Atrioventricular Conduction Axis Research Articles

Next-generation sequencing of AV nodal reentrant tachycardia patients identifies broad spectrum of variants in ion channel genes.

Atrioventricular nodal reentry tachycardia (AVNRT) is the most common form of regular paroxysmal supraventricular tachycardia. This arrhythmia affects women twice as frequently as men, and is often diagnosed in patients <40 years of age. Familial clustering, early onset of symptoms and lack of structural anomaly indicate involvement of genetic factors in AVNRT pathophysiology. We hypothesized that AVNRT patients have a high prevalence of variants in genes that are highly expressed in the atrioventricular conduction axis of the heart and potentially involved in arrhythmic diseases. Next-generation sequencing of 67 genes was applied to the DNA profile of 298 AVNRT patients and 10 AVNRT family members using HaloPlex Target Enrichment System. In total, we identified 229 variants in 60 genes; 215 missenses, four frame shifts, four codon deletions, three missense and splice sites, two stop-gain variants, and one start-lost variant. Sixty-five of these were not present in the Exome Aggregation Consortium (ExAC) database. Furthermore, we report two AVNRT families with co-segregating variants. Seventy-five of 284 AVNRT patients (26.4%) and three family members to different AVNRT probands had one or more variants in genes affecting the sodium handling. Fifty-four out of 284 AVNRT patients (19.0%) had variants in genes affecting the calcium handling of the heart. We furthermore find a large proportion of variants in the HCN1-4 genes. We did not detect a significant enrichment of rare variants in the tested genes. This could be an indication that AVNRT might be an electrical arrhythmic disease with abnormal sodium and calcium handling.

Three Dimensional Visualization of Human Cardiac Conduction Tissue in Whole Heart Specimens by High-Resolution Phase-Contrast CT Imaging Using Synchrotron Radiation.

The feasibility of synchrotron radiation-based phase-contrast computed tomography (PCCT) for visualization of the atrioventricular (AV) conduction axis in human whole heart specimens was tested using four postmortem structurally normal newborn hearts obtained at autopsy. A PCCT imaging system at the beamline BL20B2 in a SPring-8 synchrotron radiation facility was used. The PCCT imaging of the conduction system was performed with "virtual" slicing of the three-dimensional reconstructed images. For histological verification, specimens were cut into planes similar to the PCCT images, then cut into 5-μm serial sections and stained with Masson's trichrome. In PCCT images of all four of the whole hearts of newborns, the AV conduction axis was distinguished as a low-density structure, which was serially traceable from the compact node to the penetrating bundle within the central fibrous body, and to the branching bundle into the left and right bundle branches. This was verified by histological serial sectioning. This is the first demonstration that visualization of the AV conduction axis within human whole heart specimens is feasible with PCCT.

Septal Atrioventricular Junction Region: Comprehensive Imaging in Adults.

The septal atrioventricular junction is a centrally located region of the heart where the septal components of the atria and ventricles meet the aortic, mitral, and tricuspid valves. Important structures in this region include the membranous septum, the central fibrous body, the Koch triangle, the inferior pyramidal space, and the base of the interventricular septum. This small area is the home of the atrioventricular node and the atrioventricular conduction axis and has enormous importance to electrophysiologists owing to its prime role in the conduction system of the heart. The atrioventricular node lies within the triangle of Koch; and the atrioventricular bundle, or bundle of His, exits the atrioventricular node and penetrates the right fibrous trigone and runs underneath the membranous septum. The septal atrioventricular junction is a common location for intracardiac shunts such as membranous and perimembranous septal defects. Imaging classification of these defects can have important implications before surgical closure, because the atrioventricular conduction axis passes along the posteroinferior margin of most perimembranous defects. Extracardiac inflammatory and malignant pathologic conditions can extend from the mediastinum toward the inferior pyramidal space in this region through the epicardial fat planes. Although the anatomic structures are complicated, the components can be shown in exquisite detail with computed tomography (CT). In this review, the anatomic boundaries and important anatomic landmarks are examined with CT and magnetic resonance imaging. Also described are the anatomic variants of the membranous septum pertinent to percutaneous aortic valve implantation, the vascular anatomic variants, and commonly encountered pathologic conditions related to the septal atrioventricular junction. ©RSNA, 2016.

His electrogram alternans (Zhang's phenomenon) and a new model of dual pathway atrioventricular node conduction.

In contrast to the current textbook model and the current clinical index of dual pathway atrioventricular (AV) nodal conduction, here we summarize the discovery and validation of Zhang's phenomenon (originally His electrogram alternans) as a new index of dual pathway conduction. We also describe the new findings of transverse-versus-longitudinal electrical propagation within the AV node as the electrophysiological basis underlining this new index. Thus, a new index and a new model of dual pathway AV conduction are being developed. We have reviewed current literature and provided evidence supporting a new index and a new model of dual pathway AV conduction. Recent data revealed that during fast pathway conduction, electrical excitation in the AV node propagates in a superior to inferior direction across AV conduction axis and fiber orientation to reach first the superior His bundle fibers. However, this transverse conduction can fail easily within the superior nodal domain at fast rates. The failing of transverse propagation permits electrical excitation formed at the posterior/inferior nodal region to propagate longitudinally along fiber orientation in a posterior to anterior direction through the inferior nodal domain to reach the inferior His bundle (slow pathway conduction). This transverse-versus-longitudinal electrical propagation within the AV node results in a functional dissociation in the distal node and formation of dual inputs into the His bundle, providing the electrophysiological basis for the formation of Zhang's phenomenon (His electrogram alternans). Based on strong experimental data, a new index and a new model of dual pathway AV nodal conduction are emerging, although they are still awaiting clinical validation.

Clarifying the morphology of the ostium primum defect.

The 'ostium primum' defect is still frequently considered to be the consequence of deficient atrial septation, although the key feature is a common atrioventricular junction. The bridging leaflets of the common atrioventricular valve, which are joined to each other, are depressed distal to the atrioventricular junction, and fused to the crest of the muscular ventricular septum, which is bowed in the concave direction towards the ventricular apex. As a result, shunting across the defect occurs between the atrial chambers. These observations suggest that the basic deficiency in the 'ostium primum' defect is best understood as a product of defective atrioventricular septation, rather than an atrial septal defect. We have now encountered four examples of 'ostium primum' defects in mouse embryos that support this view. These were identified from a large number of mouse embryo hearts collected from a normal, outbred mouse colony and analysed by episcopic microscopy as part of an ongoing study of normal mouse cardiac development. The abnormal hearts were identified from embryos collected at embryonic days 15.5, 16.5 and 18.5 (two cases). We have analysed the features of the abnormal hearts, and compared the findings with those obtained in the large number of normally developed embryos. Our data show that the key feature of normal atrioventricular septation is the ventral growth through the right pulmonary ridge of a protrusion from the dorsal pharyngeal mesenchyme, confirming previous findings. This protrusion, known as the vestibular spine, or the dorsal mesenchymal protrusion, reinforces the closure of the primary atrial foramen, and muscularises along with the mesenchymal cap of the primary atrial septum to form the ventro-caudal buttress of the oval foramen, identified by some as the 'canal septum'. Detailed analysis of the four abnormal hearts suggests that in each case there has been failure of growth of the vestibular spine, with the result that the common atrioventricular junction found earlier during normal development now persists during cardiac development. Failure of separation of the common junction also accounts for the trifoliate arrangement of the left atrioventricular valve in the abnormal hearts. Analysis of the episcopic datasets also permits recognition of the location of the atrioventricular conduction axis. Comparison of the location of this tract in the normal and abnormal hearts shows that there is no separate formation of a ventricular component of the 'canal septum' as part of normal development. We conclude that it is abnormal formation of the primary atrial septum that is the cause of so-called 'secundum' atrial septal defects, whereas it is the failure to produce a second contribution to atrial septation (via growth of the vestibular spine) that results in the 'ostium primum' defect.

Exercises in anatomy: holes between the ventricles.

Holes between the ventricles are the commonest congenital cardiac malformations. As yet, however, there is no consensus as to how they can best be described and categorized. In this, our third exercise in cardiac anatomy, we address the issue of classification of ventricular septal defects. We begin our demonstration by analysing the normal heart. We show that the larger part of the ventricular septum is made up of its muscular component. The membranous part accounts for only a small portion, which is located centrally within the cardiac base. This small membranous part forms a boundary between the right-sided chambers and the aortic root. Holes at this site, therefore, which account for the commonest defects closed surgically, will open centrally in the cardiac base, being located postero-inferiorly relative to the supraventricular crest. We then show that the larger part of the crest itself is a free-standing muscular sleeve, which lifts the leaflets of the pulmonary valve away from the cardiac base. Only a very small part of the muscle forming the right ventricular outlet is located in the septal position. Turning our attention to malformed hearts, we show how holes between the ventricles can open centrally at the cardiac base, open to the inlet or outlet of the right ventricle or open within the substance of the apical muscular septum. We demonstrate, however, that description of such geographical location of the defects does not paint the full picture, since lesions with markedly different phenotypic features can open in comparable geographic locations. We illustrate how it is the phenotypic features, as seen from the right ventricle, which convey the crucial information for the surgeon with regard to the location of the atrioventricular conduction axis, using hearts with holes opening to the inlet of the right ventricle with muscular as opposed to partially fibrous borders to emphasize this point. We continue by showing how holes with different phenotypes can also open to the outlet of the right ventricle, the key feature in this regard being malalignment between the apical muscular septum relative to the muscular outlet septum or its fibrous remnant. Malalignment can also be found between the apical ventricular septum and the atrial septum, this being shown in a defect opening to the inlet of the right ventricle. We conclude by emphasizing that, so as to bring together all the information of surgical significance, it is necessary to take note of the geographical location of holes between the ventricles, their phenotypic features and the presence or absence of malalignment between the septal components.

63 * Ageing is associated with myocardial disarray, changes in the expression of ion channels, gap junction proteins and Ca2+ handling proteins with in the atrioventricular conduction axis

Introduction: The inferior nodal extension (INE), compact node (CN) and penetrating/His bundle (PB/HB) form the atrioventricular (AV) conduction axis and are responsible for conduction and delay of the action potential from the atria to the ventricles. With ageing, dysfunction of the AV conduction axis results in prolongation of the PR interval and AV block. Methods: We have compared the INE, CN and PB/HB from male rats 3 months old (n 9) and 2 years old (n 8). From survival curves, 3 month old rat correspond to 20 yearr old human, whereas 2 year old rat correspond to 70 year old human. Morphological characteristics of these tissues were studied using Masson's trichrome (MT) and picrosirius red (PR) on serial histological sections. Protein expression was studied using immunofluorescence and confocal microscopy. Qualitative signal intensity of proteins investigated was measured using Volocity software. Results: MT staining showed that the cells of INE, CN and PB were more loosely packed and irregularly arranged thus showing myocardial disarray in old rats. PR staining showed that total collagen content was greater in CN and PB with ageing. There was an age dependent cellular hypertrophy in all regions of the AV conduction axis. Immunohistochemistry revealed that Cx43 (the major gap junction in the heart) down regulates in PB ( P <0.05), but Cx40 (important gap junction in the atria and AV conduction axis) up regulates in INE and CN ( P <0.05) in old rats. With ageing, there was a down regulation of Nav1.5 (major cardiac Na+channel) in CN and PB ( P <0.05), up regulation of Cav1.3 (L-type Ca2+ channel) in PB ( P <0.05) and in terms of Ca2+ handling proteins, downregulation of RyR2 in CN, PB ( P <0.05) and up regulation of SERCA2a in PB ( P <0.05). There was also trend to downregulation of HCN4 in PB/HB bundle ( P =0.051) Conclusion: Ageing is associated with structural changes to the tissues in the AV conduction axis, which include myocardial disarray, fibrosis and hypertrophy. Ageing is also associated with changes in the expression of ion channels, gap junction proteins and Ca2+ handling proteins. These changes may explain the age dependent dysfunction of AV conduction axis.

263 AGEING IS ASSOCIATED WITH CHANGES IN STRUCTURE AND ION CHANNEL EXPRESSION WITHIN THE ATRIOVENTRICULAR CONDUCTION AXIS

<h3>Introduction</h3> The inferior nodal extension (INE), compact atrioventricular (AV) node and penetrating/His bundle (PB) form the AV conduction axis and are responsible for delay and propagation of the action potential from the atria to the ventricles. With ageing, dysfunction in these tissues results in prolongation of the PR interval and first, second and third degree AV block. The only treatment is implantation of permanent pacemakers, which are known to be associated with various complications. Previous studies have described age-related structural and functional changes in the AV conduction axis, but detailed examination of morphological changes (such as fibrosis and hypertrophy) as well as changes in ion channel expression with ageing have not been investigated. <h3>Methods</h3> We have compared the regions of the AV conduction axis (INE, compact AV node, CN, proximal PB, PPB and distal PB, His bundle) from 3 (n=9) and 24 (n=8) months old male rats (humanely killed in accordance with UK Animals Scientific Procedures Act 1986). From the survival curve, 3 months old rats correspond to 20 years old humans, whereas 24 months old rats correspond to ∼70 years old humans. Morphological characteristics of these tissues were studied using serial cryosections and Masson’s trichrome (MT) and picrosirius red (PR) histological stains and light and polarised microscopy. The expression of the ion channel HCN4 (responsible for pacemaking) and the gap junction channels Cx43 and Cx40 (responsible for electrical coupling between cardiac cells) was studied using immunofluorescence and confocal microscopy on sister sections to those used for histology. Qualitative signal intensity of these channels was measured using Volocity software. Statistical analysis was performed with SPSS version 20.1. <h3>Results</h3> At the structural level, we observed significant changes with ageing. MT staining showed that the cells of INE, CN, PPB and His bundle are more loosely packed and irregularly arranged in older animals. Age-dependent cellular hypertrophy was confirmed by a statistically significant increase in cell size across all regions of the AV junction. With ageing, total collagen content estimation showed a statistically significant increase in thin (but not in thick) collagen fibres in the CN, PPB and His bundle. Immunohistochemistry revealed a decrease in Cx43 expression in the INE (P=0.003), PPB (P=0.005), His bundle (P=0.02), but an increase in Cx40 expression in the INE (P=0.01) and CN (P=0.005) with ageing. There was also trend to downregulation of HCN4 expression especially in the His bundle (P=0.051). <h3>Conclusion</h3> Ageing is associated with structural changes of the AV junction tissues, which include fibrosis, hypertrophy and changes in Cx43 and Cx40 and possibly HCN4 expression. Our current findings may explain the prolongation of the PR interval with ageing observed in our previous study.

The Anatomy of the Conduction System: Implications for the Clinical Cardiologist

It is just over 100 years since details emerged of the anatomical arrangement of the histologically specialised cardiomyocytes responsible for initiation and propagation of the cardiac impulse. Shortly thereafter, histological criteria were established to permit their location in autopsied human hearts. These criteria retain their value, but can now be enhanced by molecular and immunohistochemical findings. The new techniques have advanced our knowledge of the location and detailed structure of the sinus and atrioventricular nodes, along with the atrioventricular conduction axis. They also reveal the presence of additional areas of specialised myocardium, such as the paranodal area of the terminal crest, and the atrioventricular ring tissues. In contrast, they offer no support for the notion that the pulmonary venous sleeves are histologically specialised, but do provide insights to the substrates for outflow tract tachycardias. This article is part of a JCTR special issue on Cardiac Anatomy.

21 Contrast Enhanced Micro-Computed Tomography Resolves the 3-Dimensional Morphology of the Cardiac Conduction System in Mammalian Hearts

The general anatomy of the cardiac conduction system (CCS) has been known for 100 years, but its complex irregular 3D geometry is not well understood largely because the specialised tissue cannot be easily distinguished from working myocardium. The best anatomical descriptions come from serial sectioning of preparations taken from appropriate areas of the heart. Low X-ray attenuation has formerly ruled out micro-computed tomography (micro-CT) to resolve topology of soft tissue, but incorporation of high molecular weight molecules enhances differential attenuation and allows visualisation of fine detail. Using an iodine based contrast agent, we obtained exquisite high resolution contrast enhanced micro-CT images of cardiac tissue from rat and rabbit in which the three major subdivisions of the CCS can be differentiated from the surrounding contractile myocardium, and visualised in 3D. The sinoatrial node and the associated ring bundle, the atrioventricular conduction axis (including inferior nodal extension and penetrating bundle), His bundle, bundle branches and Purkinje network can be objectively identified by differential attenuation. Purkinje fibres within the ventricles appear both as structures running on the endocardial surface and free running in the luminal cavity. Controversially, analogous structures are present in the atria, mainly on or near to the endocardial surface. Although the current findings are consistent with existing anatomical representations, the new images offer superior resolution and are the first 3D representations of the CCS within intact mammalian hearts. The method promises to improve the anatomical fidelity of computational models designed to understand complex normal and pathological conduction within the heart.

Clarifying the Surgical Morphology of Inlet Ventricular Septal Defects

Different types of ventricular septal defects (VSD) open to the inlet of the right ventricle. The atrioventricular conduction axis is markedly different within these subtypes, a feature of great surgical importance. To clarify these relationships, we have studied hearts with such VSDs from the Idriss archive at Ann and Robert H. Lurie Children's Hospital of Chicago. We selected hearts from the archive showing the different variants of inlet VSD, photographing them to show the presumed disposition of the atrioventricular conduction axis as based on previous histology studies. We differentiated between perimembranous defects, muscular defects, perimembranous defects with straddling of the tricuspid valve, and atrioventricular septal defects with shunting confined at the ventricular level. The atrioventricular conduction axis is different in the four types of inlet VSDs. In perimembranous defects opening to the inlet of the right ventricle, the axis is positioned to the right hand of the surgeon operating through the tricuspid valve, whereas it is to the left hand with the muscular inlet defect. In patients with straddling tricuspid valve, the axis arises from an anomalous posteroinferior atrioventricular node, whereas in patients with atrioventricular septal defect with exclusive ventricular shunting, the axis arises at the crux of the heart from a node located in an inferiorly displaced nodal triangle. An appreciation of these relationships should help surgeons avoid the conduction system when closing inlet VSDs.

New conduction abnormalities after TAVI—frequency and causes

Transcatheter aortic valve implantation (TAVI) is increasingly used to treat patients with aortic stenosis who are considered to be too high-risk for surgical replacement of the aortic valve. Although the procedural risks are decreasing, the occurrence of new conduction abnormalities remains a vexing issue. Both left bundle branch block and atrioventricular dissociation can affect prognosis after TAVI. Understanding the intimate relationship between the atrioventricular conduction axis and the aortic root, in addition to elucidation of factors related specifically to the procedure, devices, and patients, might help to reduce these conduction abnormalities. The purpose of this Review is to assess, and offer insights into, the available information on the frequency of new conduction abnormalities associated with TAVI, their anatomical and procedural causes, and their clinical consequences.

Contrast Enhanced Micro-Computed Tomography Resolves the 3-Dimensional Morphology of the Cardiac Conduction System in Mammalian Hearts

The general anatomy of the cardiac conduction system (CCS) has been known for 100 years, but its complex and irregular three-dimensional (3D) geometry is not so well understood. This is largely because the conducting tissue is not distinct from the surrounding tissue by dissection. The best descriptions of its anatomy come from studies based on serial sectioning of samples taken from the appropriate areas of the heart. Low X-ray attenuation has formerly ruled out micro-computed tomography (micro-CT) as a modality to resolve internal structures of soft tissue, but incorporation of iodine, which has a high molecular weight, into those tissues enhances the differential attenuation of X-rays and allows visualisation of fine detail in embryos and skeletal muscle. Here, with the use of a iodine based contrast agent (I2KI), we present contrast enhanced micro-CT images of cardiac tissue from rat and rabbit in which the three major subdivisions of the CCS can be differentiated from the surrounding contractile myocardium and visualised in 3D. Structures identified include the sinoatrial node (SAN) and the atrioventricular conduction axis: the penetrating bundle, His bundle, the bundle branches and the Purkinje network. Although the current findings are consistent with existing anatomical representations, the representations shown here offer superior resolution and are the first 3D representations of the CCS within a single intact mammalian heart.

The spectrum of double-outlet right atrium including hearts with three atrioventricular valves

Double-outlet right atrium (DORA) is characterized by simultaneous right atrial emptying into both ventricles. Ventriculoatrial septal malalignment is the cardinal morphological feature. Three cases are presented to depict two major types of DORA-DORA with a malaligned atrial septum and DORA with a malaligned ventricular septum. We describe two subtypes of each form of DORA: DORA with a malaligned atrial septum presents with either a common atrioventricular (AV) junction (guarded by a common AV valve) or with a single AV junction (due to the absence of the left AV junction). DORA with a malaligned ventricular septum may be associated with a right ventricle (RV) that is adequate for biventricular repair or a severely hypoplastic RV not compatible with biventricular repair. DORA with a malaligned ventricular septum is closely related to typical straddling of the tricuspid valve. Peculiarly, DORA with a malaligned ventricular septum presents three AV valves at the AV junction and is associated with an abnormal disposition of the AV conduction axis. Clear understanding of the morphology of these lesions is important in preventing a surgical misadventure at the crux of the heart.

Cell death in the atrioventricular canal myocardium determines ventricular activation patterns

We hypothesize that apoptosis in the AV myocardium influences maturation of atrioventricular conduction axis. We thus blocked apoptosis in chick embryonic heart and analyzed the effects of this treatment on cell death and ventricular activation patterns.ED4 chick embryos were treated with the caspase inhibitor zVAD by intrapericardial injection. Spontaneously beating hearts isolated at ED8 were stained with voltage‐sensitive dye and imaged with a high‐speed camera. Amount of apoptotic cells was analyzed at ED 7 by whole mount LysoTracker Red or active caspase immunostaining and confocal microscopy. Hearts of embryos treated with zVAD showed a significantly increased proportion of immature (base to apex) activation patterns at ED8, including ventricular activation originating from right AV junction, a pattern never observed in control hearts. The number of apoptotic cells in AV canal myocardium was decreased at ED7 in the treated hearts. Apoptosis in the AV canal myocardium is thus an important contributor to activation pattern development. Its inhibition at critical stages can lead to persistence of accessory AV connections, which form a morphological substrate for ventricular pre‐excitation.Supported by project of MSMT VZ 0021620806, LC 06061.

Molecular architecture of the human specialised atrioventricular conduction axis

The atrioventricular conduction axis, located in the septal component of the atrioventricular junctions, is arguably the most complex structure in the heart. It fulfils a multitude of functions, including the introduction of a delay between atrial and ventricular systole and backup pacemaking. Like any other multifunctional tissue, complexity is a key feature of this specialised tissue in the heart, and this complexity is both anatomical and electrophysiological, with the two being inextricably linked. We used quantitative PCR, histology and immunohistochemistry to analyse the axis from six human subjects. mRNAs for ~ 50 ion and gap junction channels, Ca 2+-handling proteins and markers were measured in the atrial muscle (AM), a transitional area (TA), inferior nodal extension (INE), compact node (CN), penetrating bundle (PB) and ventricular muscle (VM). When compared to the AM, we found a lower expression of Na v1.5, K ir2.1, Cx43 and ANP mRNAs in the CN for example, but a higher expression of HCN1, HCN4, Ca v1.3, Ca v3.1, K ir3.4, Cx40 and Tbx3 mRNAs. Expression of some related proteins was in agreement with the expression of the corresponding mRNAs. There is a complex and heterogeneous pattern of expression of ion and gap junction channels and Ca 2+-handling proteins in the human atrioventricular conduction axis that explains the function of this crucial pathway.

Anatomy of Discordant Atrioventricular Connections

The term discordant atrioventricular connections refers to the situation in which the ventricles are connected inappropriately to the atrial chambers. In most instances, the connections of the great arteries are also abnormal, with the aorta and the pulmonary trunk arising from morphologically inappropriate ventricles. This combination results in the presence of so-called congenitally corrected transposition. Double-outlet right ventricle is occasionally present, while concordant ventriculoarterial connections may be seen rarely. Most such hearts have a range of additional abnormalities, including ventricular septal defects; outflow tract obstruction, usually of the morphologically left ventricle; anomalies of the morphologically tricuspid valve; and a highly abnormal location of the specialized atrioventricular conduction axis. Some examples exhibit bizarre abnormalities of ventricular relationships and topology, including criss-cross atrioventricular connections and superoinferior ventricular relations. In describing the anatomy of these malformations, it is important to use a step-by-step segmental approach to the documentation of the connections and associated defects in each case and to avoid potentially confusing shorthand terms.

Developmental Origin, Growth, and Three-Dimensional Architecture of the Atrioventricular Conduction Axis of the Mouse Heart

The clinically important atrioventricular conduction axis is structurally complex and heterogeneous, and its molecular composition and developmental origin are uncertain. To assess the molecular composition and 3D architecture of the atrioventricular conduction axis in the postnatal mouse heart and to define the developmental origin of its component parts. We generated an interactive 3D model of the atrioventricular junctions in the mouse heart using the patterns of expression of Tbx3, Hcn4, Cx40, Cx43, Cx45, and Nav1.5, which are important for conduction system function. We found extensive figure-of-eight rings of nodal and transitional cells around the mitral and tricuspid junctions and in the base of the atrial septum. The rings included the compact node and nodal extensions. We then used genetic lineage labeling tools (Tbx2(+/Cre), Mef2c-AHF-Cre, Tbx18(+/Cre)), along with morphometric analyses, to assess the developmental origin of the specific components of the axis. The majority of the atrial components, including the atrioventricular rings and compact node, are derived from the embryonic atrioventricular canal. The atrioventricular bundle, including the lower cells of the atrioventricular node, in contrast, is derived from the ventricular myocardium. No contributions to the conduction system myocardium were identified from the sinus venosus, the epicardium, or the dorsal mesenchymal protrusion. The atrioventricular conduction axis comprises multiple domains with distinctive molecular signatures. The atrial part proliferates from the embryonic atrioventricular canal, along with myocytes derived from the developing atrial septum. The atrioventricular bundle and lower nodal cells are derived from ventricular myocardium.

Mechanism of postsystolic contraction and of multiple myocardial contractions during each single cardiac cycle

Postsystolic contraction and other forms of phenomenon of multiple myocardial contractions are characterised by secondary or even tertiary contraction that follow regular one during each single cardiac cycle, triggered by a single sinus node impulse. These additional contractions occur at circumscribed areas of different myocardial regions, in many cardiac patients and healthy subjects. The mechanism of onset and perpetuation of the phenomenon is unknown. Our hypothesis is based on idea of existence of accessory, dead-end, slow-conducting, low-voltage pathways, derived from atrioventricular node or the bundle of His. Secondary contraction could occur in the following way: sinus node impulse divides into two pathways, the main atrioventricular conduction axis that depolarises the entire myocardium and the accessory pathway that depolarises again target region of myocardium where it ends blindly. Slow conduction through such accessory pathway enables a delay of secondary depolarisation needed to overcome the absolute refractory period of the myocardium following the 'regular' contraction. Electrocardiographic signal of a postsystolic potential is not visible at body surface because the pathway is low-voltage. The purpose of multiple myocardial contractions could be, although rarely, completing of current ejection, but more often, in the case of postsystolic contraction it could be a postsystolic tightening of the myocardium which would influence the regular contraction of the next cardiac cycle with the aim to reverse or prevent ventricular remodelling. In those circumstances, regional pathological function of ventricles (deformation of remodelled ventricle during the contraction, maybe during the relaxation as well, and furthermore asynchronous, but otherwise suboptimal contraction as well) would be detected by hypothetical myocardial receptors for strain and stretch, which would activate and sustain the function of accessory dead-end pathways by a neuroendocrine feed-back mechanism. The hypothesis is supported by anatomical findings of dead-end tracts originating from atrioventricular node and disappearing in the muscular part of interventricular septum. Extensive differences in the velocity of impulse propagation, which exist along the conduction system, allow the possibility that the accessory pathways are of slow-conducting properties. Low-amplitude signal of such pathways was confirmed by our intracardiac electrophysiological recording. Feed-back mechanism based on myocardial receptors for strain and stretch is a relevant option, keeping in mind well-known receptor based regulatory mechanisms across the cardiovascular system. The phenomenon is easily detectible, but hard to explain, so even considering herein presented hypothesis implies a need for change of settled perception of myocardial kinetics, and of physiological and pathological function of conducting system.

Ion Channel Transcript Expression at the Rabbit Atrioventricular Conduction Axis

Little is known about the distribution of gap junctions and ion channels in the atrioventricular node, even though the physiology and pathology of the atrioventricular node is ultimately dependent on them. The abundance of 30 transcripts for markers, gap junctions, ion channels, and Ca(2+)-handling proteins in different regions of the rabbit atrioventricular node (nodal extension and proximal and distal penetrating bundle of His as well as atrial and ventricular muscle) was measured using a novel quantitative polymerase chain reaction technique and in situ hybridization. The expression profile of the nodal extension (slow pathway into penetrating bundle) was similar to that of the sinoatrial node. For example, in the nodal extension, in contrast to the atrial muscle and as expected for a slowly conducting tissue with pacemaker activity, there was no or reduced expression of Cx43, Na(v)1.5, Ca(v)1.2, K(v)1.4, KChIP2, and RYR3 and high expression of Ca(v)1.3 and HCN4. The expression profile of the penetrating bundle was less specialized. In situ hybridization revealed a transitional zone with reduced expression of Cx43, Na(v)1.5, and KChIP2 that may form the fast pathway into the penetrating bundle. At the atrioventricular node, the expression of gap junctions and ion channels in the nodal extension (slow pathway) and a transitional zone (putative fast pathway) as well as the penetrating bundle (output pathway) is specialized and heterogeneous and roughly matches the electrophysiology of the different regions.