Ionic remodeling in the heart: pathophysiological significance and new therapeutic opportunities for atrial fibrillation

Heart disease has long been recognized to alter cardiac electrical function. Detailed studies of disease-induced remodeling of ionic transport processes that underlie ventricular electrophysiological alterations have been performed over the past 10 years, but our knowledge of atrial ionic remodeling is more limited and has emerged much more recently. The present review focuses on recent findings regarding ionic remodeling at the atrial level, particularly with respect to two conditions that promote atrial fibrillation (AF) in well-developed clinically relevant animal models: (1) sustained atrial tachycardia and (2) ventricular tachypacing-induced congestive heart failure. Complementary data from experimental models and from observations in atrial tissue samples from patients are examined critically and integrated. Consideration is also given to potential molecular mechanisms underlying remodeling, the relationship between atrial and ventricular ionic remodeling in response to similar stimuli, and the potential relevance of insights into ionic remodeling for understanding the pathophysiology of AF and developing improved therapeutic approaches.     

Arrhythmogenic ionic remodeling: adaptive responses with maladaptive consequences.

Compensatory changes in ion transport mechanisms occur in response to a variety of cardiac disease processes. Recent work has demonstrated that these adaptive responses can produce the arrhythmogenic substrate for a variety of important cardiac rhythm disorders. Two important paradigms are atrial tachycardia-induced remodeling and ionic remodeling caused by congestive heart failure. Atrial tachycardia promotes cellular Ca(2)+ loading and downregulates a variety of ion channels, particularly L-type Ca(2)+ channels, thereby promoting the occurrence and maintenance of atrial fibrillation. Congestive heart failure alters the expression and function of a variety of membrane transport processes, including several K(+)-channels and key Ca(2)+-transport systems, favoring the occurrence of arrhythmogenic afterdepolarizations. An improved understanding of the mechanisms and consequences of arrhythmogenic ionic remodeling promises to lead to novel and improved therapeutic approaches.     

Atrial electrophysiological remodeling caused by rapid atrial activation: underlying mechanisms and clinical relevance to atrial fibrillation.

One of the most exciting developments in our understanding of atrial fibrillation (AF) over the last several years has been the recognition that AF itself modifies atrial electrical properties in a way that promotes the occurrence and maintenance of the arrhythmia, a process termed 'atrial remodeling'. The principle stimulus for AF-induced atrial remodeling is the rapid atrial rate that results: rapid regular atrial pacing produces changes similar to those caused by AF in animal models. The mechanisms of atrial tachycardia-induced remodeling have been extensively explored, and involve changes in atrial electrophysiology associated with altered ion channel function. The most important ionic change is a reduction in L-type Ca2+ current, which reduces action potential duration (APD) and APD adaptation to rate. AF-induced changes in ion channel function appear to be due both to rapid voltage- and time-dependent alterations in channel availability caused by tachycardia and to slower downregulation of messenger RNA concentrations encoding alpha-subunits of specific ion channels. Atrial remodeling likely contributes importantly to a wide variety of clinical phenomena of previously unrecognized mechanism, including atrial dysfunction after cardioversion of AF, the increasing resistance to therapy of longer-standing AF, the association of AF with other forms of supraventricular tachyarrhythmia and the tendency of paroxysmal AF to become chronic. The present paper reviews the state of knowledge regarding the mechanisms and clinical consequences for AF of atrial remodeling caused by rapid atrial activation.     

内质网应激与衰老相关性房颤的研究进展

心房颤动（房颤）是临床上最常见的心律失常之一,表现为心房重构和收缩功能障碍,且其发病率随年龄增长而增加。近年来的研究显示,内质网应激在房颤的发生发展、病理生理过程中扮演着重要角色,内质网应激是指蛋白质分泌增加或内质网蛋白折叠中断可导致内质网腔内未折叠或错误折叠的蛋白质积累,有效的内质网应激可以延缓心肌细胞的衰老,阻止房颤的发生发展。     

Atrial fibrillation: molecular biology bases

BACKGROUND: Atrial fibrillation is the most frequent form of sustained arrhythmia. In most cases the arrhythmia is acquired, in rarer cases it may occur as a familial disease with a autosomal dominant pattern of inheritance. Recent advances in molecular biology and genetics have had a major impact on our understanding of the mechanisms responsible for the initiation, maintenance and chronification of the arrhythmia. Recently, the chromosomal locus for familial atrial fibrillation has been mapped to chromosome 10q22-q23, however, so far the causative gene has not been identified. ATRIAL REMODELING: Atrial fibrillation itself modifies atrial electrical properties in a way that promotes the occurrence and maintenance of the arrhythmia, in other words "atrial fibrillation begets atrial fibrillation". The principle stimulus for atrial remodeling is the rapid atrial rate. PERSPECTIVES: It is hoped that the results of future studies will not only further improve our understanding of the mechanisms underlying atrial fibrillation but may also help to develop new therapeutic strategies.     

Novel pharmacological therapies for atrial fibrillation

PURPOSE OF REVIEW: Atrial fibrillation is a common yet difficult cardiac rhythm to treat. Limitations of the currently available medications, increasing complexity of atrial fibrillation patient populations and the prevalence of the condition have made new drug development crucial. Our understanding of the pathophysiology of atrial fibrillation has increased tremendously over the years. The importance of electrical remodeling and structural remodeling has been widely appreciated and has opened new avenues for pharmacological research. RECENT FINDINGS: Novel ion channel blockers have targeted atrial-specific ion channels or a combination of ion channels in order to maximize efficacy and minimize proarrhythmic risk. Understanding of atrial fibrillation as a metabolically complex condition with activation of multiple signaling cascades has fuelled drug development in a new direction. Exciting new drugs inhibiting fibrosis, cellular hypertrophy and improving cell-cell communication may help treat chronic atrial fibrillation in the future. SUMMARY: Continuing progress in our knowledge of the ionic and structural remodeling in atrial fibrillation will only accelerate the search for a safe antidote. In the future focal pharmacological modulation may help target specific targets in diverse populations. The potential of many of these pharmacotherapies, however, will need to be tested in large randomized trials before our faith in them is realized.     

Atrial fibrillation: evidence for genetically determined disease

PURPOSE OF REVIEW: Atrial fibrillation is traditionally regarded as a sporadic, nongenetic disorder. Nevertheless, recent growing evidence points to an important heritable basis for atrial fibrillation, with significant genetic determinants. This paper reviews recent progress in understanding the role of genetic contributors to the pathogenesis of atrial fibrillation and its familial susceptibility. RECENT FINDINGS: Population-based studies have demonstrated a significant heritable component in atrial fibrillation, with specific contributors including single-gene mutations and single-nucleotide polymorphisms. Variants in both ion-channel and nonion-channel genes have been identified as potential atrial fibrillation-risk determinants. In addition, studies have pointed to interesting combined roles of genetic and environmental factors in atrial fibrillation pathogenesis, providing insights into gene-environment interactions. Clinical studies suggest that individual genetic profiles may determine the therapeutic response of atrial fibrillation. SUMMARY: Rapidly evolving work indicates that there are important genetic determinants of atrial fibrillation, and suggests that understanding these determinants will help us both to appreciate better the underlying pathophysiology and to provide new approaches in diagnosis, prevention and treatment of this common cardiac condition.     

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.     

MicroRNA与心房颤动关系的研究进展

心房颤动是最常见的持续性心律失常,并有较高的发病率和死亡率。其流行率预计在未来几年会进一步增加。尽管在过去十年中出现了心房颤动病理生理学的新分子概念,但目前可用的治疗方法仍存在主要局限性,包括效果差和严重的副作用,如心室恶性心律失常等。心房电重构、结构重构和自主神经重构是心房颤动的发病基础,但驱动这种重构的确切机制仍不完全清楚。MicroRNA代表大量小非编码RNA的亚组,降解或抑制其靶m RNA的翻译,从而调节基因表达并在广泛的生物学过程中起重要作用。临床上,越来越多的证据表明micro RNA在心血管疾病的发生发展中发挥关键作用。     

Role of the renin-angiotensin-aldosterone system in atrial fibrillation and cardiac remodeling

PURPOSE OF REVIEW: This review summarizes recent clinical trial evidence showing a reduction in the development and recurrence of atrial fibrillation with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor-blocking agents (ARBs). It then explores the possible mechanisms for this effect based on current animal models and limited human study. RECENT FINDINGS: Post hoc analyses of trials in patients with heart failure, hypertension, or myocardial infarction have observed reductions in atrial fibrillation among patients treated with ACE inhibitors or ARBs. Recent studies of these agents in animal models of atrial fibrillation suggest that they may prevent atrial fibrillation by reversing the cardiac structural and electrical changes, known as cardiac remodeling, that lead to the development of atrial fibrillation. This concept is also supported by two prospective studies showing that ACE inhibitors and ARBs prevent the recurrence of atrial fibrillation after electrical cardioversion. SUMMARY: Inhibition of the renin-angiotensin-aldosterone system is a novel concept for the treatment of atrial fibrillation that may target the underlying substrate of atrial fibrillation. Further human research is required to determine whether ACE inhibitors and ARBs prevent atrial fibrillation, and if so, whether this is a result of blood pressure lowering alone or a specific effect of these agents. Ongoing research will establish whether ACE inhibitors or ARBs have specific benefits in patients with atrial fibrillation.     

Neue Antiarrhythmika in der Therapie des Vorhofflimmerns

During the last ten years we have made substantial progress in our understanding of the underlying mechanisms of atrial fibrillation. The high rate associated alterations in electrical and structural properties of the atria, referred to as atrial remodeling, promote the progression of atrial fibrillation. The development of new therapeutic approaches addresses three different directions: (i) prevention of atrial remodeling, especially of structural remodeling; (ii) increase of long-term efficacy of currently used drugs and improvement of their side-effect profile; and (iii) design of atria- and pathology-specific antiarrhythmic drugs without concomitant proarrhythmic effects in the ventricles. The current review outlines the pathophysiology of atrial fibrillation and focuses on electrical remodeling. The properties of new antiarrhythmic drugs for atrial fibrillation are discussed in detail.     

脂联素在心房颤动中的保护作用及其研究进展

心房颤动是临床实践中最常见的心律失常。目前确切机制仍不清楚,病理生理机制复杂,且诸多可能的机制相互关联。近年来发现脂联素与心房颤动的发生及维持密切相关。由于脂联素具有减轻体重、逆转心肌重构、增强胰岛素敏感性、抗炎、抗动脉粥样硬化、抗高血压、保护血管内皮功能等作用。因此对心房颤动的保护作用具有巨大的潜力。     

Atrial fibrillation: pathophysiology

BACKGROUND: Although several classical studies seemed to provide clear ideas on the pathophysiology of atrial fibrillation, current concepts have to be modified on the basis of more recent findings. REENTRANT CIRCUITS: Based on the findings of Garrey and of Moe & Abildskov, atrial fibrillation has long been considered as the prototype of an arrhythmia being caused by multiple, random reentrant circuits, the number of which would determine the stability of the reentrant process. Local refractory and conduction properties would determine the size of individual circuits, a hypothesis quite convincing with respect to refractoriness, but so far hard to prove with respect to conduction. The finding that rapid atrial rates shorten atrial refractory periods and reverse rate adaptation (atrial remodeling) has coined the phrase "atrial fibrillation begets atrial fibrillation", indicating that any atrial tachyarrhythmia modifies the substrate in a way that favors reentry. With intracellular calcium overload being the initial trigger, down-regulation of genes encoding for calcium channels seems to primarily account for atrial remodeling. Primarily neglected concepts on the pathophysiology of atrial fibrillation suggesting single, meandering circuits or focal activity have regained attention. Atrial fibrillation as a random phenomenon is questioned not only by the dominant role of the left atrium for the maintenance of the arrhythmia, but also by most recent data demonstrating a spatio-temporal periodicity in activation patterns. Finally, ablation studies have provided convincing evidence that there is a subset of patients with focal or at least focally induced atrial fibrillation.     

Electrophysiologic remodeling and drug treatment of atrial fibrillation

Since 1995, a number of studies have established and detailed the mechanisms of electrical and structural atrial remodeling induced by atrial fibrillation. Atrial remodeling involves many cellular components, from ionic channels to connexins. The determination of these mechanisms may help to define a new therapeutic targets of atrial fibrillation, a frequent arrhythmia that remains difficult to treat. Atrial remodeling prevention may lead to limit the evolution of the arrhythmia (early recurrences after reduction, AF secondary to atrial tachycardia, permanent AF, decrease in atrial contractility, sinus dysfunction). Except amiodarone, the usual antiarrhythmic drugs have no effect on atrial remodeling. Calcium channel inhibitors prevent early remodeling but have no effect on prolonged remodeling. Digoxin increases remodeling. Angiotensin II receptor inhibitors have been shown to prevent early AF recurrence after reduction and are very promising in such a direction. Other methods such as the one of antioxidant therapy seem to be promising and could define soon a new antiarrhythmic therapeutic class, the antiremodeling drugs.     

Use of beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers to prevent atrial fibrillation

Atrial fibrillation, the most common cardiac arrhythmia in clinical practice, causes significant burden to patients and health care systems worldwide. Attention is being paid to prevention of atrial fibrillation using drugs that retard or prevent atrial.brosis and arrhythmogenic remodeling, which lead to this arrhythmia. Agents that work through the renin-angiotensin-receptor system, the angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, are showing promise in animal and human studies.     

心房颤动致心房重构分子机制研究进展

心房颤动是临床上一种常见的心律失常,心房颤动致心房重构是近年来研究发现的一个重要的电生理现象。心房颤动本身能够导致心房电生理、功能和结构的改变。本文综述了心房颤动致心房快速的电生理变化和缓慢的蛋白质表达及其分子改变机制。通过对心房电生理重构、离子重构和蛋白质重构和超微结构及其功能变化等不同方面的全面阐述,探讨了心房重构的分子机制研究进展。防治心房颤动新的策略将取决于心房重构机制更好的理解。     

Atrial Fibrillation

Atrial Fibrillation: From Cell to Bedside. Atrial fibrillation is the most common sustained tachyarrhythmia and, as such, has become the recent focus of intense clinical and experimental interest. Because of its associated morbidity and mortality, there is a multidisciplinary effort to understand the pathophysiology that may ultimately lead to improved therapeutic options. This review concentrates on three aspects of atrial fibrillation that influence contemporary choices for treatment: an electrophysiologic basis for initiation of atrial fibrillation, anatomic and electrophysiologic remodeling, and concepts regarding its termination or prevention.     

Prevention of atrial fibrillation

PURPOSE OF REVIEW: This review summarizes current concepts on the pathophysiology of atrial fibrillation, identifying predisposing factors to guide primary and secondary preventive approaches. RECENT FINDINGS: Many factors contribute to the development and progression of atrial fibrillation, including cardiovascular diseases, age, neurohormones, genetics, diet, autonomic influences, and inflammation. Therapeutic efforts have been directed to modify this altered milieu and prevent the development of atrial electrical and structural remodeling. This nonconventional antiarrhythmic management appears to have an important role also in secondary prevention of atrial fibrillation; the indications for conventional antiarrhythmic agents are decreasing because of side effects and limited efficacy. Interventional electrophysiology techniques have been developed to target the arrhythmia substrate responsible for the initiation or maintenance of atrial fibrillation, achieving high success rates. SUMMARY: Atrial fibrillation is the most commonly treated arrhythmia and its incidence is predicted to increase. It is associated with significant morbidity and mortality. Preventive efforts should be initiated early and include diversified interventions to correct predisposing factors and modify the altered atrial substrate.