year mortality was still>50%, but the current data of long-term prognosis of CHF-REF in China were still missing. In the dead, greater than half of the deaths were due to sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) leading to sudden cardiac death (SCD). Therefore, prediction and prevention of SCD have been recognized as pivotal step toward improved outcomes. Several indicators have been recognized as potential predictors of SCD, such as hemodynamic status, electrophysiological parameters, biomarkers and inflammatory factors, but the sensitivity and specificity were not satisfied so far. The susceptibility of SCD was a heritable trait, and it has been demonstrated that single nucleotide polymorphisms (SNPs) of NOSIAP were associated with risk of SCD in several independent populations. Cellular electrophysiological study showed that overexpression of NOSIAP resulted in up-regulation of the nNOS-NO signaling pathway, which might abbreviate the action potential duration (APD) via inhibition of L-type calcium current (Ica-)L and activation of delayed rectifier potassium current (Ikr).Objective:The purposes of this multicenter, prospective study were (1) to reveal the clinical characteristics, current treatment status and long-term prognosis; and (2) to investigate the association between genetic variations of NOS1AP and prognosis of patients with CHF-rEF in Chinese Han population. Methods:Consecutive patients with CHF-rEF referred from13hospitals in China’s mainland were recruited. The CHF-rEF was diagnosed based on medical history, symptoms, physical signs and echocardiography on admission. Enrolment criteria included:CHF caused by idiopathic dilated cardiomyopathy (DCM) or ischaemic cardiomyopathy (ICM); left ventricular ejection fraction (LVEF)≤45%in DCM or≤50%in ICM and in New York Heart Association (NYHA) classes II-IV. Patients were excluded if they had incomplete clinical data, malignancies, severe systemic disease, pregnancy, or unwillingness to participate. Subjects without structural heart disease were considered as control group, and divided into ward controls and community controls. Follow-up data were obtained by regular visits at outpatient clinics or telephone contact, and the endpoints included all cause death and SCD. The independent predictors of endpoints and difference of prognosis in DCM and ICM were determined using univariate and multivariate Cox regression analyses.Participants were genotyped for6SNPs of NOS1AP and the genetic associations with mortality as well as QTc interval were analyzed. Patients with failure of genotyping, sustained arrhythmias and pacemaker dependency and using medicine that might alter QT interval were excluded. For statistical analysis, univariate and multivariate Cox regression and multiple linear regression models were used.Results:A total of2154patients with CHF-rEF were enrolled and followed up successfully in this prospective study. ACEIs/ARBs, β-blockers, diuretics and aldosterone receptor antagonists were dominant prescribed drugs with the rates of65.97%,68.29%,74.37%and74.61%, respectively. After a median follow-up of52months,850(39.46%) patients died, of whom302(35.53%) were SCD. Unadjusted rates of all-cause mortality and SCD were higher in DCM than those in ICM (p<0.001for both), but were comparable after adjustment for co-variables (p=0.387and p=0.483respectively). The predictors for mortalities in DCM and ICM were different, however, co-morbidities (eg, hypertension), advanced NHYA class, VT/VF, prolonged QRS duration, decreased LVEF and high level of creatinine were independent predictors of mortalities in the entire cohort, and ACEIs/ARB, β-blockers and statins were associated with better prognosis. Survived from sustained VT/VF episodes had the highest predictive value for SCD (HR,4.230;95%CI,2.500-7.157; P<0.001). A total of1428patients with CHF-rEF and480control subjects were genotyped. During a median follow-up period of52months,467(32.70%) patients died, of whom169(36.19%) were SCD. The A allele of rs12567209was associated with greater risk of all-cause death and SCD (HR1.381,95%CI1.124-1.698, P=0.002and HR1.645,95%CI1.184-2.287, P=0.003). After adjusting for co-variables, significances remained (HR1.309,95%CI1.054-1.624, P=0.015and HR1.601,95%CI1.129-2.271, P=0.008). The A allele was also associated with a prolonged of QTc interval by4.04ms in the entire cohort (P=0.026).Conclusions:Despite under current standard therapies, patients with CHF-rEF still had a poor prognosis in China, especially in DCM. The co-morbidities, advanced NYHA class, decreased LVEF and VT/VF were identified as independent predictors of SCD. While use of ACEIs/ARB,β-blockers and statins were multivariate predictors for survival. Independent predictors for mortality might be identified according to different etiologies and it would be useful for the prognostication and treatment of those patients individually.The A allele of rs12567209in NOSIAP not only increased the risk of all-cause death and SCD in patients with CHF-rEF, but also associate with prolongation of QTc interval in Chinese Han population, which suggesting the prognostic values of rs12567209might be mediated by other mechanisms rather than ventricular repolarization.更多还原