【作者】 徐振兴；

【导师】 钟敬泉；

【作者基本信息】 山东大学 ， 内科学， 2014， 博士

【摘要】 研究背景：心房纤颤(AF)在阵发性室上性心动过速(PSVT)患者中的患病率高于一般人群。流行病学资料显示,超过1/3的房室折返性心动过速(AVRT)患者以及18%左右的房室结折返性心动过速(AVNRT)患者伴发AF。即使经射频消融术(RFCA)成功消融房室旁路(AP)或房室结慢径路后,伴AF的PSVT患者仍有较高的AF复发率(其中：AVRT患者的AF复发率为6-26%, AVNRT为30%左右)。可见,在导致PSVT患者AF高发的机制中存在“非AP和/或房室结慢径路依赖性”因素。自主神经系统的交感神经成分和副交感神经成分广泛分布于心肌组织。研究显示,刺激心脏交感神经可以提高心肌组织肌浆网的自发性钙内流和钙释放,进而导致AF的发生。然而,心脏交感神经刺激与PSVT患者的心房易损性以及AF患病率之间的相关性目前还不得而知。心房易损性(atrial vulnerability),是被广泛应用的评价AF自发或诱发难易程度以及心房组织维持心律失常(AF)电生理特性的指标。其中,心房有效不应期离散(dERP)和心房电机械延迟(atrial electromechanical delay)是被广泛应用的评价心房易损性大小的指标。虽然目前尚无临床参考界值,大量临床研究显示,较高的dERP和心房电机械延迟与心房易损性升高密切相关。大量基础研究也显示,心房易损性的增高与Kir2.1基因多态性、粘联素40基因多态性、心房的压力和内径、年龄以及自主神经刺激密切相关。然而,在测量与评估PSVT患者的心房易损性,预测PSVT患者AF的发生,指导PSVT患者AF的一、二级预防等方面,国内外未见类似报道。由于AF患者肺静脉的电生理特性与非AF人群显著不同,肺静脉电位被认为是人类AF的重要起源。研究显示,PSVT可以导致包括肺静脉在内的远端心房组织异位搏动,进而导致AF的发生。最近,Derejko等和Rostock等分别揭示了伴持续性AF和短阵诱发AF的预激综合征(WPW)患者的APs对肺静脉有效不应期的缩短效应。因此,PSVT通过对异位搏动的诱发进而导致“非PSVT依赖性AF”这一观点被广泛用于解释PSVT患者即使经RFCA术后仍有较高的AF复发率这一临床课题。肺静脉隔离术(PVI)是被广泛应用的治疗AF的有效措施,而PVI是否可以用于预防心房易损性高(例如,高dERP)且伴发AF的PSVT患者的AF复发,目前还不得而知。研究目的：研究目的主要包括：(1)、评估心房内电机械延迟(intra-atrial electromechanical delay)和心房间电机械延迟(interatrial electromechanical delay)对PSVT患者RFCA术后AF的预测效应。(2)、确定一个dERP的界值,用于区分伴AF的PSVT患者RFCA术中是否需要进一步行PVI治疗。(3)、探讨心脏交感神经刺激与PSVT患者心房易损性的关系。方法：入选人群：第一部分,心房电机械延迟对PSVT患者AF发生的预测研究。2007年1月至2009年10月于我院行超声心动图检测和RFCA治疗的连续524名PSVT患者。第二部分,肺静脉隔离对高心房有效不应期离散的PSVT患者AF复发的预防效应的评价研究2007年1月至2009年10月于我院行射频消融治疗的伴发AF(具有心电图或24小时动态心电图证据)的67名PSVT患者。第三部分,心脏交感神经刺激与PSVT患者心房易损性的关系研究2009年1月至2011年10月于我院行RFCA治疗的768名PSVT患者。PSVT包括：AVNRT、AVRT和WPW。以上所有入选者均签署通过伦理委员会审查的知情同意书。包括p受体阻滞剂、胺碘酮、钙通道拮抗剂、地高辛等在内的对心脏电生理功能有影响的药物,停药大于5个半衰期。排除标准包括：糖尿病、身体质量指数(BMI)≥25kg/m2、甲状腺功能异常、吸烟、嗜酒、高血压以及房性心动过速(AT)。心房电机械延迟的测量：在超声心动图下测量以下三个间期用于计算心房电机械延迟。T1：体表心电图P波的起始至二尖瓣前叶舒张晚期血流频谱的起始(A峰的起始)之间的时间间隔。T2：体表心电图P波的起始至二尖瓣后叶舒张晚期血流频谱的起始(A峰的起始)之间的时间间隔。T3：体表心电图P波的起始至三尖瓣舒张晚期血流频谱的起始(A峰的起始)之间的时间间隔。其中,心房间电机械延迟=T1-T3；,心,房内电机械延迟=T2-T3。dERP的测量：分别于高位右房(HRA)、低位右房(LRA)、冠状窦远端(CS1,2)和近端(CS9,10)4个部位测量心房有效不应期。心房有效不应期(AERP)为不能夺获心房的最长刺激间期(S1S2间期)。dERP为四个部位中最大AERP和最短AERP之差。肺静脉隔离：整个肺静脉隔离的射频消融过程在三维电生理标测系统的辅助下进行(Carto, Biosense Webster, USA)。经房间隔穿刺术及肺静脉造影后,在三维电生理标测系统上标记出肺静脉入口,进入消融程序。前壁和后壁分别给予40W,45℃及30W,43℃的消融能量,冷盐水灌注17-20ml/min。每个消融的位点放电持续时间为10-20秒,放电位置与肺静脉入口保持安全距离。消融终点为肺静脉隔离即肺静脉电位消失或心房-肺静脉电隔离。随访：所有病人在规定时间或出现心悸等AF症状时进行随访。随访或出现AF症状时,应用24小时动态心电图检测患者心律。终点事件为：出现有心电图或24小时动态心电图证据的AF。统计分析：数据的统计学分析应用SPSS13.0统计学软件。连续变量资料采用均数±标准差的形式表述,并应用student-t检验进行统计学分析。分类变量资料采取X2或Fisher精确概率法进行统计学分析。应用二元logistic回归,确定与房颤发生或复发有关的因素。受试者工作特征曲线(ROC curve)用于评价dERP及心房电机械延迟对AF出现的预测效应并确定界值。P<0.05表示差异有统计学意义。结果：第一部分,心房电机械延迟对PSVT患者AF发生的预测研究。ROC曲线分析结果显示,心房内电机械延迟≥4.45msec以及心房间电机械延迟≥20.65msec可以有效预测PSVT患者RFCA术后AF的发生(95%CI分别为：0.632-0.785和0.788-0.909,P<0.05)。第二部分,肺静脉隔离对高心房有效不应期离散的PSVT患者AF复发的预防效应的评价研究。ROC曲线分析结果显示,dERP≥74.5msec可以有效预测伴AF的PSVT患者RFCA术后AF的复发(P=0.003)。PSVT消融基础上增加PVI对房颤复发率的降低未达到统计学意义(17.2%,5/29vs.29.4%,10/34,P=0.203)。而对于dERP≥74.5msec的PSVT患者增加PVI治疗可以有效预防RFCA术后AF的复发(18.2%,2/11vs.77.8%,7/9,P=0.012)。第三部分,心脏交感神经刺激与PSVT患者心房易损性的关系研究。对心脏交感神经刺激敏感的PSVT患者RFCA术后AF的发生率较不敏感者高(26.83%,11/41vs.10.96%,8/73,χ2=4.761, P＜0.05)。二元logistic回归分析结果显示,年龄、左房内径、右房内径以及交感神经刺激是PSVT患者心房易损性的显著影响因素。结论：通过该项临床观察,主要得出如下结论：(1)、心房内电机械延迟≥4.45msec以及心房间电机械延迟≥20.65msec可以有效的预测PSVT患者RFCA术后房颤的发生。(2)、对dERP≥74.5msec且伴发AF的PSVT患者,进行APs或房室结慢径路的RFCA后,进一步行PVI治疗,可以显著降低AF的复发。(3)、交感神经刺激与年龄是PSVT患者心房易损性的显著影响因素。对PSVT患者的肺静脉有效不应期进行测量和评估可以进一步明确PVI在AF复发预防中的地位。由于交感神经刺激对PSVT患者心房易损性的影响,围绕抗肾上腺素治疗(例如β受体阻滞剂)对交感神经刺激敏感PSVT患者AF的预防可展开更多有临床价值的科学研究。主要创新点：(1)、该研究通过测量与评估PSVT患者心房易损性的具体指标(dERP、心房电机械延迟),达到预测PSVT患者RFCA术后AF发生的目的,进而指导PSVT患者AF的预防。(2)、随访观察行AP或房室结慢径路消融术联合PVI术的伴AF的PSVT患者的AF复发率,并确定是否联合PVI术的dERP界值,指导临床工作。(3)、以交感神经刺激为切入点,探讨RFCA术后的PSVT患者AF仍然高发的机制。更多还原

【Abstract】 Background:Atrial fibrillation (AF) occurs more frequently in paroxysmal supraventricular tachycardia (PSVT) patients compared with the general population. Even after successful ablation of accessory pathways (APs) or slow pathway of atrioventricular node in patients with atrioventricular reentrant tachycardia (AVRT) or atrioventricular nodal reentrant tachycardia (AVNRT), there remains a high risk of AF recurrence. So "PSVT independent factors" may influence the atrial vulnerability in PSVT patients in addition to APs and/or slow pathway of atrioventricular node. The heart is innervated by both sympathetic and parasympathetic nerves, which are part of the autonomous nervous system. Stimulation of the heart sympathetic nerve can increase calcium entry and the spontaneous release of calcium from the sarcoplasmic reticulum. All of these factors promote the occurrence of AF. However, the relationship between sympathetic stimulation and atrial vulnerability in PSVT patients is currently unknown.Atrial vulnerability was widely defined as the occurrence of spontaneous and inducible AF and maintenance and perpetuation of the arrhythmia in atrial tissues according to the electrophysiological mechanisms underlying AF. The primary indexes of atrial vulnerability include dispersion of atrial effective refractory (dERP) and atrial electromechanical delay. The increases in the dERP and the atrial electromechanical delay are known to be related with an incremental atrial vulnerability, although no critical value can currently be used as a reference. Previous studies have shown that polymorphism of Kir2.1gene and connexin40gene, the pressure and diameter of the atrium, age and neural stimulation can influence atrial vulnerability. However, there is no study for detecting the atrial vulnerability in PSVT patients.Pulmonary veins (PVs) have been demonstrated to be a crucial source of human AF because their electrophysiological properties are strikingly different from those of patients without AF. Previous studies have established that PSVT might trigger remote atrial ectopy, including PVs, in turn initiating AF. Recently, the shortening effect of a history and short-lasting AF on the effective refractory periods of PVs in PSVT patients with APs have been reported by Derejko et al. and Rostock et al. The concept that PSVT begets "PSVT independent AF" in ectopy is widely accepted as an explanation for the high AF recurrence in PSVT patients. Pulmonary vein isolation (PVI) is widely accepted as the cornerstone and most commonly used catheter-based treatment for AF. Approaches to AF recurrence prevention are scarce in PSVT patients with AF episodes before radiofrequency catheter ablation (RFCA). It is unclear that whether PVI procedure can effectively prevent AF recurrence or not. Objectives:This study primarily aimed to:(1), assess whether intra-and interatrialelectromechenical delay could predict AF in PSVT patients after successful treatment by RFCA;(2), determine a predictive dERP value for performing PVI in paroxysmal supraventricular tachycardia patients;(3), determine the relationship between sympathetic stimulation and the atrial vulnerability in PSVT patients with AF. Innovations:The main innovations of this study included:(1), determine atrial electromechanicaldelay cutoff value for predicting AF occurrence in PSVT patients;(2), PSVT patients associated with AF who underwent PSVT ablation plus PVI were followed up to identify the AF prevention effect of PVI procedure;(3), determine whether the residual atrial vulnerability in addition to AP and the slow pathway of atrioventricular node in PSVT patients were associated with sympathetic stimulation or not. Methods:Study population:Part1, Atrial Electromechanical Delay Predicts Atrial Fibrillation in Paroxysmal Supraventricular Tachycardia Patients after Radiofrequency Catheter Ablation524consecutive PSVT patients undergoing electrophysiology examination at Qilu Hospital between January2007and October2009were enrolled in this study.Part2, Effect of Pulmonary Vein Isolation on Atrial Fibrillation Recurrence After Ablation of Paroxysmal Supraventricular Tachycardia in Patients with High Dispersion of Atrial Refractoriness67PSVT patients who had presented to Qilu Hospital between January2007and October2009with any AF documented by ECG or24-hour Holter before successful RFCA,Part3, Sympathetic Stimulation Affects Atrial Vulnerability in Paroxysmal Supraventricular Tachycardia Patients with Atrial Fibrillation768patients were included who were diagnosed as wolff-parkinson-white syndrome (WPW syndrome), AVNRT or AVRT and treated with RFCA at Qilu Hospital between January2009to October2011.All patients provided signed informed consent and the protocol was approved by Research and Ethics Committee of Qilu Hospital. All antiarrhythmic medications (such as beta-blockers, amiodarone and calcium channel blockers), digoxin and other drugs that have an effect on cardiac electrophysiological properties were withdrawn for＞5half-lives prior to operation. For this analysis, we excluded participants with diabetes mellitus, BMI≥25kg/m2, thyroid dysfunction, substance abuse (alcohol, caffeine and nicotine), atrial tachycardia (AT) and hypertension at baseline examination.Atrial electromechanical delay measurement:To establish the atrial electromechanical delay of the atrium, three time intervals were measured based on the echocardiographic indexes.T1:time interval from the beginning of P-wave on surface ECG to the beginning of the late diastolic wave of the lateral mitral annulus. T2:time interval from the beginning of P-wave on surface ECG to the beginning of the late diastolic wave of the septal mitral annulus.T3:time interval from the beginning of P-wave on surface ECG to the beginning of the late diastolic wave of the tricuspid annulus.Interatrial electromechanical delay was the interval from T3to T1, expressed as T1-T3.Intra-atrial electromechanical delay was the interval from T3to T2, expressed as T2-T3.dERP measurement:The atrial effective refractory period (AERP) was determined as the longest delivered coupling interval of atrial extra-stimulation that failed to capture the atrium and was determined at each of the four atrial recording sites, HRA, LRA, distal and proximal CS (respectively CS1,2and CS9,10bipoles). The dERP was defined as the longest ERP minus the shortest ERP of the four sites.Pulmonary vein isolation:Ablation was guided by use of the three-dimensional (3D) mapping system (Carto, Biosense Webster, USA). After reconstruction of the LA, each PV ostium was identified by PV venography and tagged on the3-dimensional electroanatomical map. Irrigated RF energy was delivered at40W and45℃for anterior wall, and at30W and43℃for posterior wall, with30-40s duration for each lesion and saline infusion rate of17-20mL/min. Circumferential ablation lines using a4mm tip irrigated catheter were created at a distance from the PV ostia. The goal of circumferential pulmonary vein (PV) ablation was PV isolation, which was defined as disappearance of all PV potentials or atrium-PV potential dissociation.Follow upAll patients were followed up at the outpatient clinic and whenever patients complained of palpitations or other symptoms. A24-hour Holter recording was performed during the follow-up and whenever patients had symptoms such as palpitations, dizziness, and syncope. Study end point was the occurrence of any type of AF documented by ECG or24-hour Holter. Statistical analysis:Statistical analysis was performed using SPSS13.0software. Continuous variables are reported as mean±SD, and analyzed by Student t test, χ2and Fisher exact tests were used for categorical data. A binary logistic regression analysis was used to identify significant predictors of AF recurrence. Optimal dERP, intra-and interatrial electromechanical delay cut-off levels for AF recurrence prediction was evaluated by receiver operating characteristic (ROC) curve analysis. P＜0.05was considered statistically significant.Results:Part1, Atrial Electromechanical Delay Predicts Atrial Fibrillation in Paroxysmal Supraventricular Tachycardia Patients after Radiofrequency Catheter Ablation:The ROC cure analysis revealed that intra-atrial electromechanical dela≥4.45msec and interatrial electromechanical delay≥20.65msec were the most optimal cutoff value for predicting AF in PSVT patients after RFCA (95%CI,0.632-0.785and0.788-0.909, P＜0.05, respectively).Part2, Effect of Pulmonary Vein Isolation on Atrial Fibrillation Recurrence After Ablation of Paroxysmal Supraventricular Tachycardia in Patients with High Dispersion of Atrial Refractoriness:ROC curve analysis, dERP=74.5msec effectively predicted AF recurrence in PSVT patients (P=0.003). Difference in AF recurrence rate between groups did not reach statistical significance (17.2%,5/29vs.29.4%,10/34, P=0.203). AF recurrence rate was lower in patients with dERP＞74.5msec who underwent AP or slow-pathway ablation with vs. without PVI (18.2%,2/11vs.77.8%,7/9, P=0.012).Part3, Sympathetic Stimulation Affects Atrial Vulnerability in Paroxysmal Supraventricular Tachycardia Patients with Atrial FibrillationThe prevalence of AF was higher in patients sensitive vs. not sensitive to sympathetic nerve stimulation after18months follow-up. Logistic regression analysis showed that age, right and left atrial dimension, and sympathetic stimulation were the significant influencing factors for atrial vulnerability.Conclusions:Our analysis suggested that:(1), The atria-atrial electromechanical delay≥4.45msec and Interatrial electromechanical delay≥20.65msec could effectively predict AF in post-ablation PSVT patients.(2), PVI addition after successful AP or slow-pathway of atrioventricular node ablation significantly reduced AF recurrence in PSVT patients with high atrial vulnerability (dERP＞74.5msec).(3), In PSVT patients, the age and sympathetic stimulation are important factors of atrial vulnerability and the initiation of AF.Further studies will be required to evaluate the potential of targeted anti-adrenergic therapy, such as beta-blockers, for the prevention and treatment of AF in PSVT patients. The AF prevention effect for PVI procedure may be demonstrated convincingly by the PV potential and effective refractory period measurement in PSVT patients.更多还原