Influence of chronic volume overload-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria

Whereas molecular mechanisms of atrial fibrillation (AF) have been widely investigated, there is limited information regarding interrelation between chronic volume overload and parasympathetic nervous system in the pathophysiology of AF. In this study, we investigated the influence of abdominal aorto-venocaval shunt (AVS)-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria. Interstitial fibrosis, cardiomyocyte hypertrophy and atrial enlargement, known as structural arrhythmogenic substrates for AF, took place after one month of AVS operation. Carbachol at 0.1 and 1 μM shortened the effective refractory period, acting as functional arrhythmogenic substrates, but increased the conduction velocity both in the atria of the sham-operated and AVS rats. The extents of the electrophysiological responses to carbachol in the atria of the AVS rat were greater than those in the sham-operated ones. Also, the higher inducibility and longer duration of carbachol-mediated AF were detected in the AVS atria than those in the sham-operated ones. These results showed that chronic volume overload-induced atrial remodeling promoted electrophysiological responses to cholinergic receptor stimulation in the isolated atria of rats, suggesting possible synergistic actions between structural arrhythmogenic substrate in the remodeled atria and functional arrhythmogenic substrates modulated by parasympathetic nerve activity.     

Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload

Atrial dilation is an independent risk factor for the development of atrial fibrillation (AF) and modulates the efficacy of anti-AF drugs, leading to the unsatisfactory control of AF. Pre-clinical studies showed anti-AF effects of acehytisine, a multi-ion channel inhibitor, in atria without structural and/or electrophysiological abnormalities, but information is limited regarding its anti-AF efficacy in dilated atria. We evaluated anti-AF effects of acehytisine at 4 and 10 mg/kg intravenously infused over 10 min using 8-week-old Wistar rats (n = 5; male) with atrial dilation caused by aorto-venocaval shunt (AVS). Echocardiography showed that atria were enlarged by +26.9% after one month of operation in AVS rats compared with sham-operated rats (n = 4; male). Electrophysiological examinations indicated burst pacing-induced AF reached 206 s. Acehytisine at doses of 4 and 10 mg/kg decreased the duration of burst pacing-induced AF with prolongation of Wenckebach cycle length and P wave duration in a dose-dependent manner. Importantly, the drug effectively terminated the persistent AF that was resistant to multiple programmed electrical stimulations in one rat. Therefore, these results provide in vivo evidence that acehytisine may be beneficial for preventing and terminating persistent AF in dilated atria.     

Virtual tissue engineering of the human atrium: modelling pharmacological actions on atrial arrhythmogenesis

Computational models of human atrial cells, tissues and atria have been developed. Cell models, for atrial wall, crista terminalis, appendage, Bachmann's bundle and pectinate myocytes are characterised by action potentials, ionic currents and action potential duration (APD) restitution. The principal effect of the ion channel remodelling of persistent atrial fibrillation (AF), and a mutation producing familial AF, was APD shortening at all rates. Electrical alternans was abolished by the modelled action of Dronedarone. AF induced gap junctional remodelling slows propagation velocity at all rates. Re-entrant spiral waves in 2-D models are characterised by their frequency, wavelength, meander and stability. For homogenous models of normal tissue, spiral waves self-terminate, due to meander to inexcitable boundaries, and by dissipation of excitation. AF electrical remodelling in these homogenous models led to persistence of spiral waves, and AF fibrotic remodelling to their breakdown into fibrillatory activity. An anatomical model of the atria was partially validated by the activation times of normal sinus rhythm. The use of tissue geometry from clinical MRI, and tissue anisotropy from ex vivo diffusion tensor magnetic resonance imaging is outlined. In the homogenous model of normal atria, a single scroll breaks down onto spatio-temporal irregularity (electrical fibrillation) that is self-terminating; while in the AF remodelled atria the fibrillatory activity is persistent. The persistence of electrical AF can be dissected in the model in terms of ion channel and intercellular coupling processes, that can be modified pharmacologically; the effects of anatomy, that can be modified by ablation; and the permanent effects of fibrosis, that need to be prevented.     

射频消融治疗起源于主动脉无冠窦的房性心动过速的效果

目的:探讨起源于主动脉无冠窦或其邻近组织的房性心动过速(房速)的电生理特性及射频消融治疗的效果。方法:选择阵发性房速患者10例,术中予心房或心室刺激诱发房速,分别在右心房、主动脉无冠窦内进行心房激动标测,分析体表心电图P波及窦性心律时P波特点,最后均于无冠窦内进行射频消融治疗。结果:心房刺激均能反复诱发和终止10例患者的房速,右心房的前间隔希氏束上部标测出相对提前的心房激动,但多次射频消融未成功,后于主动脉无冠窦内标测出心房激动较体表心电图提前,放电后终止10例房速的发作。房速时P波间期明显短于窦律时,差异有统计学意义(P<0.05)。术后随访(12.5±5.3)个月,均无房速复发及手术相关并发症出现。结论:经主动脉无冠窦内射频消融可作为治疗消融前间隔希氏束部位失败的一种新方法。     

典型房扑射频消融术后部分患者发生房颤的危险因素分析

目的 分析典型房扑射频消融术后部分患者发生房颤的危险因素。方法 选择2015年2月至2018年2月六安市人民医院体表心电图提示典型房扑、电生理检查均证实为三尖瓣环峡部依赖性房扑并成功给予三尖瓣峡部线性消融（CTIA）手术的患者68例,随访6～34个月。根据术后随访是否发生房颤分为两组,其中发生房颤组23例,未发生房颤组45例,比较两组患者年龄、基础疾病、P波宽度及离散度、左房内径（LAD）、左室舒张末内径（LVEDD）、左室射血分数（LVEF）及口服药物的差异。结果 两组患者的P波宽度、P波离散度、LAD、LVEDD、LVEF进行比较,差异有统计学意义（P<0.05）。logistic回归分析显示,LAD、P波宽度及离散度是典型房扑射频消融术后发生房颤的独立危险因素。结论 LAD、P波宽度及离散度是预测典型房扑射频消融术后发生房颤的重要指标。     

依贝沙坦对慢性房颤犬模型心房电重构的影响

目的:观察慢性房颤后的心房电重构(AER)现象并探讨其电生理机制,以及依贝沙坦对AER的影响,为房颤治疗提供进一步的理论基础和资料。方法:建立右心房高速起搏(500次/min)2周的慢性房颤犬模型,分为对照组(假手术组)、起搏组和药物组(起搏 依贝沙坦)3组,每组各6只犬。将6对双极记录电极分别缝于高位左、右和低位左、右心房外膜以及左、右心耳,采用心脏程序期前刺激法(S1S2),分别测量基础起搏周长为300、250和200ms时的心房有效不应期(AERP)、AERP频率适应性、AERP离散度、房颤诱发率及平均持续时间等电生理指标。结果:与对照组比较,起搏组的AERP显著缩短、频率适应性不良、AERP离散度增高、继发性房颤诱发率增高且持续时间延长(P<0.01),而药物组差异无统计学意义(P>0.05)。结论:2周快速心房起搏可导致实验犬的AER,依贝沙坦可有效地阻止AER的发生。     

Drug therapy for atrial fibrillation

Although the maintenance of sinus rhythm would be the ideal scenario for patients with atrial fibrillation (AF), recent randomised trials have questioned the value of this approach. A careful interpretation of their results showed the limited efficacy of currently available antiarrhythmic drugs in maintaining sinus rhythm, as well as their potentially serious side effects. Therefore, it is imperative to develop safer and more effective drugs for AF. Based on our improved understanding of the pathophysiology of AF and the mechanism of action of antiarrhythmic drugs, significant efforts are being made to develop new antiarrhythmic agents that would prevent electrophysiological remodelling, would be selective for the atria and, therefore, would not prolong ventricular repolarisation, thus lacking any proarrhythmic effect.     

Drug therapy for atrial fibrillation

Although the maintenance of sinus rhythm would be the ideal scenario for patients with atrial fibrillation (AF), recent randomised trials have questioned the value of this approach. A careful interpretation of their results showed the limited efficacy of currently available antiarrhythmic drugs in maintaining sinus rhythm, as well as their potentially serious side effects. Therefore, it is imperative to develop safer and more effective drugs for AF. Based on our improved understanding of the pathophysiology of AF and the mechanism of action of antiarrhythmic drugs, significant efforts are being made to develop new antiarrhythmic agents that would prevent electrophysiological remodelling, would be selective for the atria and, therefore, would not prolong ventricular repolarisation, thus lacking any proarrhythmic effect.     

Atrial fibrillation and atrial fibrosis

Atrial fibrillation (AF) is the most common arrhythmia in humans. It affects 5% of the population older than age 65 years and is projected to rise as the population ages. Experimental data from animal models of AF show that AF is associated with progressive structural and electrical remodeling of the atria. Atrial fibrosis alters atrial electrical conduction and excitability and provides a substrate for AF maintenance. However, whether fibrosis is causally related to AF or an epiphenomenon and the precise mechanisms underlying atrial fibrosis remain unclear. A variety of signaling systems involving angiotensin II and related mediators are centrally involved in atrial fibrosis. This article reviews the role that atrial fibrosis plays in AF, the mechanisms of atrial fibrosis, and emerging therapeutic approaches to AF aimed at attenuating atrial fibrosis.     

急性心房扩大对兔心房有效不应期的影响及维拉帕米的干预作用

目的:通过建立Langendorff灌流的离体兔心脏模型来研究急性心房扩大对心肌电生理参数及心房颤动(房颤)易感性的影响,了解维拉帕米对其的干预作用。方法:长耳白兔20只建立Langendorff灌流的离体兔心脏模型,随机分为对照组和维拉帕米组。起始右房压力为0,以步长为0.392kPa递增至1.176kPa,在每个压力水平分别测定窦性心动周长(SCL)、心房有效不应期(AERP);应用S1S2刺激评估房颤易感性。结果:随着右房压力由0升高至1.176kPa:(1)对照组AERP显著缩短(P<0.01),且右房压力与AERP呈显著性Spearman负等级相关(rs=-0.664,P<0.01)。(2)对照组S1S2刺激房颤诱发率显著升高(P<0.01)。(3)维拉帕米组不同右房压力水平下心肌各电生理参数及房颤诱发率均无统计学意义(P>0.05)。结论:急性心房扩大使AERP显著缩短,房颤易感性明显提高;维拉帕米可以减弱急性心房扩大对AERP的缩短作用及急性心房扩大对房颤易感性的升高作用。     

影像融合系统指导下导管消融伴双下肺静脉共同开口的心房颤动特点

目的探讨影像融合系统指导下导管消融伴双下肺静脉共同开口的心房颤动（房颤）的解剖学、电生理学和治疗学特点。方法1381例药物治疗无效的房颤患者在消融前接受磁共振血管造影或多排CT扫描,影像融合技术（CartoMerge^TM software）重建左心房和肺静脉。阵发性房颤者进行了触发灶的电生理标测。基本消融策略是在影像融合系统指导下“三环法”肺静脉隔离：两个环分别围绕两个上肺静脉,另一个环围绕双下肺静脉共同开口。结果影像融合系统成功重建1381例左心房和肺静脉并发现有12例（0．8％）为左、右下肺静脉共同开口,这种变异可分为两种形态：没有短共干的Ⅰ型双下肺静脉共同开口和有短共干的Ⅱ型双下肺静脉共同开口。多数阵发性房颤在共同开口内有触发灶。“三环法”肺静脉隔离术成功率83％。结论双下肺静脉共同开口可按有无短共干分为两型。共同开口内可能是阵发性房颤的重要病灶。在影像融合技术指导下进行“三环法”肺静脉隔离的消融策略可能是伴该种肺静脉变异的房颤患者较好的治疗方法。     

Contemporary Management of Direct Oral Anticoagulants During Cardioversion and Ablation for Nonvalvular Atrial Fibrillation

As overall prevalence of atrial fibrillation (AF) continues to rise, the number of patients who undergo ablation, or electrical/chemical cardioversion, to restore normal sinus rhythm continues to increase as well. As direct oral anticoagulants (DOACs) have continued to be incorporated into clinical practice for long-term anticoagulation for AF, experience with how best to manage use of DOACs during electrophysiologic procedures is evolving. This review is intended to provide health care providers with a summary of current evidence regarding the use of DOACs during cardioversion and catheter ablation and provide key considerations for their use during such electrophysiologic procedures. PubMed and MEDLINE were searched from inception through June 2018 for studies in humans comparing DOACs alone or against vitamin K antagonists (VKAs) in adult patients (> 18 yrs) who underwent cardioversion or AF catheter ablation using the following key words: “rivaroxaban,” “dabigatran,” “apixaban,” “edoxaban,” “non–vitamin K antagonists,” “direct or new oral anticoagulants,” “warfarin,” “vitamin K antagonists,” “cardioversion,” “ablation of atrial fibrillation,” “uninterrupted,” and “catheter ablation.” Four retrospective studies and three prospective trials comparing DOACs with VKA in patients undergoing cardioversion and three prospective studies in patients undergoing catheter ablation for AF were identified. Observational data and meta-analyses were also critically reviewed. Prospective trials to date suggest similar efficacy and safety with using DOACs in the setting of cardioversion and AF ablation compared to traditional therapy with VKA, with or without bridging. Injectable anticoagulant overlap can be avoided in patients receiving DOACs in the setting of cardioversion for AF. Minimal interruption in anticoagulation may be only necessary for AF ablation in those with highest bleeding risk, such as in renal dysfunction and where drug-drug interactions may increase risk for anticoagulant accumulation. Periprocedural advantages of DOACs include convenience, rapid and predictable onset of effect, improved patient satisfaction, and potential for reduced costs.     

Characterization of thrombogenic,endothelial and inflammatory markers in supraventricular tachycardia: a study in patients with structurally normal hearts

Patients with atrial fibrillation (AF) are at an increased risk of thromboembolism and stroke primarily from the development of thrombi within the left atrium. Pathological changes in blood constituents and atrial endothelial damage promote left atrial thrombus formation. It is not known whether factors predisposing to left atrial thrombus formation in AF are disease specific or also evident within the normal heart. The present study examined whether there are differences in platelet reactivity, endothelial function and inflammation in blood samples obtained from intracardiac and peripheral sites in subjects within structurally normal hearts. Sixteen patients with diagnosed left‐sided supraventricular tachycardia (SVT) undergoing a routine elective electrophysiological study and ablation were investigated. Blood samples were taken simultaneously from the femoral vein, right atrium and left atrium, immediately following trans‐septal puncture and prior to heparin bolus administration. Between peripheral and atrial sample sites, patients with SVT showed no change in platelet reactivity or aggregation (P‐selectin (CD62P) P = 0.91; platelet‐derived soluble CD40 ligand P = 0.9), thrombus formation (thrombin–antithrombin complex; P = 0.55), endothelial function (von Willebrand factor P = 0.75; asymmetric dimethylarginine (ADMA) P = 0.97; nitric oxide P = 0.61), or inflammation (vascular cell adhesion molecule‐1 P = 0.59; intercellular adhesion molecule‐1 (ICAM‐1) P = 0.69). However, SVT patients had lower ADMA and ICAM‐1 levels than AF patients. The present study demonstrates, for the first time, that SVT subjects with structurally normal hearts have consistent haemostatic function between atrial and peripheral sites. These results suggest that the atria of SVT patients do not contain predisposing thrombogenic, endothelial or inflammatory factors that promote and/or initiate thrombus formation.     

ELECTROPHYSIOLOGICAL PROPERTIES OF THE FIBRILLATING ATRIUM: IMPLICATIONS FOR THERAPY

1. Atrial fibrillation (AF) is the most commonly occurring cardiac dysrhythmia and remains a challenge to medical therapy. Although the disorder has been recognized for over 100 years, surprisingly very little is understood about its pathophysiology. Over the past decade, a variety of experimental and animal models of AF have been developed and these have provided insights into the mechanism of AF. 2. The pathophysiology of AF is complex. Atrial fibrillation can be caused either by a single source of very rapid impulses or, in the majority of cases, by multiple random re-entering wavelets. The notion that AF may be initiated by a single rapid firing focus and the perpetuation of AF may be partly dependent on macro re-entry around the natural atrial orifices provides a new potential curative therapy for AF by radiofrequency ablation. 3. Shortening of atrial wavelength, either by slow atrial conduction velocities, short atrial refractory periods or both, seems to predispose to development of intra-atrial re-entry and, thus, AF. The functional mechanism by which anti-arrhythmic drugs terminate AF appears to be by prolonging the wavelength and decreasing the number of re-entry wavelets. These understandings are important for the future development of effective anti-arrhythmic agents against AF. 4. The presence of a short and variable excitable gap during AF may be potentially important for termination of AF by pacing. 5. New insights are being gained into the potential role and mechanism of electrical remodelling of the atrium due to AF. Repeated induction of AF by rapid atrial pacing leads to a shortening of atrial refractoriness with loss of rate adaptation, which favours the induction and maintenance of AF. These electrophysiological changes were assumed to occur during repeated AF and to facilitate the generation of multiple re-entrant wavelets. These data suggest that prompt restoration of sinus rhythm and new novel therapy that prevents or diminishes electrical remodelling may promote maintenance of sinus rhythm after successful cardioversion.     

Atrial-selective sodium channel blockers: do they exist?

The risk of developing severe ventricular arrhythmias and/or organ toxicity by currently available drugs used to treat atrial fibrillation (AF) has prompted the development of atrial-selective antiarrhythmic agents. Until recently the principal focus has been on development of agents that selectively inhibit the ultra-rapid delayed rectifier outward potassium channels (I Kur), taking advantage of the presence of these channels in atria but not ventricles. Recent experimental studies have demonstrated important atrioventricular differences in biophysical properties of the sodium channel and have identified sodium channel blockers such as ranolazine and chronic amiodarone that appear to take advantage of these electrophysiologic distinctions and act to specifically or predominantly depress sodium channel-mediated parameters in "healthy" canine atria versus ventricles. Atrial-selective/predominant sodium channel blockers such as ranolazine effectively suppress AF in experimental models of AF involving canine isolated right atrial preparations at concentrations that produce little to no effect on ventricular electrophysiologic parameters. These findings point to atrial-selective sodium channel block as a new strategy for the management of AF. The present review examines our current understanding of atrioventricular distinctions between atrial and ventricular sodium channels and our understanding of the basis for atrial selectively of the sodium channel blockers. A major focus will be on the ability of the atrial-selective sodium channel blocking properties of these agents, possibly in conjunction with I Kur and/or I Kr blocking properties, to suppress and prevent the reinduction of AF.     

Recent advances in pharmacotherapy of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia associated with increased morbidity and mortality. Efficacy and safety of currently employed antiarrhythmic drugs (AADs) continue to be less optimal in AF. Development of newer AADs has recently been made possible through a greater understanding of electro-pathophysiology of AF. Highly specific drugs acting on atria are currently being explored, although there is little data available on effectiveness of atrial specific agents in maintaining sinus rhythm. Combining AADs and non-AADs such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase effectiveness of AADs in patients with AF. Controlled clinical trials are required to precisely define the efficacy of single agents versus various combinations in maintaining sinus rhythm in patients with AF. This review describes some of the most promising therapeutic approaches that may overcome some of the limitations of drugs used at present for the management of AF.     

血清FGF-23对心房颤动患者射频消融术后复发的预测价值

目的 探讨成纤维细胞生长因子-23(FGF-23)对心房颤动（AF）患者射频消融术后复发的预测价值。方法选取接受射频消融术治疗的AF患者132例，依射频消融术后12个月的复发情况分为复发组（41例）和未复发组（91例）。另根据患者血清FGF-23的表达水平将其分为FGF-23高表达组和FGF-23低表达组。采用彩色多普勒超声诊断仪检测左心房内径（LAD），采用酶联免疫吸附试验试剂盒检测血清FGF-23的水平。结果 与未复发组比较，复发组持续性AF比例以及LAD、血清FGF-23水平升高（P<0.05）；持续性AF以及LAD、血清FGF-23水平过高均是AF患者射频消融术后复发的危险因素（P<0.05）；经受试者工作特征（ROC）曲线分析发现，血清FGF-23、LAD及两者联合检测预测AF患者射频消融术后复发的曲线下面积分别为0.770(95%CI:0.681～0.859)、0.743(95%CI:0.651～0.836)、0.828(95%CI:0.752～0.904)。FGF-23高表达组（FGF-23≥224.42μg/L,56例）的射频消融术后复发率明显高于FGF-2...     

More types than one: multiple muscarinic receptor coupled K+ currents undergo remodelling in an experimental model of atrial fibrillation

The common cardiac arrhythmia atrial fibrillation (AF) tends to show progression in its severity, which is associated with 'remodelling': structural and electrophysiological changes that facilitate arrhythmia induction and maintenance. In this issue of the BJP, Yeh and colleagues demonstrate for the first time, down-regulation of three types of muscarinic cholinergic receptor (mAChR) coupled K+ currents (IKM2, IKM3 and IKM4) and of M2, M3 and M4 mAChR subtype proteins, in a canine model of atrial tachycardia (AT) induced remodelling. The IKMs and their extent of AT-induced remodelling were similar in left-atrial and pulmonary vein (PV) myocytes, so remodelling of M2-M4 receptor-linked currents appears not to underlie the unique contribution of PVs to AF. Parasympathetic stimulation can increase susceptibility to AF; thus remodelling of M2-M4 receptors and K+ currents could be adaptive in AT. Further work is warranted to determine whether or not remodelling of multiple mAChRs and currents also contributes to human AF.     

IKur/Kv1.5 channel blockers for the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia. Anti-arrhythmic drugs remain the mainstay of therapy, but the available class I and III anti-arrhythmic drugs are only moderately effective in long-term restoring/maintaining sinus rhythm (SR) and can produce potentially fatal ventricular pro-arrhythmia. In an attempt to identify safer and more effective anti-arrhythmic drugs, drug discovery efforts have focused on ‘atrial selective drugs’ that target cardiac ion channel(s) that are exclusively or predominantly expressed in the atria. The ultra-rapid activating delayed rectifier K⁺ current (I_Kur), carried by Kv1.5 channels, is a major repolarizing current in human atria, but seems to play no role in the ventricle. This finding offers the possibility of developing selective I_Kur blockers to restore and maintain SR without a risk of ventricular pro-arrhythmia. Several I_Kur blockers are now being developed but clinical data are still limited, so the precise role of these agents in the treatment of AF remains to be defined. In this review we analyze the possible advantages and disadvantages of the developmental I_Kur blockers as they represent the first step for the development of potential atrial selective drugs for a more effective and safer treatment and prevention of AF.