Conduction abnormalities and ventricular arrhythmogenesis: The roles of sodium channels and gap junctions

Tse, Gary; Yeo, Jie Ming

doi:10.1016/j.ijcha.2015.10.003

Cited by 70 publications

(73 citation statements)

References 192 publications

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“…Defects in linking sites of these proteins can interrupt cell adhesion, especially under conditions of increased mechanical stress or stretch, leading to cell death, progressive loss of myocardium, and fibro‐fatty replacement . As such, surviving myocardial fibers within the fibro‐fatty tissue from zones of slow conduction provide a medium for re‐entry ventricular arrhythmias . The degeneration‐inflammation model posits that the resulting cellular damage is found in tissues under high mechanical stress .…”

Section: Pathophysiology Of Arvc/dmentioning

confidence: 99%

“…15 As such, surviving myocardial fibers within the fibro-fatty tissue from zones of slow conduction provide a medium for re-entry ventricular arrhythmias. [16][17][18][19] The degeneration-inflammation model posits that the resulting cellular damage is found in tissues under high mechanical stress. 1 Indeed, this notion is in keeping with the observations that exercise increases age-related penetrance and risk of arrhythmias in ARVC/D-associated mutation carriers.…”

Section: Pathophysiology Of Arvc/dmentioning

confidence: 99%

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Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) in clinical practice

Bazoukis

Liu

et al. 2017

Journal of Arrhythmia

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Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited myocardial disease characterized by fibro‐fatty replacement of the right ventricular myocardium, and associated with paroxysmal ventricular arrhythmias and sudden cardiac death (SCD). It is currently the second most common cause of SCD after hypertrophic cardiomyopathy in young people <35 years of age, causing up to 20% of deaths in this patient population. This condition has a male preponderance and is more commonly found in individuals of Italian and Greek descent. To date, there is no single diagnostic test for ARVC/D and the diagnosis is made based on clinical, electrocardiographic, and radiological findings according to the Revised 2010 Task Force Criteria. In this review, we will discuss the mainstay treatment which includes pharmacotherapy, implantable cardioverter‐defibrillator insertion for abortion of sudden cardiac death, and in the advanced stages of the disease cardiac transplantation.

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Section: Pathophysiology Of Arvc/dmentioning

confidence: 99%

Section: Pathophysiology Of Arvc/dmentioning

confidence: 99%

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) in clinical practice

Bazoukis

Liu

et al. 2017

Journal of Arrhythmia

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“…Connexins can be found in both excitable and non-excitable tissues with different spatio-temporal patterns. For example, the cardiac myocardium has abundant expression of the isoforms Cx30.2, Cx40, Cx43, and Cx45 (Davis et al, 1995; Jongsma, 2000; Tse and Yeo, 2015). Their expression levels vary between different cardiac regions: Cx40 is only expressed in the atria; whereas in the ventricles Cx43 is extensively expressed with minimal levels of Cx40.…”

Section: Introductionmentioning

confidence: 99%

The Role of Connexins in Wound Healing and Repair: Novel Therapeutic Approaches

et al. 2016

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Gap junctions are intercellular proteins responsible for mediating both electrical and biochemical coupling through the exchange of ions, second messengers and small metabolites. They consist of two connexons, with (one) connexon supplied by each cell. A connexon is a hexamer of connexins and currently more than 20 connexin isoforms have been described in the literature thus far. Connexins have a short half-life, and therefore gap junction remodeling constantly occurs with a high turnover rate. Post-translational modification, such as phosphorylation, can modify their channel activities. In this article, the roles of connexins in wound healing and repair are reviewed. Novel strategies for modulating the function or expression of connexins, such as the use of antisense technology, synthetic mimetic peptides and bioactive materials for the treatment of skin wounds, diabetic and pressure ulcers as well as cornea wounds, are considered.

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“…The longest QRS duration and largest QTc interval were observed in the AngII‐treated GCα1‐KO model, which was the model in which the most significant decrease of Cx43 at the ID and the largest Cx43 lateralization were observed, suggesting a strong correlation between the electrical dysfunction and the Cx43 mislocalization. However, the disruption of the Cx43 and GC1 association at the ID could indirectly affect other key players of electrical conduction, notably sodium channels whose dysfunction also accounts for ventricular arrhythmias 38. Moreover, sodium channels are associated with the ID,39 and Cx43 KO is associated with decreased Nav1.5 40.…”

Section: Discussionmentioning

confidence: 99%

Newly Identified NO‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

Crassous

Shu

Huang

et al. 2017

JAHA

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BackgroundGuanylyl cyclase, a heme‐containing α1β1 heterodimer (GC1), produces cGMP in response to Nitric oxide (NO) stimulation. The NO‐GC1‐cGMP pathway negatively regulates cardiomyocyte contractility and protects against cardiac hypertrophy–related remodeling. We recently reported that the β1 subunit of GC1 is detected at the intercalated disc with connexin 43 (Cx43). Cx43 forms gap junctions (GJs) at the intercalated disc that are responsible for electrical propagation. We sought to determine whether there is a functional association between GC1 and Cx43 and its role in cardiac homeostasis.Methods and Results GC1 and Cx43 immunostaining at the intercalated disc and coimmunoprecipitation from membrane fraction indicate that GC1 and Cx43 are associated. Mice lacking the α subunit of GC1 (GCα1 knockout mice) displayed a significant decrease in GJ function (dye‐spread assay) and Cx43 membrane lateralization. In a cardiac‐hypertrophic model, angiotensin II treatment disrupted the GC1‐Cx43 association and induced significant Cx43 membrane lateralization, which was exacerbated in GCα1 knockout mice. Cx43 lateralization correlated with decreased Cx43‐containing GJs at the intercalated disc, predictors of electrical dysfunction. Accordingly, an ECG revealed that angiotensin II–treated GCα1 knockout mice had impaired ventricular electrical propagation. The phosphorylation level of Cx43 at serine 365, a protein‐kinase A upregulated site involved in trafficking/assembly of GJs, was decreased in these models.Conclusions GC1 modulates ventricular Cx43 location, hence GJ function, and partially protects from electrical dysfunction in an angiotensin II hypertrophy model. Disruption of the NO‐cGMP pathway is associated with cardiac electrical disturbance and abnormal Cx43 phosphorylation. This previously unknown NO/Cx43 signaling could be a protective mechanism against stress‐induced arrhythmia.

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Conduction abnormalities and ventricular arrhythmogenesis: The roles of sodium channels and gap junctions

Cited by 70 publications

References 192 publications

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) in clinical practice

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) in clinical practice

The Role of Connexins in Wound Healing and Repair: Novel Therapeutic Approaches

Newly Identified NO‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

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