Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias

Kléber, André G.; Rudy, Yoram

doi:10.1152/physrev.00025.2003

Cited by 931 publications

(832 citation statements)

References 349 publications

(357 reference statements)

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“…During fast impulse propagation in the atrium or ventricle, which expresses mainly Cx40 and Cx43, large inactivating V j gradients are not supposed to develop under normal physiological conditions. Inactivation may serve as a protective mechanism by which healthy cells uncouple from their compromised neighbors; partial uncoupling can also promote conduction slowing, unidirectional block, and arrhythmias [22,23]. In the atrioventricular node where conduction is normally slow, inactivation of G j could promote partial AV block whereas activation above > 60 mV V j would preserve slow conduction.…”

Section: Discussionmentioning

confidence: 99%

Cx30.2 can form heteromeric gap junction channels with other cardiac connexins

Gemel

Lin

Collins

et al. 2008

Biochemical and Biophysical Research Communications

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Since most cells in the heart co-express multiple connexins, we studied the possible heteromeric interactions between connexin30.2 and connexin40, connexin43 or connexin45 in transfected cells. Double label immunofluorescence microscopy showed that connexin30.2 extensively co-localized with each co-expressed connexin at appositional membranes. When Triton X-100 solubilized connexons were affinity purified from co-expressing cells, connexin30.2 was isolated together with connexin40, connexin43, or connexin45. Co-expression of connexin30.2 with connexin40, connexin43, or connexin45 did not significantly reduce total junctional conductance. Gap junction channels in cells co-expressing connexin30.2 with connexin43 or connexin45 exhibited voltagedependent gating intermediate between that of either connexin alone. In contrast, connexin30.2 dominated the voltage dependence when co-expressed with connexin40. Our data suggest that connexin30.2 can form heteromers with the other cardiac connexins and that mixed channel formation will influence the gating properties of gap junctions in cardiac regions that co-express these connexins. Keywords Gap Junction; Intercellular Communication; ConnexinCurrent passage between cells in the heart is facilitated by intercellular channels clustered in gap junctions. These channels are formed by docking of two hemichannels (connexons) provided by the opposing cells. Each connexon is a hexamer of subunit proteins called connexins (Cx). As demonstrated in cells expressing individual connexins, each connexin can form channels by itself (homomeric/homotypic channels), and different connexins form channels with different conductance, permeability and gating properties [1]. In cells coexpressing different connexins, heteromeric channels (containing different connexins in the same connexon) can potentially be formed [2].Many studies have shown the presence of three well characterized connexin proteins in the heart, Cx40, Cx43, and Cx45. Cx43 is most abundant in atrial and ventricular myocytes and in Purkinje fibers [3,4]. Cx40 is expressed in atrial myocardium, atrioventricular bundle and ✉Address correspondence to: Eric C. Beyer, MD PhD, University of Chicago, Department of Pediatrics MC4060, 5841 S. Maryland Ave, Chicago, IL 60637-1470, TEL: 773-834-1498.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [5,6]. Cx45 is detected in sinoatrial and atrioventricular nodes, atrioventricular bundle and branches [7,8]. NIH Public AccessRecently, another cardiac connexin, mouse Cx30.2 (human Cx31.9) was discovered [9][10][11]. Cx30.2 expression was ...

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Section: Discussionmentioning

confidence: 99%

Cx30.2 can form heteromeric gap junction channels with other cardiac connexins

Gemel

Lin

Collins

et al. 2008

Biochemical and Biophysical Research Communications

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“…In the context of cardiac tissue, this can be motivated by assuming that the cells are coupled to the others by gap junctions (Kléber and Rudy 2004). Suppose, we consider a grid of discrete cells coupled by resistors (see Eqs.…”

Section: Size and Shape Of Cardiac Tissuementioning

confidence: 99%

Negative Tension of Scroll Wave Filaments and Turbulence in Three-Dimensional Excitable Media and Application in Cardiac Dynamics

2012

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Scroll waves are vortices that occur in three-dimensional excitable media. Scroll waves have been observed in a variety of systems including cardiac tissue, where they are associated with cardiac arrhythmias. The disorganization of scroll waves into chaotic behavior is thought to be the mechanism of ventricular fibrillation, whose lethality is widely known. One possible mechanism for this process of scroll wave instability is negative filament tension. It was discovered in 1987 in a simple two variables model of an excitable medium. Since that time, negative filament tension of scroll waves and the resulting complex, often turbulent dynamics was studied in many generic models of excitable media as well as in physiologically realistic models of cardiac tissue. In this article, we review the work in this area from the first simulations in FitzHugh-Nagumo type models to recent studies involving detailed ionic models of cardiac tissue. We discuss the relation of negative filament tension and tissue excitability and the effects of discreteness in the tissue on the filament tension. Finally, we consider the application of the negative tension mechanism to computational cardiology, where it may be regarded as a fundamental mechanism that explains differences in the onset of arrhythmias in thin and thick tissue.

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“…Since reduced conduction velocity is associated with arrhythmic risk [48], this effect may help explain cardiac sensitization. Suggesting an effect on gap junctions, the electrophysiological changes observed in the MEA were similar when comparing the effects of heptanol, a gap junction inhibitor, and the combination of epinephrine and halon.…”

Section: The Combination Of Halon and Epinephrine Reduced Conduction mentioning

confidence: 99%

A possible mechanism of halocarbon-induced cardiac sensitization arrhythmias

Jing

Jesús

Iravanian

et al. 2006

Journal of Molecular and Cellular Cardiology

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Cardiac sensitization is the term used for malignant ventricular arrhythmias associated with exposure to inhaled halocarbons in the presence of catecholamines. We investigated the electrophysiological changes associated with cardiomyocyte exposure to epinephrine and a halocarbon known to be associated with cardiac sensitization (halon 1301, CF 3 Br). Cardiomyocytes (CMs) were isolated from neonatal rats and grown on multielectrode arrays (MEAs). Upon exposure to epinephrine, the CM inter-spike interval (ISI) was decreased 14% at 10 µg/L (P<0.05) and 27% at 100 µg/L (P<0.05) as compared to baseline. Halon alone (50 mg/L) mildly prolonged the field potential (FP) duration (7%). CMs exposed to combinations of epinephrine (100 µg/L) and halon (50 mg/L) for 15 min showed a blunted increase in the ISI (35±12%) and a 38% decrease in conduction velocity (P<0.05) when compared to epinephrine alone. There was no change in field potential properties, but dephosphorylated connexin 43 (Cx43) was increased 60±16% with the combination as compared to epinephrine alone (P<0.05). Treatment with okadaic acid, a phosphatase inhibitor, prevented the Cx43 dephosphorylation and the reduction in conduction velocity upon exposure to halon and epinephrine. Moreover, the electrophysiological changes induced by epinephrine and halon were indistinguishable from those seen with the gap junction inhibitor heptanol. In conclusion, the combination of a halocarbon and epinephrine results in a unique electrophysiological signature including slow conduction that may explain, in part, the basis for cardiac sensitization. The slowing of conduction is most likely related to changes in the phosphorylation state of Cx43.

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Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias

Cited by 931 publications

References 349 publications

Cx30.2 can form heteromeric gap junction channels with other cardiac connexins

Cx30.2 can form heteromeric gap junction channels with other cardiac connexins

Negative Tension of Scroll Wave Filaments and Turbulence in Three-Dimensional Excitable Media and Application in Cardiac Dynamics

A possible mechanism of halocarbon-induced cardiac sensitization arrhythmias

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