(Circulation. 1999;99:1508-1515.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Conduction Disturbances and Increased Atrial Vulnerability in Connexin40-Deficient Mice Analyzed by Transesophageal Stimulation
From the Department of Cardiology (A.H., B.S., B.L.) and Institute of Genetics (S.K., K.W.), University of Bonn (Germany).
Correspondence to Andreas Hagendorff, MD, Department of Cardiology, University of Leipzig, Johanniselle 32, 04103 Leipzig, Germany. E-mail hagendorff{at}metronet.de
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Abstract |
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Background—Recently, it has been reported that connexin40 (Cx40) deficiency in targeted mouse mutants is associated with a prolongation of P-wave and QRS complex duration on surface electrograms. The specific effects of Cx40 deficiency on sinus node function, sinoatrial, and atrioventricular conduction properties as well as on atrial vulnerability have not yet been investigated systematically by electrophysiological analysis.
Methods and Results—Fifty-two mice (18 Cx40+/+, 15 Cx40+/-, and 19 Cx40-/- mice) were subjected to rapid atrial transesophageal stimulation after anesthesia with avertin. A significant prolongation of sinus node recovery time was noticed in Cx40-/- mice compared with Cx40+/- and Cx40+/+ mice (287.8±109.0 vs 211.1±61.8 vs 204.4±60.9 ms; P<0.05). In addition, Wenckebach periodicity occurred at significantly longer atrial pacing cycle lengths in Cx40-/- mice than in Cx40+/- or Cx40+/+ mice (93.3±11.8 vs 83.9±9.7 vs 82.8±8.0 ms, P<0.05). Analysis of 27 Cx40-/- mice showed a significant increase in intra-atrial conduction time and atrioventricular conduction time compared with 52 Cx40+/- and 31 wild-type (Cx40+/+) mice. Furthermore, in Cx40-/- mice, atrial tachyarrhythmias could be induced frequently by atrial burst pacing, whereas no atrial arrhythmias were inducible in heterozygous or wild-type mice.
Conclusions—This study demonstrates that Cx40 deficiency is associated with sinoatrial, intra-atrial, and atrioventricular conduction disturbances. In atrial myocardium of the mouse, Cx40 deficiency results in increased atrial vulnerability and might contribute to arrhythmogenesis.
Key Words: atrium • proteins • conduction • electrophysiology • arrhythmia
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Introduction |
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Adjacent cardiomyocytes are connected by gap junctions, which are clusters of intercellular channels consisting of a hexameric assembly of proteins known as connexins (Cx). These gap junctional channels are responsible for the electrical coupling of cardiac myocytes.1 2 The gap junctional permeability depends on the constituent connexin.3 4 In the mammalian heart, expression of Cx37, Cx40, Cx43, Cx45, Cx46, and Cx50 mRNAs was observed and Cx40, Cx43, and Cx45 protein was detected in cardiac myocytes.5
There are interspecies differences in expression of Cx40 and Cx43.6 In mammalian heart, Cx43 is highly expressed in myocytes but absent from sinus nodal and atrioventricular (AV) nodal tissue as well as from the proximal part of the ventricular conductive myocardium in adult mouse and rat.7 8 9 Cx40 is expressed in atrial myocytes and in the His-Purkinje system of the mouse heart.9 So far, expression of Cx40 in the mouse sinus node and the compact AV node has not been reported, but Cx40 was shown to be present in the canine sinus node.10
It was found that absence of gap junctions resulted in disturbances of pulse propagation in the heart.11 12 In heterozygous Cx43 mice, a reduced cardiac conduction velocity was reported.13 14 Recently we demonstrated that P-wave duration, PQ interval, and QRS duration were significantly prolonged in Cx40-deficient mice.15 These findings were supported by Simon and coworkers,16 who reported a high prevalence of PQ prolongation and the pattern of bundle-branch block during normal sinus rhythm in Cx40-deficient mice. However, the effects of Cx40 deficiency on cardiac pulse propagation under conditions other than sinus rhythm remain unclear.
Aside from disturbances of pulse propagation, abnormalities in connexin distribution, content, and phenotype may increase anisotropy and facilitate the occurrence of unidirectional conduction blocks and heterogeneous conduction delays.17 Unidirectional conduction blocks and conduction delays are well-known pathophysiological conditions for the development of tachyarrhythmias, based on reentrant phenomena. Accordingly, it has been hypothesized that molecular and structural alterations of gap junctions resulted in an increased myocardial vulnerability and are involved in the pathophysiology of arrhythmias. This hypothesis was supported by findings from animal studies and by observations in humans with underlying heart disease. In human ventricular myocardium from hearts subject to chronic ischemia from coronary artery disease and to chronic pressure overload from aortic valve stenosis, the amount of Cx43 gap junctions was significantly reduced compared with normal ventricular myocardium.18 Both patients with coronary artery disease and patients with valvular heart disease are prone to the development of ventricular tachyarrhythmias. In the canine model, it was demonstrated that the distribution of Cx43 gap junctions was markedly altered throughout early remodeling of ventricular myocardium after infarction. In these studies, gap junctional disorganization correlated with the localization of the common central pathway of inducible ventricular reentrant tachycardias.19 20 In our study on 31 Cx40-deficient mice, 1 mouse showed a spontaneous atrial tachycardia.15 Aside from this observation, no data are available about the effects of Cx40 deficiency on atrial or ventricular vulnerability.
To evaluate cardiac pulse generation and propagation as well as susceptibility for atrial arrhythmias, electrophysiological testing by atrial stimulation is an established method. The electrophysiological effects of Cx40 deficiency have not yet been investigated. In the present study, Cx40-deficient mice were investigated by surface ECG recordings as well as by transesophageal atrial stimulation. The aim of the present study was to further analyze the impact of Cx40 deficiency on sinoatrial, intra-atrial, and atrioventricular conduction capabilities as well as on susceptibility for atrial reentrant arrhythmias in mice.
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Methods |
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Cx40 Mutant Mice
Cx40-deficient mice were generated by gene targeting as described previously.15 The genotypes of the mice were determined by polymerase chain reaction. All analysis was done on littermates generated by interbreeding mice heterozygous for Cx40.
Animals, Anesthesia, and Preparation
Male and female 8- to 16-week-old mice, weighing 25 to 35
g, were anesthetized by intraperitoneal
injection of avertin (Sigma-Chemie; 1.25%, 0.02 mL per gram body
weight). A surface 6-lead ECG was obtained by cutaneous clips at each
of the 4 limbs of the spontaneously breathing mice. The ECG channels
were amplified, filtered between 10 and 100 Hz, and sampled with a rate
of 4 kHz (Bard Stamp amplifier; Bard LabSystem). The data were stored
on optical disk. A warming light was used to stabilize body
temperature.
Surface Electrocardiographic Study
Surface ECG recordings were obtained within a time frame
of 5 minutes. The determination of time intervals was performed at the
end of each registration period. Spontaneous cycle length was
determined by averaging 10 consecutive R-R intervals. P-wave duration,
PQ interval, QR duration, QRS duration, QTmax,
and QT interval were measured by determining the earliest onset and
latest offset of atrial and ventricular deflection from 3
simultaneously recorded surface leads. As displayed
schematically in Figure 1
, QRS duration
and QTmax interval were calculated from ECG
tracings by measuring the duration between the onset of the QRS complex
and the maximum/minimum of the S, R, and T waves regarding the most
distinguishable tracing.
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Transesophageal Electrophysiological Study
For the transesophageal
electrophysiological study, a 2F pacing
catheter with four 1-mm ring electrodes and an interelectrode distance
of 2 mm (Arrow) was used. Bipolar recordings were obtained
from the distal and the proximal electrode pairs. Unipolar
recordings were obtained from each ring electrode. Unipolar
pacing was performed at electrode 1 or 2. Rapid atrial pacing was
performed with twice the diastolic threshold (Biotronik,
UHS 20). The following pacing protocol was used: Initially, a constant
atrial capture was documented. Subsequently, pacing was performed for
30 seconds with a pacing cycle length 10 ms shorter than the
spontaneous cycle length. After a period of normal sinus rhythm, pacing
was repeated with a pacing cycle length 10 ms shorter than the initial
pacing cycle length. This was repeated with a consecutive reduction of
the pacing cycle length until the minimum cycle length was reached that
was required to maintain 1:1 AV conduction. For each pacing cycle
length, sinus node recovery time was determined by measuring the
interval between the last stimulus spike and the first spontaneous
atrial depolarization after termination of pacing. In addition, the
first spontaneous cycle length after sinus node recovery time was
determined. In a subgroup of mice, atrial vulnerability was tested by
high frequency atrial burst stimulation for 10 to 12 seconds, with a
pacing cycle length of 25 ms. Burst pacing was repeated 10 times in
each animal. Occurrence and duration of inducible arrhythmias
were documented.
Statistical Analysis
Data are presented as mean±SD. A 1-way ANOVA and post
hoc Tukey B tests were used for the comparison of ECG
parameters. Probability values of <0.05 were considered
statistically significant.
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Results |
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Surface ECG
A total of 116 mice were anesthetized for surface ECG recordings. Two mice died shortly after intraperitoneal injection of avertin probably as the result of inadvertent intravascular injection. In 4 additional mice, ECG recordings were obtained, but these animals died during the waking-up period. These 6 mice were excluded from the study. Thus 110 mice were used for analysis. Among these, 31 were wild-type for Cx40 (Cx40+/+), 52 mice were heterozygous for Cx40 (Cx40+/-), and 27 were homozygous Cx40-deficient mice (Cx40-/-).
The results of the surface ECG recordings are summarized
in Table 1. Individual data are
displayed as scattergram in Figure 2. In
Cx40-/- mice, the spontaneous cycle length was
significantly longer compared with that observed in
Cx40+/- mice. Though a tendency was found toward
longer spontaneous cycle lengths, spontaneous cycle length was not
statistically different between Cx40-/- and
Cx40+/+ mice. In 2
Cx40-/- mice, a spontaneous intermittent
second-degree sinoatrial block was documented (Figure 3). Sinoatrial block was not found in
Cx40+/- or Cx40+/+ mice.
The P-wave duration was shorter in both Cx40+/+
and Cx40+/- mice than in
Cx40-/- mice. The PQ interval was significantly
longer in Cx40-/- mice compared with the PQ
interval in Cx40+/+ and
Cx40+/- mice. In addition, 4
Cx40-/- mice showed a spontaneous second- or
third-degree AV block (Figure 4). The QRS
duration was significantly longer in Cx40-/-
mice than in Cx40+/+ and
Cx40+/- mice. In summary, surface ECG
recordings revealed prolonged atrial, AV, and
ventricular conduction parameters in
Cx40-/- mice compared with both
Cx40+/+ mice and Cx40+/-
mice (Figure 5). In comparison to
Cx40+/+ mice, P-wave duration lengthened by 56%
in Cx40-/- mice, PQ interval by 15%, and QRS
duration by 30%. No significant differences were found between
Cx40+/+ and Cx40+/-
mice.
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In none of the wild-type Cx40 mice were spontaneous
supraventricular or ventricular
arrhythmias documented. One Cx40+/-
mouse showed spontaneous isolated atrial premature beats.
Ventricular arrhythmias were not found. In
Cx40-/- mice, spontaneous arrhythmias
were documented in 4 animals. Three Cx40-/-
mice exhibited isolated atrial or ventricular premature
beats, and 1 Cx40-/- mouse exhibited
spontaneous atrial tachycardia with constant
tachycardia cycle length (Figure 6).
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Transesophageal Stimulation
Transesophageal atrial pacing was performed in 55
mice. Three mice were excluded from analysis because of
anesthesia problems (1 mouse) or a sudden drop in heart
rate caused by accidental endotracheal catheterization
(2 mice). No further complications were noticed throughout or after the
investigation. Thus 18 Cx40+/+, 15
Cx40+/-, and 19 Cx40-/-
mice were studied.
The results of the transesophageal stimulation are
summarized in Table 2. The individual
results for 1:1 AV conduction time and sinus node recovery time are
displayed as scattergrams in Figure 7.
Transesophageal stimulation revealed that the 1:1 AV
conduction time was significantly shorter in
Cx40+/- and Cx40+/+ mice
(Figure 8) compared with that observed in
Cx40-deficient mice (Figure 9).
Loss of 1:1 AV conduction was always associated with a Wenckebach
periodicity. Relative to Cx40+/+ mice, the 1:1 AV
conduction time was extended by 13% in Cx40-/-
mice. No significant differences were detected in
Cx40+/+ compared with
Cx40+/- mice.
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Strong evidence was found for a sinus node entry block resulting in an
unaltered sinus nodal pulse generation despite an adequate atrial
capture in 5 Cx40-/- mice during atrial
stimulation for determination of sinus node recovery time. These mice
had to be excluded from analysis. This phenomenon was not
observed in Cx40+/- or
Cx40-/- mice. In the remaining Cx40-deficient
mice, the sinus node recovery time was found to be significantly longer
than in Cx40+/- and
Cx40+/+ mice (Figure 10). Results in
Cx40+/+ mice and in
Cx40+/- mice did not differ significantly.
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Arrhythmia Detection
Atrial vulnerability was tested by atrial burst stimulation in 8
Cx40+/+ mice, 8 Cx40+/-
mice, and 8 Cx40-/- mice. In
Cx40+/+ and Cx40+/- mice,
no evidence of inducible arrhythmias was found. In contrast,
burst pacing resulted in atrial arrhythmias in 5 of 8
Cx40-deficient mice. One mouse showed a sustained, regular
supraventricular tachycardia (Figure 11). This tachycardia was
terminated by overdrive pacing and reinducible. Thus reentry had to be
considered as the underlying pathophysiological
mechanism. In 4 Cx40-/- mice, atrial burst
pacing resulted in a nonsustained or sustained atrial
arrhythmia with irregular R-R intervals and without distinct P
waves (Figure 12). The heart rate was
similar or lower during this arrhythmia than during normal
sinus rhythm. All episodes spontaneously converted to normal sinus
rhythm.
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Discussion |
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In the present study, the effects of Cx40 deficiency on sinoatrial, intra-atrial, and AV nodal pulse propagation were studied with surface ECG recordings and transesophageal atrial stimulation. Five sets of results can be distinguished. First, Cx40 deficiency was associated with a spontaneous occurrence of sinoatrial blocks and with a prolongation of sinus node recovery time, all indicating a disturbance of sinoatrial electrophysiology. Second, Cx40 deficiency was associated with a disturbance of intra-atrial pulse propagation. Third, Cx40 deficiency was associated with a prolongation of PQ interval, with spontaneous second- or third-degree AV blocks, and with a prolongation of 1:1 AV conduction time, all indicating a decreased AV conduction capacity. Fourth, the QRS duration was significantly lengthened in Cx40-deficient mice. And finally, Cx40 deficiency was associated with an increased atrial vulnerability.
Sinoatrial Conduction Disturbances
Density of gap junctions is very low in the mammalian central
sinus node.21 22 23 Expression of Cx40 was reported in the
canine sinus node,10 but there are no data on the mouse
sinus node. In this transesophageal
electrophysiological study, strong evidence
was found for a "communication boundary" between the central sinus
node and the perinodal atrial myocardium. This conduction
disturbance affected pulse propagation in either direction:
from the sinus node to the atrium, as can be assumed from the
occurrence of spontaneous sinoatrial blocks as well as from the atrial
myocardium into the sinus node, as can be concluded from
the high incidence of sinus node entry block during atrial stimulation.
In addition, sinus node recovery time was significantly prolonged in
Cx40-deficient mice.
Atrial Conduction Disturbances
Cx40 deficiency alters the passive electrical properties and
electrophysiological characteristics of the
cardiac tissue. In contrast to mice with normal Cx40 abundance and
distribution,24 25 26 pulse propagation is decelerated in
Cx40-/- mice. In this study, the P-wave
duration was significantly prolonged in Cx40-deficient mice. This
corresponds to the abundance of Cx40 in atrial myocardium.
However, several details of the underlying pathophysiology remain
unclear. A prolongation of the P wave could be the result of various
mechanisms. One explanation would be a decrease of intra-atrial
conduction velocity in terms of a delayed depolarization of consecutive
cells without changing the vector of pulse propagation. This must be
distinguished from a prolongation of conduction time caused by a
conduction block with a consecutive prolongation of the length of
activation way. Furthermore, it remains unclear whether P-wave
prolongation accounts for effects of Cx40 deficiency in all atrial
components or whether only specific, anatomically defined conduction
pathways are affected.
Decreased AV Conduction Capacity
In Cx40-/- mice, the mean PQ interval was
significantly longer than in Cx40+/+ and
Cx40+/- mice. According to its definition, the
PQ interval reflects conduction through the AV node as well as
conduction from the high right atrium to the AV node and from the AV
node through the His bundle to the proximal Purkinje system. Because
the prolongation of PQ interval extended that of P-wave duration in
most of the Cx40-/- mice, the PQ prolongation
cannot be exclusively accounted for intra-atrial conduction delay. Thus
a decreased AV nodal conduction velocity might be assumed. However,
without an intracardiac recording of His bundle potentials, an
additive effect of an intrahisian conduction delay cannot be ruled out.
In addition to the conduction delay, a decreased 1:1 AV conduction
capacity was found in Cx40-deficient mice. The 1:1 AV conduction time
is a parameter of the effective refractory periods of the
specific conducting tissue and independent of the AV conduction
velocity. Loss of 1:1 AV conduction was associated with a typical
Wenckebach periodicity. A Wenckebach periodicity occurs most commonly
at the AV nodal level, whereas conduction disturbances at the
His bundle mainly result in a 2:1 or 3:1 block. Though it cannot be
proven without simultaneous His bundle recordings,
this finding provides evidence that the AV node is involved in the
electrophysiological effects of Cx40
deficiency. Since it is well known that the
electrophysiological properties of the AV
node rely on modulating influences of the so-called transitional AV
nodal fibers, it might be hypothesized that the effects of Cx40
deficiency on the AV nodal conduction properties are mediated by a
profound alteration of the input from perinodal tissue.
Delayed Conduction in His-Purkinje System or Ventricles
In Cx40-/--deficient mice, the QR and QRS
duration as well as QTmax and QT interval were
significantly prolonged compared with Cx40+/+ and
Cx40+/- mice. Because no evidence was found for
the existence of Cx40 gap junctions in the ventricular
working myocardium, it can be hypothesized that the
observed prolongation of conduction time is due to a conduction delay
in the bundle branches of the His-Purkinje system. However, to rule out
the possibility of intraventricular conduction
delay, determination of intraventricular conduction
velocity would be necessary.
Arrhythmogenicity
It is well known that regional unidirectional conduction blocks
and conduction delays facilitate the initiation and perpetuation of
reentrant arrhythmias. In this context, conduction
disturbances caused by alterations of gap junctional
cell-to-cell communication seem to have an important impact on
myocardial arrhythmogenicity. In the canine model, it was
demonstrated that the origin of ventricular
tachycardias caused by reentrant circuits correlated with
the localization of disturbed Cx43 gap junctional distribution in the
border zone of induced myocardial infarction.19 27 Under
these conditions, the electrophysiological
characteristics of individual myocytes in the peri-infarct tissue are
found to be normal.28 29 30 31 Therefore, in that system, the
key factor of arrhythmogenesis appeared to be a disturbance of
cell-to-cell communication.
There is evidence that not only the type of gap junctional protein but also the pattern of heterotypic and heteromeric channel formation influences the flow of electrical current.25 26 31 32 33 An alteration in number and spatial distribution of myocyte gap junctions causes heterogeneous pulse propagation, which can induce conduction delay or block and tachyarrhythmias.15 18 19 27 A decrease in the number of gap junctions might alter end-to-end connections of the myocytes differently than site-to site connections. Thus the conduction time may increase as a result of 2 different factors. First, the diminished number of gap junction channels could decrease the conduction velocity per se. Second, the vector of the electrical wave front is forced to change because of the lowered number of gap junctions resulting in prolonged activation ways.19 20 34 35 This results in a longer conduction time, a heterogenous pulse propagation, and an increased possibility to initiate and perpetuate tachycardias.
In wild-type mice, atrial or ventricular tachyarrhythmias were not inducible by atrial or ventricular stimulation.36 This finding is supported by the results of the present study. In none of the Cx40+/+ or Cx40+/- mice were atrial arrhythmias inducible by atrial burst stimulation. In contrast, atrial tachyarrhythmias were frequently detected after atrial burst stimulation in Cx40-/- mice. This underlines the function of connexins in arrhythmogenesis. The documented arrhythmias can be divided into 2 different subgroups. One type was characterized by regular atrial activation and a fast, regular ventricular activation. In this tachycardia, termination by overdrive pacing gave strong evidence for an excitable reentrant circuit as underlying mechanism. The second type was characterized by a slow and irregular ventricular activation and an absence of distinct P waves. This arrhythmia terminated spontaneously. The irregularity of R-R intervals and the absence of P waves suggest atrial fibrillation as underlying arrhythmia. To date, atrial fibrillation is interpreted as the result of multiple coexisting intra-atrial reentrant wavelets. As yet, atrial fibrillation has not been observed in mice. It was assumed to be impossible in these species because the atrial myocardial mass was thought to be too small to maintain multiple coexisting reentrant wavelets under normal circumstances. However, the reentrant circuit is determined by the length of the activation way and the conduction velocity. A marked conduction delay caused by Cx40 deficiency may facilitate coexisting wavelets even in small atria.
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Acknowledgments |
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This study was supported by DFG grants (SFB 284, project C1), the Deutsche Krebshilfe, the Fond der Chemischen Industrie, and program BMH4-CT96-1427 of the European Community to Dr Willecke.
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Footnotes |
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Authors A.H. and B.S. contributed equally to the content of this article.
Received July 31, 1998; revision received October 21, 1998; accepted November 11, 1998.
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K. Ryu, L. Li, C. M. Khrestian, N. Matsumoto, J. Sahadevan, M. L. Ruehr, D. R. Van Wagoner, I. R. Efimov, and A. L. Waldo Effects of sterile pericarditis on connexins 40 and 43 in the atria: correlation with abnormal conduction and atrial arrhythmias Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1231 - H1241. [Abstract] [Full Text] [PDF]
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Z. Qu Dynamical effects of diffusive cell coupling on cardiac excitation and propagation: a simulation study Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2803 - H2812. [Abstract] [Full Text] [PDF]
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M. Firouzi, H. Ramanna, B. Kok, H. J. Jongsma, B. P.C. Koeleman, P. A. Doevendans, W. A. Groenewegen, and R. N.W. Hauer Association of Human Connexin40 Gene Polymorphisms With Atrial Vulnerability as a Risk Factor for Idiopathic Atrial Fibrillation Circ. Res., August 20, 2004; 95(4): e29 - e33. [Abstract] [Full Text] [PDF]
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S. Verheule, T. Sato, T. Everett IV, S. K. Engle, D. Otten, M. Rubart-von der Lohe, H. O. Nakajima, H. Nakajima, L. J. Field, and J. E. Olgin Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-{beta}1 Circ. Res., June 11, 2004; 94(11): 1458 - 1465. [Abstract] [Full Text] [PDF]
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B. E.J Teunissen and M. F.A Bierhuizen Transcriptional control of myocardial connexins Cardiovasc Res, May 1, 2004; 62(2): 246 - 255. [Abstract] [Full Text] [PDF]
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D. Gros, L. Dupays, S. Alcolea, S. Meysen, L. Miquerol, and M. Theveniau-Ruissy Genetically modified mice: tools to decode the functions of connexins in the heart--new models for cardiovascular research Cardiovasc Res, May 1, 2004; 62(2): 299 - 308. [Abstract] [Full Text] [PDF]
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S. Alcolea, T. Jarry-Guichard, J. de Bakker, D. Gonzalez, W. Lamers, S. Coppen, L. Barrio, H. Jongsma, D. Gros, and H. van Rijen Replacement of Connexin40 by Connexin45 in the Mouse: Impact on Cardiac Electrical Conduction Circ. Res., January 9, 2004; 94(1): 100 - 109. [Abstract] [Full Text] [PDF]
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H. Gu, F. C. Smith, S. M. Taffet, and M. Delmar High Incidence of Cardiac Malformations in Connexin40-Deficient Mice Circ. Res., August 8, 2003; 93(3): 201 - 206. [Abstract] [Full Text] [PDF]
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J. Ausma, H. M.W. van der Velden, M.-H. Lenders, E. P. van Ankeren, H. J. Jongsma, F. C.S. Ramaekers, M. Borgers, and M. A. Allessie Reverse Structural and Gap-Junctional Remodeling After Prolonged Atrial Fibrillation in the Goat Circulation, April 22, 2003; 107(15): 2051 - 2058. [Abstract] [Full Text] [PDF]
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K. Tiemann, D. Weyer, P. C. Djoufack, A. Ghanem, T. Lewalter, U. Dreiner, R. Meyer, C. Grohe, and K. B. Fink Increasing myocardial contraction and blood pressure in C57BL/6 mice during early postnatal development Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H464 - H474. [Abstract] [Full Text] [PDF]
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T. Ohara, Z. Qu, M.-H. Lee, K. Ohara, C. Omichi, W. J. Mandel, P.-S. Chen, and H. S. Karagueuzian Increased vulnerability to inducible atrial fibrillation caused by partial cellular uncoupling with heptanol Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1116 - H1122. [Abstract] [Full Text] [PDF]
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H. M.W van der Velden and H. J Jongsma Cardiac gap junctions and connexins: their role in atrial fibrillation and potential as therapeutic targets Cardiovasc Res, May 1, 2002; 54(2): 270 - 279. [Abstract] [Full Text] [PDF]
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J. E. Olgin and S. Verheule Transgenic and knockout mouse models of atrial arrhythmias Cardiovasc Res, May 1, 2002; 54(2): 280 - 286. [Abstract] [Full Text] [PDF]
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S. Kostin, G. Klein, Z. Szalay, S. Hein, E. P Bauer, and J. Schaper Structural correlate of atrial fibrillation in human patients Cardiovasc Res, May 1, 2002; 54(2): 361 - 379. [Abstract] [Full Text] [PDF]
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C. M. Johnson, E. M. Kanter, K. G. Green, J. G. Laing, T. Betsuyaku, E. C. Beyer, T. H. Steinberg, J. E. Saffitz, and K. A. Yamada Redistribution of connexin45 in gap junctions of connexin43-deficient hearts Cardiovasc Res, March 1, 2002; 53(4): 921 - 935. [Abstract] [Full Text] [PDF]
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P. Kanagaratnam, S. Rothery, P. Patel, N. J. Severs, and N. S. Peters Relative expression of immunolocalized connexins 40 and 43 correlates with human atrial conduction properties J. Am. Coll. Cardiol., January 2, 2002; 39(1): 116 - 123. [Abstract] [Full Text] [PDF]
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T. A.B. van Veen, H. V.M. van Rijen, and T. Opthof Cardiac gap junction channels: modulation of expression and channel properties Cardiovasc Res, August 1, 2001; 51(2): 217 - 229. [Abstract] [Full Text] [PDF]
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H. Wakimoto, C. T Maguire, P. Kovoor, P. E Hammer, J. Gehrmann, J. K Triedman, and C. I Berul Induction of atrial tachycardia and fibrillation in the mouse heart Cardiovasc Res, June 1, 2001; 50(3): 463 - 473. [Abstract] [Full Text] [PDF]
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H. V. M. van Rijen, T. A. B. van Veen, M. J. A. van Kempen, F. J. G. Wilms-Schopman, M. Potse, O. Krueger, K. Willecke, T. Opthof, H. J. Jongsma, and J. M. T. de Bakker Impaired Conduction in the Bundle Branches of Mouse Hearts Lacking the Gap Junction Protein Connexin40 Circulation, March 20, 2001; 103(11): 1591 - 1598. [Abstract] [Full Text] [PDF]
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J. E. Saffitz and R. B. Schuessler Connexin-40, Bundle-Branch Block, and Propagation at the Purkinje-Myocyte Junction Circ. Res., November 10, 2000; 87(10): 835 - 836. [Full Text] [PDF]
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H. S. Tamaddon, D. Vaidya, A. M. Simon, D. L. Paul, J. Jalife, and G. E. Morley High-Resolution Optical Mapping of the Right Bundle Branch in Connexin40 Knockout Mice Reveals Slow Conduction in the Specialized Conduction System Circ. Res., November 10, 2000; 87(10): 929 - 936. [Abstract] [Full Text] [PDF]
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S. Nattel and D. Li Ionic Remodeling in the Heart : Pathophysiological Significance and New Therapeutic Opportunities for Atrial Fibrillation Circ. Res., September 15, 2000; 87(6): 440 - 447. [Abstract] [Full Text] [PDF]
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S. Kirchhoff, J.-S. Kim, A. Hagendorff, E. Thonnissen, O. Kruger, W. H. Lamers, and K. Willecke Abnormal Cardiac Conduction and Morphogenesis in Connexin40 and Connexin43 Double-Deficient Mice Circ. Res., September 1, 2000; 87(5): 399 - 405. [Abstract] [Full Text] [PDF]
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H. J. Jongsma and R. Wilders Gap Junctions in Cardiovascular Disease Circ. Res., June 23, 2000; 86(12): 1193 - 1197. [Abstract] [Full Text] [PDF]
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D. S. He and J. M. Burt Mechanism and Selectivity of the Effects of Halothane on Gap Junction Channel Function Circ. Res., June 9, 2000; 86 (11): e104 - e109. [Abstract] [Full Text] [PDF]
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H. M.W. van der Velden, J. Ausma, M. B. Rook, A. J.C.G.M. Hellemons, T. A.A.B. van Veen, M. A. Allessie, and H. J. Jongsma Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat Cardiovasc Res, June 1, 2000; 46(3): 476 - 486. [Abstract] [Full Text] [PDF]
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J. E Saffitz and K. A Yamada Closing the gap in understanding the regulation of intercellular communication Cardiovasc Res, March 1, 2000; 45(4): 807 - 809. [Full Text] [PDF]
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X. H.T. Wehrens, S. Kirchhoff, and P. A. Doevendans Mouse electrocardiography: An interval of thirty years Cardiovasc Res, January 1, 2000; 45(1): 231 - 237. [Abstract] [Full Text] [PDF]
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