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Most embryonic ventricular cardiomyocytes are quite uniform, in contrast to the adult heart, where the specialized ventricular conduction system is molecularly and functionally distinct from the working myocardium. We thus hypothesized that the preferential conduction pathway within the embryonic ventricle could be dictated by trabecular geometry. Mouse embryonic hearts of the Nkx2.5:eGFP strain between ED9.5 and ED14.5 were cleared and imaged whole mount by confocal microscopy, and reconstructed in 3D at 3.4 μm isotropic voxel size. The local orientation of the trabeculae, responsible for the anisotropic spreading of the signal, was characterized using spatially homogenized tensors (3 × 3 matrices) calculated from the trabecular skeleton. Activation maps were simulated assuming constant speed of spreading along the trabeculae. The results were compared with experimentally obtained epicardial activation maps generated by optical mapping with a voltage-sensitive dye. Simulated impulse propagation starting from the top of interventricular septum revealed the first epicardial breakthrough at the interventricular grove, similar to experimentally obtained activation maps. Likewise, ectopic activation from the left ventricular base perpendicular to dominant trabecular orientation resulted in isotropic and slower impulse spreading on the ventricular surface in both simulated and experimental conditions. We conclude that in the embryonic pre-septation heart, the geometry of the A-V connections and trabecular network is sufficient to explain impulse propagation and ventricular activation patterns. [ABSTRACT FROM AUTHOR]

Abstract: Background: Coexistence of idiopathic left fascicular ventricular tachycardia (ILFVT) and atrioventricular nodal reentrant tachycardia (AVNRT) has been rarely reported. Objectives: The study aimed at elucidating the prevalence of coexisted AVNRT in patients with ILFVT during longitudinal follow‐up. The electrophysiological properties and clinical predictors of coexisted ILFVT and AVNRT were investigated. Methods: From 1999 to 2017, a total of 108 patients (age: 33.7 ± 14.3, 84 male) with ILFVT from one tertiary center were consecutively enrolled. The prevalence of coexisted arrhythmias was explored during a longitudinal follow‐up and the electrophysiological parameters from the index procedure were compared. Results: During a mean follow‐up period of 106.8 ± 69.5 months, 21 of 108 patients (19.4%) had coexisted AVNRT. The electrophysiological study demonstrated patients with coexisted ILFVT and AVNRT were characterized by more antegrade dual AV node conduction (52.4% vs. 19.5%, P = 0.002; 9.5%), shorter antegrade slow pathway effective refractory period (285.1 ± 34.1 ms vs. 329.2 ± 69.2 ms, P = 0.034), longer retrograde fast pathway effective refractory period (368.9 ± 56.7 ms vs. 312.5 ± 95.2, P = 0.036), and less VA dissociation (19.0% vs. 60.9%, P = 0.001) than those without a coexisted AVNRT. Multivariate logistic analysis showed that presence of antegrade dual AV nodal physiology and retrograde VA conduction could predict a coexisted AVNRT in patients with ILFVT (P = 0.005, OR: 4.80, 95% CI: 1.65–14.37 and P = 0.002, OR: 0.14, 95% CI: 0.04–0.49, respectively). Conclusion: There was a high prevalence of coexisted AVNRT in patients with ILFVT during longitudinal follow‐up. The presence of antegrade dual AV nodal physiology and retrograde VA conduction can predict the coexisted AVNRT in patients with ILFVT. [ABSTRACT FROM AUTHOR]

The components of the cardiac conduction system (CCS) generate and propagate the electrical impulse that initiates cardiac contraction. These interconnected components share properties, such as automaticity, that set them apart from the working myocardium of the atria and ventricles. A variety of tools and approaches have been used to define the CCS lineages. These include genetic labeling of cells expressing lineage markers and fate mapping of dye labeled cells, which we will discuss in this review. We conclude that there is not a single CCS lineage, but instead early cell fate decisions segregate the lineages of the CCS components while they remain interconnected. The latter is relevant for development of therapies for conduction system disease that focus on reprogramming cardiomyocytes or instruction of pluripotent stem cells. [ABSTRACT FROM AUTHOR]

The morpho-functional properties of the distal section of the cardiac Purkinje network (PN) and the Purkinje-myocardial junctions (PMJs) are fundamental to understanding the sequence of electrical activation in the heart. The overall structure of the system has already been described, and several computational models have been developed to gain insight into its involvement in cardiac arrhythmias or its interaction with implantable devices, such as pacemakers. However, anatomical descriptions of the PN in the literature have not enabled enough improvements in the accuracy of anatomical-based electrophysiological simulations of the PN in 3D hearts models. In this work, we study the global distribution and morphological properties of the PN, with special emphasis on the cellular and architectural characterization of its intramural branching structure, mesh-like sub-endocardial network, and the PMJs in adult pig hearts by both histopathological and morphometric evaluation. We have defined three main patterns of PMJ: contact through cell bodies, contact through cell prolongations either thick or piliform, and contact through transitional cells. Moreover, from hundreds of micrographs, we quantified the density of PMJs and provided data for the basal/medial/apical regions, anterior/posterior/septal/lateral regions and myocardial/sub-endocardial distribution. Morphometric variables, such as Purkinje cell density and thickness of the bundles, were also analyzed. After combining the results of these parameters, a different septoanterior distribution in the Purkinje cell density was observed towards the cardiac apex, which is associated with a progressive thinning of the conduction bundles and the posterolateral ascension of intramyocardial terminal scattered fibers. The study of the PMJs revealed a decreasing trend towards the base that may anatomically explain the early apical activation. The anterolateral region contains the greatest number of contacts, followed by the anterior and septal regions. This supports the hypothesis that thin distal Purkinje bundles create a junction-rich network that may be responsible for the quick apical depolarization. The PN then ascends laterally and spreads through the anterior and medial walls up to the base. We have established the first morphometric study of the Purkinje system, and provided quantitative and objective data that facilitate its incorporation into the development of models beyond gross and variable pathological descriptions, and which, after further studies, could be useful in the characterization of pathological processes or therapeutic procedures. [ABSTRACT FROM AUTHOR]

An editorial is presented on Atrioventricular (AV) discordance, is an uncommon form of congenital heart disease. The right atrium is connected to the morphological left ventricle through the mitral valve and the left atrium to the morphologically right ventricle through the tricuspid valve. Ventricle and mitral valve are located to the right and connected to the pulmonary artery.

The specialised conducting tissues present in the ventricles are responsible for the fast distribution of the electrical impulse from the atrio-ventricular node to regions in the subendocardial myocardium. Characterisation of anatomical features of the specialised conducting tissues in the ventricles is highly challenging, in particular its most distal section, which is connected to the working myocardium via Purkinje-myocardial junctions. The goal of this work is to characterise the architecture of the distal section of the Purkinje network by differentiating Purkinje cells from surrounding tissue, performing a segmentation of Purkinje fibres at cellular scale, and mathematically describing its morphology and interconnections. Purkinje cells from rabbit hearts were visualised by confocal microscopy using wheat germ agglutinin labelling. A total of 16 3D stacks including labeled Purkinje cells were collected, and semi-automatically segmented. State-of-the-art graph metrics were applied to estimate regional and global features of the Purkinje network complexity. Two types of cell types, tubular and star-like, were characterised from 3D segmentations. The analysis of 3D imaging data confirms the previously suggested presence of two types of Purkinje-myocardium connections, a 2D interconnection sheet and a funnel one, in which the narrow side of a Purkinje fibre connect progressively to muscle fibres. The complex network analysis of interconnected Purkinje cells showed no small-world connectivity or assortativity properties. These results might help building more realistic computational PK systems at high resolution levels including different cell configurations and shapes. Better knowledge on the organisation of the network might help in understanding the effects that several treatments such as radio-frequency ablation might have when the PK system is disrupted locally. [ABSTRACT FROM AUTHOR]

Editorial. Discusses the development of the cardiac conduction system. Molecular analysis of cardiac morphogenesis; Expression of beta-galactosidase reporter gene in the developing or mature cardiac conduction systems; Patterns of contractile activity.

In the mammalian heart a conduction system of nodes and conducting cells generates and transduces the electrical signals evoking myocardial contractions. Specialized pacemaker cells initiating and controlling cardiac contraction rhythmicity are localized in an anatomically identifiable structure of myocardial origin, the sinus node. We previously showed that in mammalian embryos sinus node cells originate from cardiac progenitors expressing the transcription factors T-box transcription factor 3 (Tbx3) and Islet-1 (Isl1). Although cardiac development and function are strikingly conserved amongst animal classes, in lower vertebrates neither structural nor molecular distinguishable components of a conduction system have been identified, questioning its evolutionary origin. Here we show that zebrafish embryos lacking the LIM/ homeodomain-containing transcription factor Isl1 display heart rate defects related to pacemaker dysfunction. Moreover, 3D reconstructions of gene expression patterns in the embryonic and adult zebrafish heart led us to uncover a previously unidentified, Isl1-positive and Tbx2b-positive region in the myocardium at the junction of the sinus venosus and atrium. Through their long interconnecting cellular protrusions the identified Isl1-positive cells form a ring-shaped structure. In vivo labeling of the Isl1-positive cells by transgenic technology allowed their isolation and electrophysiological characterization, revealing their unique pacemaker activity. In conclusion we demonstrate that Isl1-expressing cells, organized as a ring-shaped structure around the venous pole, hold the pacemaker function in the adult zebrafish heart. We have thereby identified an evolutionary conserved, structural and molecular distinguishable component of the cardiac conduction system in a lower vertebrate. [ABSTRACT FROM AUTHOR]

In the adult heart, electrophysiological heterogeneity is present to guide activation and contraction. A change in electrophysiological heterogeneity, for example, during disease, can contribute to arrhythmogenesis. During development, spatial and temporal patterns of transcriptional activity regulate the localized expression of ion channels that cause electrophysiological heterogeneity throughout the heart. If we gain insight into the regulating processes that generate the electrophysiological characteristics and factors involved during development, we can use this knowledge in the search for new therapeutic targets. In this review, we discuss which factors guide the electrical patterning of atrioventricular conduction system and ventricles and how this patterning relates to arrhythmogenic disease in patients. [ABSTRACT FROM AUTHOR]

The ventricular conduction system represents the electrical wiring responsible for the co-ordination of cardiac contraction. Defects in the circuit produce a delay or conduction block and induce cardiac arrhythmias. Understanding how this circuit forms and identification of the factors important for its development thus provide insights into the origin of cardiac arrhythmias. Recent advances, using genetically modified mouse models, have contributed to our understanding of how the ventricular conduction system is established during heart development. Transgenic mice carrying different reporter genes have highlighted the conservation of the anatomy and development of the ventricular conduction system between mice and humans. Lineage tracing and retrospective clonal analysis have established the myogenic origin of the ventricular conduction system and determined properties of conductive progenitor cells. Finally, gene knock-out models reproducing human cardiac defects have led to the identification of transcription factors important for the development of the ventricular conduction system. These transcription factors operate at the levels of both conduction system morphogenesis and differentiation by controlling the expression of genes responsible for the electrical activity of the heart. In summary, defects in the ventricular conduction system are a major cause of arrhythmias, and deciphering the molecular pathways responsible for conduction system morphogenesis and the differentiation of conductive myocytes furthers our understanding of the mechanisms underlying heart disease. [ABSTRACT FROM AUTHOR]

This study examined the atrioventricular conducting system in 4 adult male hedgehogs (Hemiechinus auritus). The histological structure of these components was studied using routine histological methods. The AVN was located at the lower and anterior part of the interatrial septum, near the root of the aorta. It was almost oval and consisted of twisted cells. Internodal pathways in the hedgehog heart were not observed, but there were numerous purkinje-like fibers within the myocardium of the atrium. The AVB was a continuation of the AVN, as a compact structure, extended obliquely through the fibrous ring toward the apex of the interventricular septum, and was composed of many purkinje cells. [ABSTRACT FROM AUTHOR]

We have examined sino-atrial node (SAN) function in hearts from adult mice with heterozygous targeted disruption of the Scn5a gene to clarify the role of Scn5a-encoded cardiac Na+ channels in normal SAN function and the mechanism(s) by which reduced Na+ channel function might cause sinus node dysfunction. Scn5a+/− mice showed depressed heart rates and occasional sino-atrial (SA) block. Their isolated peripheral SAN pacemaker cells showed a reduced Na+ channel expression and slowed intrinsic pacemaker rates. Wild-type (WT) and Scn5a+/− SAN preparations exhibited similar activation patterns but with significantly slower SA conduction and frequent sino-atrial conduction block in Scn5a+/− SAN preparations. Furthermore, isolated WT and Scn5a+/− SAN cells demonstrated differing correlations between cycle length, maximum upstroke velocity and action potential amplitude, and cell size. Small myocytes showed similar, but large myocytes reduced pacemaker rates, implicating the larger peripheral SAN cells in the reduced pacemaker rate that was observed in Scn5a+/− myocytes. These findings were successfully reproduced in a model that implicated iNa directly in action potential propagation through the SAN and from SAN to atria, and in modifying heart rate through a coupling of SAN and atrial cells. Functional alterations in the SAN following heterozygous-targeted disruption of Scn5a thus closely resemble those observed in clinical sinus node dysfunction. The findings accordingly provide a basis for understanding of the role of cardiac-type Na+ channels in normal SAN function and the pathophysiology of sinus node dysfunction and suggest new potential targets for its clinical management. [ABSTRACT FROM AUTHOR]

Mechanisms of cardiac pacemaking and conduction system (CPCS) development are difficult to study, in part because of the absence of models that are physiologically similar to humans in which we can label the entire CPCS. Investigations of the adult rabbit heart have provided insight into normal and abnormal cardiac conduction. The adult and the embryonic rabbit have an endogenous marker of the entire cardiac conduction system, neurofilament 160 (NF-160). Previous work suggested that ventricular septation correlates with critical phases in avian CPCS development, in contrast to the mouse CPCS. Combining high-resolution optical mapping with immunohistochemical analysis of the embryonic rabbit heart, we investigated the significance of ventricular septation in patterning the rabbit embryonic conduction system. We hypothesized that I) completion of ventricular septation does not correlate with changes in the ventricular activation sequence in rabbit embryos and 2) CPCS anatomy determines the activation sequence of the embryonic heart. We found that preseptated (days 11–13, n = 13) and post-septated (day 15, n = 5) hearts had similar ‘apex-to-base’ ventricular excitation. PR intervals were not significantly different in either group. CPCS anatomy revealed continuity of the NF-160-positive tract connect ing the presumptive sinoatrial node, atrioventricular (AV) junction, and ventricular conduction system. The presence of collagen in the AV junction coincided with the appearance of an AV interval. We conclude that the apex-to-base ventricular activation sequence in the rabbit embryo is present before completion of ventricular septation. CPCS anatomy reflects global cardiac activation as demonstrated by high-resolution optical mapping. [ABSTRACT FROM AUTHOR]

Congenital aneurysm of the membranous portion of the ventricular septum in association with absence of atrioventricular valve 'offsetting' was diagnosed in two fetuses at 29 and 34 weeks. In the first case the fetus had a normal karyotype and no other structural heart defects, whereas in the second case there was a partial deletion of the long arm of chromosome 5 and an absent pulmonary valve syndrome. The association of absence of 'offsetting' with aneurysms of the membranous ventricular septum may represent spontaneous closure of ventricular septal defects initially extended to the inlet. [ABSTRACT FROM AUTHOR]

Attempts to synthesize results from computer simulations and experimental preparations to define the mechanisms and biophysical principles that govern normal and abnormal conduction in the heart. Action potential generation by the single cardiac cell; Fundamental biophysical principles of propagation; Mechanism of slow conduction; Mechanisms of unidirectional conduction block; Basic principles of circulating excitation and reentry.

Zebrafish and Xenopus have become popular model organisms for studying vertebrate development of many organ systems, including the heart. However, it is not clear whether the single ventricular hearts of these species possess any equivalent of the specialized ventricular conduction system found in higher vertebrates. Isolated hearts of adult zebrafish (Danio rerio) and African toads (Xenopus laevis) were stained with voltage-sensitive dye and optically mapped in spontaneous and paced rhythms followed by histological examination focusing on myocardial continuity between the atrium and the ventricle. Spread of the excitation wave through the atria was uniform with average activation times of 20 ± 2 and 50 ± 2 ms for zebrafish and Xenopus toads, respectively. After a delay of 47 ± 8 and 414 ± 16 ms, the ventricle became activated first in the apical region. Ectopic ventricular activation was propagated significantly more slowly (total ventricular activation times: 24 ± 3 vs. 14 ± 2 ms in zebrafish and 74 ± 14 vs. 35 ± 9 ms in Xenopus). Although we did not observe any histologically defined tracts of specialized conduction cells within the ventricle, there were trabecular bands with prominent polysialic acid-neural cell adhesion molecule staining forming direct myocardial continuity between the atrioventricular canal and the apex of the ventricle; i.e., the site of the epicardial breakthrough. We thus conclude that these hearts are able to achieve the apex-to-base ventricular activation pattern observed in higher vertebrates in the apparent absence of differentiated conduction fascicles, suggesting that the ventricular trabeculae serve as a functional equivalent of the HisPurkinje system. [ABSTRACT FROM AUTHOR]

minK-lacZ in the Embryonic Mouse Heart. Introduction: Due to the lack of good molecular markers, for decades the morphogenetic origin of the cardiac conduction system has been a matter of debate. More recently, the spatial expression of minK-lacZ in the adult mouse heart has been shown, for the larger part, to be coincident with the conduction tissues. Methods and Results: To trace the embryonic development of this system, we performed an analysis of the expression of this construct throughout early cardiac development. Expression was first seen at the eighth embryonic day. Subsequently, discrete rings were found at the sinuatrial, atrioventricular, interventricular, and ventriculoarterial junctions. With time, the expression became restricted to boundary regions of the heart, such as the hinges of the leaflets of the pulmonary and aortic valves, the atrioventricular rings, and the venous valves, as well as becoming incorporated into the definitive conduction tissues themselves. In the postnatal heart, the areas retaining minK-lacZ positivity outside of the definitive conduction tissues are known to be the site of origin of abnormal cardiac rhythms, suggesting that ectopic foci may derive from tissues that share a common developmental pathway with the definitive conduction system. Conclusion: Our findings suggest that the boundary regions between compartments, along with the atrioventricular conduction axis, share a common developmental pathway.(J Cardiovasc Electrophysiol, Vol. 14, pp. 383-391, April 2003). [ABSTRACT FROM AUTHOR]

Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena. [ABSTRACT FROM AUTHOR]

Studies the mechanism of atrioventricular (AV) node reentry. Perspectives pertaining to future refinement of the technical aspects involved in the ablative treatment of AV node reentrant tachycardia; Anatomical characteristics of the AV junction and AV node; Cellular electrophysiology characteristics of the AV node; Tissue components of the AV node reentrant circuit.

Anatomy of Cardiac Nodes. Concomitant with the development or catheter ablation techniques for the treatment of atrial arrhythmias, there is renewed interest In the morpho- logic arrangement of the cardiac conduction system. In this article, we revisit the anatomy of the specialized tissues, making special reference to the descriptions given at the time of their discovery. According to criteria for histologic distinction of morphologically specialized tracts set nearly 100 years ago, the penetrating bundle (of His) and the ventricular bundle branches arc tracts of specialized cells encased by insulating sheaths of fibrous tissue. In contrast, the sinus and AX nodes are recognized histologically but are not insulated from the working atrial myocardium. At its distal extent, the AX node is distinguished from the penetrating bundle not so much by cellular characteristics, but by the presence of a fibrous collar that surrounds the specialized cells. At the atrial part, a zone of histologically transitional cells interposes between the compact node and the working atrial myocardium. Transitional cells enter the triangle of Koch to join the compact node from superiorly, inferiorly, posteriorly, and from the left. Transitional cells of the sinus node, in contrast, are limited to short tongues that interdigitate with musculature of the terminal crest. Apart from a variable extension of Its tail, there are no prominent histologically discrete extensions from the sinus node into the working atrial musculature. The internodal myocardium does not contain discrete conducting tracts comparable with the ventricular bundle branches. Preferential conduction more likely reflects the arrangement of the working internodal cells and their related cellular properties. [ABSTRACT FROM AUTHOR]

Introduction: To elucidate the role of tissue structure as a determinant of the unique conduction properties of the sinus node, we compared the spatial distribution of intercellular connections at gap junctions in the sinus node to the more rapidly conducting crista terminalis and left ventricle, which have been studied previously. Methods and Results: Samples of four canine sinus nodes were prepared for electron microscopy. The total number and spatial orientation of neighboring myocytes connected by ultrastructurally identified intercalated disks and gap junctions to nine randomly selected index cells were determined by sequentially examining subserial sections. Sinus node cells were sparsely interconnected compared to the extent of interconnections observed previously in other tissues. A typical sinus node cell was connected to only 4.8 ± 0.7 neighbors compared with 11.3 ± 2.2 cells in the left ventricle and 6.4 ± 1.7 cells in the crista terminalis. Sinus node interconnections occurred at small intercalated disks that usually connected cells in partial side-to-side and end-to-end juxtaposition. In contrast, left ventricular myocytes are interconnected at large intercalated disks that adjoin many cells in pure side-to-side and end-to-end orientations. Crista terminalis myocytes are connected primarily in end-to-end fashion. The aggregate gap junction profile length per unit myocyte area was 26.5 times greater in the left ventricle and 5.0 times greater in the crista terminalis than in the sinus node. Conclusion: Sinus node myocytes exhibit small, sparsely distributed gap junctions that interconnect cells in complex patterns of lateral and terminal apposition. These structural features are consistent with the unique conduction properties of the sinus node. [ABSTRACT FROM AUTHOR]

It was generally accepted that the site of normal impulse origin within the atria was a single static focus within the sinus node. This review will examine how this model of impulse origin came about and has evolved. Early on, conflicting data suggested that the sinus node focus was not static and changed with interventions that changed heart rate, such as vagal stimulation. Furthermore, even with removal of the sinus node, a normal atrial rhythm was generated. High-resolution mapping in humans and dogs showed that the initiation of the impulse was dynamic and could be multicentric, with more than one focus initiating a single beat. Shifts in the site of origin correlated with changes in rate and were consistent with P wave changes routinely observed in the standard ECG. These studies suggested multiple pacemakers were responsible for impulse initiation. However, it was not clear how these widespread pacemakers were coordinated to function synchronously. Recent canine data suggest that the node may be partially insulated from the surrounding atrium, resulting in multicentric origin starting from a single site within the node. What has evolved is a model of impulse origin with a sinus node having discrete exit sites and a dominant pacemaker within the node that can shift to other nodal sites. Complex and changing conduction out of the node, coupled with extranodal pacemakers, which can assume dominance over the node, combine with the autonomic nervous system to control heart rate and the pattern of impulse origin within the atria. [ABSTRACT FROM AUTHOR]

Connexin Phenotypes in the Human Heart. Introduction: Gap junction channels are major determinants of intercellular resistance to current flow between cardiac myocytes. Alterations in gap junctions may contribute to development of arrhythmia substrates in patients. However, there is significant interspecies variation in the types and amounts of gap junction subunit proteins (connexins) expressed in disparate regions of mammalian hearts. To elucidate determinants of conduction properties in the human heart, we characterized connexin phenotypes of specific human cardiac tissues with different conduction properties. Methods and Results: The distribution and relative abundance of Cx37, Cx40, Cx43, Cx45, and Cx46 were studied immunohistochemically using monospecific antibodies and frozen sections of the sinoatrial node and adjacent atria, the AV node and His bundle, the bundle branches, and the left and right ventricular walls. Patterns of expression of these connexins in the human heart differed from those in previous animal studies. Sinus node gap junctions were small and sparse and contained Cx45 and apparently smaller amounts of Cx40 but no Cx43. AV node gap junctions were also small and contained mainly Cx45 and Cx40 but, unlike the sinus node, also expressed Cx43. Atrial gap junctions were larger than nodal junctions and contained moderate amounts of Cx40, Cx43, and Cx45. Junctions in the bundle branches were the largest in size and contained abundant amounts of Cx40, Cx43, and Cx45. Gap junctions in ventricular myocardium contained mainly Cx43 and Cx45; only a very small amount of ventricular Cx40 was detected in subendocardial myocyte junctions and endothelial cells of small to medium sized intramural coronary arteries. Minimal Cx37 and Cx46 immunoreactivity was detected between occasional atrial or ventricular myocytes. Conclusions: The relative amounts of individual connexins and the number and size of gap junctions vary greatly in specific regions of the human heart with different conduction properties. These differences likely play a role in regulating cardiac conduction velocity. Differences in the connexin phenotypes of specific regions of the human heart and experimental animal hearts must be considered in future experimental or modeling studies of cardiac conduction. [ABSTRACT FROM AUTHOR]