Passive pericardial constraint protects against stretch-induced vulnerability to atrial fibrillation in rabbits

Atrial fibrillation is more common in conditions with elevated atrial pressure and can be induced experimentally with acute increases in atrial pressure. We examined the effect of increased atrial pressure with and without pericardial constraint to better separate the effects of increased pressure and atrial stretch. In Langendorff-perfused rabbit hearts with intact pericardium, after ligating the pulmonary and caval veins, intra-atrial pressures were increased in a stepwise manner by adjusting the pulmonary outflow cannula. Rapid burst pacing was applied to induce atrial fibrillation at increasing intra-atrial pressures from 0 to 24 cmH(2)O. The atrial refractory period was recorded at each pressure using a single extra stimulus. The protocol was repeated after the pericardium was removed. When the pericardium was intact, atrial stretch was limited by passive constraint, and sustained atrial fibrillation could not be induced despite atrial pressures in excess of 20 cmH(2)O. In contrast, when the pericardium was removed, atrial fibrillation could be reliably induced when atrial pressure exceeded 15 cmH(2)O. This suggests that the electrophysiological effects of acute atrial volume loading rely on atrial stretch rather than increased atrial pressure alone.     

Stretch-induced alterations of human Kir2.1 channel currents

The inward rectifier potassium channel, Kir2.1, contributes to the I(K1) current in cardiac myocytes and is closely associated with atrial fibrillation. Strong evidences have shown that atrial dilatation or stretch may result in atrial fibrillation. However, the role of Kir2.1 channels in the stretch-mediated atrial fibrillation is not clear. In this study, we constructed the recombinant plasmid of KCNJ2 that encodes the Kir2.1 channel and expressed it in CHO-K1 cells. We recorded I(K1) currents using the whole-cell patch clamping technique. Our data showed that I(K1) currents were significantly larger under stretch in the hypotonic solution than under non-stretch in the iso-osmotic solution, and the activation kinetics of the Kir2.1 channel were changed markedly by stretch as well. Thus, atrial stretch in human heart might result in excessive I(K1) currents, which is likely to increase the resting membrane potential and decrease the effective refractory period, to initiate and/or maintain atrial fibrillation.     

Mechanoelectric feedback leads to conduction slowing and block in acutely dilated atria: a modeling study of cardiac electromechanics

Atrial fibrillation, a common cardiac arrhythmia, is promoted by atrial dilatation. Acute atrial dilatation may play a role in atrial arrhythmogenesis through mechanoelectric feedback. In experimental studies, conduction slowing and block have been observed in acutely dilated atria. In the present study, the influence of the stretch-activated current (I(sac)) on impulse propagation is investigated by means of computer simulations. Homogeneous and inhomogeneous atrial tissues are modeled by cardiac fibers composed of segments that are electrically and mechanically coupled. Active force is related to free Ca(2+) concentration and sarcomere length. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between conduction velocity and I(sac) under stretch. In our model, conduction slowing and block are related to the amount of stretch and are enhanced by contraction of early-activated segments. Conduction block can be unidirectional in an inhomogeneous fiber and is promoted by a shorter stimulation interval. Slowing of conduction is explained by inactivation of Na(+) channels and a lower maximum upstroke velocity due to a depolarized resting membrane potential. Conduction block at shorter stimulation intervals is explained by a longer effective refractory period under stretch. Our observations are in agreement with experimental results and explain the large differences in intra-atrial conduction, as well as the increased inducibility of atrial fibrillation in acutely dilated atria.     

The role of stretch-activated channels in atrial fibrillation and the impact of intracellular acidosis

The incidence of atrial fibrillation correlates with increasing atrial size. The electrical consequences of atrial stretch contribute to both the initiation and maintenance of atrial fibrillation. It is suggested that altered calcium handling and stretch-activated channel activity could explain the experimental findings of stretch-induced depolarisation, shortened refractoriness, slowed conduction and increased heterogeneity of refractoriness and conduction. Stretch-activated channel blocking agents protect against these pro-arrhythmic effects. Gadolinium, GsMTx-4 toxin and streptomycin prevent the stretch-related vulnerability to atrial fibrillation without altering the drop in refractory period associated with stretch. Changes the activity of two-pore K+ channels, which are sensitive to stretch and pH but not gadolinium, could underlie the drop in refractoriness. Intracellular acidosis induced with propionate amplified the change in refractoriness with stretch in the isolated rabbit heart model in keeping with the clinical observation of increased propensity to atrial fibrillation with acidosis. We propose that activation of non-specific cation stretch-activated channels provides the triggers for acute atrial fibrillation with high atrial pressure while activation of atrial two-pore K+ channels shortens atrial refractory period and increases heterogeneity of refractoriness, providing the substrate for atrial fibrillation to be sustained. Stretch-activated channel blockade represents an exciting target for future antiarrhythmic drugs.     

The role of atrial dilatation in the domestication of atrial fibrillation

Numerous clinical investigations as well as recent experimental studies have demonstrated that atrial fibrillation (AF) is a progressive arrhythmia. With time paroxysmal AF becomes persistent and the success rate of cardioversion of persistent AF declines. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to the increase in stability of the arrhythmia. However, ‘domestication of AF’ must also depend on other mechanisms since the persistence of AF continues to increase after electrical remodeling has been completed. During the first days of AF in the goat, electrical and contractile remodeling (loss of atrial contractility) followed exactly the same time course suggesting that they are due to the same underlying mechanism. Contractile remodeling not only enhances the risk of atrial thrombus formation, it also enhances atrial dilatation by increasing the compliance of the fibrillating atrium. In goats with chronic AV-block atrial dilatation increased the duration of artificially induced AF-episodes but did not change atrial refractoriness or the AF cycle length. When AF was maintained a couple of days in these animals, a shortening of the atrial refractory period did occur. However, the AF cycle length did not decrease. Long lasting episodes of AF with a long AF cycle length and a wide excitable gap suggest that in this model AF is mainly promoted by conduction disturbances. Chronic atrial stretch induces activation of numerous signaling pathways leading to cellular hypertrophy, fibroblast proliferation and tissue fibrosis. The resulting electroanatomical substrate in dilated atria is characterized by increased non-uniform anisotropy and macroscopic slowing of conduction, promoting reentrant circuits in the atria. Prevention of electroanatomical remodeling by blockade of pathways activated by chronic atrial stretch therefore provides a promising strategy for future treatment of AF.     

心房颤动与Kv1.5钾通道阻滞剂及其研究进展

心房颤动是临床常见的心律失常,药物是心房颤动的主要治疗方法。胺碘酮和心律平等药物虽然可以治疗和转复心房颤动,但长期应用会引起恶性心律失常和心脏外的副作用。抑制Kv1.5钾通道电流,可选择性延长心房肌动作电位时程及有效不应期,改善心房肌的电重构和组织重构。近年来关于Kv1.5钾通道及其阻滞剂的研究迅速发展并引起广泛关注。为进一步探讨Kv1.5钾通道是否可能成为心房颤动的治疗靶点,我们对目前相关研究进展作一综述。     

N-乙酰半胱氨酸对犬心房快速起搏电重构的影响

目的：探讨N-乙酰半胱氨酸（NAC）对犬心房快速起搏电重构的影响。方法：取16只犬,随机分为对照组和NAC干预组。NAC组按照15mg／kg／d剂量给予NAC口服6周时间。在犬右房置入电极,快速起搏右心房,诱发房颤并维持2小时。在起搏前后分别测定有效不应期（AERP）。结果：房颤后对照组AERP显著缩短,AERP频率适应性下降（P〈0．05）;而NAC组房颤前后AERP和AERP频率适应性均无明显变化。结论：在心房快速起搏致房颤2h的模型中,NAC对心房电重构具有明显的保护作用。     

Effect of atrial dilatation on the tendency of atrial arrhythmias

The arrhythmogenic effect of atrial dilatation was studied by electrophysiological investigations carried out on 24 dogs. Atrial distension was evoked by increasing the pressure in the right atrium (12 to 14 mm Hg) or by the balloon dilatation of the left atrium. Programmed electrical stimulation of the heart was used for the electrophysiological investigations. In addition to the superficial ECG leads also atrial and ventricular epicardial electrograms were obtained for the ECG recording. Acute atrial dilatation led to shortening of the atrial refractory period, whereas neither impulse conduction of the heart, nor pacemaker activity of the sinus node exhibited any alteration. Atrial dilatation resulted in pathological atrial irritability, and early or frequent atrial stimulation caused atrial tachycardia of shorter (non sustained) or longer (sustained) duration. Repetitive atrial extrasystoles in response to early stimuli could also frequently be observed during atrial dilatation. The obtained results indicate that atrial dilatation is arrhythmogenic and may lead to the development of atrial tachycardia.     

Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha}

Transgenic mice overexpressing the inflammatory cytokine TNF-alpha in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-alpha mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias (n = 8/32) in TNF1.6 but not in control mice (n = 0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias (n = 6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca(2+) normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca(2+) handling. Thus abnormalities in action potential propagation and Ca(2+) handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure.     

Mechano-electrical feedback underlying arrhythmias: the atrial fibrillation case

Mechanoelectrical feedback (MEF) has become firmly established as a mechanism in which mechanical forces experienced by myocardial tissue or cell membranes convey alterations in electrophysiologic characteristics of such tissue. Observations to date mainly concern mechanically induced changes in action potential duration, resting and active potential amplitude, enhanced pacemaker frequency, or afterdepolarizations. While some of these changes (i.e. after depolarizations) may give rise to premature beats, a role of MEF in explaining sustained ventricular tachyarrhythmias has so far been elusive. Here, we review recent findings showing that acute atrial dilatation facilitates atrial fibrillation (AF) and that two stretch-activated channel (SAC) blockers (gadolinium and GsMTx-4) are able to suppress stretch-facilitated AF. These findings strongly support a role of MEF and SACs in promoting sustained arrhythmias and point to a new class of antiarrhythmic drugs.     

Mechanical effects on arrhythmogenesis: from pipette to patient

Mechanical stimuli delivered to the precordium can, if strong enough and timed at the beginning of the T-wave, induce ventricular premature beats or runs of ventricular tachycardia and even fibrillation. On the other hand, there are reports that a properly timed “chest thump” can terminate ventricular tachycardia, or can act as pacemaker stimuli during an episode of asystole. It is likely that in these cases mechanical energy is translated to an electrical stimulus.

There are more subtle ways in which mechanical stimuli, mediated by stretch, can exert electrophysiological effects, and the most common name to describe these effects is mechanoelectrical feedback. Most studies have concentrated on acute stretch or dilatation, while the effects of chronic stretch, which may clinically be more important, are difficult to evaluate since they are accompanied by other factors, such as hypertrophy, heart failure, fibrosis, neurohumeral disturbances, and electrolyte abnormalities, all of which have arrhythmogenic effects.

There are a number of ion channels that are activated following stretch. Stretch during diastole usually leads to a depolarization, resembling a delayed afterdepolarization, which may reach threshold and initiate a ventricular premature beat. Stretch during systole usually shortens the action potential, but action potential prolongation, resulting in early afterdepolarizations has been described as well.

The arrhythmias during acute myocardial ischaemia occur in two phases: the 1A phase between 2 and 10 min following coronary artery occlusion, and the 1B phase between 18 and 30 min. Experiments will be described, indicating that the ventricular premature beats of the 1B phase, which may induce ventricular fibrillation, are caused by stretch of the border between ischaemic and normal myocardium. Briefly, 1B arrhythmias are much less frequent in the isolated perfused heart than in the heart in situ, but in working, ejecting isolated hearts, the number of 1B arrhythmias is similar to those in the in situ heart. The ventricular premature beats have a focal origin at the border, and they occur more often after a pause-induced potentiated contraction.     

脂肪因子瘦素和内脂素与心房颤动关系的研究

摘要 目的：心房颤动（Atrial fibrillation,AF）是最常见的心律失常之一,其发生机制目前尚未完全阐明。多项研究表明脂肪因子（Adipokines）中的瘦素（leptin）、内脂素（Visfatin）与心血管疾病的关系密切,本研究拟探讨瘦素、内脂素与心房颤动的关系。方法：本研究通过收集检测AF组、窦性心律组外周血及心外膜脂肪组织,检测瘦素、内脂素分泌水平来探讨瘦素、内脂素与AF发生的相关性。结果：房颤组血清内脂素的平均浓度为15.95±10.44 ng/mL,窦性心律组为20.28±12.90 ng/mL（P=0.169）;房颤组血清瘦素的平均浓度为1.48 ng/mL,窦律组为2.56 ng/mL（P=0.0027）,窦性心律组血清瘦素水平明显高于心房颤动组;心外膜脂肪组织中,瘦素在房颤组中的表达量显著低于窦性心律组（P=0.032）,内脂素在两组中的表达无显著统计学差异（P=0.06）。结论：临床患者外周血血清及心外膜脂肪组织中高水平的瘦素可能降低房颤的发生率,然而,内脂素与房颤可能不具有相关性。     

心房颤动的流行病学研究现状及进展

心房颤动(atrial fibrillation,AF)简称房颤,是最常见的心律失常之一。为了能更好的预防房颤及其并发症,国外对该病的流行病学做了较多的研究,认为房颤的患病率和发病率均随着年龄的增长不断升高,尤其是80岁以上的老年人;男性的房颤患病率一般高于女性。房颤的危险因素不局限于既往较为公认的年龄、高血压、糖尿病、肥胖等,许多新的危险因素也陆续被发现,如高尿酸血症、阻塞性睡眠呼吸暂停、剧烈运动、气候等。我国在房颤方面的研究起步较晚,目前多局限于横断面的研究,无大规模纵断面的临床研究,和国外相比有一定的差距。房颤可导致机体发生脑卒中、心力衰竭、认知功能障碍甚至死亡。本文主要对心房颤动的流行病学研究现状及进展、发生的危险因素以及对机体的不利影响进行综述。     

电刺激兔下丘脑不同部位诱发的房性心律失常

在57只麻醉家兔,用同心圆双极电极刺激右侧下丘脑外侧区、前区、后区、背内侧核、腹内侧核五个不同部位,观察到均能诱发房性早搏等房性心律失常,且存在相对特异性。在用1mA 强度电刺激时,以前三个部位的诱发率较高。如预先轻度灼伤右心房后再刺激下丘脑外侧区或前区,可显著提高房性心律失常的发生率,并使诱发房颤等严重房性心律失常的机会有所增加。在同时描记股动脉血压的家兔中,观察到房性心律失常均在血压增高时出现,并以下丘脑后区、前区、外侧区的增压反应较为显著。在下丘脑外侧区增加刺激强度时,房性心律失常的发生率不随增压平均值的增加而递增,与室性心律失常不同。切断双侧颈迷走神经干后再刺激下丘脑同一部位时,原能诱发房性早搏的家兔全部不再诱发,而原能诱发以室性早搏为主的室性心律失常的部分兔仍能发生。这些结果提示,电刺激下丘脑诱发房性心律失常的机制与室性心律失常有所不同。     

Mechanisms of perpetuation of atrial fibrillation in chronically dilated atria

The progressive nature of atrial fibrillation (AF) has been demonstrated in numerous experimental as well as clinical investigations. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to the increase in stability of the arrhythmia. However, "domestication of AF" must also depend on other mechanisms since the stability of AF continues to increase after electrical remodeling has been completed. Chronic atrial stretch induces activation of numerous signaling pathways leading to cellular hypertrophy, fibroblast proliferation and tissue fibrosis. The resulting electro-anatomical substrate is characterized by increased non-uniform anisotropy and local conduction heterogeneities facilitating reentry in the dilated atria. Atrial fibrosis may lead to disruption of the electrical side-to-side junctions between muscle bundles. This can result in electrical dissociation between neighboring muscle bundles, i.e. they become activated out-of-phase. Recent mapping studies in goats with persistent AF showed that electrical dissociation can not only occur between neighboring muscle bundles but also in the third dimension, i.e. between the epicardial layer and the endocardial bundle network. Such endo-epicardial dissociation will significantly increase the number of wavefronts which can simultaneously be present in the atrial wall. This article reviews data suggesting a role of endo-epicardial dissociation in dilated and fibrillating atria, for the self-perpetuating nature of AF as well as its possible implications for therapeutic interventions.     

Loss of atrial contractility is primary cause of atrial dilatation during first days of atrial fibrillation

Atrial fibrillation (AF) induces a progressive dilatation of the atria which in turn might promote the arrhythmia. The mechanism of atrial dilatation during AF is not known. To test the hypothesis that loss of atrial contractile function is a primary cause of atrial dilatation during the first days of AF, eight goats were chronically instrumented with epicardial electrodes, a pressure transducer in the right atrium, and piezoelectric crystals to measure right atrial diameter. AF was induced with the use of repetitive burst pacing. Atrial contractility was assessed during sinus rhythm, atrial pacing (160-, 300-, and 400-ms cycle length), and electrically induced AF. The compliance of the fibrillating right atrium was measured during unloading the atria with diuretics and loading with 1 liter of saline. All measurements were repeated after 6, 12, and 24 h of AF and then once a day during the first 5 days of AF. Recovery of the observed changes after spontaneous cardioversion was also studied. After 5 days of AF, atrial contractility during sinus rhythm or slow atrial pacing was greatly reduced. During rapid pacing (160 ms) or AF, the amplitude of the atrial pressure waves had declined to 20% of control. The compliance of the fibrillating atria increased twofold, whereas the right atrial pressure was unchanged. As a result, the mean right atrial diameter increased by approximately 12%. All changes were reversible within 3 days of sinus rhythm. We conclude that atrial dilatation during the first days of AF is due to an increase in atrial compliance caused by loss of atrial contractility during AF. Atrial compliance and size are restored when atrial contractility recovers after cardioversion of AF.     

High-density mapping of pulmonary veins and left atrium during ibutilide administration in a canine model of sustained atrial fibrillation

Ibutilide can prolong refractory period and terminate reentry. Whether ibutilide has the same effects on pulmonary vein (PV) focal discharge (FD) is unclear. We induced sustained atrial fibrillation (AF) in seven dogs by rapid left atrial (LA) pacing for 74 +/- 46 days. Ibutilide was repeatedly infused until it terminated AF (0.02 +/- 0.01 mg/kg) or when a cumulative dose was reached (0.04 mg/kg). High-resolution computerized epicardial mapping was performed. We found intermittent FD at the PVs and reentry at the PV-LA junction during AF. Ibutilide increased the cycle length of consecutive reentry from 97 +/- 13 to 112 +/- 18 ms and increased FD from 96 +/- 7 to 113 +/- 9 ms. In four dogs with both FD and reentry at the PVs, the incidence of reentry decreased from 3.5 +/- 1.9/s at baseline to 2.2 +/- 1.8/s after ibutilide administration. However, the incidence of FD remained unchanged. The conducted wave fronts between PV and LA were significantly reduced by ibutilide (10.4 +/- 2.0/s vs. 8.0 +/- 1.6/s). The ibutilide dose needed to terminate AF correlated negatively with the baseline effective refractory period of PV and LA. We conclude that ibutilide reduces reentrant wave fronts but not PV FD in a canine model of pacing-induced sustained AF. These findings suggest that the PV FD during AF is due to nonreentrant mechanisms. High doses of ibutilide may completely terminate all reentrant activity, converting AF to PV tachycardia before the resumption of sinus rhythm.     

Pacemaker lead-related macroreentrant atrial tachycardia

Macroreentrant atrial circuits are frequently associated with scarring. Previous reports have shown the possible development of scar tissue that is adjacent to pacemaker (PM) leads. However, reports of PM lead-related reentrant tachycardia are scarce. We report the case of a 63-year-old woman who presented with macroreentrant atrial tachycardia (MAT), related to the atrial trajectory of an old single-lead ventricular PM, that was successfully treated with radiofrequency ablation after a conventional electrophysiological study ruled out isthmus-dependent atrial flutter and provided sufficient data to confirm this diagnosis. This report presents a case of MAT originating around the trajectory of a PM lead, probably because of scar tissue that developed adjacent to the lead. Experimental studies have already shown that interstitial atrial fibrosis may develop adjacent to a ventricular single-lead. This finding suggests that MAT develops in patients with this specific condition. Recognizing this condition is important for managing these arrhythmias and performing safe ablation with the preservation of PM lead integrity.     

Drugs that interact with cardiac electro-mechanics: old and new targets for treatment

The concept of mechano-electrical feedback was derived from the observation that a short stretch applied to the beating heart can invoke an electrical response in the form of an afterdepolarization or a premature ventricular beat. More recent work has identified stretch-activated channels whose specific inhibition might help to treat atrial fibrillation in the near future. But the interaction between electrical and mechanical function of the heart is a continuum from short-term (within milliseconds) to long-term (within weeks or months) effects. The long-term effects of pressure overload have been well-described on the molecular and cellular level, and substances that interact with these processes are used in clinical routine in the care of patients with cardiac hypertrophy and heart failure. These treatments help to prevent lethal arrhythmias (sudden death) and potentially atrial fibrillation. The intermediate interaction between mechanical and electrical function of the heart is less well-understood. Several recently identified regulatory mechanisms may provide novel antiarrhythmic targets associated with the "intermediate" response of the myocardium to stretch.     

Cyclical stretch induces structural changes in atrial myocytes

Atrial fibrillation (AF) often occurs in the presence of an underlying disease. These underlying diseases cause atrial remodelling, which make the atria more susceptible to AF. Stretch is an important mediator in the remodelling process. The aim of this study was to develop an atrial cell culture model mimicking remodelling due to atrial pressure overload. Neonatal rat atrial cardiomyocytes (NRAM) were cultured and subjected to cyclical stretch on elastic membranes. Stretching with 1 Hz and 15% elongation for 30 min. resulted in increased expression of immediate early genes and phosphorylation of Erk and p38. A 24‐hr stretch period resulted in hypertrophy‐related changes including increased cell diameter, reinduction of the foetal gene program and cell death. No evidence of apoptosis was observed. Expression of atrial natriuretic peptide, brain natriuretic peptide and growth differentiation factor‐15 was increased, and calcineurin signalling was activated. Expression of several potassium channels was decreased, suggesting electrical remodelling. Atrial stretch‐induced change in skeletal α‐actin expression was inhibited by pravastatin, but not by eplerenone or losartan. Stretch of NRAM results in elevation of stress markers, changes related to hypertrophy and dedifferentiation, electrical remodelling and cell death. This model can contribute to investigating the mechanisms involved in the remodelling process caused by stretch and to the testing of pharmaceutical agents.