Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias

Boulaksil, Mohamed; Winckels, Stephan K.G.; Engelen, Markus A.; Stein, Mèra; Veen, Toon A.B. van; Jansen, John A.; Linnenbank, André C.; Bierhuizen, Marti F.A.; Groenewegen, W. Antoinette; Oosterhout, Matthijs F.M. van; Kirkels, J. H.; Jonge, Nicolaas de; Varró, András; Vos, Marc A.; Bakker, Jacques M.T. de; Rijen, Harold V.M. van

doi:10.1093/eurjhf/hfq092

Cited by 60 publications

(69 citation statements)

References 32 publications

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“…It seems that cardiac insufficiency consists of 2 components, the sequence of contraction on one hand and the cellular biochemical alterations on the other hand, which finally lead to progressive pathological remodeling. 25 Compared with other studies carried out on animal models of cardiac failure and on explanted hearts of patients with terminal heart failure that revealed a decrease in L-type calcium and peak sodium currents, a prolongation of action potential, a decrease in SERCA and phospholamban, an increase in catecholamine levels, and a heterogeneous distribution of Cx43, [31][32][33][34][35] our results are different in terms of the expression of the calcium handling proteins and Cx43 distribution. However, as outlined above, our paced minipigs were cardiac compensated, and it is conceivable that ultrastructural remodeling is much more pronounced in overt heart failure, as seen in tachycardia pacing studies performed on dogs.…”

Section: Preservation Of LV Function With Lv Apex Pacingcontrasting

confidence: 81%

Right or Left Ventricular Pacing in Young Minipigs With Chronic Atrioventricular Block

et al. 2012

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Background-Left ventricular (LV) dyssynchrony may occur as a result of right ventricular (RV) pacing and is a known risk factor for the development of heart failure. In children with complete atrioventricular block, pacing-induced dyssynchrony lasting for decades might be especially deleterious for LV function. To determine the hemodynamic and ultrastructural remodeling after either RV free wall or LV apical pacing, we used a chronic minipig model. Methods and Results-Fourteen piglets 8 weeks of age underwent atrioventricular node ablation and were paced from either the RV free wall or the LV apex at 120 bpm for 1 year (7 age-matched minipigs served as controls with spontaneous heart rates of 104Ϯ5 bpm). Echocardiographic examinations, pressure-volume loops, patch-clamp investigations, and examinations of connexin43, calcium-handling proteins, and histomorphology were carried out. RV free wall-paced minipigs exhibited significantly more LV dyssynchrony than LV apex-paced animals, which was accompanied by worsening of LV function (maximum LV mechanical delay/LV ejection fraction: RV free wall pacing, 154Ϯ36 ms/28Ϯ3%, LV apical pacing, 52Ϯ19 ms/45Ϯ2%, control 47Ϯ14 ms/62Ϯ1%; Pϭ0.0001). At the cellular level, both pacemaker groups exhibited a significant reduction in L-type calcium and peak sodium current, shortening of action potential duration and amplitude, increased cell capacity, and alterations in the calcium-handling proteins that were similar for RV free wall-and LV apex-paced animals. Conclusions-The observed molecular remodeling seemed to be more dependent on heart rate than on dyssynchrony. LV apical pacing is associated with less dyssynchrony, a more physiological LV contraction pattern, and preserved LV function as opposed to RV free wall pacing. (Circulation. 2012;125:2578-2587.)Key Words: cardiac pacing, artificial Ⅲ myocardial contraction Ⅲ pediatrics Ⅲ ventricular remodeling T raditionally, permanent cardiac pacing has been carried out from the endocardial right ventricular (RV) apex. In smaller children, epicardial RV pacing sites were commonly used. Several larger adult [1][2][3] and smaller pediatric studies 4 -9 so far have shown that RV pacing may result in significant left ventricular (LV) dyssynchrony and impaired LV function, including the induction of progressive LV remodeling and failure. Alternative pacing sites have been looked for, including the RV septum and epicardial LV apex or free wall. Better preservation of LV synchrony and function could be shown in small observational studies in both mentioned LV pacing sites and in 1 recently published larger retrospective pediatric survey. 10 -14 Choosing an optimal pacing position may be of special importance in children subjected to cardiac pacing lasting for decades. However, until today, a prospective long-term study comparing the effects of RV or LV pacing on LV performance and ultrastructural morphology of the heart muscle has not been performed. Our aim was to examine the effects of RV free wall as opposed to LV apical pacing on LV...

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Section: Preservation Of LV Function With Lv Apex Pacingcontrasting

confidence: 81%

Right or Left Ventricular Pacing in Young Minipigs With Chronic Atrioventricular Block

et al. 2012

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“…16 Spatial heterogeneity in Cx43 expression in our study was quantified (as described before) 17 and showed a significantly higher heterogeneous Cx43 expression in TAC operated compared with sham-operated mice. Areas almost deprived of Cx43 protein neighboured areas with normal Cx43 expression.…”

Section: N T E R U N I V E R S I T Y C a R D I O L O G Y I N S T I mentioning

confidence: 63%

Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload

Boulaksil¹,

Noorman²,

Engelen³

et al. 2010

NHJL

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“…15,19,27 Interestingly, we showed that this increase in fibrosis is more prominent in Cx43 Cre-ER(T)/fl compared with Cx43 fl/fl hearts. As a possible mechanism for the enhanced fibrosis in stressed hearts with reduced Cx43 levels, we hypothesized that reduced Cx43 levels may alter cardiomyocyte/fibroblast and fibroblast/fibroblast communication, leading to increased fibroblast proliferation and/or activity.…”

Section: Fibroblast Proliferation and Activitymentioning

confidence: 71%

“…19 A gradient of Ϸ50% was confirmed by Doppler echocardiography. Sham-operated Cx43 fl/fl (nϭ12) and Cx43 Cre-ER(T)/fl (nϭ10) mice were used as control.…”

Section: Animalsmentioning

confidence: 87%

Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity

Jansen

Veen

Jong

et al. 2012

Circ: Arrhythmia and Electrophysiology

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Background-Arrhythmogenic ventricular remodeling is hallmarked by both reduced gap junction expression and increased collagen deposition. We hypothesized that reduced connexin43 (Cx43) expression is responsible for enhanced fibrosis in the remodeled heart, resulting in an arrhythmogenic substrate. Therefore, we investigated the effect of normal or reduced Cx43 expression on the formation of fibrosis in a physiological (aging) and pathophysiological (transverse aortic constriction [TAC]) mouse model. Methods and Results-The Cx43fl/fl and Cx43 CreER(T)/fl mice were aged 18 to 21 months or, at the age of 3 months, either TAC or sham operated and euthanized after 16 weeks. Epicardial activation mapping of the right and left ventricles was performed on Langendorff perfused hearts. Sustained ventricular arrhythmias were induced in 0 of 11 aged Cx43 fl/fl and 10 of 15 Cx43Cre-ER(T)/fl mice (PϽ0.01). Cx43 expression was reduced by half in aged Cx43 CreER(T)/fl compared with aged Cx43 fl/fl mice, whereas collagen deposition was significantly increased from 1.1Ϯ0.2% to 7.4Ϯ1.3%. Aged Cx43CreER(T)/fl mice with arrhythmias had significantly higher levels of fibrosis and conduction heterogeneity than aged Cx43CreER(T)/fl mice without arrhythmias. The TAC operation significantly increased fibrosis in control compared with sham (4.0Ϯ1.2% versus 0.4Ϯ0.06%), but this increase was significantly higher in Cx43CreER(T)/fl mice (10.8Ϯ1.4%). Discoidin domain receptor 2 expression was unchanged, but procollagen peptide I and III expression and collagen type 1␣2 mRNA levels were higher in TAC-operated Cx43HZ mice. Conclusions-Reduced cellular coupling results in more excessive collagen deposition during aging or pressure overload in mice due to enhanced fibroblast activity, leading to increased conduction in homogeneity and proarrhythmia. (Circ Arrhythm Electrophysiol. 2012;5:380-390.)Key Words: arrhythmia Ⅲ collagen Ⅲ electrophysiology mapping Ⅲ connexin43 Ⅲ fibroblast I n the heart, the highly orchestrated propagation of the electric impulse balances on the delicate interplay between excitability, cell-to-cell coupling, and architecture of myocardial tissue. An important aspect of the myocardial architecture is interstitial collagen (fibrosis), which, together with connexin43 (Cx43), determines cell-to-cell coupling in ventricular myocardium. Under normal physiological conditions, the amount of collagen between the cardiomyocytes is low (Ͻ1% of total tissue volume) but contributes to the structural organization of the heart and the anisotropic character of impulse propagation. We recently showed that, in senescent mouse hearts, collagen content was increased (200%) and Cx43 expression was decreased (50%), changes that were associated with increased inducibility of ventricular tachycardias. 1 On the other hand, when the excessive deposition of fibrosis was prevented through long-term inhibition of the renin-angiotensin-aldosterone system, the normal pattern of Cx43 expression was preserved and arrhythmia vulnerability was strongly red...

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Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias

Cited by 60 publications

References 32 publications

Right or Left Ventricular Pacing in Young Minipigs With Chronic Atrioventricular Block

Right or Left Ventricular Pacing in Young Minipigs With Chronic Atrioventricular Block

Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload

Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity

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