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.     

A possible role for atrial fibroblasts in postinfarction bradycardia

Atrial fibroblasts are considered to modulate the contractile activity of the heart in response to mechanical stretch. In this study we examined whether atrial fibroblasts are possibly involved in bradyarrhythmia, which is a severe complication after myocardial infarction. For this purpose, transmembrane electrical potentials were recorded in cardiac fibroblasts near the sinoatrial node from sham-operated rats and from rats with myocardial infarction. Twenty days after infarction due to coronary artery ligation, the right atrial tissue weights and the sensitivity of the fibroblast membrane potential to mechanical stretch correlated positively with the infarct size. Cardiac growth was enhanced, but the stretch sensitivity and the resting membrane potential of the atrial fibroblasts declined between 8 and 30 days after infarction. The frequency of spontaneous atrial contractions was significantly reduced 8 days after myocardial infarction and recovered in parallel with the membrane potential of the fibroblasts. These findings suggest that changes in the susceptibility of atrial fibroblasts to mechanical stretch may contribute to bradyarrhythmia during postinfarct remodeling of the heart.     

A mathematical model of human atrioventricular nodal function incorporating concealed conduction

This work develops a mathematical model for the atrioventricular (AV) node in the human heart, based on recordings of electrical activity in the atria (the upper chambers of the heart) and the ventricles (the lower chambers of the heart). Intracardiac recordings of the atrial and ventricular activities were recorded from one patient with atrial flutter and one with atrial fibrillation. During these arrhythmias, not all beats in the atria are conducted to the ventricles. Some are blocked (concealed). However, the blocked beats can affect the properties of the AV node. The activation times of the atrial events were regarded as inputs to a mathematical model of conduction in the AV node, including a representation of AV nodal concealment. The model output was compared to the recorded ventricular response to search for and identify the best possible parameter combinations of the model. Good agreement between the distribution of interbeat intervals in the model and data for durations of 5 min was achieved. A model of AV nodal behavior during atrial flutter and atrial fibrillation could potentially help to understand the relative roles of atrial input activity and intrinsic AV nodal properties in determining the ventricular response.     

Stretch-activated non-selective cation channel: a causal link between mechanical stretch and atrial natriuretic peptide secretion

The polypeptide hormone atrial natriuretic peptide (ANP) plays vital roles in maintaining blood volume and arterial blood pressure. The recognition of clinical benefits of ANP both in healthy and diseased heart identifies ANP as a potential candidate for therapeutic strategy in the treatment of heart disease. ANP is synthesized and stored in cardiac myocytes and it is released through the exocytosis of ANP granules both constitutively and in response to stimuli. It is well known that mechanical stretch is the predominant stimulus for ANP secretion. However, the mechanistic link between mechanical stimuli and exocytosis of ANP vesicles in single atrial myocyte has not yet been demonstrated. Over the last decade, compelling evidence suggested that stretch-activated ion channels might function as mechanosensors. We showed previously that direct stretch of single atrial myocyte using two micro-electrodes activated a non-selective cation channel (SAC). So far it is not known whether activation of SAC is involved in stretch-induced ANP secretion. The present article aims to give an overview of the mechanism of mechanical stretch-stimulated ANP secretion and describes an innovative technique to detect ANP secretion from isolated rat atrial myocytes with high time-resolution. Combined with capacitance measurement and patch-clamp technique in conjunction with in situ ANP bioassay, we were able to demonstrate that SAC in rat atrial myocytes acts as a mechanosensor to transduce stretch signals into the ANP secretion pathway.     

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.     

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.     

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.     

Atrial fibrillation precipitated by acute hypovolaemia.

Six patients with varying degrees of acute cardiorespiratory failure were seen. All patients deteriorated noticeably when rapid atrial fibrillation developed. In all patients intravenous digitalis failed to slow the ventricular response, and in three patients misguided attempts at electrical cardioversion failed. Haemodynamic monitoring showed a normal or low pulmonary artery occlusion pressure in all patients. Controlled expansion of plasma volume was associated with an immediate slowing of the heart rate in all patients, and the heart rate in all patients returned to sinus rhythm within 30 minutes of transfusion. It is suggested that hypovolaemia in critically ill patients may contribute to the development of atrial fibrillation.     

左心房顿抑的影响因素和发生机制

心房顿 抑是 指与 复律 前 相比 ,心房 颤动 复律 后 心房 和 心耳 机械 功能 暂 时被 抑 制的 现象 .心房 颤动 复律 方式 、心房 颤 动持 续 的时 间、心 房的 大小 、潜在 的结 构 性心 脏 病是 影响 心房 顿 抑的 因 素 .目前 心 房顿 抑可 能的 机制 有 :单 纯 性心 房颤 动 引起 的心 房 细胞 结构 的 变化 ;心房 的心 肌 细胞 内钙 离 子的 变化 ;快速 房 性心 肌炎 和心 房纤 维 症 .这 里主 要讨 论 心房 颤动 复 律后 左心 房 和左 心耳 发 生的 顿抑 现 象 .     

Mechano-electric feedback and atrial fibrillation

Atrial fibrillation frequently occurs under conditions associated with atrial dilatation suggesting a role of mechano-electric feedback in atrial arrhythmogenesis. Although atrial arrhythmias may be due both to abnormal focal activity and reentrant mechanisms, the majority of sustained atrial arrhythmias have been ascribed to reentrant activity. Atrial stretch may contribute to focal arrhythmias by inducing afterdepolarizations and to reentrant arrhythmias by increasing the atrial surface, by shortening the refractory period and/or slowing the conduction velocity and by increasing their spatial dispersion. Experimental and clinical studies have demonstrated that changes in mechanical loading conditions may modulate the electrophysiological properties of the atria. These studies have, for the most part, involved the effects of acute stretch on atrial refractoriness. While studies in humans and intact animals yield divergent results due to the variety of loading conditions and neurohumoral influences, experimental studies in isolated preparations clearly show that atrial refractory period and action potential duration at early levels of repolarization shorten by acute atrial dilatation. Both experimental and human studies have shown that acute atrial stretch is arrhythmogenic and may induce triggered premature beats and atrial fibrillation.     

Treatment of Cardiac Arrhythmias with Synchronized Electrical Counter-shock

Synchronized electrical countershock is an intriguing new method for the treatment of ectopic tachycardias. The authors applied this treatment to 20 patients with chronic atrial fibrillation and, in 17 patients, sinus rhythm was restored immediately. An additional four patients with atrial flutter were successfully converted to sinus rhythm. One patient developed a hemiplegia two weeks after cardioversion. No other untoward side effects were observed. In two patients with ventricular fibrillation electrical countershock terminated the arrhythmia. After successful cardioversion of atrial fibrillation, a maintenance dose of quinidine is given to help maintain sinus rhythm. In spite of this precaution, one-half of the patients reverted to atrial fibrillation within a month. The quinidine was administered for two to three days in advance of cardioversion; on this regimen, 10 of 34 patients reverted to sinus rhythm on quinidine alone and did not require countershock. The exact place of this treatment of cardiac arrhythmias has not yet been clearly defined.     

上胸段硬膜外阻滞治疗慢性心力衰竭合并房颤的临床研究

目的:比较上胸段硬膜外阻滞对有无合并房颤的扩张型心肌病心衰患者的疗效差异。方法:入选40例扩张型心肌病心衰患者,根据入院心电图有无房颤分为房颤组和非房颤组。所有患者均在抗心力衰竭常规治疗基础上,给予胸段硬膜外阻滞治疗4周,比较治疗前、后NYHA心功能分级、血浆N末端脑钠肽前体(NT-pro BNP)水平、左室射血分数(LVEF)、左室舒张期内径(LVEDD)及左房前后径(LAD)的变化情况。结果:与治疗前比较,两组患者经治疗后的NYHA心功能分级、NT-pro BNP、LVEF、LVEDD及LAD均明显改善(均P0.05),差异有统计学意义,但两组间各指标治疗前后的差值无统计学意义(P0.05)。结论:对于慢性心力衰竭合并房颤的患者而言,给予抗心力衰竭常规治疗基础上联合上胸段硬膜外阻滞治疗有效,且房颤的存在与否不影响上胸段硬膜外阻滞的疗效。     

Coupled pacing improves cardiac efficiency during acute atrial fibrillation with or without cardiac dysfunction

Coupled pacing (CP), a method for controlling ventricular rate during atrial fibrillation (AF), consists of a single electrical stimulation applied to the ventricles after each spontaneous activation. CP results in a mechanical contraction rate approximately one-half the rate during AF. Paired stimulation in which two electrical stimuli are delivered to the ventricles has also been proposed as a therapy for heart failure. Although paired stimulation enhances contractility, it greatly increases energy consumption. The primary hypothesis of the present study is that CP improves cardiac function during acute AF without a similar increase in energy consumption because of the reduced rate of ventricular contractions. In a canine model, CP was applied during four stages: sinus rhythm (SR), acute AF, cardiac dysfunction (CD), and AF in the presence of cardiac dysfunction. The rate of ventricular contraction decreased in all four stages as the result of CP. In addition, we determined the changes in external cardiac work, myocardial oxygen consumption, and myocardial efficiency in the each of four stages. CP partially reversed the effects of AF and CD on external cardiac work, whereas myocardial oxygen consumption increased only moderately. In all stages but SR, CP increased myocardial efficiency because of the marked increases in cardiac work compared with the moderate increases in total energy consumed. Thus this pacing therapy may be a viable therapy for patients with concurrent atrial fibrillation and heart failure.     

Chronotropic and inotropic dependence of the myocardium in patients with rheumatic heart disease before and after amiodarone treatment

Characteristic features of the electromechanical coupling of the myocardium were studied in patients with heart failure caused by rheumatic heart disease. Experiments were performed on muscle trabeculae isolated from the right atrial auricle in the course of surgical correction of a valve defect. The trabeculae displayed two types of mechanical responses, recorded in the isometric mode, to the postrest test. In the type I response, the mechanical restitution had an ascending pattern, the interval between electrical stimuli increasing. In type II, the mechanical restitution pattern was descending. Amiodarone (1 μM) treatment of the myocardium with the type I response enhanced the postrest potentiation of the mechanical response of trabeculae by more than 30%, but it had no effect on the muscles with the type II response. All patients whose biopsy material displayed the type II response had long episodes of atrial fibrillation. It is conceivable that the observed differences in the rhythm inotropic dependence of the human myocardium in rheumatic heart disease reflect different degrees of cardiomyocyte remodeling. The direction of this process is determined by the range of adaptive changes in intracellular structures, primarily, the sarcoplasmic reticulum.     

Clinical Characteristics,Management, and Control of Permanent vs. Nonpermanent Atrial Fibrillation: Insights from the RealiseAF Survey

Background

Atrial fibrillation can be categorized into nonpermanent and permanent atrial fibrillation. There is less information on permanent than on nonpermanent atrial fibrillation patients. This analysis aimed to describe the characteristics and current management, including the proportion of patients with successful atrial fibrillation control, of these atrial fibrillation subsets in a large, geographically diverse contemporary sample.

Methods and Results

Data from RealiseAF, an international, observational, cross-sectional survey of 10,491 patients with atrial fibrillation, were used to characterize permanent atrial fibrillation (N = 4869) and nonpermanent atrial fibrillation (N = 5622) patients. Permanent atrial fibrillation patients were older, had a longer time since atrial fibrillation diagnosis, a higher symptom burden, and were more likely to be physically inactive. They also had a higher mean (SD) CHADS₂ score (2.2 [1.3] vs. 1.7 [1.3], p<0.001), and a higher frequency of CHADS₂ score ≥2 (67.3% vs. 53.0%, p<0.001) and comorbidities, most notably heart failure. Physicians indicated using a rate-control strategy in 84.2% of permanent atrial fibrillation patients (vs. 27.5% in nonpermanent atrial fibrillation). Only 50.2% (N = 2262/4508) of permanent atrial fibrillation patients were controlled. These patients had a longer time since atrial fibrillation diagnosis, a lower symptom burden, less obesity and physical inactivity, less severe heart failure, and fewer hospitalizations for acute heart failure than uncontrolled permanent atrial fibrillation patients, but with more arrhythmic events. The most frequent causes of hospitalization in the last 12 months were acute heart failure and stroke.

Conclusion

Permanent atrial fibrillation is a high-risk subset of atrial fibrillation, representing half of all atrial fibrillation patients, yet rate control is only achieved in around half. Since control is associated with lower symptom burden and heart failure, adequate rate control is an important target for improving the management of permanent atrial fibrillation patients.     

Cardiac fibroblasts and the mechano-electric feedback mechanism in healthy and diseased hearts

Cardiac arrhythmia is a serious clinical condition, which is frequently associated with abnormalities of mechanical loading and changes in wall tension of the heart. Recent novel findings suggest that fibroblasts may function as mechano-electric transducers in healthy and diseased hearts. Cardiac fibroblasts are electrically non-excitable cells that respond to spontaneous contractions of the myocardium with rhythmical changes of their resting membrane potential. This phenomenon is referred to as mechanically induced potential (MIP) and has been implicated in the mechano-electric feedback mechanism of the heart. Mechano-electric feedback is thought to adjust the frequency of spontaneous myocardial contractions to changes in wall tension, which may result from variable filling pressure. Electrophysiological recordings of single atrial fibroblasts indicate that mechanical compression of the cells may activate a non-selective cation conductance leading to depolarisation of the membrane potential. Reduced amplitudes of MIPs due to pharmacological disruption of F-actin and tubulin suggest a role for the cytoskeleton in the mechano-electric signal transduction process. Enhanced sensitivity of the membrane potential of the fibroblasts to mechanical stretch after myocardial infarction correlates with depression of heart rates. It is assumed that altered electrical function of cardiac fibroblasts may contribute to the increased risk of post-infarct arrhythmia.     

Atrial remodeling in atrial fibrillation and association between microRNA network and atrial fibrillation

Atrial fibrillation (AF) remains one of the leading causes of morbidity and mortality in the world which are related to palpitations, fainting, congestive heart failure or stroke. The mechanism for atrial fibrillation has been identified as electrical remodeling, structure remodeling and intracellular calcium handling remodeling. microRNAs (miRNAs) have recently emerged as one of the important factors in regulating gene expression. So far, thousands of miRNA genes have been found in diverse animals with the function of regulating cell death, cell proliferation, haematopoiesis and even participate in the processing of cardiovascular disease. In this review, we summarize the mechanism of AF and the association of microRNAs network with AF. We provide a potential perspective of miRNAs as the therapeutic target for AF.     

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.