Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model

Bikou, Olympia; Thomas, Dierk; Trappe, Kerstin; Lugenbiel, Patrick; Kelemen, Kamilla; Koch, Martin; Soucek, Radim; Voss, Frederik; Becker, Rüdiger; Katus, Hugo A.; Bauer, Alexander

doi:10.1093/cvr/cvr209

Cited by 143 publications

(118 citation statements)

References 37 publications

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“…Furthermore, the RA of the PAH dogs contained a higher level of unphosphorylated Cx43 and more heterogeneous Cx43 expression than the RA of the control dogs. Previous studies have demonstrated that heterogeneous Cx43 expression may enhance susceptibility to arrhythmia, 18,19 as it is associated with dispersed impulse conduction. Taken together, our findings suggest that regional changes and greater heterogeneity of Cx43 expression provide the substrate for AF/AFL vulnerability in PAH dogs.…”

Section: Discussionmentioning

confidence: 99%

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Zhao¹,

Deng²,

Jiang³

et al. 2015

Hypertension

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S upraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL), are common in patients with pulmonary arterial hypertension (PAH) and are associated with poor outcomes.1,2 In 1 study, restoration and maintenance of sinus rhythm were invariably associated with clinical improvement and recovery. 3 However, it is difficult to treat AF/AFL in patients with PAH because existing antiarrhythmic agents have substantial side effects in patients with PAH.Previous studies have suggested that increased sympathetic nerve activation could contribute to disease severity in patients with PAH. 4,5 A recent study by Chen et al 6 demonstrated that pulmonary artery denervation decreased pulmonary arterial pressure and increased functional capacity. Our previous study showed that renal denervation attenuates pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental PAH.7 In a dog model with rapid atrial or ventricular pacing, a reduction in sympathetic tone or cardiac sympathetic denervation achieved by ablating extrinsic cardiac or renal sympathetic nerves was shown to be useful for controlling atrial arrhythmia. [8][9][10] However, to the best of our knowledge, the effect of sympathetic nerve activity on vulnerability to atrial arrhythmia in PAH has not been evaluated. The purpose of this study was to test the hypothesis that the activity of intrinsic and extrinsic cardiac nerves has an important role in vulnerability to atrial arrhythmia in a model of PAH. MethodsAdditional methodological details for each of the sections below are described in the online-only Data Supplement.Abstract-Atrial arrhythmia, which includes atrial fibrillation (AF) and atrial flutter (AFL), is common in patients with pulmonary arterial hypertension (PAH), who often have increased sympathetic nerve activity. Here, we tested the hypothesis that autonomic nerves play important roles in vulnerability to AF/AFL in PAH. The atrial effective refractory period and AF/AFL inducibility at baseline and after anterior right ganglionated plexi ablation were determined during left stellate ganglion stimulation or left renal sympathetic nerve stimulation in beagle dogs with or without PAH. Then, sympathetic nerve, β-adrenergic receptor densities and connexin 43 expression in atrial tissues were assessed. The sum of the window of vulnerability to AF/AFL was increased in the right atrium compared with the left atrium at baseline in the PAH dogs but not in the controls. The atrial effective refractory period dispersion was increased in the control dogs, but not in the PAH dogs, during left stellate ganglion stimulation. The voltage thresholds for inducing AF/AFL during anterior right ganglionated plexi stimulation were lower in the PAH dogs than in the controls. The AF/AFL inducibility was suppressed after ablation of the anterior right ganglionated plexi in the PAH dogs. The PAH dogs had higher sympathetic nerve and β1-adrenergic receptor densities, increased levels of nonphosphorylated connexin 43, and heterogeneo...

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Section: Discussionmentioning

confidence: 99%

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Zhao¹,

Deng²,

Jiang³

et al. 2015

Hypertension

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“…A recent paper showed that overexpression of connexin43 in atrial tissue prevents atrial fibrillation in the porcine burst-pacing model (36). Another group also performed gene transfer of connexins (connexin40 or connexin43) using a similar animal model (37).…”

Section: Discussionmentioning

confidence: 99%

Stretch of Atrial Myocytes Stimulates Recruitment of Macrophages via ATP Released Through Gap-Junction Channels

et al. 2012

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Abstract. Atrial inflammation is critical to atrial fibrillation initiation and progression. Although left atrial dilatation is a risk factor for atrial fibrillation, the mechanism linking atrial dilatation and inflammation is unclear. We evaluated the mechanisms underlying infiltration of macrophages induced by stretch of atrial myocytes. Murine macrophages were co-cultured with HL-1 murine atrial myocyte-derived cells. Mechanical stretch applied to atrial myocytes induced transwell macrophage migration. The gap junction-channel blocker carbenoxolone and the non-specific ATP-signaling modifiers apyrase and pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate inhibited the enhanced migration. Mechanical stretch of atrial myocytes induced transient increase in extracellular ATP concentration, which was inhibited by carbenoxolone. siRNA knockdown of pannexin-2 inhibited ATP release and macrophage migration. Mice underwent transverse aortic constriction or sham procedure. Transverse aortic constriction procedure induced macrophage infiltration. Daily carbenoxolone administration significantly inhibited macrophage infiltration in the atrium. Thus, mechanical stretch of atrial myocytes induces macrophage migration by ATP released through gap-junction channels, at least in part, in vitro. Administering a gap junction family-channel blocker inhibited this inflammatory change in vivo.

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“…Concerning the results of our study, we could hypothesize that the stimuli we used may act differently on connexin expression, modulating Cx43 while Cx40 could be influenced by other conditions not tested in the present study. A recent study on animals suggest that downregulation of Cx43 is of major importance in determining myocardial susceptibility to AF development (Bikou et al 2011), although this finding needs further validation in humans.…”

Section: Myocardial Hypoxia/ischemia and Atrial Fibrillationmentioning

confidence: 97%

Reversible atrial gap junction remodeling during hypoxia/reoxygenation and ischemia: a possible arrhythmogenic substrate for atrial fibrillation

Severino¹,

Narducci²,

Pedicino³

et al. 2012

gpb

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Abstract. Alteration of cardiomyocyte gap-junctions and component connexins (Cx) has been suggested to contribute to the development of atrial fibrillation (AF), including postoperative AF. We tested different possible stimuli, such as hypoxia and ischemia, influencing Cx43 and Cx40 expression and distribution in cultured atrial cells (HL-1) and reversibility of these processes after reoxygenation. Western-blot analysis and immunostaining using anti-Cx43, anti-Cx40 and anti-zonula occludens polyclonal antibodies were performed. HL-1 cells exposed to hypoxia for 24 and 48 h showed a reduction of Cx43 protein levels by 75% and 90% respectively (p < 0.001). During reoxygenation following 24 h of hypoxia, Cx43 levels increased to reach the basal level within 48 h, while they remained at low level during reoxygenation following 48 h of hypoxia. Furthermore, atrial cardiomyocytes subjected to simulated ischemia (SI) were incubated in normoxic and hypoxic conditions for 3, 6, 9, 12 h. Atrial cardiomyocytes subjected to SI in addition to normoxia showed a progressive reduction of Cx43 levels beginning from 3 h. During SI and hypoxia, atrial Cx43 levels showed an initial decrease after 3 h with a subsequent rescue beginning from 6 h of exposure (p = 0.001). Hypoxia and ischemia per se downregulate Cx43 protein expression in atrial cardiomyocytes, but protein downregulation is reversible, depending on hypoxia duration and the association of the two triggers. These alterations characterize several conditions and might contribute to the generation of an arrhythmogenic substrate leading to AF onset and/or maintenance.

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Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model

Abstract: Our results highlight the contribution of Cx43 to the pathophysiology of AF and demonstrate the viability of gene therapy for prevention of atrial arrhythmias.

Cited by 143 publications

References 37 publications

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Stretch of Atrial Myocytes Stimulates Recruitment of Macrophages via ATP Released Through Gap-Junction Channels

Reversible atrial gap junction remodeling during hypoxia/reoxygenation and ischemia: a possible arrhythmogenic substrate for atrial fibrillation

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Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model

Abstract: Our results highlight the contribution of Cx43 to the pathophysiology of AF and demonstrate the viability of gene therapy for prevention of atrial arrhythmias.

Cited by 143 publications

References 37 publications

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension

Stretch of Atrial Myocytes Stimulates Recruitment of Macrophages via ATP Released Through Gap-Junction Channels

Reversible atrial gap junction remodeling during hypoxia/reoxygenation and ischemia: a possible arrhythmogenic substrate for atrial fibrillation

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Reversible atrial gap junction remodeling during hypoxia/reoxygenation and ischemia: a possible arrhythmogenic substrate for atrial fibrillation