Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs.

Atrial electrical remodeling is thought to be the cause of the maintenance of atrial fibrillation (AF). Although the initiation and maintenance of AF is partially associated with autonomic nervous tone, vagally mediated AF does not tend to become permanent. Therefore, the effects of preceding vagal stimulation (VS) on the atrial effective refractory period (ERP) under electrical remodeling conditions were investigated in anesthetized dogs. Atrial ERPs were measured at 5 sites before and after a 7-h period of atrial rapid pacing in the control group. In the VS group, the vagus nerve was stimulated for 20 min before a period of atrial rapid pacing. Atrial rapid pacing shortened the ERP at each site in the control group (electrical remodeling). On the other hand, atrial rapid pacing after VS did not shorten the ERP at any site in the VS group. Tetrodotoxin, which was administered into the fatty tissue overlying the right atrial side of the right pulmonary vein junctions, blocked the protective effect of VS against the shortening of the ERP induced by atrial rapid pacing. In contrast, atropine did not interfere with such protective effects. These results suggest that VS prior to atrial rapid pacing protects the atrium from atrial electrical remodeling.     

Region-specific, pacing-induced changes in repolarization in rabbit atrium: an example of sensitivity to the rare

OBJECTIVE: In subsets of patients paroxysmal firing of ectopic foci in pulmonary veins or coronary sinus is an important cause of atrial fibrillation. This appears to represent a rare event overriding a dominant sinus mechanism to alter the rhythmic firing of the atrium. Hence, we tested the hypothesis that a rare stimulation pattern might alter the myocardial substrate, making it more susceptible to the initiation of arrhythmias. METHODS: In isolated right and left rabbit atria, a "rare" burst pacing protocol (BPP) was applied as follows: over 3 h, preparations were driven for 4.5 min from sinus node (SN) or Bachmann's bundle (BB) regions at cycle length (CL)=400 ms followed by 30 s of stimulation from coronary sinus (CS) or pulmonary vein (PV) at CL=200 ms. Microelectrodes were used to record action potentials at the end of 4.5 min of pacing at CL=400 ms. We then intervened with 5-min bigeminal pacing to probe atrial vulnerability to arrhythmias: S1 was delivered from SN or BB and S2 from CS or PV, respectively. S1-S2 interval was the shortest eliciting a propagated response. RESULTS: BPP shortened repolarization in CS and PV regions but not in SN or BB, resulting in increased dispersion of repolarization in right and decreased in left atria. Propranolol, atropine and losartan failed to alter the decrease in repolarization induced by BPP whereas apamin, nifedipine and ryanodine prevented BPP effects. Before BPP, bigeminy did not induce arrhythmias in either atrium, but after BPP, bigeminy significantly increased the incidence of arrhythmias in the right atrium. CONCLUSIONS: BPP from foci outside the regions of dominant activation alters dispersion of atrial repolarization. Modulation of apamin-sensitive channels may contribute to the shortening of repolarization in CS and PV regions. Alterations of atrial repolarization gradient create an arrhythmogenic substrate and may be an early step in atrial electrophysiologic remodeling.     

犬快速心房起搏房颤模型肺静脉及心房组织心肌纤维化定量分析

目的：探讨持续性房颤时肺静脉及心房结构重构的变化,以期进一步阐明房颤的发病机制。方法：将18只健康杂种犬随机分为对照组（n=8）和房颤组（n=10）。房颤组犬以400次／分快速心房起搏制备房颤模型。10周后分别取两组犬的左上肺静脉（LSPV）、左房峡部（LAI）、右心耳（RAA）处心肌进行心肌纤维定量分析,并进行对照研究。结果：房颤组各部位Ⅲ型胶原含量显著高于对照组,分别为肺静脉3301．97±309．70对1404．56±178．02、左心房峡部2477．86±190．43对1479．20±187．17、右心耳2045．92±139．43对1417．07±139．43。房颤组Ⅲ型胶原的含量肺静脉组织显著高于左房峡部,左房峡部显著高于右心耳（P〈0．05）,且存在明显的梯度差。结论：快速心房起搏可导致肺静脉和心房组织纤维化程度增加,发生结构重构。肺静脉、左房峡部和右心耳心肌纤维化的程度存在显著的梯度差异,可能是结构重构的关键部位,在房颤维持过程中起重要作用。     

Clinical assessment of antiarrhythmic agents for paroxysmal atrial fibrillation guided by modification of electrophysiologic arrhythmogenicity

INTRODUCTION: Rapid atrial pacing alters atrial electrophysiology, promoting initiation and maintenance of atrial fibrillation (AF). The aim of this study was to assess differences in the electrophysiologic properties of atrial tissue between patients with and without AF episodes and to determine whether electrophysiologic properties can predict the clinical efficacy of antiarrhythmic agents. METHODS AND RESULTS: Sixty patients were studied, 33 with documented episodes of paroxysmal atrial fibrillation (PAF) and 27 control patients. Atrial effective refractory period (AERP), atrial vulnerability, and intra-atrial conduction time were measured at baseline and after rapid constant atrial pacing for 5 minutes at rates of 130, 150, 170, and 190 beats/min. The clinical efficacy of antiarrhythmic agents for PAF prophylaxis was assessed over 14 months with an antiarrhythmic agent identical to that administered intravenously, and the antiarrhythmic agent effects on AERP, atrial vulnerability, and intra-atrial conduction time were assessed. AERP shortening and atrial vulnerability increase were significantly larger in the PAF group. Antiarrhythmic agents that were clinically effective in suppressing PAF significantly attenuated AERP shortening, but antiarrhythmic agents that were clinically ineffective did not. CONCLUSION: Changes in AERP and atrial vulnerability observed after rapid atrial pacing are considered indicative of the electrophysiologic substrate of PAF. Attenuation of AERP and atrial vulnerability by antiarrhythmic agents might be useful in predicting their clinical efficacy.     

维拉帕米对家兔快速心房起搏所致心房结构和电重构的影响

目的:观察L-钙离子通道阻断剂维拉帕米对家兔快速心房起搏所致结构和电重构的作用. 方法:将24只家兔随机分为:对照组、快速起搏组和维拉帕米组.经颈内静脉将电极置入兔右心房.分别测定各组在0、2、4、6和8 h(记为P0、P2、P4、P6、P8)时的心房有效不应期(AERP200,和AERP150).左心房和肺静脉心肌袖组织行HE染色观察组织学改变. 结果:快速心房起搏组在不同基础刺激作用下AERP缩短,AERP200-AERP150的频率适应性不良,P8与起搏前P0比较差异显著(P<0.05).左心房和肺静脉心肌袖组织学改变明显.维拉帕米组AERP基本无改变(P>0.05),AERP200-150,频率适应性维持.左心房和肺静脉心肌袖与起搏组相比组织学改变较轻.结论:维拉帕米可以抑制快速心房起搏所致电重构,但不能逆转结构重构.     

Electrical and structural remodeling: role in the genesis and maintenance of atrial fibrillation

Atrial fibrillation (AF) and congestive heart failure (CHF) are 2 frequently encountered conditions in clinical practice. Both lead to changes in atrial function and structure, an array of processes known as atrial remodeling. This review provides an overview of ionic, electrical, contractile, neurohumoral, and structural atrial changes responsible for initiation and maintenance of AF. In the last decade, many studies have evaluated atrial remodeling due to AF or CHF. Both conditions often coexist, which makes it difficult to distinguish the contribution of each. Because of atrial stretch in the setting of hypertension or CHF, atrial remodeling frequently occurs long before AF arises. Alternatively, AF may lead to electrical remodeling, that is, shortening of refractoriness due to the high atrial rate itself. In many experimental AF or rapid atrial pacing studies, the ventricular rate was uncontrolled. In those studies, atrial stretch due to CHF may have interfered with the high atrial rate to produce a mixed type of electrical and structural remodeling. Other studies have dissected the individual role of AF or atrial tachycardia from the role CHF plays in atrial remodeling. Atrial fibrillation itself does not lead to structural remodeling, whereas this is frequently produced by hypertension or CHF, even in the absence of AF. Primary and secondary prevention programs should tailor treatment to the various types of remodeling.     

Remodeling in atrial fibrillation

BACKGROUND: Atrial fibrillation is associated with alterations in atrial electrophysiology that facilitate the initiation and persistence of the arrhythmia. This process was termed electrical remodeling in atrial fibrillation. The underlying cellular and molecular mechanisms have intensively been investigated over the past few years in patients with atrial fibrillation and in different experimental models. The results, that have substantially improved the understanding of the pathophysiology of atrial fibrillation, are reviewed. CELLULAR AND MOLECULAR MECHANISMS: On the cellular level, atrial fibrillation leads to a strong shortening and an impaired rate adaptation of the action potential as well as to changes in action potential morphology. Atrial fibrillation is associated with an altered gene expression of the L-type calcium channel (ICa,L) and of potassium channels (Ito, IK1, IKACh). The molecular mechanisms of intraatrial conduction slowing are less well understood, changes in the expression or distribution of gap junction proteins or a decrease of the fast sodium inward channel (INa) have been reported in some studies. A trigger of initiation for electrical remodeling is an overload of the cytoplasm with Ca2+ and a consecutive decrease of the systolic calcium gradient, furthermore changes in calcium-handling proteins are detectable in atrial fibrillation. CONCLUSION: These changes in the cellular and molecular milieu importantly determine the clinical course and the efficacy of therapeutical interventions in atrial fibrillation. The clinical relevance and potential new therapeutic approaches are discussed in the last part.     

心房有效不应期离散度与心房颤动

心房颤动是临床最常见的心律失常之一,有较高的致残率及致死率,关于心房颤动的机制有较多的学说,目前研究已经证实心房电重构能够促进心房颤动的发生与维持,心房电重构包括心房有效不应期的缩短,心房有效不应期离散度的增加及局部电传导的减慢,现就心房有效不应期离散度与心房颤动的关系及其影响机制做一综述。     

Atrial fibrillation: mechanistic insights from biatrial (and triatrial) mapping

Percutaneous radiofrequency ablation of pulmonary vein potentials has been shown to eliminate atrial fibrillation in a subset of patients characterized by frequent and repetitive paroxysms of atrial fibrillation. However, pulmonary vein disconnection has had only limited success at curing patients with persistent atrial fibrillation. In those patients, left atrial substrate modification and linear ablation strategies have had substantially higher success rates. Furthermore, in other patients, elimination of right atrial triggers (superior vena cava) or modification of right atrial substrate has been required for elimination of atrial fibrillation. Finally, the realization that the coronary sinus is a third atrial chamber that can both initiate and maintain atrial fibrillation has provided new understanding to the pathogenesis of atrial fibrillation. From a clinical perspective, only careful anatomic and mapping strategies specifically aimed at each subset of patients with atrial fibrillation will allow for pattern recognition and establish which mechanisms are responsible for initiation and maintenance of atrial fibrillation. Only the latter will allow for increased long-term success rates of ablation of atrial fibrillation.     

伊布利特逆转犬48小时房颤心房肌电重构作用研究

目的探讨国产富马酸伊布利特逆转犬48h房颤心房肌电重构的作用。方法健康成年杂种犬20只,随机分为快速起搏组（Pacing组,10只）和假手术组（Sham组,10只）。Pacing组通过右侧股静脉置入起搏电极,600次／min频率起搏高右房（HRA）制备房颤模型。48h后终止起搏,在心电和血液动力学监测下,给予国产富马酸伊布利特0．001m·kg^-1·min^-1静脉推注,房颤转复或累计剂量达0．04mg／kg停止给药。观察给药前后HRA的有效不应期（ERP,BCL=300ms）、传导速度（CV）、折返波长（WL）、频率自适应性、房颤诱发率等心房肌电生理指标的变化。结果Pacing组在起搏停止后,8只犬恢复窦律,2只犬持续房颤,给予伊布利特后1min内房颤终止。起博48h后,Pacing组ERP、CV、WL较Sham组减少,频率自适应性较Sham组降低,房颤诱发率明显增加;而给药后均恢复到起博前及Sham组水平。结论国产富马酸伊布利特能够逆转犬高右房快速起搏48h的心房肌电重构,有预防阵发性房颤发生的作用。其电药理学作用机制为：延长房颤时的心房不应期、心房肌电传导的速度及折返波长,提高心房肌频率的自适应性。     

Effect of atrial overdrive pacing on pulmonary vein focal discharge in patients with atrial fibrillation.

AIMS: Recently, it has been shown that atrial fibrillation may be caused by spontaneously discharging foci located predominantly in the pulmonary veins. However, the effect of atrial overdrive pacing on these pulmonary vein foci has not been studied. METHODS AND RESULTS: In 58 patients with drug refractory paroxysmal or persistent atrial fibrillation we performed radiofrequency catheter ablation of arrhythmogenic triggers inside the pulmonary veins and/or an ostial pulmonary vein isolation with conventional mapping and ablation technology. Continuous bigeminal pattern of discharge from one or more arrhythmogenic pulmonary veins was recorded in 14 patients. Atrial overdrive pacing resulted in suppression of pulmonary vein 'focus' activity in all patients. The longest mean atrial pacing cycle length resulting in overdrive suppression was 587+/-114 ms. Independent of pacing rate and duration, bigeminal pulmonary vein focus activity reemerged 2.5+/-3.7s after cessation of pacing. Overdrive suppression of the pulmonary vein focus was incomplete in 9 pacing attempts, and resulted in induction of atrial fibrillation from the same vein in 3 of 31 pacing manoeuvres. At 2 years follow-up 79% of these patients were free of atrial fibrillation, 55% without antiarrhythmic drugs, 24% on previously ineffective antiarrhythmic drug therapy. CONCLUSION: Stable pulmonary vein 'focus' activity in patients with atrial fibrillation can be suppressed by atrial overdrive pacing. However, 'proarrhythmic' effects of atrial overdrive pacing, such as induction of atrial fibrillation, were also seen.     

Contemporary approach to ablation of paroxysmal atrial fibrillation

Pulmonary veins have been shown to play an important role in the initiation and maintenance of paroxysmal atrial fibrillation. Seg-mental ostial isolation of the pulmonary veins results in cure in about 2/3 of the patients. This approach does not address non-pulmonary venous triggers of atrial fibrillation or the importance of the left atrium itself. Left atrial circumferential ablation has also been shown to be efficacious in patients with paroxysmal atrial fibrillation. This approach seems to address not only the various triggers of atrial fibrillation but also the left atrial substrate. Recently, a randomized study compared the 2 strategies and showed that left atrial ablation is superior to segmental ostial isolation. This review will highlight the anatomy and electrophysiology of the pulmonary veins, and the possible mechanisms by which they initiate and maintain paroxysms of atrial fibrillation. Segmental ostial isolation of the pulmonary veins and left atrial ablation will be compared as well.     

Pre-implant determinants of adequate long-term function of single lead VDD pacemakers.

AIMS: An inherent limitation of single lead VDD pacing is the inability to stimulate the atria. Reprogramming and upgrading the pacemaker system may be required when sinus node dysfunction, atrial undersensing, or atrial fibrillation develop. We evaluated whether routine clinical information is sufficient to select patients to benefit in long-term from VDD pacing. METHODS AND RESULTS: We collected data on 12-lead and monitored electrocardiograms and routine clinical information at implantation of a VDD pacing system in 350 consecutive patients with grade II or III atrioventricular conduction block. The age at implantation was 74.5 +/- 8.0 years, and the follow-up lasted 1.5 +/- 1.5 years. The cumulative maintenance of VDD pacing mode was 91.%. Loss of VDD mode was due to permanent atrial fibrillation in 16 (4.6%), sinus node dysfunction in six (1.7%). atrial undersensing in 11 (3.1%). Chronic atrial fibrillation developed in 23% of patients who had heart enlargement in chest x-ray and a history of paroxysmal atrial fibrillation or flutter. A criterion of normal sinus rate at implantation sufficiently predicted adequate sinus node function. Poor atrial sensing was not predicted by pre-implant characteristics. CONCLUSIONS: According to our data, adequate sinus-driven atrial rate and no history of paroxysmal atrial fibrillation and cardiac enlargement predict maintenance of the VDD pacing mode in elderly patients treated for heart block. Routine information available at implantation is sufficient to guide acceptance of single lead VDD pacing therapy.     

Heterogeneous pulmonary vein myocardial cell repolarization implications for reentry and triggered activity

BACKGROUND: Myocardial cells in the pulmonary veins (PVs) are thought to play a major role in the initiation and maintenance of atrial arrhythmias, including atrial fibrillation. However, systematic single-cell microelectrode recordings from different regions in intact PV-atrial tissues are lacking. OBJECTIVES: The purpose of this study was to determine the transmembrane action potential properties of myocardial cells in different regions of the PV and the left atrium (LA) and assess their arrhythmogenic potential during perfusion with isoproterenol (ISO) and rapid atrial pacing. METHODS: Glass microelectrode recordings of action potentials were made from the left PV and the LA in Langendorff-perfused young (3-4 month) male rats (Fisher344) (n = 9). RESULTS: Action potential duration (APD) of atrial and PV cells had similar duration at a pacing cycle length (CL) of 200 ms. However, shortening of the pacing CL to 100 ms led to heterogeneous repolarization of PV cells. Mid-PV cells had a significantly higher maximum slope of APD restitution than atrial or other PV sites. Intra-PV conduction block developed at rates when LA and proximal PV cells manifested 1:1 capture. Perfusion of ISO and rapid atrial pacing promoted the emergence of early afterdepolarization (EAD) and triggered beats in two out of nine tissues, causing premature atrial activation. No difference in resting potential or AP amplitude could be detected among the PV and LA cells. CONCLUSIONS: PV myocardial cells develop marked heterogeneity in repolarization, and there is a slight ease of developing EAD and triggered activity in response to rapid pacing and ISO infusion.     

Impact of pulmonary vein isolation on atrial vagal activity and atrial electrical remodeling

Objective Mechanisms of pulmonary vein isolation (PVI) for atrial fibrillation remain controversy.This study aimed to investigate the impact of PVI on vagal modulation to atria.Methods Eighteen adult mongrel dogs under general anesthesia were randomly divided into two groups.Bilateral cervical sympathovagal trunks were decentralized and sympathetic effects was blocked by metoprolol administration.Atrial electrical remodeling (AER) was established by rapid right atrial pacing at the rate of 600 bpm for 30 minutes.PVI was performed in group A.Atrial effective refractory period (ERP),vulnerability window (VW) of atrial fibrillation,and sinus rhythm cycle length (SCL) were measured at baseline and during vagal stimulation before and after atrial rapid pacing with and without PVI at fight atrial appendage (RAA),left atrial appendage (LAA),distal coronary sinus (CSd) and proximal coronary sinus (CSp).Results (1) Effects of PVI on vagal modulation:Shortening of SCL during vagal stimulation decreased significantly after PVI compared with that before PVI in group A (P＜0.001).Shortening of ERP during vagal stimulation decreaseed significantly after PVI compared with that before PVI (P＜0.05).VW of atrial fibrillation during vagal stimulation decreased significantly after PVI compared with that before PVI (P＜0.05).(2) Effects of PVI on AER:shortening of ERP before and after atrial rapid pacing increased significantly at baseline and vagal stimulation in group B compared with that in group A (P＜0.05).VW during vagal stimulation increased significantly after atrial rapid pacing in group B (P＜0.05).Conclusion PVI attenuates the vagal modulation to the atria,thereby decreases the susceptibility to atrial fibrillation mediated by vagal activity.PVI releases AER,which maybe contributes to the vagal denervation.Our study indicates that PVI not only can eradicate triggered foci but also modify substrates for AF.(J Geriatr Cardiol 2008;5:28-32)     

Physiological cardiac pacing: Current status

Adverse hemodynamics of right ventricular (RV) pacing is a well-known fact. It was believed to be the result of atrio-ventricular (AV) dyssynchrony and sequential pacing of the atrium and ventricle may solve these problems. However, despite maintenance of AV synchrony, the dual chamber pacemakers in different trials have failed to show its superiority over single chamber RV apical pacing in terms of death, progression of heart failure, and atrial fibrillation (AF). As a consequence, investigators searched for alternate pacing sites with a more physiological activation pattern and better hemodynamics. Direct His bundle pacing and Para-Hisian pacing are the most physiological ventricular pacing sites. But, this is technically difficult. Ventricular septal pacing compared to apical pacing results in a shorter electrical activation delay and consequently less mechanical dyssynchrony. But, the study results are heterogeneous. Selective site atria pacing (atrial septal) is useful for patients with atrial conduction disorders in prevention of AF.     

左房快速起搏对肺静脉口及心房肌电重构的影响

目的探讨左房快速起搏对肺静脉口、左右心耳电重构的影响。方法运用快速起搏左心耳的方法建立心房颤动(AF)模型,在起搏前及起搏后的第1,3,5,7d对左、右心耳;左上、左下肺静脉口;右上、右下肺静脉口的有效不应期(ERP)、ERP频率适应性、ERP离散度及心房间的传导时间进行测定。采用S1S2程序刺激,基础起搏周长(PCL)分别为400,300,200ms,S2为200ms,以5ms的步长递减。程序刺激结合Burst刺激对上述心房部位进行AF的诱发,记录AF的发生率。在第8天关闭起搏器,采用上述相同方法对起搏停止后即刻;2,4,6,24h的上述各部位的ERP进行测定。结果起搏1d后各个基础起搏周长下各部位的ERP明显缩短,ERP频率适应性降低,ERP离散度增大(P<0.05),而心房间传导时间无明显变化(P>0.05);起搏终止后各部位的ERP逐渐延长,但起搏终止后6hERP与快速起搏前相比仍有明显缩短(P<0.05);24h后ERP基本恢复到起搏前水平,两者相比无明显差异(p>0.05);随着起搏时间的延长各部位AF的诱发率逐渐增高(P<0.05)。结论快速心房起搏不仅引起心房肌电重构,亦引起肺静脉电重构。     

Prävention von Vorhofflimmern durch Schrittmacherstimulation

Several prospective randomized clinical trials have reported that atrial-based "physiological" pacing is associated with a lower incidence of paroxysmal and permanent atrial fibrillation than single-chamber ventricular pacing in patients with conventional pacemaker indication. Whether atrial pacing itself is antiarrhythmic remains still uncertain. By contrast, right ventricular pacing is considered to beget atrial fibrillation, even in preserved AV synchrony during dual-chamber pacing. A number of clinical trials investigated the impact of sitespecific atrial pacing and advanced atrial pacing algorithms on the secondary prevention of atrial fibrillation. Multisite pacing (dual-site right atrial or biatrial pacing) was demonstrated to add only minimal benefit for the prevention of atrial fibrillation. By contrast, in some studies septal pacing and specific atrial pacing algorithms were reported to reduce the recurrence of atrial fibrillation in selected patients. At present, however, it remains unclear how to identify these patients. In clinical practice, the effectiveness of specific atrial pacing algorithms and/or septal pacing has to be tested out in the individual case. These therapeutic options should be considered in patients with a conventional indication for antibradycardia pacing and, additionally, symptomatic atrial fibrillation.     

Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites

OBJECTIVE: Atrial fibrillation is often initiated by bursts of ectopic activity arising in the pulmonary veins. We have previously shown that a 3-h intermittent burst pacing protocol (BPP), mimicking ectopic pulmonary vein foci, shortens action potential duration (APD) locally at the pulmonary vein-atrial interface (PV) while having no effect elsewhere in rabbit atrium. This shortening is Ca(2+) dependent and is prevented by apamin, which blocks small conductance Ca(2+)-activated K(+) channels (SK(Ca)). The present study investigates the ionic and molecular mechanisms whereby two apamin-sensitive SK(Ca) channels, SK2 and SK3, might contribute to the regional APD changes. METHODS: Microelectrode and patch clamp techniques were used to record APDs and apamin-sensitive currents in isolated rabbit left atria and cells dispersed from PV and Bachmann's bundle (BB) regions. SK2 and SK3 mRNA and protein levels were quantified, and immunofluorescence was used to observe channel protein distribution. RESULTS: There was a direct relationship between APD shortening and apamin-sensitive current in burst-paced but not sham-paced PV. Moreover, apamin-sensitive current density increased in PV but not BB after BPP. SK2 mRNA, protein, and current were increased in PV after BPP, while SK2 immunostaining shifted from a perinuclear pattern in sham atria to predominance at sites near or at the PV membrane. CONCLUSIONS: BPP-induced acceleration of repolarization in PV results from SK2 channel trafficking to the membrane, leading to increased apamin-sensitive outward current. This is the first indication of involvement of Ca(2+)-activated K(+) currents in atrial remodeling and provides a possible basis for evolution of an arrhythmogenic substrate.