心房重构在房颤中的作用

房颤的发病机制非常复杂,与心房的重构(包括电学重构、解剖重构和自主神经系统重构)密切相关.房颤可诱导离子通道蛋白表达和(或)功能异常,进而反馈性地促进心房功能性折返基质的形成,发生电学重构;循环往复的电学重构造成心房基质的改变,失活的心房肌细胞被纤维组织替代,心房逐渐纤维化,出现解剖重构;与此同时,心房广泛的纤维化进一步阻碍电冲动的传导,反过来加重电学重构;自主神经系统重构可通过正向反馈环机制促进房颤的维持和复发.早期治疗心房重构可延迟甚至预防房颤的发生和发展.     

Morphological remodeling in atrial fibrillation

In the recent years, a tremendous amount has been learned about the pathophysiology of atrial fibrillation (AF). AF induces electrophysiological changes in the atria causing a perpetuation of the arrhythmia ("electrical remodeling"). Besides such AF-induced electrophysiological changes, which involve the downregulation of L-type calcium channels and thereby the calcium inward current, AF induces structural and ultrastructural changes in atrial tissue ("structural remodeling"). Calcium-dependent tissue alterations are induced by proteases and phosphatases like calpain and calcineurin. Furthermore, cardiac diseases like hypertension, heart failure, etc. activate the atrial angiotensin II system, and thereby, a progressive pro-arrhythmogenic atrial fibrosis is induced. Besides first clinical trials assessing the antiarrhythmic effects of angiotensin II receptor blockers in patients with AF, experimental data suggest that viral gene transfer can be used to transform fibroblasts to electrically conducting cardiomyocytes. This highly interesting methodology may be helpful to restore electrical conduction in fibrotic cardiac tissue.     

Structural remodeling in atrial fibrillation

Atrial fibrillation occurs and maintains itself in the context of a morphologically and functionally altered atrial substrate that can be induced by stressors such as underlying diseases (cardiac or noncardiac) or aging. The resultant structural remodeling is a slow process that progressively affects myocytes and the myocardial interstitium, and takes place from as early as the first days of atrial tachyarrhythmia. The left atrium, and particularly its posterior wall, is the location where remodeling is concentrated to the greatest extent. The mechanisms that underlie the remodeling process in atrial fibrillation have not yet been completely elucidated, although experimental and clinical investigations have indicated a number of signaling systems, inflammation, oxidative stress, atrial stretching and ischemia as factors involved in the cascade of events that leads to atrial fibrillation. The aim of this Review is to provide a comprehensive overview of the morphological changes that characterize the fibrillating atrial myocardium at histological and ultrastructural levels, and the established and hypothetical pathogenetic mechanisms involved in structural remodeling. This article also highlights the emerging therapies being developed to prevent progression of atrial fibrillation.     

MMP-9 in atrial remodeling in patients with atrial fibrillation

IntroductionAtrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. The impact of matrix metalloproteinases (MMPs) on structural atrial remodeling and sustainment of AF in patients with persistent and permanent AF is unresolved.ObjectivesThe aim was to evaluate MMP-9 and its tissue inhibitor-1 (TIMP-1) as markers of atrial remodeling in patients with persistent AF (PAF) who underwent electrical cardioversion (ECV) and in patients with permanent AF (continuous AF, CAF).Patients and methodsPlasma levels of MMP-9 and TIMP-1, clinical findings, and echocardiographic parameters were evaluated in 39 patients with AF and in 14 controls with sinus rhythm.ResultsThe concentrations of MMP-9 were significantly higher in patients with PAF and CAF compared to controls. There was a significant increase of MMP-9 after ECV in the persistent AF group. The values of TIMP-1 were not significantly different between the groups. In patients with AF, MMP-9 levels were positively related to posterior wall thickness of the LV (r = 0.356, P = 0.049) and body mass index (r = 0.367, P = 0.046).ConclusionElevated levels of MMP-9 were related to the occurrence and maintenance of AF. This suggests that MMP-9 can be a marker of atrial remodeling in patients with AF. Regulation of the extracellular collagen matrix might be a potential therapeutic target in AF.     

MicroRNAs and atrial fibrillation: new fundamentals

Atrial fibrillation (AF) is the most commonly encountered clinical arrhythmia associated with pronounced morbidity, mortality, and socio-economic burden. This pathological entity is associated with an altered expression profile of genes that are important for atrial function. MicroRNAs (miRNAs), a new class of non-coding mRNAs of around 22 nucleotides in length, have rapidly emerged as one of the key players in the gene expression regulatory network. The potential roles of miRNAs in controlling AF have recently been investigated. The studies have provided some promising results for our better understanding of the molecular mechanisms of AF. In this review article, we provide a synopsis of the studies linking miRNAs to cardiac excitability and other processes pertinent to AF. To introduce the main topic, we discuss basic knowledge about miRNA biology and our current understanding of mechanisms for AF. The most up-to-date research data on the possible roles of miRNAs in AF initiation and maintenance are presented, and the available experimental results on miRNA and AF are discussed. Some speculations pertinent to the subject are made. Finally, perspectives on future directions of research on miRNAs in AF are provided.     

心房颤动与心房重构的最新进展

心房颤动（房颤,AF）是引起心血管发病和死亡的重要原因.房颤是常见的由一系列心脏疾病引起心房重构的终点事件,其本身也能引起心房重构从而促进心律失常的发展[1].随着人们对心房重构的机制及其在房颤进展中作用的逐渐认识,对离子通道调控机制和作用靶点的研究也有了较深入的发展.本文将重点综述这方面的进展.     

心房顿抑与房颤后心房重构

心房颤动(房颤)复律后左房机械功能异常,其后将房颤恢复窦性心律时出现一过性的左心房和左心耳机械功能的异常称为心房顿抑,发生率约为38%～80%.房颤持续时间越长,心房顿抑越严重、持续时间越长,更易形成心耳血栓及房颤复发.近年研究提示,造成心房顿抑的原因与房颤后的心房重构有关.房颤诱导心房发生重构包括电重构、结构重构及缝隙连接重构.缝隙连接重构与心房电重构、结构重构均有关联,参与房颤的发生与持续,可能是心房顿抑发生的原因之一.本文就心房顿抑及与房颤后心房重构的关系进行综述,并对未来的研究方向作一展望.     

心房结构重构与心房颤动

房颤是临床最常见的心律失常之一.Feinberg等[1]对全球4个主要人群的流行病学调查结果显示,房颤发生率随年龄的增加而增加.中国一项来源于29 079例30～85岁患者的房颤流行病学调查显示,房颤患病率为0.77％,标准化率为0.61％,年龄分组显示患病率有随年龄增加的趋势[2].随着人口老龄化的发展,房颤的患病率必将不断攀升.然而房颤的确切发病机制并不十分清楚,临床治疗效果仍不理想.因此,从房颤的发生及维持机制方面入手,寻找预防和治疗房颤的新方法、新手段势在必行.     

基质金属蛋白酶与心房颤动患者心房结构重构的研究进展

心房颤动（简称房颤）是成人最常见的心律失常之一。心房的结构重构是心房颤动发生和维持的重要机制之一,包括心房肌细胞超微结构改变、心房肌间质改变和心房扩大。各种心脏疾病、心律失常或衰老均可以导致心房结构重构。心房间质组织纤维化是房颤发生的重要机制,间质纤维化可导致心房内径扩张、心房壁变薄和心房结构重构。心房纤维化与扩张导致房内及房间传导的延迟、心房传导各相异性增加,均有利于折返的形成,是导致房颤发生、发展的重要原因。     

快速心房起搏引起猪心房颤动时心房结构的变化及替米沙坦的预防作用

目的建立猪实验性心房颤动(atrial fibrillation,AF)模型,观察心房结构重构的变化和替米沙坦(TMST)干预的作用,测定血管紧张素转化酶2(ACE2)和胶原蛋白-Ⅰ的变化。方法将18头猪按随机数字表分为对照组(NC组)、快速心房起搏组(RAP组)、RAP+TMST组。闭胸法建立猪的持续性AF模型,超声测量实验前、后心室收缩末期左、右心房面积(LAESA、RAESA)变化;应用程序刺激检测AF的诱发率和持续时间;通过伊红(HE)染色、Masson染色和蛋白印迹法(Western blot)检测ACE2和胶原蛋白-Ⅰ的变化。结果与RAP组相比,RAP+TMST组LAESA、RAESA扩大减轻,AF诱发率降低、持续时间缩短,胶原蛋白-Ⅰ减少,而ACE2表达明显增加。RAESA与胶原蛋白-Ⅰ呈正相关关系(r1=0.956,P<0.01),RAESE与ACE2、ACE2与胶原蛋白-Ⅰ均呈负相关关系(r2=-0.966,r3=-0.948,P<0.01)。结论猪AF模型心房肌出现结构重构的病理表现,ACE2表达失衡与AF结构重构密切相关;TMST可降低AF的发生率及持续时间,明显改善心房结构重构。     

肾素-血管紧张素-醛固酮系统在心房颤动中对心房重构的影响

心房颤动（房颤）是临床上常见的与年龄增长密切相关的心律失常之一。如今，风湿性心脏病所致房颤的发病率已有所减少，但其他易感因素如高血压病、冠心病、心力衰竭等的发病率正不断增高，且房颤患者发生脑卒中的危险性也在增高…。对房颤机制的研究发现，心房重构即心房组织结构和电生理特性的变化，是这种心律失常发生发展的物质基础。[第一段]     

心房颤动患者离子重构的分子基础

目的　研究心房颤动 (AF)患者离子重构的分子基础。方法　以先天性心脏病 (CHD)和风湿性心脏病 (RHD)持续窦性心律 (SR)患者为对照 ,应用半定量RT PCR法检测RHD伴阵发性AF(PAF)慢性AF 6个月 (AF 6M )和慢性AF >6个月 (AF >6M )患者心房肌L 型电压依赖钙通道α1c亚基 (LVDCCα1c)、电压依赖KV4 3钾通道α亚基 (VDKV4 3α)和电压依赖钠通道α亚基 (VDSCα)mRNA的表达。结果　SR组内CHD患者与RHD患者LVDCCα1c、VDKV4 3α和VDSCα的mRNA表达差别无明显性 ;与对照组相比 ,各组AF患者VDSCα的表达没有改变 ;LVDCCα1c在AF >6M患者中的表达显著下降 ,而在PAF和AF 6M患者中的表达有不同程度下调 ,但无统计学意义 ;LVDCCα1cmRNA表达与心房率、左、右心房内径成明显负相关 ,并且其表达随AF分数增高逐渐下降 ;单因素协方差分析 (ANOVA)矫正心房内径的影响 ,AF >6M患者α1cmRNA表达仍明显下降 (P <0 0 1)。KV4 3αmRNA在PAF、AF 6M和AF >6M患者中的表达均显著降低。KV4 3钾通道α亚单位mRNA表达与AF分数、左心房内径和平均心房率均成明显负相关 ,经ANOVA剔除左心房内径的影响 ,各组mRNA表达较SR组仍显著下降 (P <0 0 5 )。结论　L 型钙通道和KV4 3钾通道转录水平下调是相应ICaL和Ito1重构的分子基础 ,基因表     

Molecular basis of electrical remodeling in atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is often associated with other cardiovascular disorders and diseases. AF can lead to thromboembolism, reduced left ventricular function and stroke, and, importantly, it is independently associated with increased mortality. AF is a progressive disease; numerous lines of evidence suggest that disease progression results from cumulative electrophysiological and structural remodeling of the atria. There is considerable interest in delineating the molecular mechanisms involved in the remodeling that occurs in the atria of patients with AF. Cellular electrophysiological studies have revealed marked reductions in the densities of the L-type voltage-gated Ca2+ current, I(Ca,L), the transient outward K+ current, I(TO), and the ultrarapid delayed rectifier K+ current, I(Kur), in atrial myocytes from patients in chronic AF. Similar (but not identical) changes in currents are evident in myocytes isolated from a canine model of AF and, in this case, the changes in currents are correlated with reduced expression of the underlying channel forming subunits. In both human and canine AF, the reduction in I(Ca,L) appears to be sufficient to explain the observed decreases in action potential duration and effective refractory period that are characteristic features of the remodeled atria. In addition, expression of the sarcoplasmic reticulum Ca2+ ATPase is reduced, suggesting that calcium cycling is affected in AF. These recent studies suggest that calcium overload and perturbations in calcium handling play prominent roles in AF-induced atrial remodeling. Although considerable progress has been made, further studies focused on defining the detailed structural, cellular and molecular changes that accompany the different stages of AF in humans, as well as in animal models of AF, are clearly warranted. It is anticipated that molecular insights gleaned from these studies will facilitate the development of improved therapeutic approaches to treat AF and to prevent the progression of the arrhythmia.     

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.     

胺碘酮对特发性房颤心房重构逆转作用观察

目的 :探讨胺碘酮对特发性房颤的治疗及对逆转心房心肌重构的作用。方法 :选择 1998- 0 6～ 2 0 0 0 - 0 7住院的特发性房颤患者 （除外房颤持续时间小于 6月和阵发性房颤间隔小于 1月 ,每次持续时间少于 48h者 ） 94例。随机分为胺碘酮治疗组 32例 ,普罗帕酮治疗组 32例及安慰剂组 30例。治疗前后行心电图、心脏超声、肝、肾功及甲状腺功能检查。出院后嘱患者 1,3,6 ,12月复查上述项目 1次。结果 :胺碘酮与普罗帕酮治疗组 ,均可使特发性房颤复律 ,但胺碘酮组较普罗帕酮组复律时间稍长 （约 1周 ） ,维持窦性心律的作用中 ,胺碘酮优于普罗帕酮组 ,12月后转复成功率分别为 81%和 5 6 % ,与安慰剂组自动复律 2 0 % （6 / 30 ）比较有显著差异 （P<0 .0 1）。随访 1,3,6 ,12月胺碘酮组左心房直径缩小 ,左心室舒张早期经二尖瓣血流的最高值 （E峰值 ）和左心房收缩时经二尖瓣血流的最大值 （A峰值 ）、E/ A增大。1,3,6 ,12月间比较有显著性差异 （P<0 .0 1） ,普罗帕酮组上述指标有所改善 ,但差异不显著 （P>0 .0 5 ） ,安慰剂组则无变化。结论 :胺碘酮对特发性房颤复律及对逆转心房心肌重构安全有效     

比索洛尔对持续性非瓣膜性心房颤动患者心房结构重构的影响

目的观察比索洛尔对持续性非瓣膜性心房颤动患者心房结构重构及C反应蛋白(CRP)的影响,并探讨其可能关系。方法将85例持续性非瓣膜性心房颤动患者,分为比索洛尔组(48例)和地高辛组(37例),随访观察(9.8±1.3)个月,治疗前后检测CRP和超声心动图观察左心房结构变化。结果比索洛尔组治疗后左心房内径(41.8±4.2)mmvs(39.7±5.3)mm,CRP 3.9 mg/Lvs3.5 mg/L,均较治疗前明显下降,差异有统计学意义(P<0.01),而地高辛组治疗前后左心房内径(41.8±4.6)mmvs(42.3±5.2)mm,CRP 3.8 mg/Lvs3.5 mg/L,差异无统计学意义(P>0.05)。比索洛尔组的左心房内径和CRP下降幅度与地高辛组比较,差异有统计学意义(P<0.01)。相关分析显示,左心房内径变化与CRP变化呈显著正相关(r=0.218,P=0.045)。结论比索洛尔可改善持续性非瓣膜性心房颤动患者的心房结构重构,并减轻炎性反应。     

Molecular mechanisms of remodeling in human atrial fibrillation

An important acknowledgement of the last several years is that atrial fibrillation (AF) modifies the electrical properties of the atrium in a way that promotes its occurrence and maintenance. This arrhythmogenic electrophysiological remodeling is well established, but can not explain by itself that 'AF begets AF'. This review describes molecular changes involving rapid functional alterations and slower changes in protein expression that cause electrical remodeling and contractile dysfunction in AF. An important molecular feature of AF is the reduction in L-type Ca(2+) channel function and protein expression. This reduction may serve to protect the cell against a potentially lethal Ca(2+) overload resulting from the increased activation rate in AF. Further, the review discusses the possible role of proteolytic systems, notably the calpains, as a mechanism linking Ca(2+) overload to reduced protein expression. Thus, it appears that the elaborate molecular changes in AF are directed primarily at protecting the myocyte from cellular stress. However, such early protection occurs at the expense of electrophysiological changes that promote the long-term maintenance of AF.