Discontinuous Conduction in Mouse Bundle Branches Is Caused by Bundle-Branch Architecture

Veen, Toon A.B. van; Rijen, Harold V.M. van; Kempen, Marjan J. A. van; Miquerol, Lucile; Opthof, Tobias; Gros, Daniël; Vos, Marc A.; Jongsma, Habo J.; Bakker, Jacques M.T. de

doi:10.1161/circulationaha.105.547893

Cited by 30 publications

(21 citation statements)

References 49 publications

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“…It is also known that during developmental stages of the rodent heart two other gap junction isoforms (Cx40 and Cx45) can be expressed by ventricular cardiomyocytes [19], [20]. These isoforms form in the adult stage the gap junctions within the specialized cardiac conduction system [21]. In our specimen, labeling against Cx40 did not reveal intercellular signals between the cardiomyocytes rather than positive signals only in the endothelium of the vessels (data not shown).…”

Section: Discussionsupporting

confidence: 46%

Assembly of the Cardiac Intercalated Disk during Pre- and Postnatal Development of the Human Heart

et al. 2014

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BackgroundIn cardiac muscle, the intercalated disk (ID) at the longitudinal cell-edges of cardiomyocytes provides as a macromolecular infrastructure that integrates mechanical and electrical coupling within the heart. Pathophysiological disturbance in composition of this complex is well known to trigger cardiac arrhythmias and pump failure. The mechanisms underlying assembly of this important cellular domain in human heart is currently unknown.MethodsWe collected 18 specimens from individuals that died from non-cardiovascular causes. Age of the specimens ranged from a gestational age of 15 weeks through 11 years postnatal. Immunohistochemical labeling was performed against proteins comprising desmosomes, adherens junctions, the cardiac sodium channel and gap junctions to visualize spatiotemporal alterations in subcellular location of the proteins.ResultsChanges in spatiotemporal localization of the adherens junction proteins (N-cadherin and ZO-1) and desmosomal proteins (plakoglobin, desmoplakin and plakophilin-2) were identical in all subsequent ages studied. After an initial period of diffuse and lateral labelling, all proteins were fully localized in the ID at approximately 1 year after birth. Nav1.5 that composes the cardiac sodium channel and the gap junction protein Cx43 follow a similar pattern but their arrival in the ID is detected at (much) later stages (two years for Nav1.5 and seven years for Cx43, respectively).ConclusionOur data on developmental maturation of the ID in human heart indicate that generation of the mechanical junctions at the ID precedes that of the electrical junctions with a significant difference in time. In addition arrival of the electrical junctions (Nav1.5 and Cx43) is not uniform since sodium channels localize much earlier than gap junction channels.

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Section: Discussionsupporting

confidence: 46%

Assembly of the Cardiac Intercalated Disk during Pre- and Postnatal Development of the Human Heart

et al. 2014

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“…We found that expression of Cx40 and Na v 1.5 was drastically reduced in the VCS after removal of Tbx5 ( Figure 5). The proximal AV bundle and distal AV bundle/bundle branches were identified by their anatomic location, acetylcholinesterase activity (12,(17)(18)(19), and contactin-2 expression (20). Tbx5 fl/fl controls demonstrated high Cx40 and Na v 1.5 expression throughout the molecularly defined VCS, whereas Tbx5 minKCreERT2 animals demonstrated dramatic Values are mean ± SD.…”

Section: Figurementioning

confidence: 99%

TBX5 drives Scn5a expression to regulate cardiac conduction system function

et al. 2012

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Cardiac conduction system (CCS) disease, which results in disrupted conduction and impaired cardiac rhythm, is common with significant morbidity and mortality. Current treatment options are limited, and rational efforts to develop cell-based and regenerative therapies require knowledge of the molecular networks that establish and maintain CCS function. Recent genome-wide association studies (GWAS) have identified numerous loci associated with adult human CCS function, including TBX5 and SCN5A. We hypothesized that TBX5, a critical developmental transcription factor, regulates transcriptional networks required for mature CCS function. We found that deletion of Tbx5 from the mature murine ventricular conduction system (VCS), including the AV bundle and bundle branches, resulted in severe VCS functional consequences, including loss of fast conduction, arrhythmias, and sudden death. Ventricular contractile function and the VCS fate map remained unchanged in VCS-specific Tbx5 knockouts. However, key mediators of fast conduction, including Na v 1.5, which is encoded by Scn5a, and connexin 40 (Cx40), demonstrated Tbx5-dependent expression in the VCS. We identified a TBX5-responsive enhancer downstream of Scn5a sufficient to drive VCS expression in vivo, dependent on canonical T-box binding sites. Our results establish a direct molecular link between Tbx5 and Scn5a and elucidate a hierarchy between human GWAS loci that affects function of the mature VCS, establishing a paradigm for understanding the molecular pathology of CCS disease. IntroductionThe cardiac conduction system (CCS) consists of a network of specialized cardiomyocytes that generate and propagate the electrical impulses that organize cardiac contraction. The CCS is composed of the slowly propagating atrial nodes, including the sinoatrial (SA) and atrioventricular (AV) nodes, and the rapidly propagating ventricular conduction system (VCS), including the AV (His) bundle and right and left bundle branches. The VCS is uniquely adapted for fast conduction in order to rapidly transmit the electrical impulse governing ventricular contraction from the AV node to the ventricular apex. Disorders of the VCS are common, carry significant morbidity, and are poorly understood from a molecular perspective.The transcriptional networks required to maintain function of the adult CCS are undefined. Our current understanding of the molecular mediators of CCS function stems largely from heritable monogenic disorders and mouse models that have identified a limited number of genes essential for maintaining cardiac rhythm, most of which encode ion channels and their interacting partners (reviewed in ref. 1). Similar approaches have also begun to uncover the transcriptional networks required for CCS development (reviewed in ref.2). Recent genome-wide association studies (GWAS) have identified loci implicated in ECG interval variation (3-8), providing candidate genes with potentially important roles in CCS function in the general population. Specifically, numerous loci near genes e...

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“…However, 8- to 10-week-old Scn5a ± mice have several cardiac electrical defects such as decreased atrial and atrioventricular conduction and increased susceptibility to pacing-induced ventricular arrhythmias (Papadatos et al, 2002). Following this initial report, the model was further analyzed to investigate the potential pathophysiological mechanisms involved in the progressive evolution of SCN5A -related PCCD (Royer et al, 2005; van Veen et al, 2005). It was found that in addition to atrial and atrioventricular conduction, ventricular conduction was also decreased.…”

Section: A Model For the Brugada Syndrome And Conduction Disorders: Tmentioning

confidence: 99%

Mouse Models of SCN5A-Related Cardiac Arrhythmias

Derangeon¹,

Montnach²,

Baró³

et al. 2012

Front. Physio.

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Mutations of SCN5A gene, which encodes the α-subunit of the voltage-gated Na+ channel NaV1.5, underlie hereditary cardiac arrhythmic syndromes such as the type 3 long QT syndrome, cardiac conduction diseases, the Brugada syndrome, the sick sinus syndrome, a trial standstill, and numerous overlap syndromes. Patch-clamp studies in heterologous expression systems have provided important information to understand the genotype-phenotype relationships of these diseases. However, they could not clarify how SCN5A mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of these diseases and for the overlapping syndromes. Genetically modified mice rapidly appeared as promising tools for understanding the pathophysiological mechanisms of cardiac SCN5A-related arrhythmic syndromes and several mouse models have been established. This review presents the results obtained on these models that, for most of them, recapitulate the clinical phenotypes of the patients. This includes two models knocked out for Nav1.5 β1 and β3 auxiliary subunits that are also discussed. Despite their own limitations that we point out, the mouse models still appear as powerful tools to elucidate the pathophysiological mechanisms of SCN5A-related diseases and offer the opportunity to investigate the secondary cellular consequences of SCN5A mutations such as the expression remodeling of other genes. This points out the potential role of these genes in the overall human phenotype. Finally, they constitute useful tools for addressing the role of genetic and environmental modifiers on cardiac electrical activity.

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Discontinuous Conduction in Mouse Bundle Branches Is Caused by Bundle-Branch Architecture

Cited by 30 publications

References 49 publications

Assembly of the Cardiac Intercalated Disk during Pre- and Postnatal Development of the Human Heart

Assembly of the Cardiac Intercalated Disk during Pre- and Postnatal Development of the Human Heart

TBX5 drives Scn5a expression to regulate cardiac conduction system function

Mouse Models of SCN5A-Related Cardiac Arrhythmias

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