Spatially resolved multiomics of human cardiac niches.

The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system1. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+ and IgA+ plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.

Lack of evidence for longitudinal dissociation of the atrioventricular conduction axis.

Longitudinal dissociation of the aggregated specialized cardiomyocytes within the non-branching portion of atrioventricular conduction axis has proved a controversial topic for both morphologists and electrophysiologists. We have now used morphological methods, including three-dimensional assessment, to revisit, in human, canine, and bovine hearts, the presence or absence of interconnections between the aggregated cardiomyocytes making up the non-branching bundle. We analyzed three datasets from human and canine hearts, and two from bovine hearts, using longitudinal and orthogonal serial histological sections. In addition, we assessed three hearts using translucent India ink injected specimens, permitting assessment of the three-dimensional arrangement of the cardiomyocytes. Using the longitudinal sections, we found numerous oblique interconnections between the groups of specialized cardiomyocytes. When assessing orthogonal sections, we noted marked variation in the grouping of the cardiomyocytes. We interpreted this finding as evidence of bifurcation and convergence of the groups seen in the longitudinal sections. The three-dimensional assessment of the bovine material confirmed the presence of the numerous interconnections. The presence of multiple connections between the cardiomyocytes in the non-branching bundle rules out the potential for longitudinal dissociation.

Anatomical study of the cardiac conduction system in swine hearts.

The cardiac conduction system (CCS) is crucial for regulating heartbeats; therefore, clinicians and comedicals involved in cardiovascular medicine treatment must have a thorough understanding of the CCS structure and function. However, anatomical education of the CCS based on actual dissection and observation is uncommon, although such educational methodology promotes three-dimensional structural understanding of the observed object. Based on previous studies, we examined the CCS structure in the heart of a swine (pig, Sus scrofa domestica) which has been used in the biological, medical and anatomical curricula as science teaching materials, by using macroscopic dissection procedures. Most CCS structures in a young pig heart were successfully identified and illustrated on a macroscopic scale. The atrioventricular bundle (His bundle) was located on the lower edge of the membranous interventricular septum and was clearly distinguished from the general myocardial fibres by its colour and fibre arrangement direction. Following the atrioventricular bundle towards the atrium or ventricle with properly removing the endocardium and myocardium, the atrioventricular node or the right and left bundles appeared respectively. In contrast, the sinoatrial node was not identified. The anatomy of the CCS in young pig hearts was essentially similar to that previously reported in humans and several domestic animals. Our findings of the CCS in young pig hearts are expected to be useful for medical and anatomical education for medical and comedical students, young clinicians and comedical workers.

Miniseries 1-Part II: the comparative anatomy of the atrioventricular conduction axis.

AIMS: The arrangement of the conduction axis is markedly different in various mammalian species. Knowledge of such variation may serve to question the validity of using animals as prospective models for design of systems for clinical use. METHODS AND RESULTS: We compared the arrangement of the atrioventricular conduction axis in human, murine, canine, porcine, and bovine hearts, examining serially sectioned datasets from 20 human, 16 murine, 3 porcine, 5 canine, and 1 bovine hearts. We also analysed computed tomographic datasets obtained from bovines and one human heart. Unlike the situation in the human heart, there is no formation of an atrioventricular fibrous membranous septum in the murine, canine, porcine, nor bovine hearts. Canine, porcine, and bovine hearts also lack an infero-septal recess, when defined as a fibrous plate supporting the buttress of the atrial septum. In these species, half of the non-coronary leaflet is directly opposed to the ventricular septal surface. CONCLUSION: There is a long right-sided non-branching component of the axis, which skirts the attachment of the non-coronary sinus of the aortic root. In the bovine heart, moreover, the left bundle branch usually extends intramyocardially as a solitary tape before surfacing and ramifying on the left ventricular septal surface. The difference in the atrioventricular conduction axis between species may influence the anatomical substrates for atrioventricular re-entry tachycardia, as well as providing inferences for assessing the risks of transcatheter implantation of the aortic valve. Further studies are now needed to assess these possibilities.

Similarities and differences in the arrangement of the atrioventricular conduction axis in the canine compared to the human heart.

BACKGROUND: Subtle differences exist between dog and human, despite use of the dog as a model for cardiac surgical and electrophysiological research. OBJECTIVE: The purpose of this study was to investigate the differences in the atrioventricular conduction axis and adjacent structures between dogs and humans. METHODS: We prepared 33 human and 5 canine hearts for serial histologic sections of the atrioventricular conduction axis, making correlations with gross anatomic findings. We additionally examined and photographed 15 intact normal human hearts obtained from infants undergoing autopsy. Furthermore, we interrogated a computed tomographic dataset from a human adolescent and from 2 autopsied canine hearts, both with normal cardiac anatomy. RESULTS: All canine hearts lacked an inferoseptal recess, with the noncoronary leaflet of the aortic valve and the right fibrous trigone having direct attachments to the septal surface of the left ventricular outflow tract. This correlated with an extensive nonbranching component of the ventricular conduction axis, which skirted half of the noncoronary aortic sinus. This anatomic arrangement was observed in 2 of 15 of autopsied infant hearts. In the human hearts with an inferoseptal recess, the relatively shorter nonbranching bundle is embedded within the fibrous tissue forming its right wall. CONCLUSION: We found a major difference between canine and the majority of human hearts, namely, the presence or absence of an inferoseptal recess. When this recess is absent, as in the canine heart and in some human hearts, a greater proportion of the atrioventricular conduction axis is found within the circumference of the subaortic outflow tract.

Morphometric analysis of cardiac conduction fibers in horses and dogs, a comparative histological and immunohistochemical study with findings in human hearts.

The principal function of the ventricular conduction system is rapid electrical activation of the ventricles. The aim of this study is to conduct a morphometric study to pinpoint the morphological parameters that define cardiac conduction cells, allowing us to distinguish them from other cells. Five male horse hearts and five male dog hearts were used in the study. The hearts were fixed in a 5% formaldehyde solution. Histological sections of 5 µm thickness were acquired and stained with hematoxylin-eosin and Masson's trichrome and cardiac conduction cells and their junctions were identified by desmin, connexin 40 and a PAS method. We found statistically significant differences in cardiac conduction fibers density and thickness, which was much higher in horses than in dogs (p = 0.000 for both values). By comparing the measured parameters of the cells in both species, we determined that cardiac conduction cells area and diameters were greater in horses than in dogs (p = 0.000 for all values). In dogs there are more junctions (30.8%) than in horses (26.1%), a statistically significant difference (p = 0.041). Our findings regarding the cardiac conduction fibers distribution in the animal species studied becomes new knowledge that contributes to the morphological study of this component of the cardiac conduction system and also makes it possible to locate exactly the site with the highest density of cardiac conduction fibers as a contribution to the cardiological study of these structures that lead to the prevention of ventricular arrhythmias and the identification of their treatment site.

Anatomy of the cardiac conduction system.

The specialized cardiomyocytes that constitute the conduction system in the human heart, initiate the electric impulse and result in rhythmic and synchronized contraction of the atria and ventricles. Although the atrioventricular (AV) conduction axis was described more than a century ago by Sunao Tawara, the anatomic pathway for propagation of impulse from atria to the ventricles has been a topic of debate for years. Over the past 2 decades, there has been a resurgence of conduction system pacing (CSP) by implanting pacing leads in the His bundle region in lieu of chronic right ventricular pacing that is associated with worse clinical outcomes. The inherent limitations of implanting the leads in the His bundle region has led to the emergence of left bundle branch area pacing in the past 3 years as an alternative strategy for CSP. The clinical experience from performing CSP has helped electrophysiologists gain deeper insight into the anatomy and physiology of cardiac conduction system. This review details the anatomy of the cardiac conduction system, and highlights some of the recently published articles that aid in better understanding of the AV conduction axis and its variations, the knowledge of which is critical for CSP. The remarkable evolution in technology has led to visualization of the cardiac conduction system using noninvasive, nondestructive high-resolution contrast-enhanced micro-computed tomography imaging that may aid in future CSP. We also discuss from anatomical perspective, the differences seen clinically with His bundle pacing and left bundle branch area pacing.

Morphological variations of the conduction system in the atrioventricular zone and its clinical relationship in different species.

Atrioventricular node is responsible for delaying the passage of the electrical impulse to ventricles in order to protect them from fast depolarizations coming from the atria. The importance of this study is to identify the morphological variations of the components of atrioventricular zone that affect the conduction system and its clinical relationship in different species of mammals. We analyzed ten human hearts, nine from horses, eight from pigs, and five from dogs without a clinical history of cardiac pathologies. Histological section thickness of 5 µm were obtained with a microtome and stained with hematoxylin-eosin and Masson's trichrome. We observed both an increase in collagen fibers and a decrease in the size of P cells (nodal pacemaker cells) within the atrioventricular node in dogs, horses and pigs in cases that presented cartilage in fibrous body. The percentage of fundamental substance in atrioventricular node was significantly higher in dogs and the percentage of collagen fibers was higher in pigs, both than in humans. The presence of cartilaginous metaplasia in cardiac fibrous skeleton from different species decreases the size of atrioventricular node and its cells and increases the percentage of collagen fibers within the node, which can reduce the transmission of the electrical impulse to ventricles and therefore predispose to the presentation of ventricular arrhythmias. Morphometric analysis has allowed us to objectively quantify each of the components of AV node and compare them in the different species.

Anatomy of the Atrioventricular Junction, Atrioventricular Grooves, and Accessory Pathways.

Accessory pathways that bypass all or part of the normal atrioventricular conduction system traverse the atrioventricular junction. The atrioventricular junction comprises of a limited septal component and much more extensive right and left parietal components. Its composition forms a plane of insulation between atrial and ventricular myocardium, preventing direct continuity between them. Typical accessory atrioventricular pathways located anywhere along the atrioventricular junction are muscle bundles or may involve muscle around the walls of coronary sinus aneurysms or coronary veins. Increasingly, variants or unusual accessory pathways, some involving an accessory node, are reported in clinical studies.

The ox atrioventricular conduction axis compared to human in relation to the original investigation of sunao tawara.

It was Sunao Tawara who, in 1906, established the foundations for knowledge of the arrangement of the atrioventricular conduction axis in man and other mammals. Study of the hearts of ungulates was a central part in his investigation, which assessed other species, including man. He described several subtle differences between the mammals. We have now ourselves studied the cardiac conduction tissue of the ox heart, comparing our findings with our knowledge of the arrangement in man, and providing new insights into the differences illustrated by Tawara. It is, perhaps, surprising that these differences, although subtle, have not attracted more attention. We show that the major difference is the fact that the noncoronary aortic sinus in the ox heart is mainly supported by the myocardium of the ventricular septum, whereas in the human heart the sinus, and its leaflet, are in fibrous contiguity with the aortic leaflet of the mitral valve. It is this feature that determines the difference in the arrangement of the conduction axis between the species. We also show that the emergence of the left bundle branch on the left ventricular aspect of the muscular septum is more variable than previously described. Clin. Anat. 33:383-393, 2020. © 2019 Wiley Periodicals, Inc.

Electrophysiological parameters and anatomical evaluation of left bundle branch pacing in an in vivo canine model.

INTRODUCTION: Left bundle branch pacing (LBBP), a form of conduction system pacing in addition to His bundle pacing (HBP), can potentially maintain left ventricular electrical synchrony with better sensing and a low and stable capture threshold. METHODS: We performed both HBP and LBBP using a canine model (n = 3; male; weight 30-40 kg). The electrocardiogram (ECG), intracardiac electrogram characteristics, and pacing parameters were compared between HBP and LBBP. The hearts were isolated and stained by Lugol's iodine (5%) to assess the relative locations of the leads in relation to the conduction system. RESULTS: The average potential to ventricle interval was longer with HBP compared to LBBP (26.67 ± 3.06 ms vs 12.67 ± 1.15 ms; P = .002). There were also notable differences in the pacing parameters between HBP and LBBP: R-wave amplitude (2.67 ± 0.42 mV vs 11.33 ± 3.06 mV; P = .008), pacing impedance (423.3 ± 40.4 vs 660.0 ± 45.8; P = .003), and threshold (2.30 ± 0.66 V/0.4ms vs 0.67 ± 0.15 V/0.4 ms; P = .014). The paced morphology of ECG was similar to the intrinsic with HBP while a right bundle branch block pattern was noted with LBBP. The anatomical evaluation revealed the location of the leads and the average lead depth was significantly more with LBBP as compared to HBP (12.33 ± 1.53 mm vs1.83 ± 0.29 mm; P < .0001). Furthermore, with LBBP, the tip of the lead helix was noted to be around the LBB. CONCLUSION: This in vivo canine model study confirms the significant differences between HBP and LBBP. Furthermore, this model provides a precise anatomic evaluation of the location and the depth of the leads in relation to the conduction system.

Variants of accessory pathways.

Variant accessory pathways include atriofascicular, nodofascicular, nodoventricular, atrio-Hisian, and fasciculoventricular pathways. Atriofascicular pathways are the most common with others occurring rarely. The anatomical descriptions, electrocardiographic findings, electrophysiologic findings, and clincial manifestations are discussed.

[Transcatheter aortic valve implantation and conduction disturbances]. / Implantation percutanée de valve aortique et troubles conductifs.

Transcatheter aortic valve implantation (TAVI) is currently becoming the treatment of choice for patients with calcific aortic stenosis. Despite several technical improvements, the incidence of conduction disturbances has not diminished and remains TAVI's major complication. These disturbances include the occurrence of left bundle branch block and/or high-grade atrioventricular block often requiring pacemaker implantation. The proximity of the aortic valve to the conduction system (conduction pathways) accounts for the occurrence of these complications. Several factors have been identified as carrying a high risk of conduction disturbances like the presence of pre-existing right bundle branch block, the type of valve implanted, the volume of aortic and mitral calcifications, the size of the annulus and the depth of valve implantation. Left bundle branch block is the most frequent post TAVI conduction disturbance. Whereas the therapeutic strategy for persistent complete atrioventricular block is simple, it becomes complex in the presence of fluctuating changes in PR interval and left bundle branch block duration. The QRS width threshold value (150-160 ms) indicative of the need for pacemaker implantation is still being debated. Although there are currently no recommendations regarding the management of these conduction disturbances, the extension of TAVI indications to patient at low surgical risk calls for a standardization of our practice. However, a decision algorithm was recently proposed by a group of experts composed of interventional cardiologists, electrophysiologists and cardiac surgeons. There are still uncertainties about the appropriate timing of pacemaker implantation and the management of new onset left bundle branch block.

Visualization of interpolated atrial fiber orientation using evenly-spaced streamlines.

BACKGROUND: Mathematical models of electrical propagation in the atria necessitate the specification of fiber orientation, often visualized over the epicardial and endocardial surfaces. Clear graphical representation of an orientation field over a surface remain challenging, which hinders the comparison between published models. METHOD: A method for the placement of evenly-spaced streamlines over a triangulated surface is proposed. Streamlines tangent to an orientation field are integrated, starting from a set of seed points. Distribution of seed points can be either uniformly random or located in the vicinity of existing streamlines. Stopping conditions are designed to prevent streamlines from getting closer than a threshold referred to as the separation distance. At each iteration, the longest among candidate streamlines is kept. Streamlines are finally rendered on the surface as tubes. The outcome is assessed subjectively by visual inspection and objectively by measuring average streamline length and average lateral distance between streamlines. RESULTS: Fiber orientation fields are conveniently created by angle-based interpolation from fiber tracts manually drawn based on literature review. The zebra-like representation of evenly-spaced streamlines enables clear identification of local fiber orientation. The results show that streamline density can be controlled since the lateral distance between streamlines is guaranteed to vary between 1 and 2 times the separation distance. Average streamline length can be increased by using more seed points, which offers a trade-off between quality and speed. CONCLUSION: Evenly-spaced streamline visualization of fiber orientation facilitates the description and the comparison of fiber structure in computer models of the atria.

Intra-procedural evaluation of the cavo-tricuspid isthmus anatomy with different techniques: comparison of angiography and intracardiac echocardiography.

Cavo-tricuspid isthmus (CTI) anatomies are highly variable, and specific anatomies lead to a difficult CTI ablation. This study aimed to compare the clinical utility of angiography and intracardiac echocardiography (ICE) in evaluating CTI anatomies, and to investigate the impact of the CTI anatomy on the procedure when the ablation tactic was adjusted to the anatomy. This study included 92 consecutive patients who underwent a CTI ablation. The CTI morphology was assessed with both right atrial angiography and ICE before the ablation, and the ablation tactic was adjusted to the anatomy. The mean CTI length was 34 ± 9 mm. On ICE imaging, 21 (23%) patients had a flat CTI, while 41 (45%) had a concave CTI with a mean depth of 5.6 ± 2.7 mm. The remaining 30 (32%) had a distinct pouch with a mean depth of 6.4 ± 2.3 mm, located at the posterior, middle, and anterior isthmus in 15, 14, and 1 patients, respectively. The Eustachian ridge (ER) was visualized in 46 (50%) patients. On angiography, a pouch and ER were detected in 22 and 15 patients, but not in the remaining 8 and 31, respectively. A complete CTI block line was created in all patients without any complications. The CTI anatomy did not significantly impact any procedural parameters. ICE was superior to angiography in evaluating the detailed CTI anatomy, especially pouches and the ER. An adjustment of the ablation tactic to the anatomy could overcome the procedural difficulties of the CTI ablation in cases with specific anatomies.

Is it feasible to offer 'targeted ablation' of ventricular tachycardia circuits with better understanding of isthmus anatomy and conduction characteristics?

Successful mapping and ablation of ventricular tachycardias remains a challenging clinical task. Whereas conventional entrainment and activation mapping was for many years the gold standard to identify reentrant circuits in ischaemic ventricular tachycardia ablation procedures, substrate mapping has become the cornerstone of ventricular tachycardia ablation. In the last decade, technology has dramatically improved. In parallel to high-density automated mapping, cardiac imaging and image integration tools are increasingly used to assess the structural ventricular tachycardia substrate. The aim of this review is to describe the technologies underlying these new mapping systems and to discuss their possible role in providing new insights into identification and visualization of reentrant tachycardia mechanisms.

HNK-1 in Morphological Study of Development of the Cardiac Conduction System in Selected Groups of Sauropsida.

Human natural killer (HNK)-1 antibody is an established marker of developing cardiac conduction system (CCS) in birds and mammals. In our search for the evolutionary origin of the CCS, we tested this antibody in a variety of sauropsid species (Crocodylus niloticus, Varanus indicus, Pogona vitticeps, Pantherophis guttatus, Eublepharis macularius, Gallus gallus, and Coturnix japonica). Hearts of different species were collected at various stages of embryonic development and studied to map immunoreactivity in cardiac tissues. We performed detection on alternating serial paraffin sections using immunohistochemistry for smooth muscle actin or sarcomeric actin as myocardial markers, and HNK-1 to visualize overall staining pattern and then positivity in specific myocyte populations. We observed HNK-1 expression of various intensity distributed in the extracellular matrix and mesenchymal cell surface of cardiac cushions in most of the examined hearts. Strong staining was found in the cardiac nerve fibers and ganglia in all species. The myocardium of the sinus venosus and the atrioventricular canal exhibited transitory patterns of expression. In the Pogona and Crocodylus hearts, as well as in the Gallus and Coturnix ones, additional expression was detected in a subset of myocytes of the (inter)ventricular septum. These results support the use of HNK-1 as a conserved marker of the CCS and suggest that there is a rudimentary CCS present in developing reptilian hearts. Anat Rec, 302:69-82, 2019. © 2018 Wiley Periodicals, Inc.

[Acute coronary occlusion - possible to diagnose in patients with left bundle branch block]. / Akut kranskärls­ocklusion möjlig att diagnostisera även vid vänstergrenblock.

Electrocardiographic diagnosis of acute coronary occlusion can be difficult in the setting of left bundle branch block. If presumably new bundle branch block is considered equivalent to ST-elevation myocardial infarction, unnecessary coronary angiographies will be performed. On the other hand, the diagnosis of an acute coronary occlusion should not be delayed. Presence of concordant ST-segment changes are specific, but not sensitive, findings in the diagnosis of acute coronary occlusion in patients with left bundle branch block.

New Insights on Verapamil-Sensitive Idiopathic Left Fascicular Tachycardia.

Verapamil-sensitive left fascicular monomorphic ventricular tachycardia (LF-VT) was first described ~4 decades ago. Our knowledge regarding this arrhythmia is evolving continuously. The current review aims to highlight up to date aspects of this arrhythmia focusing on its ECG recognition, new considerations of the reentrant circuit, ablation targets in inducible and non-inducible patients and the approach to LF-VT with multiform morphology.

Clarifying the anatomy of the atrioventricular node artery.

BACKGROUND: Reports of conduction abnormalities necessitating permanent pacemaker implantation due to atrioventricular node artery injury and increasing evidence of stenosis of the atrioventricular node artery in cases of sudden death are of unsolved clinical importance. Unfortunately, technical issues associated with physical and virtual dissections of the atrioventricular conduction axis make it difficult to accurately assess its arterial supply. METHODS: We used a specialized dissection technique to gather anatomical information on the atrioventricular node artery and described them using attitudinally appropriate terminology. RESULTS: The mean number of atrioventricular node artery branches was 1.6 in 103 submacroscopic examinations and 2.3 in 17 histological reconstructions. The artery had 5 origins in the modified AHA anatomy guidelines: distal RCA (#3), 10.4%; right posterior interventricular artery (#4PI), 7.3%; proximal RCA posterolateral branch (proximal #4PL), 76.8%; distal RCA posterolateral branch detouring the coronary sinus (distal #4PL), 1.8%; distal LCX (#13), 3.7%. Histological examination revealed that most atrioventricular node arteries immediately left the distal compact node (71.8%), suggesting that they supply mainly the proximal part of the AV conduction axis. The artery to the atrioventricular node tended to originate from the medial and atrial aspect of RCA posterolateral branch, and supplied adjacent structures within the inferior pyramidal space before entering the compact atrioventricular node. CONCLUSIONS: Based on the visualisation of the atrioventricular conduction axis and its arterial supply, we herein provide the 'gold standard' for understanding the origin, course and distribution of the artery to the atrioventricular node.