(Circulation. 1996;94:571-577.)
© 1996 American Heart Association, Inc.
Articles |
Atrioventricular Junctional Tissue
Discrepancy Between Histological and Electrophysiological Characteristics
the Departments of Clinical and Experimental Cardiology (J.M.T. de B., J.T.V., P.L., B.T., M.J.J.), Anatomy and Embryology (A.F.M.M., J.L.M.V.), and Cardiovascular Pathology (A.E.B.), Academic Medical Center; the Interuniversity Cardiology Institute of the Netherlands, Amsterdam; and the Cardiology Department (M.A.M.), Royal Prince Alfred Hospital, Sydney, Australia.
Correspondence to Dr Mark McGuire, Cardiology Department, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
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Abstract |
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Background Previous work has demonstrated that cells with AV nodal-type action potentials are not confined to Koch's triangle but may extend along the AV orifices. The aim of this study was to examine the histological and electrophysiological characteristics of this tissue.
Methods and Results Studies were performed in isolated, blood-perfused dog and pig hearts. Microelectrode recordings revealed cells with nodal-type action potentials around the tricuspid and mitral valve rings. These cells were found within 1 to 2 mm of the valve annuli. A zone of cells with intermediate action potentials, 
1 cm wide, separated cells with nodal-type action potentials from cells with atrial-type action potentials in the body of the atria. In cells with nodal-type action potentials, adenosine caused a reduction in action potential amplitude (49±2 versus 33±2 mV, mean±SE; P<.001), upstroke velocity (2.5±0.2 versus 2.0±0.2 V/s, P<.05), and duration (150±4 versus 96±8 ms, P<.001). The light microscopic appearance of AV junctional cells was similar to that of myocytes in the body of the atrium. A polyclonal antibody raised against connexin-43 bound to atrial and ventricular tissue but not to the AV junctional tissue or AV nodal region. The absence of connexin-43 correlated with the sites of cells with nodal-like action potentials. With pacing techniques, the AV junctional tissue in the region of the posterior AV nodal approaches could be electrically dissociated from atrial, AV nodal, and ventricular tissue. AV nodal echoes were induced with ventricular pacing in three dog hearts. In each case, retrograde conduction was through the slow pathway, and anterograde conduction was through the fast pathway. During echoes, activation of AV junctional cells preceded atrial activation during retrograde slow pathway conduction, but these cells were not activated during anterograde fast pathway conduction.
Conclusions AV junctional cells around both annuli are histologically similar to atrial cells but resemble nodal cells in their cellular electrophysiology, response to adenosine, and lack of connexin-43. The light microscopic appearance of AV junctional cells is a poor guide to their action potential characteristics. The AV junctional cells in the posterior AV nodal approaches appear to participate in slow pathway conduction. These cells may be the substrate of the slow "AV nodal" pathway.
Key Words: atrioventricular node • tachyarrhythmias • electrophysiology • catheter ablation • action potential
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Introduction |
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Previous work has demonstrated that the "slow pathway" potential described by Haissaguerre et al1 arises from a band of cells with nodal-like action potentials found in the posterior approaches to the AV node.2 These cells are part of a ring of cells with nodal-type action potentials that surround the tricuspid annulus.2 Paes de Carvalho and de Almeida3 described similar cells as early as 1960, and Wit et al4 demonstrated cells with nodal-like action potentials in the mitral valve leaflets. However, the histological appearance of the cells and their relation to the atria and the AV node are unclear. The aim of this study was to correlate the histological and electrophysiological characteristics of the cells around both AV annuli by means of microelectrode recordings, light microscopy, response of cells to adenosine, and staining for the gap junctional protein connexin-43.
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Methods |
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This study conformed to the guiding principles of the American Physiological Society. Studies were performed in isolated blood-perfused hearts obtained from four New Yorkshire pigs (age, 6 to 8 weeks; weight, 18 to 26 kg) and nine mature mongrel dogs (weight, 18 to 32 kg).
Experimental Preparation
The methods of preparation and perfusion of isolated hearts have been described previously.2 5 In short, animals were premedicated with azaperon (12 mg/kg IM) and atropine (500 µg IM) and then anesthetized with sodium pentobarbital (35 mg/kg IV) and metomidaat (5 mg/kg IV). After excision, the heart was perfused with a mixture of blood and Tyrode's solution through a cannula placed in the aortic root. The temperatures of the endocardium and coronary sinus effluent were monitored and maintained at 37.0°C to 37.5°C by warming of the perfusate and partly surrounding the heart in a heating jacket. Access to the right atrial cavity was through an incision running from the inferior to the superior vena cava. The left atrium was opened by an incision running from one of the pulmonary veins to the base of the left atrial appendage. Extracellular recording electrodes were placed near the His bundle and at various sites on the atrial endocardium (see below). The sinus node was excised, and isoproterenol (0.5 to 1.5 µg/min) was infused in some preparations to facilitate the demonstration of VA conduction.
Microelectrode Recordings
Recordings were made with microelectrodes with tip resistances of 15 to 30 M
. The indifferent electrode consisted of a fine silver wire coated with silver chloride, the tip of which was placed in the thin layer of fluid covering the endocardium, as close to the microelectrode as possible. Maximum action potential upstroke velocity (dV/dtmax) was measured with a continuous analog differentiator. Diacetyl monoxime (final concentration, 10 to 15 mmol/L) was added to the perfusate to dampen cardiac contraction to decrease the chance that the microelectrode tip would break and to help maintain cellular impalement. Diacetyl monoxime 10 to 20 mmol/L has a marked negatively inotropic effect but has little effect on the action potential.6
Microelectrode recordings were made around the tricuspid annulus alone (n=4), the mitral annulus alone (n=4), or both mitral and tricuspid annuli (n=2). In all cases, a blunt probe was placed under the AV valve to determine the point of reflection of the valve from the ventricular endocardium. A pin was then placed through the valve at the point of reflection to serve as a reference for recordings and as a marker for subsequent anatomical studies. Then, sites on the atrial side of the pin were examined. These recordings were made at intervals of 1 to 2 mm along a line perpendicular to the valve annulus, extending 13 to 15 mm from the annulus. Several cells were impaled at each site. The recording sites were in the posterolateral, lateral, or anterior regions of the valve rings. After completion of this protocol, recordings were made at random sites around the valve ring to confirm that the findings were representative of the entire preparation.
To study the effect of adenosine on the action potentials, a stable microelectrode impalement was obtained; then, 5 mg adenosine was administered through the aortic cannula. This dose was chosen because it reliably induced complete heart block lasting 20 to 180 seconds. We attempted to maintain the impalement until the action potential had returned to the baseline value. The effect of adenosine was studied in 5 atrial cells, 10 intermediate cells, and 5 nodal-type cells (see below).
Signals from the microelectrode and extracellular signals were recorded with an eight-channel thermal array recorder at paper speeds of 200 mm/s and were digitized (14-bit accuracy) and recorded with an eight-channel DAT recorder (DTR 1801, Biologic).
Histology
Blocks were cut from the left and right AV valve rings at the sites of microelectrode recordings. In addition, blocks were cut from two or three other sites around the AV valve rings. Sections of 5 µm were cut perpendicular to the AV valve ring and stained with hematoxylin and eosin, elastic van Gieson's, and acid phosphotungstic stains and were examined with light microscopy.
Staining for Connexin-43
Staining for connexin-43 was performed in five dog hearts. The methods were described previously.7 In brief, polyclonal antibodies were raised in rabbits against an oligopeptide corresponding to amino acids 314 through 322 of the connexin-43 molecule. Specimens from the AV junction were fixed for 2 to 12 hours in a methanol-acetone-water mixture, dehydrated in a graded series of ethanol followed by chloroform, and then embedded in Paraplast Plus (Monoject). Sections of 7 to 15 µm were cut, and after deparaffination, immunologic staining was performed by use of the unconjugated peroxidase method.8
Statistical Analysis
Values are expressed as mean±SEM. The effects of adenosine on action potential characteristics were assessed with a paired t test.
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Results |
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Electrophysiological Properties of AV Junctional Cells
In all hearts, cells with nodal-like electrophysiological properties were found around the mitral and tricuspid valve annuli (Figs 1
and 2). These cells had the following properties: low resting membrane potentials of between -55 and -65 mV, dV/dtmax of <5 V/s, low action potential amplitude of between 45 and 65 mV with little or no overshoot, and postrepolarization refractoriness (ie, extrastimuli delivered after repolarization of the preceding beat resulted in the action potential of the extra beat having decreased amplitude and upstroke velocity). These cells also demonstrated Wenckebach-type behavior in response to rapid atrial pacing. Phase 4 depolarization was found in approximately half of these cells, and in some cells the upstroke of the action potential had multiple components similar to that described previously in AV nodal cells.9
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As the microelectrode was moved away from the AV annulus, the characteristics of the action potentials changed gradually over a distance of 1 cm, becoming more atrial-like (Fig 2). A similar change from nodal-type action potentials to atrial-type action potentials was found at the AV annulus if the microelectrode was driven deep to the endocardium. Nodal-type action potentials were found close to the endocardial surface; intermediate-type action potentials, in the subendocardial layers; and atrial-type action potentials, in the deeper layers.
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Effect of Adenosine on AV Junctional Cells
The Table and Fig 3 summarize the effect of adenosine on atrial and AV junctional cells. In atrial cells, adenosine caused no significant change in action potential dV/dtmax, amplitude, or maximum diastolic potential but caused a significant reduction in action potential duration. In AV junctional cells with nodal-like action potentials and baseline dV/dtmax of <5 V/s, adenosine decreased dV/dtmax, amplitude, and action potential duration but did not alter the maximum diastolic potential. In cells with intermediate action potentials (dV/dtmax of 5 to 60 V/s in the baseline state), adenosine decreased action potential amplitude and duration, increased dV/dtmax, and made the maximum diastolic potential more negative.
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Histology
In the region of the AV valve rings, cells were separated by greater amounts of intercellular connective tissue than in the body of the atrium. The amount of connective tissue increased progressively as the valve leaflet was approached. The shapes, sizes, and arrangements of myocytes from sites around the AV valve rings were similar to those of cells in the body of the atrium except at two sites: the region surrounding the AV node and the anterior part of the tricuspid annulus. Myocytes in the region close to the AV node were typical of nodal and transitional cells as described previously.10 11 In the anterior region of the tricuspid annulus, myocytes were arranged in a whorled or basketlike configuration similar to that of the compact node10 rather than in sheets as found elsewhere in the atria.
Staining for Connexin-43
Ventricular myocardium and the body and upper part of the atrial myocardium stained positively for connexin-43 (Fig 4). In Fig 4, the specificity of the immunoreaction is apparent from the localized staining in the sarcolemma and the absence of staining of connective tissue. Connexin-43 was absent from the 2 mm of atrial tissue closest to the valve annulus, particularly on the endocardial surface, but became more abundant as the distance from the valve annulus increased. The absence of connexin-43 correlated with the position of the cells with most nodal-like action potentials, whereas regions with more abundant connexin-43 revealed cells with atrial-type action potentials (Fig 4). In regions with intermediate amounts of connexin-43, action potentials were intermediate between nodal and atrial types.
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Extracellular Signals From AV Junctional Tissue
In all preparations, it was possible to record extracellular potentials from the AV junctional tissue in the posterior approaches to the AV node as described previously.1 2 Typically, these potentials were of low amplitude (0.1 to 0.5 mV) and low frequency as described previously,1 2 although in one heart they were of much larger amplitude (Fig 5). Rapid pacing or premature stimuli decreased the frequency and amplitude of the signal as described previously.1 2 In three preparations, it was possible to record extracellular potentials from the AV junctional tissue even when the nearby atrial tissue was not activated (Fig 5).
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Relation of AV Junctional Tissue Activation to Slow Pathway Conduction
During atrial pacing, premature atrial stimuli that were conducted to the His-Purkinje system and ventricle sometimes were not conducted to the nodal tissue in the slow pathway region, indicating that this tissue could be dissociated from the His-Purkinje system and the ventricle (Fig 6).
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Anterograde dual AV nodal pathways as defined by discontinuous AV conduction curves were not demonstrable in any animal, but it was possible to induce AV nodal echoes with ventricular pacing in three dogs (Fig 7). These echoes used a slow pathway for retrograde conduction and a fast pathway for anterograde conduction because the HA interval was considerably longer than the AH interval. The site of the earliest atrial activation during retrograde slow pathway conduction was posterior to the AV node near the coronary sinus orifice. In all cases, it was necessary to attain a critical delay in the HA interval before echoes were elicited, and in all cases the HV interval during the anterograde limb of the echo beat was identical to the HV interval of sinus beats or atrial paced beats, indicating that the anterograde limb of the circuit used the AV node-His-Purkinje system for anterograde conduction. During echoes, the nodal-type tissue in the region between the coronary sinus and tricuspid annulus was activated before the earliest atrial activation during the retrograde limb of the echo but was not activated during the anterograde limb of the circuit (Fig 7). In no case could echo beats be elicited if the retrograde impulse was blocked proximal to the nodal-type tissue in the region between the coronary sinus and tricuspid annulus.
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Discussion |
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The presence of cells with nodal- or transitional-type action potentials in the AV valves has been documented.3 4 12 The aim of the present study was to describe the electrophysiological and anatomic features of the AV junctional tissue and to examine its relation to the AV node. In a previous study, we demonstrated that a sleeve of nodal-type tissue was present around the tricuspid annulus and that activation of part of this tissue, in the posterior approaches to the AV node, coincided spatially and temporally with "slow pathway potentials" in the extracellular electrogram.2 In the present study, we have demonstrated that a similar sleeve of nodal-type tissue is present around the mitral annulus. Except in the perinodal region, the AV junctional tissue has histological characteristics similar to those of atrial tissue, but the cellular electrophysiology is similar to nodal tissue (Fig 8
). Like the AV node,13 the AV junctional tissue responds to adenosine with a reduction in action potential amplitude and dV/dtmax. Like the sinus and AV nodes and unlike working myocardium, the AV junctional tissue is devoid of significant amounts of connexin-43.14
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What Is the Function of the AV Junctional Tissue?
The physiological function of AV junctional cells with nodal characteristics is unknown, but they probably perform no useful function in adult mammals and are merely remnants of embryological structures. In normal adult mammalian hearts, the atria are electrically insulated from the ventricles by fibrous tissue except at the site of the AV node. Slow conduction in the AV node results in AV delay. In lower vertebrates, however, the myocardial cells that make up the AV junction are in electric continuity with atria and ventricles, and the AV delay depends on the properties of the AV junctional cells themselves. In the embryonic mammal heart, AV delay is present before the AV node has developed; this is caused by slow conduction in the AV junction.15 In these cells, as in the AV node, slow conduction results from a lack of fast sodium channels15 and a relative lack of the gap junctional protein connexin-43.7 This entire AV junctional region later is incorporated into the atria and forms their lower rim. This has been demonstrated with molecular cell markers used to distinguish the individual components of the developing heart.16 The present study shows that the myocardium of the AV junction has maintained some of its original electric and molecular characteristics.
The presence of these cells may also explain why in certain congenital cardiac abnormalities, eg, corrected transposition of the great arteries, a normally functioning AV node may be present at sites distant from the usual site of the AV node. In these cases, the presence of nodal-type cells in the AV junctional tissue presumably results in the ectopic AV connection having nodal-type properties.
Is the AV Junctional Tissue in the Posterior Approaches to the AV Node the Substrate of the Slow AV Nodal Pathway?
The AV junctional tissue is found in the posterior AV nodal approaches close to the tricuspid annulus. Mapping and catheter ablation studies indicate that this also is the site of the slow "AV nodal" pathway.1 17 18 19 20 21 22 23 Slow pathway potentials have been used successfully to guide the delivery of radiofrequency energy to ablate the slow pathway.1 21 Depolarization of the AV junctional tissue in this region coincides temporally with the slow component of slow pathway potentials.2 The AV junctional cells in the posterior nodal approaches have nodal-like action potentials and thus have the characteristics necessary for slow conduction. Adenosine suppresses conduction in both the slow pathway and the AV junctional cells. The AV junctional cells in the posterior nodal approaches are in electric continuity with the atria and AV node but can be electrically dissociated from the atria and the AV node fast pathway through pacing techniques. Moreover, these AV junctional cells are depolarized before the earliest atrial activation during retrograde slow pathway conduction but are not depolarized during anterograde fast pathway conduction. Thus, it is possible that these cells are the substrate of the slow pathway. We cannot prove, however, that this is the case because it is possible that the AV junctional cells are merely bystander cells that do not participate in slow pathway conduction. The location and electrophysiological properties of this tissue and its relation to slow pathway conduction, however, suggest that it is a likely candidate for the substrate of the slow pathway.
Our observation that the AV junctional cells in the posterior approaches to the AV node have a longer refractory period than the anterior input to the AV node (fast pathway) during anterograde conduction is not inconsistent with the possibility that they are the slow pathway. Many humans and animals with retrograde dual pathways do not have evidence of anterograde dual pathways.24 25 In these cases, the slow pathway presumably cannot be identified because it has a refractory period equal to or longer than the fast pathway during anterograde conduction. In all of our preparations with dual retrograde pathways, the refractory period of the AV junctional tissue in the posterior exit from the AV node was shorter than in the anterior or fast pathway exit during retrograde conduction.
The AV junctional cells may play a role in the genesis of other cardiac arrhythmias. Automaticity has been demonstrated in these cells, and slow conduction near the AV junction may play a role in other reentrant arrhythmias such as atrial flutter.26 In contrast to our finding of cells with nodal-type action potentials, Frame and coworkers27 found "fast-response"–type action potentials in cells around the tricuspid ring in a dog model of atrial flutter. The reasons for this difference in findings are unclear, but it is possible that Frame et al impaled cells further from the tricuspid annulus.
Study Limitations and Unanswered Questions
As discussed above, we cannot be certain that the AV junctional tissue in the posterior nodal approaches is the substrate of the slow pathway. Correlation of AV junctional tissue activation with anterograde slow pathway conduction might be helpful in this respect, but we were unable to find an animal with demonstrable dual anterograde AV nodal pathways. One possible reason is that the refractory period of the anterograde fast pathway was equal to or less than the refractory period of the anterograde slow pathway in all cases.
During retrograde slow pathway conduction, the earliest atrial excitation occurs near the coronary sinus orifice, 5 to 10 mm from the posterior limit of the compact AV node. If the AV junctional tissue is the substrate of the slow pathway, it is unclear why excitation travels within this tissue for some distance before breaking through to the atrium. There appears to be no anatomic barrier or separation between the AV junctional tissue and the nearby atrial tissue at sites between the AV node and coronary sinus orifice. It is possible that atrial cells and AV junctional cells are not well coupled in this region and that the absence of the gap junctional protein connexin-43 demonstrated in the present study may be a reflection of this poor coupling.
What Is the AV Node?
The current study raises questions that cannot be answered by traditional models of the AV node. The AV node cannot be defined as the region in which AN- and N-type action potentials11 are found because cells with similar action potentials are found around the entire mitral and tricuspid valve annuli. Moreover, the cells with nodal-type action potentials in the tricuspid annulus (and possibly those in the mitral annulus) appear to be contiguous and continuous with cells with nodal-type action potentials in the anatomic region of the traditional AV node. Nor does it appear that light microscopy is accurate at defining what AV nodal tissue is because the AV junctional cells have nodal-type action potentials but appear to be similar to atrial cells.
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Acknowledgments |
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Dr McGuire was supported in part by a Neil Hamilton Fairley Fellowship of the National Health and Medical Research Council of Australia, Woden, Australia. Dr Thibault is supported by a fellowship from the McLaughlin Foundation, Toronto, Ontario, Canada. P. Loh is supported by a fellowship from the Deutsche Forschungsgemeinschaft, Bonn, Germany. We wish to thank Charly Belterman for technical assistance and Dr D. Gros of Marseilles, France, for supplying the polyclonal antibody.
Received August 29, 1995; revision received January 16, 1996; accepted January 22, 1996.
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References |
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W. M.H Hoogaars, A. Tessari, A. F.M Moorman, P. A.J de Boer, J. Hagoort, A. T Soufan, M. Campione, and V. M Christoffels The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart Cardiovasc Res, June 1, 2004; 62(3): 489 - 499. [Abstract] [Full Text] [PDF]
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H. Dobrzynski, V. P. Nikolski, A. T. Sambelashvili, I. D. Greener, M. Yamamoto, M. R. Boyett, and I. R. Efimov Site of Origin and Molecular Substrate of Atrioventricular Junctional Rhythm in the Rabbit Heart Circ. Res., November 28, 2003; 93(11): 1102 - 1110. [Abstract] [Full Text] [PDF]
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P. Loh, S. Y. Ho, T. Kawara, R. N.W. Hauer, M. J. Janse, G. Breithardt, and J. M.T. de Bakker Reentrant Circuits in the Canine Atrioventricular Node During Atrial and Ventricular Echoes: Electrophysiological and Histological Correlation Circulation, July 15, 2003; 108(2): 231 - 238. [Abstract] [Full Text] [PDF]
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V. P. Nikolski, S. A. Jones, M. K. Lancaster, M. R. Boyett, and I. R. Efimov Cx43 and Dual-Pathway Electrophysiology of the Atrioventricular Node and Atrioventricular Nodal Reentry Circ. Res., March 7, 2003; 92(4): 469 - 475. [Abstract] [Full Text] [PDF]
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J. Kautzner, R. Cihák, V. Vancura, and J. Bytesník Coincidence of idiopathic ventricular outflow tract tachycardia and atrioventricular nodal reentrant tachycardia Europace, January 1, 2003; 5(3): 215 - 220. [Abstract] [Full Text] [PDF]
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S. Iwai, S. M. Markowitz, K. M. Stein, S. Mittal, D. J. Slotwiner, M. K. Das, J. D. Cohen, S. C. Hao, and B. B. Lerman Response to Adenosine Differentiates Focal From Macroreentrant Atrial Tachycardia: Validation Using Three-Dimensional Electroanatomic Mapping Circulation, November 26, 2002; 106(22): 2793 - 2799. [Abstract] [Full Text] [PDF]
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D. Franco and J. M. Icardo Molecular characterization of the ventricular conduction system in the developing mouse heart: topographical correlation in normal and congenitally malformed hearts Cardiovasc Res, February 1, 2001; 49(2): 417 - 429. [Abstract] [Full Text] [PDF]
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D. Medkour, A. E. Becker, K. Khalife, and J. Billette Anatomic and Functional Characteristics of a Slow Posterior AV Nodal Pathway : Role in Dual-Pathway Physiology and Reentry Circulation, July 14, 1998; 98(2): 164 - 174. [Abstract] [Full Text] [PDF]
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