心房颤动和缝隙连接

心肌细胞缝隙连接 (GJ)与心房颤动 (简称房颤 )有密切关系。各种病因引起的GJ的异常变化可引起心房肌细胞动作电位传导速度的明显延缓及传导安全性增加 ,并可增加心房肌细胞不均一各向异性从而促进房颤的产生 ,而房颤引起的GJ重构对房颤的维持也起重要作用     

心脏缝隙连接蛋白基因变异与心房颤动

<正>心房颤动(房颤)是一种多因素疾病,大多数继发于严重的器质性心脏病或存在明确的危险因素;但也有2%¹6%的房颤患者,无明显的已知危险因素和基础心脏病,称作特发性房颤或孤立性房颤,此类房颤多与遗传因素密切相关。然而,造成这种心律失常的始动因素和维持因素尚不明确,导致对此类房颤的预防和干预存在难度。随着分子生物学技术和细胞电生理技术的快速发展,房颤的分子遗传学病因研究取得了重大进展,为揭示房颤的发生、发展机制带来了曙光[1-2]。陆续有学者发现与房颤相关的系列基因座位和基因,如10q22-q24、6q14-q16、5p13、10p11-q21基因座,及     

缝隙连接蛋白40和心房颤动

随着对心房颤动机制越来越深入的了解,缝隙连接蛋白在其中扮演的作用日益受到重视。缝隙连接蛋白中的连接蛋白40在心房颤动过程中数量、分布、及分子结构都发生了变化。连接蛋白40基因突变及多态性增加了心房颤动的易患性,尽管连接蛋白40在心房颤动发生和维持中的具体机制尚未完全阐明,但一些针对连接蛋白的药物应用于心律失常有较好的效果。现就连接蛋白40与心房颤动的关系进行综述。     

心脏缝隙连接和心律失常

心脏缝隙连接是心肌细胞间直接联系并交换信息的重要途径 ,它的分布及功能对于心肌的电传播起着重要作用。在许多心脏疾病中 ,心肌组织都有缝隙连接的改变 ,这种改变似与心律失常的易发性有关。缝隙连接与心律失常之间是相互作用 ,相互影响的。人们正将缝隙连接作为新的药物作用靶点进行研究 ,以期找到对抗心律失常的新方法。     

缝隙连接蛋白和心房颤动的研究进展

<正>心房颤动是临床最常见的心律失常,在一般人群中,心房颤动发病率为0.4%~1.0%,且发病率随年龄的增长而急剧增加[1]。心房颤动是栓塞事件的独立危险因素,可以引起心房内血栓、脑栓塞等严重并发症。栓塞事件随着年龄显著增高,是我国老年人发病率、致死率较高的一种疾病[2]。近年研究发现,缝隙连接蛋白的空间分布异常可导致心律失常的发生,其在心房颤动的心房电重构、结构重构中扮演着重要角色,直接参与心房颤动的发生与持续。本文就将连接蛋     

缝隙连接蛋白与心房颤动

缝隙连接蛋白是心肌细胞间电传导的结构基础,其在左右心房的分布具有各自的特点,而缺氧、炎症和心肌纤维化等各种病理性因素使缝隙连接蛋白在结构和功能上出现重构,体内pH值和多种蛋白激酶途径可影响其重构;心房缝隙连接蛋白的重排,导致心房内传导速度和各向异性增加,从而成为心房颤动的解剖学基础;心房颤动又促进心房内缝隙连接蛋白的重构,进而又促进了心房颤动的维持。     

异型缝隙连接通道和磷酸化对心脏缝隙连接通透性的影响

缝隙连接 (GJ)是连接相邻细胞的通道 ,它由细胞间的缝隙连接蛋白 (Cx)构成。这些通道在体内参与了生物信息传播等重要的生理过程。由不同种Cx组成的GJ通道明显不同于由单种Cx组成的同型GJ通道的通透特性。Cx密度和分布的改变与心律失常相关。磷酸化作用可使GJ通道尤其是异型GJ通道的通透性下降。     

异型缝隙连接通道和磷酸化对心脏缝隙连接的调变

目的 检测由缝隙连接蛋白(connexin，Cx)43和Cx45组成的多种异型缝隙连接通道(her—eromultimeric gap junction channels，HGJC)和磷酸化对缝隙连接(gap junction，GJ)的调变作用。方法 将转染了编码为Cx43或Cx45的DNA后的Hela细胞放置在一起共同培养组成双侧和单侧异型GJ通道。显微注射若丹明123(rhodamine123，Rh)检测经200nmol／L十四(烷)酰佛波醇乙酸酯(12-0-tetrade—canoylphorbol-13-acetae，TPA)处理前后，在紫外光显示下由Cx43和Cx45所组成的不同GJ通道对荧光染料的偶联率(coupling ratio)。结果 在不同的GJ中，同型GJ通道Cx43(homotypie Cx43，HoCx43)偶联率最高。从Cx45侧注入荧光染料的单侧异型GJ通道45(mono-heteromeric Cx45-Cx43／45，MH45)偶联率较之从Cx43／45侧注入荧光染料的MH45、双侧异型GJ通道Cx43／45(bi-heteromeric Cx43／45，BH43／45)及同型GJ通道Cx45(homotypic Cx45，HoCx45)等的偶联率是最低的。根据HoCx43或HoCx45通道的偶联率对各型通道偶联率进行标准化处理。BH43／45和MH43通道的偶联率均较HoCx43降低。对MH45通道来说，从Cx43／45侧注射的通道偶联率大于从Cx45侧注射的偶联率。TPA处理后HoCx43的偶联率降低，而当Cx43和Cx45组合成BH43／45和MH43通道后其偶联率下降更显著。结论 Cx43和Cx45共同表达可构成BH43／45、MH43和MH45等异型通道，而这些通道可降低细胞间的通讯并对磷酸化的作用不敏感。单侧异型GJ通道的偶联率取决于染料注射的方向。     

缝隙连接与心脏疾病

缝隙连接是存在于相邻组织细胞间特殊的膜通道结构,为相邻细胞间电和代谢信号的直接通路,在人体绝大部分组织中表达。缝隙连接对于心脏的冲动传导极为重要,研究发现其表达、分布重构、结构和功能的改变与诸多心脏疾病,如冠心病、心肌病及心律失常等具有相关性。心肌细胞再生能力有限,因此,通过有效的骨髓间充质干细胞移植治疗,改善心肌细胞的电生理异常和心肌重构,将为临床上治疗心脏疾病提供广阔的空间。     

缝隙连接与心脏的传导

细胞之间动作电位或兴奋的传导称为胞间传导 ,可兴奋细胞间的电耦联是通过一种特殊的胞间结构而实现 ,这种结构即是缝隙连接 (gapjunction ,GJ)。现已证实 ,心脏的正常传导和引起心律失常的异常传导都与缝隙连接直接相关。目前 ,缝隙连接是心电学基础与临床研究的共同热点。一、缝隙连接的基本概念心肌细胞间的连接主要由闰盘 (intercalateddisk)构成。闰盘由桥粒 (desmosome)、粘附膜 (fasciaadherents)和缝隙连接三部分组成。桥粒是紧密贴附在一起的细胞膜 ,能将各个心肌细胞紧密连接在一起 ,其功能目前尚不明了 ,但其电阻很高 ,离子很难…     

Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria

OBJECTIVES: To elucidate the structural basis for the electrophysiologic remodeling induced by chronic atrial fibrillation (AF), we investigated connexin40 and connexin43 (Cx40 and Cx43) expression and distribution in atria of patients with and without chronic AF and in an animal model of AF with additional electrophysiologic investigation of anisotropy (ratio of longitudinal and transverse velocities). BACKGROUND: Atrial fibrillation is a common arrhythmia that has a tendency to become persistent. Since gap junctions provide the syncytial properties of the atrium, changes in expression and distribution of intercellular connections may accompany the chronification of AF. METHODS: Atrial tissues isolated from 12 patients in normal sinus rhythm at the time of cardiac surgery and from 12 patients with chronic AF were processed for immunohistology and immunoblotting for the detection of the gap junction proteins. The functional study of the cardiac tissue anisotropy was performed in rat atria in which AF was induced by 24 h of rapid pacing (10 Hz). RESULTS: Immunoblotting revealed that AF did not induce any significant change in Cx43 content in human atria. In contrast, a 2.7-fold increase in expression of Cx40 was observed in AF. Immunohistologic analysis indicated that AF resulted in an increase in the immunostaining of both connexins at the lateral membrane of human atrial cells. A similar spatial redistribution of the Cx43 signal was seen in isolated rat atria with experimentally-induced AF. In addition, AF in rat atria resulted in decreased anisotropy with slightly enhanced transverse conduction velocity. CONCLUSIONS: This experimental study showed that AF is accompanied by spatial remodeling of gap junctions that might induce changes in the biophysical properties of the tissue.     

Disorganization of gap junction distribution in dilated atria of patients with chronic atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is an arrhythmia associated with functional and morphological remodeling of atria. We investigated the distribution and the expression of connexins in atrial tissues from patients with chronic AF and left atrial dilatation (AD). METHODS AND RESULTS: Immunohistochemistry was performed in atrial tissues obtained during cardiac surgery from patients with chronic AF + AD (n = 11), sinus rhythm (SR, n = 11) and SR + AD (n = 4). In SR patients (control), the connexin (Cx) 43 labeling of the intercalated disks seen en-face was characterized by small central spots surrounded by larger spots at the periphery. In the left atria from AF + AD patients, the area of the intercalated disk was significantly enlarged. Although peripheral Cx43 labeling was preserved, there was a striking loss of central labeling spots. The area occupied by gap junctions was slightly but significantly larger than that of the control. The left atria from patients with SR + AD showed gap junction disorganization analogous to AF + AD. The labeling patterns of Cx40 were essentially similar to those of Cx43. Conclusions In chronic AF with AD, gap junctions at the intercalated disk are disorganized, resulting most likely from AD but not from AF itself. This gap junction remodeling might be involved in altered atrial conduction properties, but its potential arrhythmogenic role remains unclear.     

Cardiac gap junctions and connexins: their role in atrial fibrillation and potential as therapeutic targets

In the heart, changes in velocity and in patterns of conduction of myocardial electrical activity can affect cardiac rhythm and the coordination of contraction. Abnormal electrical coupling between cardiomyocytes through gap junctions is, therefore, considered an important factor in various pathophysiologic conditions. In the present report we summarize the literature on gap junctions and their structural proteins, the connexins, in the normal and fibrillating atrium. Putative implications of the recently reported remodelling of atrial gap junctions for stability of the arrhythmia will be discussed. Also the reversibility of the remodelling process will be addressed in the light of a potentially new therapeutic target for controlling the progression of atrial fibrillation (AF).     

心脏自主神经与心房颤动

自主神经可以改变心房传导和不应期，导致自律性异常、折返及触发活动，从而影响房颤的发生、维持、终止。肺静脉电隔离术联合神经节消融术能有效地提高房颤消融成功率并降低复发率。     

Cardiac myocytes express multiple gap junction proteins.

Electrical propagation in the normal heart occurs via intercellular transfer of current at gap junctions. Alterations in intercellular coupling in the diseased heart are critical in the pathogenesis of reentrant ventricular arrhythmias. Until recently only a single gap junction protein was known to couple cardiac myocytes. We have now identified and sequenced two additional distinct gap junction proteins (connexins) expressed in the mammalian heart. The sequences differ in their predicted cytoplasmic regulatory domains. Expression of all three connexins by canine ventricular myocytes has been confirmed by Northern blotting and by immunohistochemistry with connexin-specific antisera. Immunoelectron microscopy confirmed that all three connexins are localized to myocyte gap junctions. The presence of multiple connexins in myocyte gap junctions suggests novel mechanisms for regulating cardiac electrical coupling.     

Cardiac gap junction channels show quantitative differences in selectivity

Several proteins including connexin40 (Cx40) and connexin43 (Cx43) form gap junctions between cells of the heart; they may be found separately or may be coexpressed. These connexins form channels with differing conductance and permeability properties. Cx40 and Cx43 are each required for normal electrical conduction between cells in different regions of the heart. We hypothesized that the major difference between these connexins might be in their selective intercellular passage of small molecules such as second messengers, which can be assessed using biologically inert fluorescent probes. Therefore, we designed experimental paradigms to quantitate the permeability properties of these cardiac connexins using simultaneous measurement of junctional conductance (g(j)) by the double whole-cell patch-clamp technique and intercellular transfer of Lucifer Yellow (LY) by fluorescence microscopy. These studies were performed in HeLa cells stably transfected with Cx40 or Cx43 or cotransfected with both connexins. We found that homotypic Cx43 channels were about 5 times more permeable to LY than homotypic Cx40 channels (flux of approximately 1560 versus approximately 300 molecules/channel per second). Channels between heterotypic (Cx40-Cx43) cell pairs and between pairs of coexpressing cells exhibited intermediate LY permeability. The permeability ratio for LY relative to monovalent cation (K+) ranged from 0.0025 for Cx40 to 0.028 for Cx43. These permeability ratios suggest that the connexins are highly selective for solutes in the size and charge range of many second messengers. Moreover, the data indicate that coexpression of connexins does not generate unique permeability characteristics, but rather results in an intermediate permeability for solutes involved in metabolic/biochemical coupling.     

Cardiac image integration implications for atrial fibrillation ablation

Cardiac image registration using computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and fluoroscopy is currently being investigated and clinically used for atrial fibrillation (AF) ablation. Cardiac image registration, in the context of left atrium, is intermodal, with the acquired image and the real-time reference image residing in different image spaces, and involves optimization, where one image space is transformed into the other. Geometry-based methods, which include using fiducial points and/or surface-based techniques, are usually used for cardiac image registration. During fiducial point registration, fiducial points are either external skin markers or manually determined by marking anatomical landmarks, using mapping catheters. Usually, a minimum of three non collinear points are needed for optimal registration. Recently, a catheter placed inside the coronary sinus has also been used as a fiducial marker for the purpose of registration. During surface registration, the process involves characterizing surfaces in each of the images and deriving the best transformation between them. Unlike rigid body registration, such as has been extensively used in imaging the brain, cardiac image registration is unique and challenging. In addition to the errors inherent in intermodal registration, such as errors in pixel and voxel dimension and errors due to fiducial point selection, there are errors specific to cardiac image registration, i.e., errors due to cardiac motion during the cardiac cycle and due to respiration. This review addresses the basic principles of registration and the inherent registration errors as they relate to cardiac imaging and registration.