低强度迷走神经刺激在心房颤动治疗中的研究进展

心房颤动（房颤）是临床上最常见的心律失常之一,心房炎症和心脏自主神经重构是房颤触发和维持的重要机制,主要表现为心房的炎症因子水平升高、星状神经节或心脏表面神经节丛的神经放电增加。研究表明,低强度迷走神经刺激能够抑制星状神经节或心脏表面神经节丛放电及心房炎症,从而降低房颤负荷。但目前临床上仍缺乏个体化的低强度迷走神经刺激治疗方案,深入探索低强度迷走神经刺激的保护机制有助于该治疗方式的进一步发展。     

低强度迷走神经刺激对心房颤动影响的研究进展

研究发现迷走神经刺激并不都是致心律失常的,也可能有抗心律失常作用。颈部迷走神经刺激引起的心房颤动(简称房颤)是强度依赖性的,高强度迷走神经刺激有利于房颤的发生,而低强度的迷走神经刺激对房颤的发生没有影响。低强度迷走神经刺激,无论是刺激双侧神经,还是单侧神经,均可通过抑制心脏自主神经系统功能,预防和逆转房颤诱导的心房重构的发生,为临床上治疗房颤提供一种新的选择。     

低强度耳屏迷走神经刺激治疗心房颤动的研究进展

近年来,迷走神经成为心房颤动的潜在治疗靶点。研究发现,低强度耳屏迷走神经刺激可抑制心房颤动,延缓心房重构。本文就其机制和研究进展进行综述。     

迷走神经兴奋与心房颤动的相互关系和影响

心房颤动和迷走神经兴奋引起心房电生理特性的改变类似,包括心房不应期缩短,不应期离散度增加、传导速度减慢以及引发肺静脉处快速电活动等,但其具体机制不同;同时心房颤动与迷走神经兴奋间又存在相互影响,所以深入研究心房颤动与迷走神经的关系对加深心房颤动的认识及指导心房颤动的治疗很有意义。     

迷走神经刺激对心房颤动影响的双重作用

迷走神经刺激（VNS）可通过缩短心房有效不应期（AERP）和动作电位时程（APD）、增加AERP和APD离散度、促进心房电重构等机制诱发和维持心房颤动（简称房颤）,但最近有实验表明VNS除了致房颤作用外,在一定条件下具有治疗作用,低强度VNS可以抑制房颤的诱发,选择性房室结VNS可以控制房颤时快速心室率,但VNS治疗房颤的作用还面临着一些问题,仍需进一步研究。     

外源性与内源性自主神经刺激对心房颤动诱发性的影响

目的探讨心脏外源性与内源性自主神经刺激对心房颤动(房颤)诱发性的影响。方法16只成年犬静脉麻醉后,分离右颈迷走神经干(VST);再行右侧开胸手术,暴露靠近右上肺静脉的心脏脂肪垫(内含心脏自主神经丛,即GP),将1根电极导管固定贴靠于右上肺静脉,使其头端电极贴靠右上肺静脉与左房交界处,进行程序期前刺激,采用2倍、4倍、10倍阈值的刺激强度进行基础程序期前刺激(control),并测量相应的心房不应期(ARP)及房颤诱发窗宽(WOV);再分别加用VST刺激或GP刺激,测量在相应刺激条件下程序期前刺激所获得的ARP及WOV。结果平均基础心率(HR)为153±22次/min,VST刺激下HR为79±44次/min,GP刺激下HR为87±99次/min(后二者比较,P>0·05)。最短的ARP在control状态下为101±20ms、VST刺激下为90±17ms、GP刺激下为91±13ms,VST刺激下及GP刺激下均较control明显缩短(P<0·05),VST刺激下与GP刺激下的差异无统计学意义(P>0·05)。三者的累计WOV分别为control22±34ms、VST刺激下44±45ms、GP刺激下99±75ms,三者间每两者的差异均有统计学意义(P<0·05)。结论在降低心率相近的情况下,电刺激心脏内源性自主神经丛与电刺激心脏外源性自主神经引起的不应期缩短相近,但前者更容易诱发房颤。     

盐酸关附甲素在犬迷走神经性心房颤动模型中的作用

目的研究盐酸关附甲素终止心房颤动(简称房颤)的疗效,并探讨其抗心律失常作用的机制。方法30只杂种犬,在刺激双侧迷走神经的基础上给予快速心房刺激诱发房颤,随机分为生理盐水对照组、盐酸关附甲素低剂量组(15mg/kg)和高剂量组(22.5mg/kg)。观察盐酸关附甲素终止房颤和预防房颤再诱发的作用,以及对心房电生理指标的影响。结果对照组仅1只房颤终止;盐酸关附甲素低剂量组共9只房颤终止,均在注射第一剂药物后(P<0.01);高剂量组共8只房颤终止,7只在第一剂药物注射后,1只在第二剂药物注射后(P<0.01);盐酸关附甲素两个剂量组均显著延长心房不应期30ms以上;两个剂量均延长窦性周长、P波时限、PR间期、PR段、QT间期、QT-c间期、JT间期;盐酸关附甲素可预防房颤再诱发,低剂量组有6只,高剂量组有5只,均明显高于对照组(P<0.01)。结论盐酸关附甲素能够终止房颤,总有效率达87.5%,显著延长心房有效不应期可能是其抗心律失常作用机制之一;盐酸关附甲素可预防房颤再次诱发,有效率达50%以上。     

去自主神经条件下迷走神经刺激对肺静脉不同部位有效不应期的影响

目的探讨去自主神经条件下迷走神经刺激对肺静脉不同部位有效不应期(ERP)的影响。方法10只成年健康杂种犬,常规戊巴比妥钠麻醉,气管插管,接呼吸机,暴露并切断双侧颈迷走神经干,破坏颈交感神经节。双侧开胸,刺激电极分别与左、右心耳、左房及四支肺静脉缝合,行程序刺激,观察在基础状态、双侧强迷走刺激及阿托品作用时肺静脉不同部位ERP的变化。结果迷走神经刺激明显缩短肺静脉不同部位的ERP,而阿托品则可拮抗这种缩短。结论迷走神经刺激缩短肺静脉的ERP并参与房颤的发生。     

犬迷走神经性心房颤动模型的建立

目的制作犬迷走神经性心房颤动模型,评价可行性和持续性。方法针状电极分别插入颈部双侧迷走神经干,以3V-5V的电压/10Hz-20Hz的频率,刺激双侧迷走神经,在心率出现明显下降后,给予频率为10Hz-20Hz,电压为3V-5V的快速脉冲起搏刺激右心房,诱发心房颤动。结果迷走神经刺激的平均电压/频率为4.4V±0.7V/16.8Hz±3.3Hz,心率由基础的(171±26)次/分降为(97±8)次/分;在给予平均电压/频率为3.5V±0.6V/11.5Hz±2.2Hz的右心房起搏刺激后,36只杂种犬中31只(86.1%)成功诱发出持续性心房颤动,且在保持迷走神经刺激下,持续时间超过90分钟。结论本实验建立的犬迷走神经性心房颤动模型容易诱发,持续时间长,为评估抗心率失常药物对心房颤动的作用提供可靠的方法。     

犬左上肺静脉电刺激诱发心房颤动的电生理机制探讨

为探讨肺静脉异位电活动诱发心房颤动 (简称房颤 )的机制 ,选用 2 5只犬 ,将自制的 18导联环状标测电极置于左上肺静脉外膜上 ,从肺静脉远端采取S1S1、S1S2 两种刺激方法诱发房颤 ,记录房颤从发生到结束的全过程。结果 :2 2只犬完成试验。S1S1连续刺激、S1S2 程序刺激均可诱发房颤 ,在 2min内 3,10只犬分别被诱发 ;S1S2 诱发房颤的肺静脉标测图的特点是S2 较短 (15 2 .5± 6 .3ms) ;在S1S1持续刺激 19只犬诱发的 2 1次房颤事件中 ,有三类特征性肺静脉标测图 ,所占比例分别为 14 .2 9%、9.5 2 %、2 3.81% ,其共同点是肺静脉 左房传导速度突然递增。第一类是传导速度的递增造成心房激动的联律间期不断缩短 ,肺静脉异位刺激本身诱发房颤 ,第二、三类是传导速度的递增造成心房激动的长间歇 ,长间歇之后肺静脉异位刺激之外的逸搏或异位刺激诱发房颤。结论 :肺静脉异位刺激可使肺静脉和心房发生电重构 ,来自于肺静脉异位刺激或之外的激动可诱发房颤。     

低强度自主神经节刺激对心房电生理特性的影响

目的研究6h低强度自主神经节（GP）刺激对犬心房电生理性质的影响。方法22只成年杂种犬开胸暴露心脏,在左右心房、左右心耳及肺静脉缝置多极电极导管用以记录和刺激。实验组16只犬同时在左上GP及右前GP予以6h低强度高频刺激（0．1—1．0V）,使心率下降10％。对照组6只犬在心房远离GP处给于同样6h低强度刺激（无心房激动）。刺激前、刺激开始时及6h刺激后测定各部位有效不应期（ERP）及心房颤动（房颤）易颤窗口（WOV）。结果在实验组犬中,GP刺激开始时ERP及WOV较刺激前差异均无统计学意义,GP刺激6h后各部位ERP均显著缩短,总WOV显著增加（127＋35对0对0,P〈O．05）。对照组中,刺激前、刺激开始时及刺激6h后ERP及WOV（3±2对0对0,P〉0．05）差异均无统计学意义。结论6h低强度GP刺激可致心房电生理性质显著改变,并有利于房颤发生,提示长期低强度自主神经系统激活可形成有利于房颤发生的电生理基质。     

脊髓刺激干预自主神经治疗心房颤动的研究进展

<正>药物治疗是心房颤动(房颤)治疗的基础,但其研究进展缓慢且抗心律失常药物本身又具有致心律失常作用。尽管房颤射频消融术在2014年ACC发布的房颤诊治指南中的推荐级别有所上升,但消融的适应人群仍然有限,且缺乏硬终点的前瞻性随机对照试验。而Cox迷宫术,手术复杂、并发症多,手术的死亡率达1%²%。因此进一步探索房颤的机制及其新的治疗靶点仍是研究的热点之一。越来越多的证据支持自主神经系统(ANS)在房颤的触发和维持中     

Comparison of atrial fibrillation inducibility by electrical stimulation of either the extrinsic or the intrinsic autonomic nervous systems

Objectives  To study the effects of bilateral vagosympathetic nerve stimulation (VNS) and ganglionated plexi stimulation (GPS) on atrial refractoriness and inducibility of atrial fibrillation (AF). Methods  Studies were performed in fourteen adult mongrel dogs anesthetized with Na-pentobarbital, 30 mg/kg. VNS was achieved by insertion of wires into the left and right VN trunks. An octapolar catheter was attached to contact the right superior pulmonary vein (RSPV) and other octapolar catheter electrodes were sutured to the right atrial (RA) free wall and appendage (RAA). GPS was performed via a plaque electrode sutured to the fat pad containing the anterior right (AR) GP. VNS and GPS were matched to decrease heart rate by ∼50%. Programmed stimulation delivered from the RSPV or RAA at 2×, 4× and 10× threshold (TH) allowed the determination of atrial refractory period (ARP) and the AF inducibility. The latter was quantitated by the cumulative window of vulnerability (WOV), i.e., the longest minus the shortest coupling interval during which AF was induced at 2×, 4×, 10×, TH combined. Results  Programmed electrical stimulation at the RSPV showed that the ARP was significantly shorter for both VNS and GPS than baseline (baseline, 113 ± 22 ms; VNS, 94 ± 26 ms; GPS, 85 ± 31 ms) but there was no significant difference in ARP between VNS and GPS. In contrast, the cumulative WOV was significantly wider with GPS (39 ± 36 ms) than either the baseline state (1 ± 1 ms) or with VNS (14 ± 26 ms), p < 0.05. Moreover, pacing from RAA showed a significantly greater cumulative WOV for VNS (33 ± 36 ms) vs both baseline and GPS (1 ± 4 ms and 15 ± 26 ms, respectively, p < 0.05). The heart rate slowing caused by GPS and VNS was not significantly different, 82 ± 11/min vs 82 ± 7/min. Conclusions  These data indicate a distinct functional separation of autonomic nerve innervation to the atria from the extrinsic and intrinsic nervous systems. AF is more liable to occur due to intrinsic nerve stimulation at the PVs whereas peripheral atrial sites are more readily inducible for AF due to the extrinsic neural input. Supported, in part by grant #0650077Z from the American Heart Association (SSP), grant #K23HL069972 from the National Heart, Lung and Blood Institute (SSP) and from the Helen and Wil Webster Research Fund of the Oklahoma University Research Foundation.     

Vagal responses induced by endocardial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation

BACKGROUND: Elimination of vagal inputs into the left atrium (LA) may be necessary for successful catheter ablation of atrial fibrillation (AF). These vagal inputs are clustered in autonomic ganglia (AG) that are close to the pulmonary vein antrum (PVA) borders, but whether standard intracardiac echocardiography (ICE)-guided PVA isolation (PVAI) affects these inputs is unknown. OBJECTIVE: The purpose of this study was to assess whether standard ICE-guided PVAI affects vagal responses induced by endocardial AG stimulation in the LA. METHODS: Twenty consecutive patients undergoing first-time PVAI (group 1) and 20 consecutive patients undergoing repeat PVAI for AF recurrence (group 2) were enrolled in the study. Before ablation, electrical stimulation (20 Hz, pulse duration 10 ms, voltage range 12-20 V) was performed through an 8-mm-tip ablation catheter. Based on prior data, regions around all four PVA borders were carefully mapped and stimulated to localize AG inputs. A positive stimulated vagal response was defined as atrioventricular (AV) block, asystole, or increase in mean RR interval by >50%. Locations of positive vagal responses were recorded wth biplane fluoroscopy and CARTO. All patients then underwent standard ICE-guided PVAI by an operator blinded to the locations of vagal responses. Stimulation of the AG locations was then repeated postablation. RESULTS: Patients (age 54 +/- 11 years, 30% female, ejection fraction 54% +/- 7%) had a history of paroxysmal (75%) and persistent (25%) AF. In group 1, vagal responses were induced in all 20 patients around a mean of 3.8 +/- 0.4 PVAs per patient. The most common response was asystole (53%), mean RR slowing >50% (28%), and AV block (20%). Postablation, vagal responses could no longer be induced in all 20 patients. A diminished response was induced (RR slowing <50%) in 2/20 patients around one PVA each. In group 2, vagal responses were not induced in any of the 20 repeat patients. Stimulation capture postablation was confirmed because transient, nonsustained (<30 seconds) AF or atrial flutter was induced in all 40 patients with stimulation, whether vagal responses were induced or not. CONCLUSIONS: Standard ICE-guided PVAI eliminates vagal responses induced by AG stimulation. Responses are not seen in patients presenting for repeat PVAI, despite clinical recurrence of AF.     

迷走神经介导性心房颤动和六小时快速起搏介导性心房颤动的回复性质研究

目的 在迷走神经介导性心房颤动(房颤)和6h快速起搏介导的房颤模型中研究心房动作电位时限(APD)的回复性质.方法 18只犬随机分为迷走神经介导性房颤组(A组,n=8)和6h快速起搏介导性房颤组(B组,n=10).两组犬麻醉后开胸,暴露心脏,分别在多个肺静脉及心房部位记录单相APD.以APD复极90％(APD90)的时间为纵坐标、以其前的舒张间期为横坐标构建不同部位的APD回复曲线.结果 在A组,迷走神经刺激显著缩短每一部位的APD90、使回复曲线变平坦(斜率＜1)并抑制APD交替的发生,但同时迷走神经刺激增加房颤的诱发性和持续时间[(13±3)s对(5±1)s,P＜0.05].在B组,6h快速起搏缩短APD、使回复曲线变陡峭(斜率＞1)并促进APD交替的发生,同时房颤的发生率和持续时间增加[(10±3)s对(5±1)s,P＜0.05].结论 迷走神经介导性房颤和6h快速起搏介导的房颤具有不同的回复性质,提示不同机制的房颤具有不同的心房回复性质.     

Post-operative atrial fibrillation management by selective epicardial vagal fat pad stimulation

Purpose  Post-operative atrial fibrillation (POAF) is a common complication after cardiac surgery and often leads to poorly tolerated fast ventricular rates. Negative dromotropic drugs are not always effective and may not be well tolerated in heart failure patients. Aim of this study is to verify if high-frequency stimulation of the right inferior fat pad (RIFPS) allows an effective decrease in ventricular rate (VR) during POAF. Methods  We enrolled 32 consecutive patients submitted to bypass; during surgery, a temporary heart wire was implanted in a site where RIFPS evoked a functional AV block. During POAF, RIFPS was delivered from the heart wire to decrease VR. Results  Intra-operative RIFPS evoked complete AV block in 29 patients (91%). Fourteen patients (44%) developed POAF (mean VR 127 ± 12 bpm). In these patients, RIFPS achieved a 25% reduction of VR and complete AV block with 6.0 ± 1.9 and 7.5 ± 1.8 V (duration 0.2 ms, frequency 50 Hz), respectively. Conclusion  Epicardial RIFPS represents an effective and feasible technique to decrease VR during POAF. A. Della Scala and L. Kornet are employees of Medtronic. No other conflicts of interest exist.