This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jongsma, H. J. Articles by Wilders, R. Search for Related Content PubMed PubMed Citation Articles by Jongsma, H. J. Articles by Wilders, R. Related Collections Remodeling Arrythmias-basic studies Cell biology/structural biology

(Circulation Research. 2000;86:1193.)
© 2000 American Heart Association, Inc.

MiniReview

Gap Junctions in Cardiovascular Disease

Habo J. Jongsma, Ronald Wilders

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

	Abstract

Top Abstract Introduction Structure and Properties of... Gap Junction Distribution in... Distribution of Gap Junctions... Gap Junctions and Conduction... Concluding Remarks References

 
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

	Introduction

Top Abstract Introduction Structure and Properties of... Gap Junction Distribution in... Distribution of Gap Junctions... Gap Junctions and Conduction... Concluding Remarks References

 
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.

	Structure and Properties of Gap Junction Channels

Top Abstract Introduction Structure and Properties of... Gap Junction Distribution in... Distribution of Gap Junctions... Gap Junctions and Conduction... Concluding Remarks References

 
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

	Gap Junction Distribution in Normal Myocardium

Top Abstract Introduction Structure and Properties of... Gap Junction Distribution in... Distribution of Gap Junctions... Gap Junctions and Conduction... Concluding Remarks References

 
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 reports^{12 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 ventricle^{20 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)microscopic^{21 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

	Distribution of Gap Junctions in Diseased Myocardium

Top Abstract Introduction Structure and Properties of... Gap Junction Distribution in... Distribution of Gap Junctions... Gap Junctions and Conduction... Concluding Remarks References

 
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}

	Gap Junctions and Conduction Velocity

Top Abstract Introduction Structure and Properties of... Gap Junction Distribution in... Distribution of Gap Junctions... Gap Junctions and Conduction... Concluding Remarks References

 
Effective g_j
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 (g_j, 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, g_j 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 g_j per ID between neighboring cells is 3 to 12 µS.

View larger version (13K): [in this window] [in a new window]   Figure 1. Effects of cytoplasmic access resistance on gj. A, Effective gj (corrected for cytoplasmic access resistance) versus gap junctional surface area, contrasted with the uncorrected value obtained by multiplying single-channel conductance by the number of gap junctional channels. B, Data from panel A replotted as conductance per unit surface area.

Conduction Velocity
Next, we assessed the importance of g_j 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) g_j (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

View larger version (27K): [in this window] [in a new window]   Figure 2. Computer simulations of action potential propagation in linear strands of human ventricular cells with an effective gj between cells. A, Diagram of longitudinal and transverse strands. B, Longitudinal and transverse conduction velocity versus gj. C, Gap junctional and cytoplasmic resistivity versus gj. Note logarithmic ordinate scale.

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 g_j: it decreases by only 9 cm/s (13%) upon halving the conductance. _T is more sensitive to changes in g_j: it decreases by 36% upon halving the conductance. The relative insensitivity of _L to changes in g_j can be explained in terms of gap junctional resistivity, which we computed from g_j 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 g_j values as small as 2.5 µS, whereas for transverse conduction, gap junctional resistivity is much larger than cytoplasmic resistivity at all values of g_j (dashed line with open squares). Thus, we conclude that conduction velocity, particularly _L, is only moderately sensitive to changes in effective g_j. 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 g_j 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.

	Concluding Remarks

Top Abstract Introduction Structure and Properties of... Gap Junction Distribution in... Distribution of Gap Junctions... Gap Junctions and Conduction... Concluding Remarks References

 
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 experimental^{48 49 50} and theoretical^{44 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.

	Acknowledgments

 
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.

	References

Top Abstract Introduction Structure and Properties of... Gap Junction Distribution in... Distribution of Gap Junctions... Gap Junctions and Conduction... Concluding Remarks References

 

1. Bruzzone R, White TW, Paul DL. Connections with connexins: the molecular basis of direct intercellular signaling. Eur J Biochem. 1996;238:1–27.[Medline] [Order article via Infotrieve]
2. Bruzzone R, White TW, Goodenough DA. The cellular Internet: on-line with connexins. Bioessays. 1996;18:709–718.[Medline] [Order article via Infotrieve]
3. Kumar NM, Gilula NB. The gap junction communication channel. Cell. 1996;84:381–388.[Medline] [Order article via Infotrieve]
4. Gros DB, Jongsma HJ. Connexins in mammalian heart function. Bioessays. 1996;18:719–730.[Medline] [Order article via Infotrieve]
5. Brink PR, Cronin K, Banach K, Peterson E, Westphale EM, Seul KH, Ramanan SV, Beyer EC. Evidence for heteromeric gap junction channels formed from rat connexin43 and human connexin37. Am J Physiol. 1997;273:C1386–C1396.
6. Francis D, Stergiopoulos K, Ek-Vitorin JF, Cao FL, Taffet SM, Delmar M. Connexin diversity and gap junction regulation by pHi. Dev Genet. 1999;24:123–136.[Medline] [Order article via Infotrieve]
7. Beardslee MA, Laing JG, Beyer EC, Saffitz JE. Rapid turnover of connexin43 in the adult rat heart. Circ Res. 1998;83:629–635.[Abstract/Free Full Text]
8. Van Kempen MJA, Ten Velde I, Wessels A, Oosthoek PW, Gros D, Jongsma HJ, Moorman AFM, Lamers WH. Differential connexin distribution accommodates cardiac function in different species. Microsc Res Tech. 1995;31:420–436.[Medline] [Order article via Infotrieve]
9. Gros D, Jarry-Guichard T, Ten Velde I, De Mazière A, Van Kempen MJA, Davoust J, Briand JP, Moorman AFM, Jongsma HJ. Restricted distribution of connexin40, a gap junctional protein, in mammalian heart. Circ Res. 1994;74:839–851.[Abstract/Free Full Text]
10. Coppen SR, Severs NJ, Gourdie RG. Connexin45 (6) expression delineates an extended conduction system in the embryonic and mature rodent heart. Dev Genet. 1999;24:82–90.[Medline] [Order article via Infotrieve]
11. Coppen SR, Kodama I, Boyett MR, Dobrzynski H, Takagishi Y, Honjo H, Yeh HI, Severs NJ. Connexin45, a major connexin of the rabbit sinoatrial node, is co-expressed with connexin43 in a restricted zone at the nodal-crista terminalis border. J Histochem Cytochem. 1999;47:907–918.[Abstract/Free Full Text]
12. Kanter HL, Laing JG, Beyer EC, Green KG, Saffitz JE. Multiple connexins colocalize in canine ventricular gap junctions. Circ Res. 1993;73:344–350.[Abstract/Free Full Text]
13. Davis LM, Rodefeld ME, Green K, Beyer EC, Saffitz JE. Gap junction protein phenotypes of the human heart and conduction system. J Cardiovasc Electrophysiol. 1995;6:813–822.[Medline] [Order article via Infotrieve]
14. Coppen SR, Dupont E, Rothery S, Severs NJ. Connexin45 expression is preferentially associated with the ventricular conduction system in mouse and rat heart. Circ Res. 1998;82:232–243.[Abstract/Free Full Text]
15. Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at a microscopic level: electrical description of myocardial architecture and its application to conduction. Circ Res. 1995;76:366–380.[Abstract/Free Full Text]
16. De Mazière AM, Scheuermann DW. Structural changes in cardiac gap junctions after hypoxia and reoxygenation: a quantitative freeze-fracture analysis. Cell Tissue Res. 1990;261:183–194.[Medline] [Order article via Infotrieve]
17. Shibata Y, Nakata K, Page E. Ultrastructural changes during development of gap junctions in rabbit left ventricular myocardial cells. J Ultrastruct Res. 1980;71:258–271.[Medline] [Order article via Infotrieve]
18. Wilders R, Jongsma HJ. Limitations of the dual voltage clamp method in assaying conductance and kinetics of gap junction channels. Biophys J. 1992;63:942–953.[Abstract/Free Full Text]
19. Kaprielian RR, Gunning M, Dupont E, Sheppard MN, Rothery SM, Underwood R, Pennell DJ, Fox K, Pepper J, Poole-Wilson PA, et al. Downregulation of immunodetectable connexin43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle. Circulation. 1998;97:651–660.[Abstract/Free Full Text]
20. Shibata Y, Yamamoto T. Freeze-fracture studies of gap junctions in vertebrate cardiac muscle cells. J Ultrastruct Res. 1979;67:79–88.[Medline] [Order article via Infotrieve]
21. Green CR, Peters NS, Gourdie RG, Rothery S, Severs NJ. Validation of immunohistochemical quantification in confocal scanning laser microscopy: a comparative assessment of gap junction size with confocal and ultrastructural techniques. J Histochem Cytochem. 1993;41:1339–1349.[Abstract]
22. Hoyt RH, Cohen ML, Saffitz JE. Distribution and three-dimensional structure of intercellular junctions in canine myocardium. Circ Res. 1989;64:563–574.[Abstract/Free Full Text]
23. Luke RA, Saffitz JE. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest. 1991;87:1594–1602.
24. Smith JH, Green CR, Peters NS, Rothery S, Severs NJ. Altered patterns of gap junction distribution in ischemic heart disease: an immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am J Pathol. 1991;139:801–821.[Abstract]
25. Sepp R, Severs NJ, Gourdie RG. Altered patterns of cardiac intercellular junction distribution in hypertrophic cardiomyopathy. Heart. 1996;76:412–417.[Abstract/Free Full Text]
26. Peters NS, Green CR, Poole-Wilson PA, Severs NJ. Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. Circulation. 1993;88:864–875.[Abstract/Free Full Text]
27. Matter A. A morphometric study on the nexus of rat cardiac muscle. J Cell Biol. 1973;56:690–696.[Abstract/Free Full Text]
28. Gourdie RG, Severs NJ, Green CR, Rothery S, Germroth P, Thompson RP. The spatial distribution and relative abundance of gap-junctional connexin40 and connexin43 correlate to functional properties of components of the cardiac atrioventricular conduction system. J Cell Sci. 1993;105:985–991.[Abstract]
29. Bruzzone R, Haefliger JA, Gimlich R, Paul D. Connexin40, a component of gap junctions in vascular endothelium, is restricted in its ability to interact with other connexins. Mol Biol Cell. 1993;4:7–20.[Abstract]
30. Valiunas V, Weingart R, Brink PR. Formation of heterotypic gap junction channels by connexins 40 and 43. Circ Res. 2000;86:E42–E49.
31. Wang X, Gerdes AM. Chronic pressure overload cardiac hypertrophy and failure in guinea pigs, III: intercalated disc remodeling. J Mol Cell Cardiol. 1999;31:333–343.[Medline] [Order article via Infotrieve]
32. Uzzaman M, Honjo H, Takagishi Y, Emdad L, Magee AI, Severs NJ, Kodama I. Remodeling of gap-junctional coupling in hypertrophied right ventricles of rats with monocrotaline-induced pulmonary hypertension. Circ Res. 2000;86:871–878.[Abstract/Free Full Text]
33. Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation. 1997;95:988–996.[Abstract/Free Full Text]
34. Matsushita T, Oyamada M, Fujimoto K, Yasuda Y, Masuda S, Wada Y, Oka T, Takamatsu T. Remodeling of cell-cell and cell-extracellular matrix interactions at the border zone of rat myocardial infarcts. Circ Res. 1999;85:1046–1055.[Abstract/Free Full Text]
35. Elvan A, Huang XD, Pressler ML, Zipes DP. Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs. Circulation. 1997;96:1675–1685.[Abstract/Free Full Text]
36. van der Velden HM, van Kempen MJ, Wijffels MC, van Zijverden M, Groenewegen WA, Allessie MA, Jongsma HJ. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol. 1998;9:596–607.[Medline] [Order article via Infotrieve]
37. van der Velden HM, Ausma J, Rook MB, Hellemons AJ, van Veen TAA, Allessie MA, Jongsma HJ. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc Res. In press.
38. Simon AM, Goodenough DA, Paul DL. Mice lacking connexin40 have cardiac conduction abnormalities characteristic of atrioventricular block and bundle branch block. Curr Biol. 1998;8:295–298.[Medline] [Order article via Infotrieve]
39. Hagendorff A, Schumacher B, Kirchhoff S, Luderitz B, Willecke K. Conduction disturbances and increased atrial vulnerability in connexin40-deficient mice analyzed by transesophageal stimulation. Circulation. 1999;99:1508–1515.[Abstract/Free Full Text]
40. Verheule S, van Batenburg CA, Coenjaerts FE, Kirchhoff S, Willecke K, Jongsma HJ. Cardiac conduction abnormalities in mice lacking the gap junction protein connexin40. J Cardiovasc Electrophysiol. 1999;10:1380–1389.[Medline] [Order article via Infotrieve]
41. Bukauskas FF, Weingart R. Temperature dependence of gap junction properties in neonatal rat heart cells. Pflugers Arch. 1993;423:133–151.[Medline] [Order article via Infotrieve]
42. Bukauskas FF, Jordan K, Bukauskiene A, Bennett MV, Lampe PD, Laird DW, Verselis VK. Clustering of connexin 43-enhanced green fluorescent protein gap junction channels and functional coupling in living cells. Proc Natl Acad Sci U S A. 2000;97:2556–2561.[Abstract/Free Full Text]
43. Priebe L, Beuckelmann DJ. Simulation study of cellular electric properties in heart failure. Circ Res. 1998;82:1206–1223.[Abstract/Free Full Text]
44. Shaw RM, Rudy Y. Ionic mechanisms of propagation in cardiac tissue: roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. Circ Res. 1997;81:727–741.[Abstract/Free Full Text]
45. Chapman RA, Fry CH. An analysis of the cable properties of frog ventricular myocardium. J Physiol (Lond). 1978;283:263–282.[Abstract/Free Full Text]
46. Taggart P, Sutton PMI, Opthof T, Coronel R, Trimlett R, Pugsley W, Kallis P. Inhomogeneous transmural conduction during early ischemia in patients with coronary artery disease. J Mol Cell Cardiol. 2000;32:621–630.[Medline] [Order article via Infotrieve]
47. Spach MS, Heidlage JF, Dolber PC, Barr RC. Electrophysiological effects of remodeling cardiac gap junctions and cell size: experimental and model studies of normal cardiac growth. Circ Res. 2000;86:302–311.[Abstract/Free Full Text]
48. Rohr S, Kucera JP, Kléber AG. Slow conduction in cardiac tissue, I: effects of a reduction of excitability versus a reduction of electrical coupling on microconduction. Circ Res. 1998;83:781–794.[Abstract/Free Full Text]
49. Wilders R, Verheijck EE, Joyner RW, Golod DA, Kumar R, van Ginneken ACG, Bouman LN, Jongsma HJ. Effects of ischemia on discontinuous action potential conduction in hybrid pairs of ventricular cells. Circulation. 1999;99:1623–1629.[Abstract/Free Full Text]
50. Wagner MB, Namiki T, Wilders R, Joyner RW, Jongsma HJ, Verheijck EE, Kumar R, Golod DA, Goolsby WN, van Ginneken ACG. Electrical interactions among real cardiac cells and cell models in a linear strand. Am J Physiol. 1999;276:H391–H400.[Abstract/Free Full Text]
51. Wang Y, Rudy Y. Action potential propagation in inhomogeneous cardiac tissue: safety factor considerations and ionic mechanism. Am J Physiol. 2000;278:H1019–H1029.[Abstract/Free Full Text]
52. Spach MS. Anisotropy of cardiac tissue: a major determinant of conduction? J Cardiovasc Electrophysiol. 1999;10:887–890.[Medline] [Order article via Infotrieve]
53. Spach MS, Barr RC. Effects of cardiac microstructure on propagating electrical waveforms. Circ Res. 2000;86:E23–E28.

This article has been cited by other articles:

				N. J. Severs, A. F. Bruce, E. Dupont, and S. Rothery Remodelling of gap junctions and connexin expression in diseased myocardium Cardiovasc Res, October 1, 2008; 80(1): 9 - 19. [Abstract] [Full Text] [PDF]

				B. Yang, Y. Lu, and Z. Wang Control of cardiac excitability by microRNAs Cardiovasc Res, September 1, 2008; 79(4): 571 - 580. [Abstract] [Full Text] [PDF]

				J. L. Manias, I. Plante, X.-Q. Gong, Q. Shao, J. Churko, D. Bai, and D. W. Laird Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant Cardiovasc Res, August 15, 2008; (2008) cvn203v2. [Abstract] [Full Text] [PDF]

				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]

				T. Sato, T. Ohkusa, H. Honjo, S. Suzuki, M.-a. Yoshida, Y. S. Ishiguro, H. Nakagawa, M. Yamazaki, M. Yano, I. Kodama, et al. Altered expression of connexin43 contributes to the arrhythmogenic substrate during the development of heart failure in cardiomyopathic hamster Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1164 - H1173. [Abstract] [Full Text] [PDF]

				A. Mertens, O. Stiedl, S. Steinlechner, and M. Meyer Cardiac dynamics during daily torpor in the Djungarian hamster (Phodopus sungorus) Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2008; 294(2): R639 - R650. [Abstract] [Full Text] [PDF]

				R. H. Keldermann, K. H. W. J. ten Tusscher, M. P. Nash, R. Hren, P. Taggart, and A. V. Panfilov Effect of heterogeneous APD restitution on VF organization in a model of the human ventricles Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H764 - H774. [Abstract] [Full Text] [PDF]

				A. O. Verkerk, A. C.G. van Ginneken, T. A.B. van Veen, and H. L. Tan Effects of heart failure on brain-type Na+ channels in rabbit ventricular myocytes: Reply Europace, February 1, 2008; 10(2): 257 - 258. [Full Text] [PDF]

				E. Kizana, C. Y. Chang, E. Cingolani, G. A. Ramirez-Correa, R. B. Sekar, M. R. Abraham, S. L. Ginn, L. Tung, I. E. Alexander, and E. Marban Gene Transfer of Connexin43 Mutants Attenuates Coupling in Cardiomyocytes: Novel Basis for Modulation of Cardiac Conduction by Gene Therapy Circ. Res., June 8, 2007; 100(11): 1597 - 1604. [Abstract] [Full Text] [PDF]

				R. Papp, M. Gonczi, M. Kovacs, G. Seprenyi, and A. Vegh Gap junctional uncoupling plays a trigger role in the antiarrhythmic effect of ischaemic preconditioning Cardiovasc Res, June 1, 2007; 74(3): 396 - 405. [Abstract] [Full Text] [PDF]

				S. A. Jones, M. R. Boyett, and M. K. Lancaster Declining Into Failure: The Age-Dependent Loss of the L-Type Calcium Channel Within the Sinoatrial Node Circulation, March 13, 2007; 115(10): 1183 - 1190. [Abstract] [Full Text] [PDF]

				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]

				M. Amino, K. Yoshioka, T. Tanabe, E. Tanaka, H. Mori, Y. Furusawa, W. Zareba, M. Yamazaki, H. Nakagawa, H. Honjo, et al. Heavy ion radiation up-regulates Cx43 and ameliorates arrhythmogenic substrates in hearts after myocardial infarction Cardiovasc Res, December 1, 2006; 72(3): 412 - 421. [Abstract] [Full Text] [PDF]

				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]

				P. Kojodjojo, P. Kanagaratnam, O. R. Segal, W. Hussain, and N. S. Peters The Effects of Carbenoxolone on Human Myocardial Conduction: A Tool to Investigate the Role of Gap Junctional Uncoupling in Human Arrhythmogenesis J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1242 - 1249. [Abstract] [Full Text] [PDF]

				T. A.B. van Veen, H. V.M. van Rijen, M. J.A. van Kempen, L. Miquerol, T. Opthof, D. Gros, M. A. Vos, H. J. Jongsma, and J. M.T. de Bakker Discontinuous Conduction in Mouse Bundle Branches Is Caused by Bundle-Branch Architecture Circulation, October 11, 2005; 112(15): 2235 - 2244. [Abstract] [Full Text] [PDF]

				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]

				S Chakrabarti and A G Stuart Understanding cardiac arrhythmias Arch. Dis. Child., October 1, 2005; 90(10): 1086 - 1090. [Abstract] [Full Text] [PDF]

				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]

				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]