Yao, J. A. et al. Remodeling of gap junctional channel function in epicardial border zone of healing canine infarcts. Circ. Res. 92, 437-443

Dept of Pharmacology and Center for Molecular Therapeutics, Columbia University, 630 West 168th St, PH7W, New York, NY 10032, USA.
Circulation Research (Impact Factor: 11.02). 03/2003; 92(4):437-43. DOI: 10.1161/01.RES.0000059301.81035.06
Source: PubMed


The epicardial border zone (EBZ) of canine infarcts has increased anisotropy because of transverse conduction slowing. It remains unknown whether changes in gap junctional conductance (Gj) accompany the increased anisotropy. Ventricular cell pairs were isolated from EBZ and normal hearts (NZ). Dual patch clamp was used to quantify Gj. At a transjunctional voltage (Vj) of +10 mV, side-to-side Gj of EBZ pairs (9.2+/-3.4 nS, n=16) was reduced compared with NZ side-to-side Gj (109.4+/-23.6 nS, n=14, P<0.001). Gj of end-to-end coupled cells was not reduced in EBZ. Steady-state Gj of both NZ and EBZ showed voltage dependence, described by a two-way Boltzmann function. Half-maximal activation voltage in EBZ was shifted to higher Vj in positive and negative directions. Immunoconfocal planimetry and quantification showed no change in connexin43 per unit cell volume or surface area in EBZ. Decreased side-to-side coupling occurs in EBZ myocytes, independent of reduced connexin43 expression, and is hypothesized to contribute to increased anisotropy and reentrant arrhythmias.

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Available from: Andrew L Wit, Dec 21, 2015
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    • "Anisotropic conductivities in the normal myocardium were assigned values as in [26], matching canine conduction velocities reported by Roberts et al [27]. Within the GZ, the transverse conductivity was decreased by 90% to match reported conduction velocities [15], thus reflecting connexin 43 (Cx43) downregulation and lateralization [28]. "
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    ABSTRACT: Ventricular tachycardia, a life-threatening regular and repetitive fast heart rhythm, frequently occurs in the setting of myocardial infarction. Recently, the peri-infarct zones surrounding the necrotic scar (termed gray zones) have been shown to correlate with ventricular tachycardia inducibility. However, it remains unknown how the latter is determined by gray zone distribution and size. The goal of this study is to examine how tachycardia circuits are maintained in the infarcted heart and to explore the relationship between the tachycardia organizing centers and the infarct gray zone size and degree of heterogeneity. To achieve the goals of the study, we employ a sophisticated high-resolution electrophysiological model of the infarcted canine ventricles reconstructed from imaging data, representing both scar and gray zone. The baseline canine ventricular model was also used to generate additional ventricular models with different gray zone sizes, as well as models in which the gray zone was represented as different heterogeneous combinations of viable tissue and necrotic scar. The results of the tachycardia induction simulations with a number of high-resolution canine ventricular models (22 altogether) demonstrated that the gray zone was the critical factor resulting in arrhythmia induction and maintenance. In all models with inducible arrhythmia, the scroll-wave filaments were contained entirely within the gray zone, regardless of its size or the level of heterogeneity of its composition. The gray zone was thus found to be the arrhythmogenic substrate that promoted wavebreak and reentry formation. We found that the scroll-wave filament locations were insensitive to the structural composition of the gray zone and were determined predominantly by the gray zone morphology and size. The findings of this study have important implications for the advancement of improved criteria for stratifying arrhythmia risk in post-infarction patients and for the development of new approaches for determining the ablation targets of infarct-related tachycardia.
    Full-text · Article · Jul 2013 · PLoS ONE
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    • "The initial thought was that these channels allowed for transverse conduction leading to slowing of conduction in the longitudinal direction and subsequent reentrant arrhythmias. Subsequent studies showed that the channels on the lateral membranes were non-functional (Yao et al., 2003) and that the anisotropic ratio, which would be expected to decrease if transverse conduction were increased, actually was larger in injured myocardium. Attempts have been made to identify the mechanisms by which lateralization occurs (Kieken et al., 2009) as well as identify therapies which limit loss of gap junctional coupling (Kjolbye et al., 2008; Wiegerinck et al., 2009). "
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    ABSTRACT: Background: The proinflammatory cytokine Interleukin-1β (IL-1β), which increases in the heart post myocardial infarction (MI), has been shown to cause loss of Connexin43 (Cx43) function, an event known to underlie formation of the arrhythmogenic substrate. Omega 3 Fatty acids exhibit antiarrhythmic properties and impact IL-1β signaling. We hypothesize that Omega-3 fatty acids prevent arrhythmias in part, by inhibiting IL-1β signaling thus maintaining functional Cx43 channels. Methods: Rat neonatal myocytes or Madin-Darby Canine Kidney Epithelial (MDCK) cells grown in media in the absence (Ctr) or presence of 30 μM docosahexaenoic acid (DHA, an Omega-3 Fatty acid) were treated with 0.1 μM activated IL-1β. We determined Cx43 channel function using a dye spread assay. Western blot and immunostaining were used to examine Cx43 levels/localization and downstream effectors of IL-1β. In addition we used a murine model of MI for 24 h to determine the impact of an Omega-3 fatty acid enriched diet on Cx43 levels/localization post MI. Results: IL-1β significantly inhibited Cx43 function in Ctr cells (200.9 ± 17.7 μm [Ctr] vs. 112.8 ± 14.9 μm [0.1 uM IL-1β], p<0.05). However, DHA-treated cells remained highly coupled in the presence of IL-1β [167.9 ± 21.9 μm [DHA] vs. 164.4 ± 22.3 μm [DHA + 0.1 uM IL-1β], p<0.05, n = 4]. Additionally, western blot showed that IL-1β treatment caused a 38.5% downregulation of Cx43 [1.00 au [Ctr] vs. 0.615 au (0.1 μM IL-1β) which was completely abolished in DHA-treated cells (0.935 au [DHA] vs. 1.02 au [DHA + 0.1 μM IL-1β), p < 0.05, n = 3]. Examination of the downstream modulator of IL-1β, NFκβ showed that while hypoxia caused translocation of NFκβ to the nucleus, this was inhibited by DHA. Additionally we found that a diet enriched in Omega-3 Fatty acids inhibited lateralization of Cx43 in the post-MI murine heart as well as limited activation of fibroblasts which would lead to decreased fibrosis overall. Conclusions: Omega 3 Fatty acid treatment inhibited IL-1β-stimulated loss of Cx43 protein, and more importantly, inhibited loss of Cx43 function by inhibiting translocation of NFκβ. In the intact heart a diet enriched in Omega 3 Fatty Acids limited loss of Cx43 at the intercalated disk in the heart following MI. These data suggest that one of cardio-protective mechanisms by which Omega 3 Fatty acids work includes prevention of the pro-arrhythmic loss of Cx43 post MI and the attenuation of cardiac fibrosis after injury.
    Preview · Article · Jul 2012 · Frontiers in Physiology
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    • "Normal conductivity values were used for the non-infarct tissue. BZ conductivity values were assigned based on previous studies reporting a 90% decrease in transverse coupling [3]. "
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    ABSTRACT: The role of the 3D infarct structure in arrhythmia generation and maintenance in hearts with myocardial infarction cannot be fully elucidated through experimental techniques alone. Our aim was to develop methodology to construct a high resolution computational model of the infarcted canine heart using magnetic resonance (MRI) and diffusion tensor images (DTI) and then to use the resulting model to study post-infarction ventricular tachycardia (VT). Segmentation of the MRI and DTI stacks using image processing techniques provided accurate representations of the myocardium, the infarct scar, and the border zone (BZ) surrounding the scar. Realistic electrophysiological properties were assigned to each region. Simulations using the novel model revealed that postinfarction VT is initiated and maintained by reentrant circuits located within the BZ.
    Full-text · Conference Paper · Oct 2008
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