Slow Conduction and Enhanced Anisotropy Increase the Propensity for Ventricular Tachyarrhythmias in Adult Mice With Induced Deletion of Connexin43

Rijen, Harold V.M. van; Eckardt, Dominik; Degen, Joachim; Theis, Martin; Ott, Thomas; Willecke, Klaus; Jongsma, Habo J.; Opthof, Tobias; Bakker, Jacques M.T. de

doi:10.1161/01.cir.0000117402.70689.75

Cited by 268 publications

(281 citation statements)

References 31 publications

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“…38 However, some recent investigations have shown that the slowing of impulse propagation depends on more severe reductions in Cx43 abundance. 3,39 The fluidity of cholesterol-rich domains in plasma membrane is important to gap junctional coupling. 40 In our experimental animals, the membrane-enrichment by cholesterol will decrease the fluidity and impair the coupling.…”

Section: Discussionmentioning

confidence: 99%

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Lin

Yeh

et al. 2005

Laboratory Investigation

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The effects of hypercholesterolemia on the myocardium per se include electrophysiological and mechanical alterations. Since gap junctions are essential in electromechanical coupling throughout the heart, we examined the correlation between the temporal expression of cardiac connexin 43 (Cx43), contractile function, and conduction velocity in cholesterol-fed rabbits. After a 12-week feeding period, serum cholesterol levels gradually increased (Po0.001). In contrast, expression of cardiomyocyte Cx43 protein progressively decreased (60% reduction at 12 weeks, Po0.001). Such a reduction was also demonstrated by immunoconfocal microscopy, which further showed redistribution of Cx43 gap junctions at the lateral cell membrane. The downregulation of Cx43 protein was associated with increased levels of Cx43 mRNA (3.5 -fold at 12 weeks, Po0.001) and phosphorylated c-Jun N-terminal kinase (three-fold at 12 weeks, P ¼ 0.001). Functionally, although fractional shortening of the left ventricle remained unchanged throughout the feeding protocol, the cholesterol-fed rabbits had a reduced cardiac cycle-dependent variation of integrated backscatters, a decreased mitral ring systolic velocity, and an increased modified Tei index (all Po0.001), all of which indicated impaired intrinsic myocardial contractility and attenuated ventricular systolic performance. In Langendorff-perfused hearts of cholesterol-fed rabbits, decreased conduction velocity was observed (Po0.005). Withdrawal of the cholesterol-enriched diet for 18 weeks restored the contractile parameters and Cx43 protein expression. These findings suggest that Cx43 is highly involved in the molecular mechanism of hypercholesterolemia-induced cardiac contractile dysfunction and dysrhythmias.

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Section: Discussionmentioning

confidence: 99%

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Lin

Yeh

et al. 2005

Laboratory Investigation

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“…In particular, the intercellular electrical uncoupling of ventricular cardiomyocytes also represents a major role in arrhythmogenesis during chronic ischemic heart disease 3. The gap‐junctional protein connexin 43 (Cx43) coordinates with cardiomyocyte activation and allows intercellular communication,4 whereas its downregulation and nonuniformity increases the risk of ventricular arrhythmia directly 5. Inhibiting interleukin‐1β (IL‐1β) following MI increases the expression of Cx43, thereby representing a novel antiarrhythmic property 6.…”

Section: Introductionmentioning

confidence: 99%

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

Shi

et al. 2017

JAHA

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BackgroundWith chronic ischemia after myocardial infarction, the resulting scar tissue result in electrical and structural remodeling vulnerable to an arrhythmogenic substrate. The cholinergic anti‐inflammatory pathway elicited by vagal nerve via α7 nicotinic acetylcholine receptors (α7‐nAChR) can modulate local and systemic inflammatory responses. Here, we aimed to clarify a novel mechanism for the antiarrhythmogenic properties of vagal nerve during the ischemic cardiomyopathy (ICM).Methods and ResultsLeft anterior descending artery of adult male Sprague‐Dawley rats was ligated for 4 weeks to develop ICM. Western blot revealed that eliciting the cholinergic anti‐inflammatory pathway by nicotine treatment showed a significant reduction in the amounts of collagens, cytokines, and other inflammatory mediators in the left ventricular infarcted border zone via inhibited NF‐κB activation, whereas it increased the phosphorylated connexin 43. Vagotomy inhibited the anti‐inflammatory, anti‐fibrosis, and anti‐arrhythmogenic effect of nicotine administration. And immunohistochemistry confirmed that the nicotine administration‐induced increase of connexin 43 was located in intercellular junctions. Furthermore nicotine treatment suppressed NF‐κB activation in lipopolysaccharide‐stimulated RAW264.7 cells, and α‐bungarotoxin (an α7‐nAChR selective antagonist) partly inhibited the nicotine‐treatment effect. In addition, 4‐week nicotine administration slightly improved the cardiac function, increased cardiac parasympathetic tone, decreased the prolonged QTc, and decreased the arrhythmia score of programmed electric stimulation‐induced ventricular arrhythmia.ConclusionsEliciting the cholinergic anti‐inflammatory pathway exerts anti‐arrhythmogenic effects against ICM‐induced ventricular arrhythmia accompanied by downregulation of cytokines, downgenerating of collagens, decrease in sympathetic/parasympathetic ratio, and prevention of the loss of phosphorylated connexin 43 during ICM. Our findings may suggest a promising therapy for the generation of ICM‐induced ventricular arrhythmia by eliciting the cholinergic anti‐inflammatory pathway.

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“…It is well appreciated that altered expression and/or distribution of Cx43-containing gap junctions are common features of diseased myocardium (1)(2)(3). Recent studies have demonstrated that cardiac-specific loss of Cx43 is sufficient to slow myocardial conduction velocity and induce unidirectional block resulting in an arrhythmogenic substrate and sudden cardiac death (SCD) in mice (4,5). However, it is less well understood how gap junctions are regulated and maintained at the ICD.…”

Section: Introductionmentioning

confidence: 99%

N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility

Levin

Xiong

et al. 2008

Journal of Molecular and Cellular Cardiology

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Cardiac-specific deletion of the murine gene (Cdh2) encoding the cell adhesion molecule, Ncadherin, results in disassembly of the intercalated disc (ICD) structure and sudden arrhythmic death. Connexin 43 (Cx43)-containing gap junctions are significantly reduced in the heart after depleting N-cadherin, therefore we hypothesized that animals expressing half the normal levels of N-cadherin would exhibit an intermediate phenotype. We examined the effect of N-cadherin haploinsufficiency on Cx43 expression and susceptibility to induced arrhythmias in mice either wild-type or heterozygous for the Cx43 (Gja1)-null allele. An increase in hypophosphorylated Cx43 accompanied by a modest decrease in total Cx43 protein levels was observed in the N-cadherin heterozygous mice. Consistent with these findings N-cadherin heterozygotes exhibited increased susceptibility to ventricular arrhythmias compared to wild-type mice. Quantitative immunofluorescence microscopy revealed a reduction in size of large Cx43-containing plaques in the N-cadherin heterozygous animals compared to wild-type. Gap junctions were further decreased in number and size in the N-cad/Cx43 compound heterozygous mice with increased arrhythmic susceptibility compared to the single mutants. The scaffold protein, ZO-1, was reduced at the ICD in N-cadherin heterozygous cardiomyocytes providing a possible explanation for the reduction in Cx43 plaque size. These data provide further support for the intimate relationship between N-cadherin and Cx43 in the heart, and suggest that germline mutations in the human N-cadherin (Cdh2) gene may predispose patients to increased risk of cardiac arrhythmias.

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Slow Conduction and Enhanced Anisotropy Increase the Propensity for Ventricular Tachyarrhythmias in Adult Mice With Induced Deletion of Connexin43

Cited by 268 publications

References 31 publications

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility

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