(Circulation. 1997;95:988-996.)
© 1997 American Heart Association, Inc.
Articles |
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
the Department of Cardiology, St Mary's Hospital (N.S.P.) and Imperial College School of Medicine (N.S.P., N.J.S.), London, UK; and Departments of Pharmacology (N.S.P., A.L.W.) and Medicine (J.C.), College of Physicians and Surgeons, Columbia University, New York, NY.
Correspondence to Dr Nicholas S. Peters, Academic Cardiology, St Mary's Hospital, Praed St, London W2 1NY, UK. E-mail n.peters@ic.ac.uk.
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Abstract |
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Background Slow, nonuniform conduction caused by abnormal gap-junctional coupling of infarct-related myocardium is thought to be a component of the arrhythmogenic substrate. The hypothesis that changes in gap-junctional distribution in the epicardial border zone (EBZ) of healing canine infarcts define the locations of reentrant ventricular tachycardia (VT) circuits was tested by correlating activation maps of the surviving subepicardial myocardial layer with immunolocalization of the principal gap-junctional protein, connexin43 (Cx43).
Methods and Results The EBZ overlying 4-day-old anterior infarcts in three dogs with inducible VT and three noninducible dogs was mapped with a high-resolution electrode array and systematically examined by standard histology and confocal immunolocalization of Cx43. The thickness of the EBZ was significantly less in the hearts with (538±257 µm) than without (840±132 µm; P<.05) VT. At the interface with the underlying necrotic cells, the EBZ myocardium showed a marked disruption of gap-junctional distribution, with Cx43 labeling abnormally arrayed longitudinally along the lateral surfaces of the cells. In the EBZ of all hearts, the disrupted Cx43 labeling extended part of the way to the epicardial surface, with the most superficial epicardial myocytes having the normal transversely orientated pattern. Only in the hearts with inducible VT did the disorganization extend through the full thickness of the surviving layer at sites correlating with the location of the central common pathways of the figure-of-8 reentrant VT circuits.
Conclusions Altered gap-junctional distribution is part of the early remodeling of myocardium after infarction, and by defining the location of the common central pathway of the reentrant VT circuits, it may be a determinant of VT susceptibility.
Key Words: connexin • immunohistochemistry • anisotropy • conduction • mapping
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Introduction |
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In addition to alterations in active membrane properties of cardiac cells,1 the passive properties of the myocardium may have an important role in the genesis of cardiac arrhythmias.2 3 4 Central among the determinants of these passive properties are the gap junctions, which are responsible for electrical coupling of cardiac myocytes and intercellular conductance.2 5 6 7 The distribution of gap junctions influences the conduction of the electrical impulse through the myocardium and is responsible for its anisotropic properties.
It is recognized that fibrosis may play an important role in the formation of an anatomic substrate for arrhythmias. During aging, intercellular connections in the atria may become separated by connective tissue and anisotropic conduction becomes slowed and nonuniform.2 8 This nonuniformity of anisotropy may be an important cause of reentrant propagation in the atria. Similarly, in the ventricles, a marked disruption of gap-junctional distribution in surviving myocytes abutting the densely fibrotic scar of healed infarcts9 10 may cause nonuniformity of the anisotropic conduction, also leading to reentry.11 12
Nonuniform anisotropy, caused by conduction that is of normal velocity in the direction parallel with the myocardial fibers but slow and nonuniform in the transverse direction, has been shown to be associated with reentry in the EBZ of myocardial infarcts in a canine model within 4 days after coronary artery occlusion.6 11 12 13 In this phase of early healing, fibrotic scarring of the myocardium has not yet occurred, and there is partial recovery of the active membrane properties of the surviving myocytes from the marked depression that occurred during the acute phase after coronary occlusion.12 14 15 The altered myocardial conduction properties that promote the reentrant arrhythmias characteristic of this model 4 days after infarction do not, therefore, appear to be entirely dependent on either abnormal action potential generation or fibrosis.
Disorganization of gap-junctional intercellular coupling similar to that previously described in the fully healed phase after infarction9 10 could be a cause of arrhythmogenic nonuniformity of anisotropic conduction in the early phase after infarction, before fibrotic scarring. The aim of the present study was to investigate this hypothesis in canine infarcts studied 4 days after coronary occlusion, by determining Cx43 gap-junctional organization in regions of the infarct border zone in which reentrant circuits causing sustained VT were mapped.
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Methods |
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Canine Model of Myocardial Infarction
Six mongrel dogs (weighing 28 to 32 kg) underwent two-stage ligation of LAD 5 to 10 mm from its origin while under sodium pentobarbital anesthesia (30 mg/kg IV). Four days later, the dogs were reanesthetized, the chest was opened through a median sternotomy, and the heart was suspended in a pericardial cradle exposing the infarcted anterior left ventricular surface. The experimental setup has been described previously.11 16
Electrophysiological Study
Recording Instrumentation
A 9x13-cm flexible polymer sheet (0.3 mm thick) containing 292 bipolar electrodes was aligned with the LAD and sutured to the left ventricular epicardial surface over the anterior and lateral aspects of the infarct (Fig 1A
).16 A switch box was used to select between two overlapping but separate electrode configurations within the array. One configuration consisted of 196 electrodes that covered most of the left ventricle (Fig 1A). The second, higher-density configuration of 196 electrodes was confined to a central region that was 6x6 cm (Fig 1A). This was the area of interest for the anatomic study. In this center square, each bipole consisted of two 1-mm-diameter silver disks positioned 2 mm apart. The distance between the centers of each bipolar pair was 5 mm vertically and 7.5 mm horizontally. These bipolar electrodes were used to record electrical activity from the subepicardial myocardium overlying the transmural infarct (the EBZ) and the surrounding myocardium. The signal from each bipole was preamplified, multiplexed, digitized, and stored, along with leads II and III of the surface ECG, the blood pressure, and the voice log, on magnetic tape as described previously.11 16 Ventricle-stimulating electrodes (Fig 1A) were embedded in the recording electrode array (basal, lateral, and center) or sutured to the myocardium separately (LAD).16
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Experimental Protocol
For induction of VT, standard programmed stimulation protocols were used from each of the four stimulation sites (Fig 1A
). Sustained VT was induced in three of the six dogs included in this report and was defined as having a monomorphic QRS configuration and not terminating spontaneously for 
30 sec or degenerating into ventricular fibrillation. In the other three dogs, VT could not be induced, although they had extensive anterior myocardial infarction. The methods for determining activation times of bipolar electrograms (drawing isochrones and designating regions of conduction block during analysis of the magnetic tapes) have been described in detail previously.11 16
Anatomic Study
Histological Examination of the Infarct Border Zone
After completion of the electrophysiological studies, the heart was fibrillated by injection of 20 mL Zamboni's fixative (2% paraformaldehyde, 0.2% picric acid, 0.1 mol/L PBS, pH 7.4)17 into the LAD, distal to the occlusion. The electrode array was removed after the locations of the four corners of the central 6x6-cm electrode configuration were marked with epicardial sutures to enable precise correlation of the morphology with the electrophysiological properties of this region of the EBZ. After removal of the heart, the square of left ventricular wall that had been underlying the central square of electrodes was immediately excised, and its epicardial surface was divided into 25 equal squares of 12x12 mm (Fig 1B) through incision of the epicardial surface to a depth of 
5 mm, so that the segments remained attached to the underlying ventricular wall (Fig 1B). The tissue was then immersed in 100 mL Zamboni's fixative for 2 to 6 hours. A designated corner of each of the 25 incised segments, while still attached to the ventricular wall, was tagged with a small epicardial suture to permit later orientation (Fig 1B). The incisions in the epicardial surface were completed to divide the 6x6-cm square into the 25 component segments. Each segment was dehydrated and embedded in wax according to standard histological procedures.18
Sections (10 µm thick) of the transmural faces (containing EBZ overlying the necrotic infarct) of each segment that were orientated toward the LAD and base of the heart were immunolabeled for Cx43 (detailed below). Because the epimyocardial fiber axis runs approximately perpendicular to the LAD,11 12 sectioning and immunolabeling of the LAD and basal faces of the segments in this way permit examination of approximately longitudinally sectioned (base) and transversely sectioned (LAD) EBZ. Adjacent wax sections were stained with Masson's trichrome stain to help distinguish infarcted from surviving myocytes. For more detailed examination of the EBZs, the wax-embedded segments were further hemisected transmurally and parallel with the fiber axis, and the newly derived basal faces were sectioned and immunolabeled to provide intermediate data points. A 1x1-cm segment of noninfarcted posterior left ventricular wall was also prepared in this way.
Immunolocalization of Cx43
The primary antiserum used to localize cardiac gap-junctional Cx43 was raised against a synthetic peptide matching residues 131 to 142 of the cytoplasmically exposed segment of the Cx43 molecule.19 20 Full details of the production and characterization of the polyclonal antiserum19 20 21 22 and its use and validation in immunohistochemistry9 19 23 24 have been described previously.
The 10-µm sections of the LAD and basal transmural faces of each segment were dewaxed, rehydrated, and incubated in a trypsin solution for 10 minutes at room temperature to reexpose antigenic sites.23 25 The sections were treated with 0.1 mol/L L-lysine containing 0.1% Triton X-100 before incubation with the primary antiserum (dilution 1:10) for 1 hour at 37°C, followed by secondary antibody treatment with swine anti-rabbit fluoroscein isothiocyanate (1:20 dilution) for 1 hour and mounting. Appropriate controls were run in parallel.
Confocal Laser Scanning Microscopy
Immunolabeled sections were examined through the use of confocal laser scanning microscopy with a BioRad Lasersharp 600, with the blue high-sensitivity filter block inserted for optimal excitation and detection of fluoroscein, and the digitized images were stored on computer. Each transmural section was examined at low power to determine the overall tissue architecture and distribution of Cx43 label and at higher power to detect the precise distribution at the cellular level. Maps of Cx43 gap-junctional organization in each 6x6-cm EBZ specimen were derived by systematic examination of the transmural immunolabeled sections of each segment; the overall thickness of the surviving subepicardial myocardial layer was mapped across the specimen, and within this layer, gap-junctional organization was assessed and divided into normal and abnormal patterns of distribution (described in detail in "Results").
Where appropriate, results are expressed as mean±SD, and data were compared with the use of two-sample t tests of the pooled values from each group with statistical significance defined as a value of P<.05.
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Results |
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All six dogs developed extensive infarction of the anterior and lateral left ventricle after occlusion of the LAD and were studied 4 days after surgery. In three of the dogs, sustained monomorphic VT was reproducibly initiated (10 to 15 times in each experiment) by programmed stimulation, whereas no VT could be initiated in three experiments. Activation maps in the three experiments in which sustained VT was induced described complete reentrant circuits in the EBZ (described below).
Anatomy of the EBZ
Standard Light Microscopy
Fig 2 shows standard light micrographs of EBZ and, for each, a confocal micrograph of detail of an adjacent tissue section immunolabeled for Cx43. Standard light microscopy was used to obtain a general overview of EBZ histology to correlate with the distribution of Cx43 immunolabeling, and it readily distinguished the intact myocytes of the EBZ from the underlying infarcted myocytes (Figs 2A and 2C) in all six hearts that were examined, regardless of whether sustained VT could be induced. The myocytes of the EBZ had normal histological features on standard light microscopy, including intact cross-striations and an absence of pathological contractures (Fig 2E). Although the densely stained membranes of the intercalated disks were occasionally visible, no such membranes were apparent in abnormal locations. The surviving border zone myocytes interdigitated in a complex manner with the underlying necrotic tissue containing inflammatory cells (Fig 2). The absence of blue-green staining that is characteristic of collagen with Masson's trichrome staining indicated an absence of new collagen deposition and that the fibrotic healing process was not yet evident.
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Patterns and Distribution of Cx43 Immunolabeling
Cx43 immunohistochemistry demonstrated minimal spurious fluorescence in the regions shown to be necrotic by light microscopy (Figs 2B, 2D, and 2F), whereas focal labeling of the surviving myocytes of the EBZ was substantial. With confocal examination of the immunolabeled basal and LAD transmural faces of all 25 segments from each of the six infarct border zones, the thickness of the surviving EBZ was measured. The depth of Cx43 labeling concurred with the depth to which there were apparently viable myocytes on Masson's trichrome staining. The total thickness of the EBZ was therefore considered to be the thickness through which there was clear Cx43 labeling and was determined from the mean of six randomly selected points across the face of each segment. Maps showing the depth measurement of the EBZ on the LAD and basal transmural faces of the 25 component segments of each of the three arrhythmogenic border zones are shown in Fig 3. The mean thickness of the EBZ was significantly less in the three dogs with inducible VT (538±257 µm) than in those without VT (840±132 µm; P<.05). The thinnest parts of the EBZs of the noninducible dogs were >220 µm thick, but all of the inducible dogs had extensive areas in which the border zone myocardium was <220 µm thick (Fig 3).
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Despite the observations that the cells in the EBZ overlying the necrotic region had a normal histological appearance on standard light microscopy and all showed Cx43 immunolabeling, many of the surviving subepicardial myocytes in all sections of all six EBZs that were examined showed a marked disturbance in the distribution of Cx43 (Fig 2) compared with normal myocardium (Fig 4). Particularly in the deeper layers of the EBZ, the Cx43 gap junctions were distributed mainly along the lateral interfaces between myocytes, appearing as longitudinally oriented arrays (Fig 2). In contrast, myocytes of the subepicardial myocardium from the noninfarcted posterior wall (Fig 4) had the normal Cx43 gap-junctional distribution consisting of a transversely oriented pattern18 23 24 consistent with the positions characteristic of the intercalated disks of normal ventricular myocardium. This disturbed gap-junctional pattern was a universal finding in the intact myocytes immediately abutting the necrotic tissue and extended through the border zone toward the epicardial surface to a distance of 340±260 µm (n=100 pooled from all six hearts, with no significant differences between hearts), to a maximum of 840 µm, from the interface with the necrotic myocardium. For most of the sections examined from all hearts, this region of disturbed gap-junctional distribution did not extend throughout the full thickness of the EBZ, the labeling of the myocytes closest to the epicardium being in the normal transversely oriented pattern like that of the intact posterior wall (Fig 2A). The EBZ in such regions was categorized as showing partial-thickness gap-junctional disarray. Fig 2 shows a few orderly transverse arrays of label suggestive of normal intercalated disks in the upper most layer of subepicardial cells, but most of the cells in the thin layer of surviving cells in the EBZ have the abnormal longitudinally arrayed gap-junctional distribution. However, in some regions of the EBZ of only those experiments with sustained VT, the layer of disturbed gap-junctional distribution extended throughout the entire thickness of the surviving EBZ to the epicardial surface (full-thickness gap-junctional disarray). Fig 5 shows diagrammatically these two patterns of gap-junctional distribution in the border zone myocardium: partial-thickness disarray (characteristic of all six hearts) and full-thickness disarray (only in hearts with inducible VT).
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Anatomic-Electrophysiological Correlations
Activation Maps of EBZ
In each of the three experiments in which sustained monomorphic VT was induced, the reentrant circuit was mapped in the EBZ. Fig 6 (upper panels) shows activation maps of one complete cycle of the sustained VT in each of these experiments. These maps are plotted from the activation times of the electrograms recorded in the central 6x6-cm square from where the tissue was taken for the morphological studies and therefore correspond with the morphological data. In the time window shown in Fig 6A (upper panel), for example, earliest activation occurred in the region of myocardium between the 0- and 10-ms isochrones (indicated by the asterisk). The sequence of isochrones spreading from this region (indicated by the filled arrows) shows that the wave front moved toward the LAD margin (isochrones 10 to 50) and then divided into two wave fronts. One wave front turned to the left, toward the apical margin of the electrode array, and then traveled toward the left lateral margin (isochrones 60 to 150) and back toward the LAD margin around a line of block indicated by the thick black line to complete a reentrant cycle. The other wave front, which turned to the right on the map (toward the basal margin), also traveled toward the left lateral margin (isochrones 60 to 150), where it coalesced with the wave front from the left side and returned to complete a reentrant cycle. This wave front moved around a second line of block (thick black line) that was parallel and to the right of the first line of block. The region between the parallel lines of block (isochrones 180, through 0, to 30) is common to both reentrant wave fronts in this figure-of-8 pattern and is called the common central pathway. The lines of block were not present during sinus rhythm (not shown) and therefore were functional. Maps of the functional reentrant circuits in the other two experiments are indicated by the arrows in Figs 6B and 6C, and data from the larger configuration of 196 electrodes (see "Methods") confirmed that all circuits were complete.
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Correlation Between Electrical Activation Maps and Gap-Junctional Distribution Maps
For each dog, low-power confocal images of the immunolabeled basal (longitudinally sectioned) faces of each segment were used to determine the location of the regions of full-thickness and partial-thickness gap-junctional disarray. For the purpose of image analysis, if at least one complete and continuous row of myocytes traversing the face being examined comprised cells showing the normal pattern of transversely orientated clusters of gap junctions, the disturbance of distribution was considered to be partial thickness. If there was no row of myocytes showing the normal pattern, the region was classified as full thickness. With this technique, the complete map of data points for the 6x6-cm square of subepicardial myocardium from the three arrhythmogenic infarct border zones is shown in Fig 6 (lower panels). Comparison between the upper and lower panels of Fig 6 shows that for each reentrant circuit, the area of full-thickness gap-junctional disarray coincides with the location of the common central pathway. In each case, no full-thickness disarray was found outside this region. The area of full-thickness disarray also defines the approximate positions and lengths of the lines of functional block, dependent on the extent of the longitudinal interface between the area of full-thickness disturbance and the surrounding partial-thickness disturbance. A comparison of the data in Figs 6 and 4 indicates that the regions of full-thickness disarray were the thinnest regions of the EBZ. Only the inducible dogs had extensive areas in which the border zone myocardium was <200 µm thick, and these areas almost invariably formed part of the common central pathway of the circuit. None of the noninducible dogs had any points of full-thickness disturbance of gap-junctional distribution (data not shown).
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Discussion |
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Nonuniform Anisotropic Conduction: Abnormal Gap-Junctional Distribution as a Possible Cause
Cardiac myocytes have previously been shown to survive on the subepicardial surface of transmural infarcts caused by LAD occlusion in the canine heart12 26 27 28 and form the anatomic substrate for the reentrant VT that occurs during the healing phase at 3 to 5 days in this model. The basis for reentry within the EBZ relates to anisotropy of conduction, which has uniform features in normal myocardium3 but shows nonuniformity in the infarct border zone11 leading to further slowing of conduction transverse to the myocardial fiber axis. Nonuniformity of conduction is associated with the development of reentrant circuits causing VT.11 Our findings that the overall standard histological appearance of the surviving border zone cells showed no detectable abnormality are in accord with earlier studies in this model,12 which although not specifically addressing the organization of gap junctions, revealed intercalated disks of normal appearance and location.12 In the present study, standard histology with Masson's trichrome staining served the dual role of distinguishing viable from infarcted myocytes with which Cx43 localization in adjacent sections could be correlated, and indicating the extent of fibrotic scarring. That there was no detectable increase in connective tissue deposition in the EBZ myocardium at this early stage after infarction is consistent with previous observations in this model6 12 and indicates that unlike older healed infarcts9 10 and aging atrial tissue,8 29 increased connective tissue is not the cause of the nonuniform anisotropy in this model.
Although other connexin isoforms have been detected in mammalian myocardium,30 31 32 Cx43 is the most abundant, and it appears to be the most important physiologically in the working myocardium of the ventricle. A novel and important finding in the present study was that the distribution of Cx43 in the surviving cells of the EBZ was markedly disturbed as early as 4 days after infarction. In contrast with normal ventricular myocardium,18 23 24 33 immunolocalization revealed Cx43 gap junctions to be abnormally distributed, suggesting disruption of the normal pattern of intercellular coupling. This abnormality of distribution was a universal finding in the cell layers closest to the necrotic infarct, and in the thinner regions of the border zone, it extended through the full thickness of the surviving subepicardial myocardial layer. However, in regions in which there were more surviving cell layers and a thicker EBZ, the abnormal Cx43 gap-junctional distribution was present only in the deeper portion of the border zone, with a normal pattern in the overlying tissue.
Changes in Gap-Junctional Distribution in Early Postinfarction Remodeling
Previous investigations of disturbances of gap-junctional function in myocardial ischemia have concentrated principally on the early phase34 35 36 37 and have demonstrated significant uncoupling of myocytes after several minutes' ischemia,36 37 38 rapidly followed by the onset of irreversible cell damage with apparent loss of recognizable gap-junctional membrane.37 These and other39 alterations of coupling would contribute to slowing and nonuniformity of conduction and, therefore, potential arrhythmogenesis.40 Most studies of the morphology of infarct-related myocardium in which gap-junctional organization has been investigated (recently reviewed41 ) have been confined to the period late after infarction, when mature fibrotic scarring has occurred.9 10 In this late phase, there is marked disruption of intercalated disk and gap-junctional organization closely related to the fibrotic infarct with reductions in the quantity of gap-junctional membrane10 and in the number of cells to which each myocyte is connected, and through Cx43 immunohistochemistry, healed human infarct border zone shows a disorganization of gap-junctional distribution9 that is indistinguishable from that observed in the present study.9 10 The finding that profound alterations of Cx43 gap-junctional distribution in the surviving infarct-related myocytes occur within 4 days after infarction and before fibrotic healing has occurred indicates that this is an early pathophysiological response of these infarct-related cells and represents early postinfarction remodeling.
Role of Abnormal Gap-Junctional Distribution in Formation of Reentrant Circuits
The period of inducible VT caused by reentrant circuits 4 days after LAD occlusion is not only before fibrotic healing has occurred but also coincident with the return of the active membrane properties of the surviving myocytes toward normal.12 Nevertheless, the border zone has nonuniformly anisotropic characteristics,11 and the thinner the layer of surviving subepicardial myocardium, the more likely it is that a reentrant circuit will be inducible.12 40 42 This implies that the substrate for reentrant circuits in this context is dependent, at least in part, on properties of overall tissue structure rather than due only to abnormalities of individual cell behavior, since the latter might be expected to be largely independent of the thickness of the cell layer. Reentry in this model might therefore be due to a generalized abnormality of interaction of the myocytes adjacent to the infarct, which becomes more important when constituting a greater proportion of a thinner surviving cell layer, and suggests that the tissue of the common central pathway may have an abnormality that distinguishes it from the surrounding tissue, defining the lines of functional block at the longitudinal confines of this abnormality. The observation that the reentrant circuits are located in the region with the thinnest layer of surviving subepicardial myocardium has been reported in this model.40 42 43 The key finding of the present study, however, is that the common central pathway defining the position of the circuit and the lines of functional block can be localized to the area in which the disturbance of Cx43 gap-junctional distribution spans the entire depth of the surviving subepicardial myocardial layer. The development of reentrant circuits is facilitated when anisotropic propagation is rendered nonuniform,13 and the grossly disrupted pattern of gap-junctional distribution demonstrated in this study would also be expected to result in nonuniformity and to promote reentry. This expectation is borne out by the association between the regions of full-thickness Cx43 gap-junctional disruption and the location of the circuit in each case.
How Might Altered Gap-Junctional Coupling Define the Location of Reentrant Circuits?
The mechanism by which the change in gap-junctional distribution influences the location and characteristics of the reentrant circuit has yet to be determined. The abnormal redistribution of gap junctions to the lateral interfaces between myocytes might be expected to enhance side-to-side coupling, thereby improving transverse conduction and reducing (rather than increasing) the arrhythmogenicity of the tissue by reducing the degree of anisotropy. The redistribution should, however, be considered in the context of other changes of electrophysiological significance in the infarct border zone myocytes.14 15 43 Although the functional status of the gap junctions in these border zone cells is unknown, the results of in vitro studies would suggest that the hypoxia, acidosis, and hypercalcemia that may exist in this tissue would attenuate gap-junctional coupling44 and reduce conductance particularly in the transverse direction.45 46 Indeed, one might speculate that the redistribution of gap junctions in the present study is a compensatory mechanism in response to enhanced anisotropy of conduction produced by metabolic uncoupling. Furthermore, possible changes of connexin isoform expression, which have been observed in myocardial hypertrophy47 and for which a similar explanation of a compensatory gap-junctional alteration has been proposed, have yet to be examined in myocardium of the EBZ as a possible component of the remodeling process.
If the observed changes represent morphological compensation for profound metabolic uncoupling, one might further speculate that the zone of full-thickness disturbance, which would indicate a region with enhanced anisotropy, would have an even greater tendency than normal to support longitudinal conduction more than transverse. As a propagating wave front through the common central pathway reaches the end of the region of full-thickness disturbance, its outer edges would tend to encounter myocardium with only a partial-thickness disturbance of junctional distribution signifying better coupling, particularly in the more superficial cell layers. Therefore, propagation would be improved transversely and start turning laterally. Once transverse conduction in this direction extends beyond the line of full-thickness disturbance, propagation will then occur longitudinally (in the opposite direction) through the excitable tissue lateral to, and previously protected from depolarization by, the enhanced anisotropy defining the lines of functional block. At the other end of the region of full-thickness gap-junctional disturbance, the parallel wave fronts in the outer pathways will, by the same mechanism, start to propagate transversely and turn medially to coalesce, thus defining the limits of the lines of functional block.
Such a hypothesis remains to be examined, but the results of the present study indicate, for the first time, a direct association between the pattern of disturbance of gap-junctional distribution and the presence and location of functional reentrant circuits and support the concept that under pathological conditions, myocardial remodeling results in changes in gap-junctional organization that may be causally related to enhanced arrhythmogenicity.
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Acknowledgments |
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This work was supported by grant R37-HL-31393 from the National Heart, Lung, and Blood Institute, National Institutes of Health; grant F268 from the British Heart Foundation, UK; and a Wellcome Trust Travelling Fellowship. We thank Stephen Rothery and the late Izzy Sanchez for their technical expertise.
Received May 9, 1996; revision received September 25, 1996; accepted October 3, 1996.
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References |
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S. Kanno, A. Kovacs, K. A. Yamada, and J. E. Saffitz Connexin43 as a determinant of myocardial infarct size following coronary occlusion in mice J. Am. Coll. Cardiol., February 19, 2003; 41(4): 681 - 686. [Abstract] [Full Text] [PDF]
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C. Cabo and P. A. Boyden Electrical remodeling of the epicardial border zone in the canine infarcted heart: a computational analysis Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H372 - H384. [Abstract] [Full Text] [PDF]
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J. R. de Groot A little gap junctional uncoupling too much Cardiovasc Res, December 1, 2002; 56(3): 350 - 352. [Full Text] [PDF]
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E. J. Ciaccio Premature excitation and onset of reentrant ventricular tachycardia Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1703 - H1712. [Abstract] [Full Text] [PDF]
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H. S. Duffy, P. L. Sorgen, M. E. Girvin, P. O'Donnell, W. Coombs, S. M. Taffet, M. Delmar, and D. C. Spray pH-Dependent Intramolecular Binding and Structure Involving Cx43 Cytoplasmic Domains J. Biol. Chem., September 20, 2002; 277(39): 36706 - 36714. [Abstract] [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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K. Oahara, Y. Miyauchi, T. Ohara, M. C. Fishbein, S. Zhou, M.-H. Lee, W. J. Mandel, P.-S. Chen, and H. S. Karagueuzian Downregulation of Immunodetectable Atrial Connexin4O in a Canine Model of Chronic Left Ventricular Myocardial Infarction: Implications to Atrial Fibrillation Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2002; 7(2): 89 - 94. [Abstract] [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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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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G. Chu, A. N. Carr, K. B. Young, J.W. Lester, A. Yatani, A. Sanbe, M. C. Colbert, S. M. Schwartz, K. F. Frank, P. D. Lampe, et al. Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure Cardiovasc Res, April 1, 2002; 54(1): 105 - 116. [Abstract] [Full Text] [PDF]
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A. L. Wit and M. J. Janse Reperfusion Arrhythmias and Sudden Cardiac Death: A Century of Progress Toward an Understanding of the Mechanisms Circ. Res., October 26, 2001; 89(9): 741 - 743. [Full Text] [PDF]
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D. E. Gutstein, G. E. Morley, D. Vaidya, F. Liu, F. L. Chen, H. Stuhlmann, and G. I. Fishman Heterogeneous Expression of Gap Junction Channels in the Heart Leads to Conduction Defects and Ventricular Dysfunction Circulation, September 4, 2001; 104(10): 1194 - 1199. [Abstract] [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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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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E. J. Ciaccio, A. C. Tosti, and M. M. Scheinman Relationship Between Sinus Rhythm Activation and the Reentrant Ventricular Tachycardia Isthmus Circulation, July 31, 2001; 104(5): 613 - 619. [Abstract] [Full Text] [PDF]
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M. Ruiz-Meana, D. Garcia-Dorado, S. Lane, P. Pina, J. Inserte, M. Mirabet, and J. Soler-Soler Persistence of gap junction communication during myocardial ischemia Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2563 - H2571. [Abstract] [Full Text] [PDF]
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J. R de Groot, F. J.G Wilms-Schopman, T. Opthof, C. A Remme, and R. Coronel Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart Role of electrical cellular coupling Cardiovasc Res, May 1, 2001; 50(2): 362 - 372. [Abstract] [Full Text] [PDF]
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M. S. Spach Mechanisms of the Dynamics of Reentry in a Fibrillating Myocardium : Developing a Genes-to-Rotors Paradigm Circ. Res., April 27, 2001; 88(8): 753 - 755. [Full Text] [PDF]
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 J. M. Burt, A. M. Fletcher, T. D. Steele, Y. Wu, G. T. Cottrell, and D. T. Kurjiaka Alteration of Cx43:Cx40 expression ratio in A7r5 cells Am J Physiol Cell Physiol, March 1, 2001; 280(3): C500 - C508. [Abstract] [Full Text] [PDF]
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D. J. Huelsing, A. E. Pollard, and K. W. Spitzer Transient outward current modulates discontinuous conduction in rabbit ventricular cell pairs Cardiovasc Res, March 1, 2001; 49(4): 779 - 789. [Abstract] [Full Text] [PDF]
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M. S. Hanna, J. Coromilas, M. E. Josephson, A. L. Wit, and N. S. Peters Mechanisms of Resetting Reentrant Circuits in Canine Ventricular Tachycardia Circulation, February 27, 2001; 103(8): 1148 - 1156. [Abstract] [Full Text] [PDF]
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D. E. Gutstein, G. E. Morley, H. Tamaddon, D. Vaidya, M. D. Schneider, J. Chen, K. R. Chien, H. Stuhlmann, and G. I. Fishman Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43 Circ. Res., February 16, 2001; 88(3): 333 - 339. [Abstract] [Full Text] [PDF]
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J. M. Pastore and D. S. Rosenbaum Role of Structural Barriers in the Mechanism of Alternans-Induced Reentry Circ. Res., December 8, 2000; 87(12): 1157 - 1163. [Abstract] [Full Text] [PDF]
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M. J. Schalij, L. Boersma, M. Huijberts, and M. A. Allessie Anisotropic Reentry in a Perfused 2-Dimensional Layer of Rabbit Ventricular Myocardium Circulation, November 21, 2000; 102(21): 2650 - 2658. [Abstract] [Full Text] [PDF]
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C. Cabo, H. Schmitt, and A. L. Wit New Mechanism of Antiarrhythmic Drug Action : Increasing L-Type Calcium Current Prevents Reentrant Ventricular Tachycardia in the Infarcted Canine Heart Circulation, November 7, 2000; 102(19): 2417 - 2425. [Abstract] [Full Text] [PDF]
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M. A. Beardslee, D. L. Lerner, P. N. Tadros, J. G. Laing, E. C. Beyer, K. A. Yamada, A. G. Kleber, R. B. Schuessler, and J. E. Saffitz Dephosphorylation and Intracellular Redistribution of Ventricular Connexin43 During Electrical Uncoupling Induced by Ischemia Circ. Res., October 13, 2000; 87(8): 656 - 662. [Abstract] [Full Text] [PDF]
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G. Taimor Cardiac gap junctions: good or bad? Cardiovasc Res, October 1, 2000; 48(1): 8 - 10. [Full Text] [PDF]
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S. P. Thomas, L. Bircher-Lehmann, S. A. Thomas, J. Zhuang, J. E. Saffitz, and A. G. Kleber Synthetic Strands of Neonatal Mouse Cardiac Myocytes : Structural and Electrophysiological Properties Circ. Res., September 15, 2000; 87(6): 467 - 473. [Abstract] [Full Text] [PDF]
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