© 2000 American Heart Association, Inc.
MiniReview |
Gap Junctions in Cardiovascular Disease
From the Department of Medical Physiology, University Medical Center Utrecht, Utrecht, the Netherlands.
Correspondence to Habo J. Jongsma, Department of Medical Physiology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, Netherlands. E-mail h.j.jongsma{at}med.uu.nl
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Abstract |
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 Top Abstract IntroductionStructure and Properties of...Gap Junction Distribution in...Distribution of Gap Junctions...Gap Junctions and Conduction...Concluding RemarksReferences |
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Abstract—Connexins, the protein molecules forming gap junction channels, are reduced in number or redistributed from intercalated disks to lateral cell borders in a variety of cardiac diseases. This "gap junction remodeling" is considered to be arrhythmogenic. Using a simple model of human ventricular myocardium, we found that quantitative remodeling data extracted from the literature gave rise to only small to moderate changes in conduction velocity and the anisotropy ratio. Especially for longitudinal conduction, cytoplasmic resistivity (and thus cellular geometry) is much more important than commonly realized. None of the remodeling data gave rise to slow conduction on the order of a few centimeters per second.
Key Words: connexins • conduction velocity • arrhythmia • computer simulation
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Introduction |
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TopAbstractIntroductionStructure and Properties of...Gap Junction Distribution in...Distribution of Gap Junctions...Gap Junctions and Conduction...Concluding RemarksReferences |
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Gap junctions, specialized membrane structures consisting of arrays of intercellular channels, connect adjacent cells in many tissues and organs, thereby providing chemical and electrical communication. In the heart, gap junctions provide the pathways for intercellular current flow, enabling coordinated action potential propagation. Recently, numerous reports have been published suggesting that changes in gap junction distribution, density, and properties may be involved in the initiation and persistence of various cardiac arrhythmias. In the present review, we summarize the data presented in these reports and discuss functional implications.
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Structure and Properties of Gap Junction Channels |
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TopAbstractIntroductionStructure and Properties of...Gap Junction Distribution in...Distribution of Gap Junctions...Gap Junctions and Conduction...Concluding RemarksReferences |
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In the past decade, the structure and properties of gap junction channels have been extensively documented, as discussed in several recent reviews.1 2 3 4
Mammalian gap junction channels are built of connexins encoded by a
family of closely related genes. All connexins consist of 4 highly
conserved 
-helical membrane-spanning segments separated by 2
extracellular and 1 intracellular loop. The amino and carboxy terminals
are located intracellularly. Fifteen members of the mammalian connexin
family have been identified. They differ mainly in the sequence of
their intracellular loops and carboxy terminals. Between
cardiomyocytes, 3 connexins have been detected at the
protein level: connexin40 (Cx40), connexin43 (Cx43), and connexin45
(Cx45) (named by their putative molecular mass in kilodaltons).
One gap junction channel is formed by head-to-head docking of 2 hemichannels (connexons), each composed of 6 connexin molecules hexagonally arranged around an aqueous pore. Because docking is mediated by relatively conserved extracellular loops, many connexons composed of one kind of connexin can combine with connexons made of other connexins to form heterotypic gap junction channels. A connexon may also be composed of different connexins5 (heteromeric connexon). In the heart, different connexins colocalize in gap junction plaques, but it is unknown whether heterotypic and/or heteromeric gap junction channels exist in the cardiovascular system.
Gap junction channels are permeable to substances with a molecular
weight of <
1 kDa. Permeability depends on connexin type and charge
of the permeating molecule. Gap junction channels behave as gated ion
channels. In cardiomyocytes, single-channel conductances
range from 20 pS for homotypic Cx45 channels to 75 pS for Cx43
channels and to 200 pS for Cx40 channels. Gap junction conductance
is modulated by transjunctional voltage, by
[H+]i6 and
[Ca2+]i, by the
phosphorylation state of the connexins, and by
extracellular fatty acid composition.
Connexin expression is also modulated. Hormones can upregulate or downregulate connexin content. In neonatal rat heart cells in vitro, cAMP can dramatically upregulate Cx43 expression with a concomitant increase in conduction velocity of the action potential. The turnover of connexins is remarkably fast. In the adult rat heart, for example, the half-life is 1.3 hours.7
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Gap Junction Distribution in Normal Myocardium |
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TopAbstractIntroductionStructure and Properties of...Gap Junction Distribution in...Distribution of Gap Junctions...Gap Junctions and Conduction...Concluding RemarksReferences |
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In myocardium, connexins are regionally expressed: Cx43 is found throughout the heart, with the possible exception of the nodal tissues and parts of the conduction system.4 In mammalian species, Cx40 is expressed in atrial tissue (with the exception of the rat heart) and in the proximal conduction system (with the exception of the guinea pig heart).8 9 Cx45 expression seems to be limited to nodal tissues and the conduction system,10 11 but some reports12 13 claim a much more widespread distribution, probably because of the use of a not completely specific anti-Cx45 antibody.14 No other connexins have been detected between cardiomyocytes to date.
In adult ventricles, gap junctions exclusively contain
Cx438 and are located predominantly in the intercalated
disk (ID) region between cells. The anisotropic conductive properties
of ventricular myocardium are dependent on the
geometry of the interconnected cells and the number, size, and location
of the gap junction plaques between them.15 Many
(immuno)-histochemical and (electron)microscopic studies have
addressed these issues. Gap junction plaques consist of arrays of more
or less closely packed 9- to 10-nm particles, representing
individual channels. Under normal conditions, rat gap junction plaques
appear to contain 15% particle-free space,16 whereas
rabbit gap junction plaques particles are contiguous.17 In
terms of junctional conductance, there is little difference, because
the lower number of channels per square micrometer is
largely offset by the decrease in access resistance18 (see
below). Mean gap junction plaque area ranges from 0.21
µm2 in the human ventricle19 to
0.45 µm2 in the rat
ventricle20 21 and to 4
µm2 in the canine ventricle.22 In
the latter case, this area was 1.5 µm2
for approximately half of the plaques and 6.6
µm2 for the other half. From
(electron)microscopic21 22 23 and (immuno)histochemical
assessment,19 21 24 25 26 it appears that larger gap
junction plaques are located in interplicate regions of the ID (ie, in
regions running more or less parallel with the long axis of the cells)
and that smaller ones are located in plicate regions. Hoyt et
al22 estimated 80% of total gap junction area per cell to
be located in interplicate regions, where the gap junctions can serve
both longitudinal and transverse conduction.
Ventricular myocytes are connected by IDs to 10 neighbor
cells.22 26 Conduction velocity is determined by gap
junction plaque area in each of these IDs. Total gap junction plaque
area per ID is 47 to 94 µm2 in
rats,27 42 or 13.6 µm2 in
dogs,22 23 and 10 µm2 in
humans.26
In the atrium, gap junction plaques contain both Cx43 and Cx40.9 13 Most often, Cx43 and Cx40 are localized in the same plaques without preferential location of either connexin in lateral cell borders or ID plaques.9 No data are available to calculate the gap junction plaque area per ID in the atrium.
In ventricular myocardium, expression of Cx40 is limited to the conduction system.8 In most mammalian species, no Cx43 is present in the proximal part (His bundle, bundle branches), whereas in the more distal regions of the bundle branches and the Purkinje fibers, Cx40 and Cx43 are coexpressed.28 In Xenopus oocytes, Cx43 and Cx40 cannot form functional heterotypic gap junction channels,29 and it was suggested that the connexin distribution in the proximal conduction system would serve to propagate the action potential rapidly to distal parts without current loss via gap junctions to the surrounding septal myocytes. However, in mammalian cells, the incompatibility of Cx40 and Cx43 connexons seems less clear-cut.30 In mouse hearts, Cx45 is expressed throughout the atrioventricular node, His bundle, and bundle branches.10 The expression of Cx40 is limited to the core of the His bundle and bundle branches.10
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Distribution of Gap Junctions in Diseased Myocardium |
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TopAbstractIntroductionStructure and Properties of...Gap Junction Distribution in...Distribution of Gap Junctions...Gap Junctions and Conduction...Concluding RemarksReferences |
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In virtually all cardiac diseases predisposing to arrhythmias, changes in the distribution and number of gap junctions (gap junction remodeling) have been reported. In advanced ischemic disease, a narrow zone consisting of
5 layers of
cells bordering healed myocardial infarctions was
detected.24 In this zone, the normal distribution of gap
junctions in end-to-end–located IDs was disrupted with a shift of
Cx43-containing spots to the lateral cell borders without changes in
spot size. Normal, ischemic, and hypertrophied human left
ventricles showed equally sized plaques of anti-Cx43 staining, but the
total amount of Cx43 was reduced by 40% in the diseased
hearts.26 The number of IDs per cell was not different in
normal and diseased hearts, which implies that cellular geometry had
not dramatically changed. On the other hand, in reversibly
ischemic and hibernating human ventricle, a reduction of Cx43
plaque size of 23% and 33%, respectively, was observed in the
affected regions,19 with no changes in normal
myocardium. In these experiments, a shift of Cx43 spots
from an end-to-end location to a lateral location was observed; this
shift was also reported in hypertrophic
cardiomyopathy.25
In a guinea pig model of congestive heart failure, an overall reduction
of Cx43 of 37% was observed at the congestive heart failure stage
after 6 months of aortic banding, whereas at the compensated
hypertrophy stage, no changes were seen.31
Recently, a 35% decrease in gap junction area per ID was
reported32 after 4 weeks of right ventricular
hypertrophy caused by monocrotaline-induced
pulmonary hypertension in the rat, concomitant with a 30%
decrease in longitudinal conduction velocity
(
L). At the same time, numerous Cx43-positive
spots appeared along the lateral borders of the cells. Conduction
velocity in the transverse direction (T) and
total Cx43 content, as judged by immunoblotting, were
not affected. The authors concluded that the redistribution of gap
junction plaques may explain the reduced anisotropy ratio
(L/T). However, the
observed 55% increase in cell diameter may also play a role. Peters et
al33 demonstrated a close correlation between the
inducibility of figure-of-8 reentrant arrhythmias in epicardial
tissue bordering 4-day-old infarcts in canine ventricles and the
disruption of gap junction distribution. Especially viable cells close
to and sometimes interdigitating with necrotic cells of the infarcted
region showed extensive Cx43 labeling of lateral cell borders.
It appears that lateralization of gap junctions is a prominent feature of diseased myocardium. It is not completely clear, however, to what extent this lateralization can contribute to altered conduction properties, because it was recently shown34 that in rat ventricular cells bordering healed infarcts, many of the lateral gap junction plaques are located in invaginations of the sarcolemma into the cell interior, thereby not contributing to cell-to-cell communication. A comparable observation has been made in right ventricular hypertrophy.32
Although quantitative data are scarce, another common finding in diseased myocardium is a 30% to 40% reduction of gap junction area per ID. In (post)ischemic ventricles, this reduction is limited to a few cell layers around the affected area, whereas in hypertrophic ventricles, the reduction is more widespread. From this observation alone or together with an increased density of lateral gap junction plaques, one would predict a reduced anisotropy ratio. In one study,23 an increased anisotropy ratio has been suggested to occur in infarct border zones. This increase was partly due to a reduction in lateral (interplicate) gap junction density and partly to a decrease in the number of cells having side-to-side connections with neighboring cells.
Changes in gap junction density and distribution in diseased atrial tissue are less well documented. In rapidly paced dog atria, an increase in Cx43-positive spots was reported,35 especially at lateral cell borders. In goat atrium, no apparent changes in Cx43 density and distribution after 16 weeks of sustained atrial fibrillation (AF) were found,36 37 although some dephosphorylation had occurred. Cx40 protein was absent in 0.15- to 0.6-mm patches of atrial tissue after 16 weeks of AF without a reduction in Cx40 mRNA. The patchy reduction of Cx40 protein was evident after 2 weeks of AF, around the same time that AF became sustained. Whether this reduction in Cx40 is causally related to the persistence of AF remains to be determined.
Data on the involvement of gap junction remodeling in arrhythmias originating in the conduction system or in nodal tissue are just beginning to be reported.38 39 40
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Gap Junctions and Conduction Velocity |
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TopAbstractIntroductionStructure and Properties of...Gap Junction Distribution in...Distribution of Gap Junctions...Gap Junctions and Conduction...Concluding RemarksReferences |
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Effective gj
We carried out some simple computer simulations to test the effects of changes in density and distribution of gap junctions on conduction velocity of the action potential. First, we determined the effective gap junctional conductance (gj, corrected for electrical field effects caused by cytoplasmic access resistance) by use of our previously published model18 and by assuming the Cx43 single-channel conductance to be 75 pS at 37°C41 and all channels to be in their conducting state (but see Reference 42 ). Figure 1A
shows that the effects of cytoplasmic
access resistance are already apparent for relatively small gap
junctions and become more prominent with increasing gap junction size.
For gap junctions >0.5 µm2, the effective
conductance is <50% of the value obtained by simply adding up the
individual conductances of all channels in a given area (uncorrected
conductance), and for gap junctions >4
µm2, effective conductance is even <20%.
Consequently, gj per unit surface area is not
constant but decreases with increasing gap junction size (Figure 1B). Effective conductance is 0.3 to 0.5
µS/µm2 for small to moderately sized gap
junctions (0.3 to 1.5 µm2) and <0.2
µS/µm2 for large gap junctions (>5
µm2). As discussed above, gap junctional
surface area commonly ranges between 10 and 40
µm2 per ID. If an average effective conductance
of 0.3 µS/µm2 is used, effective
gj per ID between neighboring cells is 3 to 12
µS.
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Conduction Velocity
Next, we assessed the importance of gj for
conduction velocity. We stimulated the leftmost cell in a linear strand
of 50 cells at a frequency of 1 Hz and computed the conduction velocity
across the middle third of the strand. Cells were either arranged end
to end or side by side, and neighboring cells were connected through a
constant (effective) gj (Figure 2A). We used the human
ventricular cell model of Priebe and
Beuckelmann43 in a numerical representation of the
cable equation similar to that explored by Shaw and
Rudy,44 with a value of 150 
cm for cytoplasmic
resistivity.45
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To obtain L values of 70 cm/s as reported
for human ventricles,46 a conductance of 7.0 µS is
required (Figure 2B
). This agrees well with the above value of 3
to 12 µS estimated from morphometric data. The same conductance of
7.0 µS results in T of 30 cm/s. Under normal
conditions, L is quite insensitive to changes
in gj: it decreases by only 9 cm/s (13%) upon
halving the conductance. T is more sensitive
to changes in gj: it decreases by 36% upon
halving the conductance. The relative insensitivity of
L to changes in gj can
be explained in terms of gap junctional resistivity, which we computed
from gj and cell dimensions (Figure 2C).
For longitudinal conduction (solid line with filled circles in Figure 2C), gap junctional resistivity falls below the cytoplasmic
resistivity of 150 cm (horizontal dotted line) at
gj values as small as 2.5 µS, whereas for
transverse conduction, gap junctional resistivity is much larger than
cytoplasmic resistivity at all values of gj
(dashed line with open squares). Thus, we conclude that conduction
velocity, particularly L, is only moderately
sensitive to changes in effective gj. In
addition, cell dimensions (ratio of cell length to cell width) may play
a major role in determining the (anisotropy of) conduction velocity.
This is consistent with the conclusion of Spach et
al47 that cell size may be more important than gap
junction distribution.
Functional Implications
The simulation results constitute important caveats for the
interpretation of quantitative data from (immuno)histochemical or
(electron)microscopic studies. A reduction in total gap junction
content by as much as 40% without changes in the size of the gap
junction plaques, as observed in diseased human hearts,26
may by itself have only moderate effects on conduction velocity. If
normal gj between cells is 5 µS, a 40%
reduction to 3 µS results in an 11% decrease in
L from 65 to 58 cm/s and a 27% decrease in
T from 24 to 18 cm/s (Figure 2B). The
associated anisotropy ratio increases by 22% from 2.7 to 3.3. In other
cases, overall gap junction content remained unchanged, but a shift to
lateral cell borders occurred.25 32 A 40% shift would
reduce L by 11% and increase
T by 25%, resulting in a 29% decrease in the
anisotropy ratio. If the new lateral gap junctions are located
intracellularly,32 34 T may not
change at all.
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Concluding Remarks |
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TopAbstractIntroductionStructure and Properties of...Gap Junction Distribution in...Distribution of Gap Junctions...Gap Junctions and Conduction...Concluding RemarksReferences |
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In many studies involving the remodeling of gap junctions in diseased ventricular tissue, the authors have concluded that a decrease in conduction velocity may enhance the propensity to reentrant arrhythmias. However, the present analysis of the limited data available indicates that the reduction in conduction velocity or the changes in anisotropy ratio may actually be moderate. Certainly, the changes observed would not bring the substrate in the realm of slow conduction as addressed in several recent experimental48 49 50 and theoretical44 51 studies. Our analysis indicates that cytoplasmic resistivity and cellular geometry are much more important than commonly realized, a conclusion also advocated by Spach and colleagues.15 47 52 53
We did not incorporate disease-induced changes in membrane ionic and gap junction channel properties in our analysis. Undoubtedly, such pathophysiological changes further complicate the understanding of arrhythmogenesis in acute ischemia, chronic myocardial infarction, hypertrophy, and heart failure.
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Acknowledgments |
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This review was partly supported by the Research Council for Earth and Life Sciences (ALW), with financial aid from the Netherlands Organization for Scientific Research (NWO).
Received March 16, 2000; accepted April 14, 2000.
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T. Nakagami, H. Tanaka, P. Dai, S.-F. Lin, T. Tanabe, H. Mani, K. Fujiwara, H. Matsubara, and T. Takamatsu Generation of reentrant arrhythmias by dominant-negative inhibition of connexin43 in rat cultured myocyte monolayers Cardiovasc Res, July 1, 2008; 79(1): 70 - 79. [Abstract] [Full Text] [PDF]
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H. Zhang, Y. Zhao, M. Lei, H. Dobrzynski, J. H. Liu, A. V. Holden, and M. R. Boyett Computational evaluation of the roles of Na+ current, iNa, and cell death in cardiac pacemaking and driving Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H165 - H174. [Abstract] [Full Text] [PDF]
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D. Sedmera, A. Wessels, T. C. Trusk, R. P. Thompson, K. W. Hewett, and R. G. Gourdie Changes in activation sequence of embryonic chick atria correlate with developing myocardial architecture Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1646 - H1652. [Abstract] [Full Text] [PDF]
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S. Bagwe, O. Berenfeld, D. Vaidya, G. E. Morley, and J. Jalife Altered Right Atrial Excitation and Propagation in Connexin40 Knockout Mice Circulation, October 11, 2005; 112(15): 2245 - 2253. [Abstract] [Full Text] [PDF]
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S. Poelzing, B. J. Roth, and D. S. Rosenbaum Optical measurements reveal nature of intercellular coupling across ventricular wall Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1428 - H1435. [Abstract] [Full Text] [PDF]
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T. A.B. van Veen, M. Stein, A. Royer, K. Le Quang, F. Charpentier, W. H. Colledge, C. L.-H. Huang, R. Wilders, A. A. Grace, D. Escande, et al. Impaired Impulse Propagation in Scn5a-Knockout Mice: Combined Contribution of Excitability, Connexin Expression, and Tissue Architecture in Relation to Aging Circulation, September 27, 2005; 112(13): 1927 - 1935. [Abstract] [Full Text] [PDF]
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K. W. Hewett, L. W. Norman, D. Sedmera, R. J. Barker, C. Justus, J. Zhang, S. W. Kubalak, and R. G. Gourdie Knockout of the neural and heart expressed gene HF-1b results in apical deficits of ventricular structure and activation Cardiovasc Res, August 15, 2005; 67(3): 548 - 560. [Abstract] [Full Text] [PDF]
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J. Yoshioka, R. N. Prince, H. Huang, S. B. Perkins, F. U. Cruz, C. MacGillivray, D. A. Lauffenburger, and R. T. Lee Cardiomyocyte hypertrophy and degradation of connexin43 through spatially restricted autocrine/paracrine heparin-binding EGF PNAS, July 26, 2005; 102(30): 10622 - 10627. [Abstract] [Full Text] [PDF]
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H. Zhang, C. J. Garratt, J. Zhu, and A. V. Holden Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans Cardiovasc Res, June 1, 2005; 66(3): 493 - 502. [Abstract] [Full Text] [PDF]
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H. V.M. van Rijen, J. M.T. de Bakker, and T. A.B. van Veen Hypoxia, electrical uncoupling, and conduction slowing: Role of conduction reserve Cardiovasc Res, April 1, 2005; 66(1): 9 - 11. [Full Text] [PDF]
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J. P.P. Smits, M. W. Veldkamp, and A. A.M. Wilde Mechanisms of inherited cardiac conduction disease Europace, January 1, 2005; 7(2): 122 - 137. [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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A. Rodriguez-Sinovas, D. Garcia-Dorado, M. Ruiz-Meana, and J. Soler-Soler Enhanced effect of gap junction uncouplers on macroscopic electrical properties of reperfused myocardium J. Physiol., August 15, 2004; 559(1): 245 - 257. [Abstract] [Full Text] [PDF]
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T. L. Christie, R. Mui, T. W. White, and G. Valdimarsson Molecular cloning, functional analysis, and RNA expression analysis of connexin45.6: a zebrafish cardiovascular connexin Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1623 - H1632. [Abstract] [Full Text] [PDF]
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A. P Moreno Biophysical properties of homomeric and heteromultimeric channels formed by cardiac connexins Cardiovasc Res, May 1, 2004; 62(2): 276 - 286. [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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J. R de Groot and R. Coronel Acute ischemia-induced gap junctional uncoupling and arrhythmogenesis Cardiovasc Res, May 1, 2004; 62(2): 323 - 334. [Abstract] [Full Text] [PDF]
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P. E.M. Martin and W.H. Evans Incorporation of connexins into plasma membranes and gap junctions Cardiovasc Res, May 1, 2004; 62(2): 378 - 387. [Abstract] [Full Text] [PDF]
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C. E Conrath, R. Wilders, R. Coronel, J. M.T de Bakker, P. Taggart, J. R de Groot, and T. Opthof Intercellular coupling through gap junctions masks M cells in the human heart Cardiovasc Res, May 1, 2004; 62(2): 407 - 414. [Abstract] [Full Text] [PDF]
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S. Kostin, S. Dammer, S. Hein, W. P Klovekorn, E. P Bauer, and J. Schaper Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis Cardiovasc Res, May 1, 2004; 62(2): 426 - 436. [Abstract] [Full Text] [PDF]
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Z. Qu, H. S. Karagueuzian, A. Garfinkel, and J. N. Weiss Effects of Na+ channel and cell coupling abnormalities on vulnerability to reentry: a simulation study Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1310 - H1321. [Abstract] [Full Text] [PDF]
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K. H. W. J. ten Tusscher, D. Noble, P. J. Noble, and A. V. Panfilov A model for human ventricular tissue Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1573 - H1589. [Abstract] [Full Text] [PDF]
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H. V.M. van Rijen, D. Eckardt, J. Degen, M. Theis, T. Ott, K. Willecke, H. J. Jongsma, T. Opthof, and J. M.T. de Bakker Slow Conduction and Enhanced Anisotropy Increase the Propensity for Ventricular Tachyarrhythmias in Adult Mice With Induced Deletion of Connexin43 Circulation, March 2, 2004; 109(8): 1048 - 1055. [Abstract] [Full Text] [PDF]
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D. Garcia-Dorado, A. Rodriguez-Sinovas, and M. Ruiz-Meana Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion Cardiovasc Res, February 15, 2004; 61(3): 386 - 401. [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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J. R. de Groot, T. Veenstra, A. O. Verkerk, R. Wilders, J. P.P. Smits, F. J.G. Wilms-Schopman, R. F. Wiegerinck, J. Bourier, C. N.W. Belterman, R. Coronel, et al. Conduction slowing by the gap junctional uncoupler carbenoxolone Cardiovasc Res, November 1, 2003; 60(2): 288 - 297. [Abstract] [Full Text] [PDF]
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J. R de Groot, C. A Schumacher, A. O Verkerk, A. Baartscheer, J. W.T Fiolet, and R. Coronel Intrinsic heterogeneity in repolarization is increased in isolated failing rabbit cardiomyocytes during simulated ischemia Cardiovasc Res, September 1, 2003; 59(3): 705 - 714. [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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N. Bursac, K.K. Parker, S. Iravanian, and L. Tung Cardiomyocyte Cultures With Controlled Macroscopic Anisotropy: A Model for Functional Electrophysiological Studies of Cardiac Muscle Circ. Res., December 13, 2002; 91 (12): e45 - e54. [Abstract] [Full Text] [PDF]
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B. R Kwak, D. C Shah, and F. Mach A starting point for structure function relationships in the canine pulmonary veins Cardiovasc Res, September 1, 2002; 55(4): 703 - 705. [Full Text] [PDF]
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D. Garcia-Dorado, M. Ruiz-Meana, F. Padilla, A. Rodriguez-Sinovas, and M. Mirabet Gap junction-mediated intercellular communication in ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 456 - 465. [Abstract] [Full Text] [PDF]
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M.-D. Drici, L. Baker, P. Plan, J. Barhanin, G. Romey, and G. Salama Mice Display Sex Differences in Halothane-Induced Polymorphic Ventricular Tachycardia Circulation, July 23, 2002; 106(4): 497 - 503. [Abstract] [Full Text] [PDF]
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O. Bernus, R. Wilders, C. W. Zemlin, H. Verschelde, and A. V. Panfilov A computationally efficient electrophysiological model of human ventricular cells Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2296 - H2308. [Abstract] [Full Text] [PDF]
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H. M. W. van der Velden, R. Wilders, and H. J. Jongsma Atrial fibrillation-induced gap junctional remodeling J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1709 - 1709. [Full Text] [PDF]
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M. Allessie, J. Ausma, and U. Schotten Electrical, contractile and structural remodeling during atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 230 - 246. [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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T. Kawara, R. Derksen, J. R. de Groot, R. Coronel, S. Tasseron, A. C. Linnenbank, R. N.W. Hauer, H. Kirkels, M. J. Janse, and J. M.T. de Bakker Activation Delay After Premature Stimulation in Chronically Diseased Human Myocardium Relates to the Architecture of Interstitial Fibrosis Circulation, December 18, 2001; 104(25): 3069 - 3075. [Abstract] [Full Text] [PDF]
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R. Schulz, M. V Cohen, M. Behrends, J. M Downey, and G. Heusch Signal transduction of ischemic preconditioning Cardiovasc Res, November 1, 2001; 52(2): 181 - 198. [Full Text] [PDF]
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F. G. Akar, B. J. Roth, and D. S. Rosenbaum Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H533 - H542. [Abstract] [Full Text] [PDF]
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M.W Veldkamp, A.O Verkerk, A.C.G van Ginneken, A Baartscheer, C Schumacher, N de Jonge, J.M.T de Bakker, and T Opthof Norepinephrine induces action potential prolongation and early afterdepolarizations in ventricular myocytes isolated from human end-stage failing hearts Eur. Heart J., June 1, 2001; 22(11): 955 - 963. [Abstract] [PDF]
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C. W. Lo Role of Gap Junctions in Cardiac Conduction and Development : Insights From the Connexin Knockout Mice Circ. Res., September 1, 2000; 87(5): 346 - 348. [Full Text] [PDF]
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S. Kostin and J. Schaper Tissue-Specific Patterns of Gap Junctions in Adult Rat Atrial and Ventricular Cardiomyocytes In Vivo and In Vitro Circ. Res., May 11, 2001; 88(9): 933 - 939. [Abstract] [Full Text] [PDF]
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