Impaired Conduction in the Bundle Branches of Mouse Hearts Lacking the Gap Junction Protein Connexin40

Rijen, Harold V. M. van; Veen, Toon A.B. van; Kempen, Marjan J. A. van; Wilms‐Schopman, Francien J.G.; Potse, Mark; Krueger, Olaf; Willecke, Klaus; Opthof, Tobias; Jongsma, Habo J.; Bakker, Jacques M.T. de

doi:10.1161/01.cir.103.11.1591

Cited by 124 publications

(88 citation statements)

References 41 publications

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“…25 Moreover, conduction velocity in the His bundle branches of the mouse is not faster than in the working myocardium. 12 Another major difference between mouse and human is that the mouse heart contracts 10 times more often per time unit than the human heart.…”

Section: Discussionmentioning

confidence: 99%

Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

et al. 2005

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Background— We have previously linked hereditary progressive cardiac conduction defect (hereditary Lenègre’s disease) to a loss-of-function mutation in the gene encoding the main cardiac Na + channel, SCN5A . In the present study, we investigated heterozygous Scn5a -knockout mice ( Scn5a +/− mice) as a model for hereditary Lenègre’s disease. Methods and Results— In Scn5a +/− mice, surface ECG recordings showed age-related lengthening of the P-wave and PR- and QRS-interval duration, coinciding with previous observations in patients with Lenègre’s disease. Old but not young Scn5a +/− mice showed extensive fibrosis of their ventricular myocardium, a feature not seen in wild-type animals. In old Scn5a +/− mice, fibrosis was accompanied by heterogeneous expression of connexin 43 and upregulation of hypertrophic markers, including β-MHC and skeletal α-actin. Global connexin 43 expression as assessed with Western blots was similar to wild-type mice. Decreased connexin 40 expression was seen in the atria. Using pangenomic microarrays and real-time PCR, we identified in Scn5a +/− mice an age-related upregulation of genes encoding Atf3 and Egr1 transcription factors. Echocardiography and hemodynamic investigations demonstrated conserved cardiac function with aging and lack of ventricular hypertrophy. Conclusions— We conclude that Scn5a +/− mice convincingly recapitulate the Lenègre’s disease phenotype, including progressive impairment with aging of atrial and ventricular conduction associated with myocardial rearrangements and fibrosis. Our work provides the first demonstration that a monogenic ion channel defect can progressively lead to myocardial structural anomalies.

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Section: Discussionmentioning

confidence: 99%

Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

et al. 2005

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“…The corresponding gap junctional channels are involved in electrical impulse propagation and coordinated contraction of the heart (4). The expression of these connexins is restricted to specialized compartments: Cx43 is the major connexin in the working myocytes of atria and ventricles (5, 6); Cx40 is detected in the atrioventricular (AV) conduction system and in atrial working myocytes (7,8). Cx45 is abundantly expressed in the sinoatrial (SA) node and the AV conduction system (9-11).…”

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confidence: 99%

“…right bundle branch block and impaired left bundle branch conduction (7). The unrestricted ablation of Cx43 in mice caused postnatal death as a consequence of major heart defects (6).…”

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confidence: 99%

Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node

Kreuzberg

Schrickel

Ghanem

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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In the mammalian heart, gap junction channels between electrically coupled cardiomyocytes are necessary for impulse propagation and coordinated contraction of atria and ventricles. Recently, mouse connexin30.2 (Cx30.2) was shown to be expressed in the cardiac conduction system, predominantly in sinoatrial and atrioventricular (AV) nodes. The corresponding gap junctional channels expressed in HeLa cells exhibit the lowest unitary conductance (9 pS) of all connexin channels. Here we report that Cx30.2 slows down the propagation of excitation through the AV node. Mice expressing a LacZ reporter gene instead of the Cx30.2 coding region (Cx30.2 LacZ/LacZ ) exhibit a PQ interval that is Ϸ25% shorter than in WT littermates. By recording atrial, His, and ventricular signals with intracardiac electrodes, we show that this decrease is attributed to significantly accelerated conduction above the His bundle (atrial-His interval: 27.9 ؎ 5.1 ms in Cx30.2 LacZ/LacZ versus 37.1 ؎ 4.1 ms in Cx30.2 ؉/؉ mice), whereas HV conduction is unaltered. Atrial stimulation revealed an elevated AV-nodal conduction capacity and faster ventricular response rates during induced episodes of atrial fibrillation in Cx30.2 LacZ/LacZ mice. Our results show that Cx30.2 contributes to the slowdown of impulse propagation in the AV node and additionally limits the maximum number of beats conducted from atria to ventricles. Thus, it is likely to be involved in coordination of atrial and ventricular contraction and to fulfill a protective role toward pathophysiological states such as atrial tachyarrhythmias (e.g., atrial fibrillation) by preventing rapid conduction to the ventricles potentially associated with hemodynamic deterioration.atrial fibrillation ͉ cardiac connexins ͉ conductive myocardium ͉ coordinated cardiac contraction G ap junctions are intercellular conduits that allow direct communication between neighboring cells. Two hemichannels, one contributed by each adjacent cell, form a pore that permits diffusion of ions, metabolites, and peptides Ͻ1.8 kDa molecular mass (1, 2). The protein subunits of these channels are the connexins (Cx) that are encoded by a multigene family, including 20 members in mice (3).It has been known for several years that three different connexins, i.e., Cx40, Cx43, and Cx45, are expressed by cardiac myocytes. The corresponding gap junctional channels are involved in electrical impulse propagation and coordinated contraction of the heart (4). The expression of these connexins is restricted to specialized compartments: Cx43 is the major connexin in the working myocytes of atria and ventricles (5, 6); Cx40 is detected in the atrioventricular (AV) conduction system and in atrial working myocytes (7,8). Cx45 is abundantly expressed in the sinoatrial (SA) node and the AV conduction system (9-11).Generation of Cx-deficient mice for Cx40, Cx43, and Cx45 helped to elucidate the involvement of these connexins in proper heart function. Targeted deletion of Cx40 in mice resulted in right bundle branch block and impaired left bu...

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“…Cx40, Cx43 and Cx45 are the most abundant connexin isoforms of the working mammalian myocardial cells and the conduction system. Cx40 is mainly expressed in the atrium and in the conduction system [44][45][46][47][48][49], while Cx43 can be found both in atrial and ventricular cells but not in sinoatrial and atrioventricular nodes [46,[48][49][50][51][52][53][54][55]. Cx45 is preferentially expressed in sinoatrial and atrioventricular nodes, His-bundle and bundle branches [56][57][58].…”

Section: The Distribution Of Gap Junctionsmentioning

confidence: 99%

Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?

Szentmiklósi¹,

Szentandrássy²,

Hegyi³

et al. 2014

CPD

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The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling.Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR.Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

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Impaired Conduction in the Bundle Branches of Mouse Hearts Lacking the Gap Junction Protein Connexin40

Abstract: Our data show that (1) in mice, a continuity exists between the common bundle and the septum, and (2) Cx40 deficiency results in right bundle-branch block and impaired left bundle-branch conduction.

Cited by 124 publications

References 41 publications

Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node

Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?

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Impaired Conduction in the Bundle Branches of Mouse Hearts Lacking the Gap Junction Protein Connexin40

Abstract: Our data show that (1) in mice, a continuity exists between the common bundle and the septum, and (2) Cx40 deficiency results in right bundle-branch block and impaired left bundle-branch conduction.

Cited by 124 publications

References 41 publications

Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

Mouse Model of SCN5A -Linked Hereditary Lenègre’s Disease

Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node

Chemistry, Physiology, and Pharmacology of &#946;.-Adrenergic Mechanisms in the Heart. Why are .&#946;-Blocker Antiarrhythmics Superior?

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Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?