Induction of atrial fibrillation in mice by rapid transesophageal atrial pacing

Schrickel, Jan W.; Bielik, H.; Yang, Alexander; Schimpf, Rainer; Шлевков, Н. Б.; Burkhardt, Dietmar; Meyer, Rainer; Grohé, Christian; Fink, Klaus; Tiemann, Klaus; Lüderitz, Berndt; Lewalter, Thorsten

doi:10.1007/s003950200052

Cited by 59 publications

(59 citation statements)

References 21 publications

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“…Parasympathetic stimulation is known to facilitate AF by increasing the frequency of re-entry circuits by shortening the wavelength 29 and thereby permitting more re-entry circles to coexist. However, similar to previous studies showing the general inducibility of atrial tachyarrhythmias with burst pacing, even without vagal stimulation, 30 we were able to induce AF before and after CC administration in a significant proportion of both WT and transgenic Kv4DN mice. In the present data, inducibility was already high at baseline (10/16 Kv4DN, 7/13 LMC), which might account for a lack of a further increase in AF/AT inducibility rates under CC administration.…”

Section: Discussionsupporting

confidence: 91%

“…In various studies, the baseline AF inducibility rates have differed remarkably in mice, ranging from 0% 13 up to 50% 14,31 and even 90%. 30 Interestingly, in younger (2-3 months) mice, lower baseline AF inducibility rates were found than in studies focusing on older mice. Similar to our findings (in 7-11 month-old mice) a high inducibility rate was found in 5-7 month-old mice, with a 100% inducibility in the male subgroup.…”

Section: Discussionmentioning

confidence: 92%

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In Vivo Effect of a Dominant Negative Kv4.2 Loss-of-Function Mutation Eliminating Ito,f on Atrial Refractoriness and Atrial Fibrillation in Mice

Odening

Nerbonne²,

Bode

et al. 2009

Circ J

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he most common arrhythmia in humans is atrial fibrillation (AF), with increasing prevalence and incidence with aging. 1 Electrical remodeling resulting in a shortening of the atrial action potential duration (APD) and of the atrial effective refractory period (AERP) is known to promote AF, 2 whereas drug-induced prolongation of APD and the AERP reduces its occurrence. [3][4][5] Recent evidence suggests that mutations in the genes responsible for voltage-gated K + -channels play an important role in the subset of human patients with familial AF. 6-8 These mutations lead to a shortening of the APD and AERP by a gain of function in IKs or IK1 and thereby facilitate AF.In line with these findings in humans with familial AF, transgenic mice overexpressing Kir2.1, which leads to augmentation of the IK1 current, show a shortening of APD and AERP, as well as an increase in the occurrence of spontaneous AF. 9 Spontaneous AF was also demonstrated in transgenic mouse models with atrial fibrosis because of either the expression of a constitutively-active form of transforming growth factor (TGF)-β1 10 or an overexpression of tumor necrosis factor (TNF)-α, 11 even in the absence of changes in the APD. 10 Similarly, targeted deletion of connexin40 (Cx40 -/-) slowed atrial and atrioventricular (AV) conduction, and increased vulnerability to AF 12 after transesophageal stimulation.Interestingly, in the TNF-α heart failure mouse model, the incidence of spontaneous and inducible AF increases with age, predominantly in males, 11 indicating a similar influence of age and gender as seen in human patients.In experimental studies, the feasibility of inducing AF using in vivo programmed stimulation has been demonstrated in mice; in wild-type (WT) animals, transvenous electrophysiological (EP) studies showed that after administration of the parasympathetic drug carbachol, which is known to facilitate AF and hence is used as standard model for AF induction, the majority (>70%) of animals had AF induced. 13 Several mutations protect against pacing-induced AF: in an IKACh knock-out mouse model, AF was inducible after carbachol only in WT animals, but not in knock-out mice. 14 In another mouse model, the overexpression of HERG markedly reduced AF inducibility after carbachol administration, despite shortening of the APD, predominantly at slow heart rates, presumably because of a prolonged post-repolarization refractoriness, an increased repolarization reserve and the lack of electrical alternans. 15 Genetic alterations of the atria that either shorten the APD and AERP (eg, by augmenting potassium currents such as IKs or IK1) or manipulations that slow atrial conduction (Cx40 -/-or TGF-β1/TNF-α overexpression) lead to increased vulnerability for AF in mice, and both the elimi-

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 92%

In Vivo Effect of a Dominant Negative Kv4.2 Loss-of-Function Mutation Eliminating Ito,f on Atrial Refractoriness and Atrial Fibrillation in Mice

Odening

Nerbonne²,

Bode

et al. 2009

Circ J

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“…Inducibility and incidence of atrial and ventricular tachyarrhythmias were tested by using programmed (up to three short-coupled extra beats) and burst stimulation protocols as described in ref. 40. To estimate AV-nodal pulse propagation to the ventricles during atrial tachycardias, ventricular frequency was analyzed during the induced episodes of atrial fibrillation.…”

Section: Methodsmentioning

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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110

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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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“…Nevertheless, it has been reported that the mouse atria are able to sustain fibrillation 14,17,25,26 . Thus, despite the small sizes of mouse atria, our knockout mouse allowed for the investigation of the mechanisms underlying the genesis and maintenance of AF.…”

Section: Study Limitationsmentioning

confidence: 99%

Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation

et al. 2008

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Induction of atrial fibrillation in mice by rapid transesophageal atrial pacing

Cited by 59 publications

References 21 publications

In Vivo Effect of a Dominant Negative Kv4.2 Loss-of-Function Mutation Eliminating Ito,f on Atrial Refractoriness and Atrial Fibrillation in Mice

In Vivo Effect of a Dominant Negative Kv4.2 Loss-of-Function Mutation Eliminating Ito,f on Atrial Refractoriness and Atrial Fibrillation in Mice

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

Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation

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