Decreased Connexin 43 and Increased Fibrosis in Atrial Regions Susceptible to Complex Fractionated Atrial Electrograms

Xu, Li; Shi, Haifeng; Tan, H.S.; Wang, Xinhua; Zhou, Li; Gu, Jun

doi:10.1159/000210398

Cited by 30 publications

(19 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, we did not observe a faster activation rate most likely because of a reduction in the CV because of a higher cell density in the late-stage group and/or a reduction in the expression of I Na channels and Cx43. These results agree with recent studies that showed a significant reduction in Cx43 due to AF both in pigs (5) and humans (18), in which this reduction was also associated with an increased complexity of the electrophysiological activity.…”

Section: Discussionsupporting

confidence: 93%

Role of atrial tissue remodeling on rotor dynamics: an in vitro study

Climent

Guillem

Fuentes

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

The objective of this article is to present an in vitro model of atrial cardiac tissue that could serve to study the mechanisms of remodeling related to atrial fibrillation (AF). We analyze the modification on gene expression and modifications on rotor dynamics following tissue remodeling. Atrial murine cells (HL-1 myocytes) were maintained in culture after the spontaneous initiation of AF and analyzed at two time points: 3.1 ± 1.3 and 9.7 ± 0.5 days after AF initiation. The degree of electrophysiological remodeling (i.e., relative gene expression of key ion channels) and structural inhomogeneity was compared between early and late cell culture times both in nonfibrillating and fibrillating cell cultures. In addition, the electrophysiological characteristics of in vitro fibrillation [e.g., density of phase singularities (PS/cm2), dominant frequency, and rotor meandering] analyzed by means of optical mapping were compared with the degree of electrophysiological remodeling. Fibrillating cell cultures showed a differential ion channel gene expression associated with atrial tissue remodeling (i.e., decreased SCN5A, CACN1C, KCND3, and GJA1 and increased KCNJ2) not present in nonfibrillating cell cultures. Also, fibrillatory complexity was increased in late- vs. early stage cultures (1.12 ± 0.14 vs. 0.43 ± 0.19 PS/cm2, P < 0.01), which was associated with changes in the electrical reentrant patterns (i.e., decrease in rotor tip meandering and increase in wavefront curvature). HL-1 cells can reproduce AF features such as electrophysiological remodeling and an increased complexity of the electrophysiological behavior associated with the fibrillation time that resembles those occurring in patients with chronic AF.

show abstract

Section: Discussionsupporting

confidence: 93%

Role of atrial tissue remodeling on rotor dynamics: an in vitro study

Climent

Guillem

Fuentes

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Other studies (3,23) in patterned cardiac cell monolayers with a region of slow or zig-zag conduction have shown that intrinsic heterogeneities in microscale tissue structure at the boundary of the central zone can be unmasked by loading effects during rapid pacing, leading to unidirectional conduction block and spiral wave formation. These in vitro studies are consistent with recent microstructural modeling studies demonstrating that in critical regimes near the onset of conduction block, microscopic variations in source-load mismatch at the boundary between well-coupled and poorly coupled regions can facilitate the escape of focal wavefronts that may increase the likelihood of reentry (16).Because these heterogeneous regions of slow conduction have been viewed as potential triggers of arrhythmia, their identification as possible sites for catheter ablation (24,28,42) is important. Unfortunately, the nature of conduction inside and near these regions is tortuous, giving rise to complex fractionated electrograms (CFEs) whose features are a consequence of wavefront collisions, conduction slowing, and wavebreak (9, 22), making it difficult to determine which area to target.…”

supporting

confidence: 83%

“…Because these heterogeneous regions of slow conduction have been viewed as potential triggers of arrhythmia, their identification as possible sites for catheter ablation (24,28,42) is important. Unfortunately, the nature of conduction inside and near these regions is tortuous, giving rise to complex fractionated electrograms (CFEs) whose features are a consequence of wavefront collisions, conduction slowing, and wavebreak (9,22), making it difficult to determine which area to target.…”

mentioning

confidence: 99%

A microstructural model of reentry arising from focal breakthrough at sites of source-load mismatch in a central region of slow conduction

Hubbard

Henriquez

2014

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Hubbard ML, Henriquez CS. A microstructural model of reentry arising from focal breakthrough at sites of source-load mismatch in a central region of slow conduction. Am J Physiol Heart Circ Physiol 306: H1341-H1352, 2014. First published March 7, 2014; doi:10.1152/ajpheart.00385.2013.-Regions of cardiac tissue that have a combination of focal activity and poor, heterogeneous gap junction coupling are often considered to be arrhythmogenic; however, the relationship between the properties of the cardiac microstructure and patterns of abnormal propagation is not well understood. The objective of this study was to investigate the effect of microstructure on the initiation of reentry from focal stimulation inside a poorly coupled region embedded in more wellcoupled tissue. Two-dimensional discrete computer models of ventricular monolayers (1 ϫ 1 cm) were randomly generated to represent heterogeneity in the cardiac microstructure. A small, central poorly coupled patch (0.40 ϫ 0.40 cm) was introduced to represent the site of focal activity. Simulated unipolar electrogram recordings were computed at various points in the tissue. As the gap conductance of the patch decreased, conduction slowed and became increasingly complex, marked by fractionated electrograms with reduced amplitude. Near the limit of conduction block, isolated breakthrough sites occurred at single cells along the patch boundary and were marked by long cell-to-cell delays and negative deflections on electrogram recordings. The strongest determinant of the site of wavefront breakthrough was the connectivity of the brick wall architecture, which enabled current flow through small regions of overlapping cells to drive propagation into the well-coupled zone. In conclusion, breakthroughs at the size scale of a single cell can occur at the boundary of source-load mismatch allowing focal activations from slow conducting regions to produce reentry. These breakthrough regions, identifiable by distinct asymmetric, reduced amplitude electrograms, are sensitive to tissue architecture and may be targets for ablation. focal activity; source-load mismatch; cardiac reentry; gap junction uncoupling; unipolar electrogram recording PATHOLOGICAL CHANGES, such as decreased expression of connexin43 and high levels of fibrosis, create regions of slow conduction that can facilitate arrhythmogenesis in the heart (13,26,33). In regions of slow conduction, gap junction uncoupling reduces electrical load, making it easier for focal (ectopic) beats to form while at the same time increasing the likelihood of tortuous, "zig-zag" conduction and unidirectional conduction block, two major mechanisms underlying reentry in diseased cardiac tissue (8,20,35,40). In particular, the boundary between poorly coupled diseased tissue and wellcoupled healthy tissue has been identified as a critical region of high source-load mismatch, and a number of experimental studies (11,32,34,41) have been used to understand how the interplay between focal activations and the underlying tissue structure of th...

show abstract

“…Furthermore, the RA of the PAH dogs contained a higher level of unphosphorylated Cx43 and more heterogeneous Cx43 expression than the RA of the control dogs. Previous studies have demonstrated that heterogeneous Cx43 expression may enhance susceptibility to arrhythmia, 18,19 as it is associated with dispersed impulse conduction. Taken together, our findings suggest that regional changes and greater heterogeneity of Cx43 expression provide the substrate for AF/AFL vulnerability in PAH dogs.…”

Section: Discussionmentioning

confidence: 99%

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Zhao¹,

Deng²,

Jiang³

et al. 2015

Hypertension

View full text Add to dashboard Cite

S upraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL), are common in patients with pulmonary arterial hypertension (PAH) and are associated with poor outcomes.1,2 In 1 study, restoration and maintenance of sinus rhythm were invariably associated with clinical improvement and recovery. 3 However, it is difficult to treat AF/AFL in patients with PAH because existing antiarrhythmic agents have substantial side effects in patients with PAH.Previous studies have suggested that increased sympathetic nerve activation could contribute to disease severity in patients with PAH. 4,5 A recent study by Chen et al 6 demonstrated that pulmonary artery denervation decreased pulmonary arterial pressure and increased functional capacity. Our previous study showed that renal denervation attenuates pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental PAH.7 In a dog model with rapid atrial or ventricular pacing, a reduction in sympathetic tone or cardiac sympathetic denervation achieved by ablating extrinsic cardiac or renal sympathetic nerves was shown to be useful for controlling atrial arrhythmia. [8][9][10] However, to the best of our knowledge, the effect of sympathetic nerve activity on vulnerability to atrial arrhythmia in PAH has not been evaluated. The purpose of this study was to test the hypothesis that the activity of intrinsic and extrinsic cardiac nerves has an important role in vulnerability to atrial arrhythmia in a model of PAH. MethodsAdditional methodological details for each of the sections below are described in the online-only Data Supplement.Abstract-Atrial arrhythmia, which includes atrial fibrillation (AF) and atrial flutter (AFL), is common in patients with pulmonary arterial hypertension (PAH), who often have increased sympathetic nerve activity. Here, we tested the hypothesis that autonomic nerves play important roles in vulnerability to AF/AFL in PAH. The atrial effective refractory period and AF/AFL inducibility at baseline and after anterior right ganglionated plexi ablation were determined during left stellate ganglion stimulation or left renal sympathetic nerve stimulation in beagle dogs with or without PAH. Then, sympathetic nerve, β-adrenergic receptor densities and connexin 43 expression in atrial tissues were assessed. The sum of the window of vulnerability to AF/AFL was increased in the right atrium compared with the left atrium at baseline in the PAH dogs but not in the controls. The atrial effective refractory period dispersion was increased in the control dogs, but not in the PAH dogs, during left stellate ganglion stimulation. The voltage thresholds for inducing AF/AFL during anterior right ganglionated plexi stimulation were lower in the PAH dogs than in the controls. The AF/AFL inducibility was suppressed after ablation of the anterior right ganglionated plexi in the PAH dogs. The PAH dogs had higher sympathetic nerve and β1-adrenergic receptor densities, increased levels of nonphosphorylated connexin 43, and heterogeneo...

show abstract

Decreased Connexin 43 and Increased Fibrosis in Atrial Regions Susceptible to Complex Fractionated Atrial Electrograms

Cited by 30 publications

References 55 publications

Role of atrial tissue remodeling on rotor dynamics: an in vitro study

Role of atrial tissue remodeling on rotor dynamics: an in vitro study

A microstructural model of reentry arising from focal breakthrough at sites of source-load mismatch in a central region of slow conduction

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Contact Info

Product

Resources

About