Septal Accessory Pathway: Anatomy,Causes for Difficulty,and an Approach to Ablation

Accessory pathway (AP) ablation is one of the most satisfying invasive electrophysiology procedures associated with high success rates and relatively few complications. Nevertheless, when APs are found on the cardiac septum, ablative procedures become complex, and unique pitfalls need to be avoided.These difficulties with septal ablation are magnified in the pediatric population. The relatively small heart, rapid nodal conduction, and proximity of the arterial system specifically complicate septal ablation in children. The electrophysiologist must use every tool in his or her armamentarium, including exact delineation of pathway location, identification of pathway potentials, detection of the presence of pathway slant, etc. In addition, an exact knowledge of the complex anatomy of the cardiac septum, including the posteroseptal space, the aortic cusp region, and the proximity of the AV conduction system and coronary vessels, becomes mandatory.In this review, we describe the developmental anatomy and regional anatomy of septal accessory pathways. We then discuss approaches to map specific to pathways in particularly problematic regions at or near the septum, including venous and aortic cusp related accessory pathways.     

Visualization and functional characterization of the developing murine cardiac conduction system

The cardiac conduction system is a complex network of cells that together orchestrate the rhythmic and coordinated depolarization of the heart. The molecular mechanisms regulating the specification and patterning of cells that form this conductive network are largely unknown. Studies in avian models have suggested that components of the cardiac conduction system arise from progressive recruitment of cardiomyogenic progenitors, potentially influenced by inductive effects from the neighboring coronary vasculature. However, relatively little is known about the process of conduction system development in mammalian species, especially in the mouse, where even the histological identification of the conductive network remains problematic. We have identified a line of transgenic mice where lacZ reporter gene expression delineates the developing and mature murine cardiac conduction system, extending proximally from the sinoatrial node to the distal Purkinje fibers. Optical mapping of cardiac electrical activity using a voltage-sensitive dye confirms that cells identified by the lacZ reporter gene are indeed components of the specialized conduction system. Analysis of lacZ expression during sequential stages of cardiogenesis provides a detailed view of the maturation of the conductive network and demonstrates that patterning occurs surprisingly early in embryogenesis. Moreover, optical mapping studies of embryonic hearts demonstrate that a murine His-Purkinje system is functioning well before septation has completed. Thus, these studies describe a novel marker of the murine cardiac conduction system that identifies this specialized network of cells throughout cardiac development. Analysis of lacZ expression and optical mapping data highlight important differences between murine and avian conduction system development. Finally, this line of transgenic mice provides a novel tool for exploring the molecular circuitry controlling mammalian conduction system development and should be invaluable in studies of developmental mutants with potential structural or functional conduction system defects.     

Electrophysiology and anatomy of embryonic rabbit hearts before and after septation

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 1) 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 postseptated (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 connecting 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.     

Cardiac electrophysiology consultative experience at the epicenter of the COVID-19 pandemic in the United States

BackgroundThe COVID-19 pandemic has greatly altered the practice of cardiac electrophysiology around the world for the foreseeable future. Professional organizations have provided guidance for practitioners, but real-world examples of the consults and responsibilities cardiac electrophysiologists face during a surge of COVID-19 patients is lacking.MethodsIn this observational case series we report on 29 consecutive inpatient electrophysiology consultations at a major academic medical center in New York City, the epicenter of the pandemic in the United States, during a 2 week period from March 30-April 12, 2020, when 80% of hospital beds were occupied by COVID-19 patients, and the New York City metropolitan area accounted for 10% of COVID-19 cases worldwide.ResultsReasons for consultation included: Atrial tachyarrhythmia (31%), cardiac implantable electronic device management (28%), bradycardia (14%), QTc prolongation (10%), ventricular arrhythmia (7%), post-transcatheter aortic valve replacement conduction abnormality (3.5%), ventricular pre-excitation (3.5%), and paroxysmal supraventricular tachycardia (3.5%). Twenty-four patients (86%) were positive for COVID-19 by nasopharyngeal swab. All elective procedures were canceled, and only one urgent device implantation was performed. Thirteen patients (45%) required in-person evaluation and the remainder were managed remotely.ConclusionOur experience shows that the application of a massive alteration in workflow and personnel forced by the pandemic allowed our team to efficiently address the intersection of COVID-19 with a range of electrophysiology issues. This experience will prove useful as guidance for emerging hot spots or areas affected by future waves of the pandemic.     

Cardiac Conduction System: Delineation of Anatomic Landmarks With Multidetector CT

Major components of the cardiac conduction system including the sinoatrial node (SAN), atrioventricular node (AVN), the His Bundle, and the right and left bundle branches are too small to be directly visualized by multidetector CT (MDCT) given the limited spatial resolution of current scanners. However, the related anatomic landmarks and variants of this system a well as the areas with special interest to electrophysiologists can be reliably demonstrated by MDCT. Some of these structures and landmarks include the right SAN artery, right atrial cavotricuspid isthmus, Koch triangle, AVN artery, interatrial muscle bundles, and pulmonary veins. In addition, MDCT has an imperative role in demarcating potential arrhythmogenic structures. The aim of this review will be to assess the extent at which MDCT can outline the described anatomic landmarks and therefore provide crucial information used in clinical practice.     

Development of the cardiac pacemaking and conduction system

The heartbeat is initiated and coordinated by a heterogeneous set of tissues, collectively referred to as the pacemaking and conduction system (PCS). While the structural and physiological properties of these specialized tissues has been studied for more than a century, distinct new insights have emerged in recent years. The tools of molecular biology and the lessons of modern embryology are beginning to uncover the mechanisms governing induction, patterning and developmental integration of the PCS. In particular, significant advances have been made in understanding the developmental biology of the fast conduction network in the ventricles--the His-Purkinje system. Although this progress has largely been made by using animal models such as the chick and mouse, the insights gained may help explain cardiac disease in humans, as well as lead to new treatment strategies.     

结构植物学在中国的五十年发展

结构植物学由植物解剖学发展而来,是植物学的一个重要分支学科.本文根据其近代的发展,分别就植物发育解剖学向植物发育生物学的发展、植物比较解剖学向植物系统发育生物学的发展,以及环境生态结构植物学三个主要部分简要介绍了50年来在我国的发展,并对它们的发展趋势进行了预测.     

结构植物学在中国的五十年发展

结构植物学由植物解剖学发展而来 ,是植物学的一个重要分支学科。本文根据其近代的发展 ,分别就植物发育解剖学向植物发育生物学的发展、植物比较解剖学向植物系统发育生物学的发展 ,以及环境生态结构植物学三个主要部分简要介绍了 5 0年来在我国的发展 ,并对它们的发展趋势进行了预测     

Specification of the mouse cardiac conduction system in the absence of Endothelin signaling

Coordinated contraction of the heart is essential for survival and is regulated by the cardiac conduction system. Contraction of ventricular myocytes is controlled by the terminal part of the conduction system known as the Purkinje fiber network. Lineage analyses in chickens and mice have established that the Purkinje fibers of the peripheral ventricular conduction system arise from working myocytes during cardiac development. It has been proposed, based primarily on gain-of-function studies, that Endothelin signaling is responsible for myocyte-to-Purkinje fiber transdifferentiation during avian heart development. However, the role of Endothelin signaling in mammalian conduction system development is less clear, and the development of the cardiac conduction system in mice lacking Endothelin signaling has not been previously addressed. Here, we assessed the specification of the cardiac conduction system in mouse embryos lacking all Endothelin signaling. We found that mouse embryos that were homozygous null for both ednra and ednrb, the genes encoding the two Endothelin receptors in mice, were born at predicted Mendelian frequency and had normal specification of the cardiac conduction system and apparently normal electrocardiograms with normal QRS intervals. In addition, we found that ednra expression within the heart was restricted to the myocardium while ednrb expression in the heart was restricted to the endocardium and coronary endothelium. By establishing that ednra and ednrb are expressed in distinct compartments within the developing mammalian heart and that Endothelin signaling is dispensable for specification and function of the cardiac conduction system, this work has important implications for our understanding of mammalian cardiac development.     

Induction and patterning of the cardiac conduction system

The cardiac conduction system (CCS) is the component of the heart that initiates and maintains a rhythmic heartbeat. As the embryonic heart forms, the CCS must continue to develop and mature in a coordinated manner to ensure that proper pace making potential and distribution of action potential is maintained at all stages. This requires not only the formation of distinct and disparate components of the CCS, but the integration of these components into a functioning whole as the heart matures. Though research in this area of development may have lagged behind other areas of heart development, in recent years there has been much progress in understanding the ontogeny of the CCS and the developmental cues that drive its formation. This is largely due to studies on the avian heart as well as the use of molecular biology approaches. This review gives a perspective on advances in understanding the development of the vertebrate CCS, and reports new data illuminating the mechanism of conduction cell determination and maintenance in the mammalian heart. As much of our knowledge about the development of the CCS has been derived from the chick embryo, one important area facing the field is the relationship and similarities between the structure and development of avian and mammalian conduction systems. Specifically, the morphology of the distal elements of the mammalian CCS and the manner in which its components are recruited from working cardiomyocytes are areas of research that will, hopefully, receive more attention in the near future. A more general and outstanding question is how the disparate components of all vertebrate conduction systems integrate into a functional entity during embryogenesis. There is mounting evidence linking the patterning and formation of the CCS to instructive cues derived from the cardiac vasculature and, more specifically, to hemodynamic-responsive factors produced by cardiac endothelia. This highlights the need for a greater understanding of the biophysical forces acting on, and created by, the cardiovascular system during embryonic development. A better understanding of these processes will be necessary if therapeutics are to be developed that allow the regeneration of damaged cardiac tissues or the construction of biologically engineered heart tissues.     

Inter-model consistency and complementarity: learning from ex-vivo imaging and electrophysiological data towards an integrated understanding of cardiac physiology

Computational models of the heart at various scales and levels of complexity have been independently developed, parameterised and validated using a wide range of experimental data for over four decades. However, despite remarkable progress, the lack of coordinated efforts to compare and combine these computational models has limited their impact on the numerous open questions in cardiac physiology. To address this issue, a comprehensive dataset has previously been made available to the community that contains the cardiac anatomy and fibre orientations from magnetic resonance imaging as well as epicardial transmembrane potentials from optical mapping measured on a perfused ex-vivo porcine heart. This data was used to develop and customize four models of cardiac electrophysiology with different level of details, including a personalized fast conduction Purkinje system, a maximum a posteriori estimation of the 3D distribution of transmembrane potential, the personalization of a simplified reaction-diffusion model, and a detailed biophysical model with generic conduction parameters. This study proposes the integration of these four models into a single modelling and simulation pipeline, after analyzing their common features and discrepancies. The proposed integrated pipeline demonstrates an increase prediction power of depolarization isochrones in different pacing conditions.     

Cardiac Arrhythmias In Congenital Heart Diseases

Arrhythmias figure prominently among the complications encountered in the varied and diverse population of patients with congenital heart disease, and are the leading cause of morbidity and mortality. The incidence generally increases as the patient ages, with multifactorial predisposing features that may include congenitally malformed or displaced conduction systems, altered hemodynamics, mechanical or hypoxic stress, and residual or postoperative sequelae. The safe and effective management of arrhythmias in congenital heart disease requires a thorough appreciation for conduction system variants, arrhythmia mechanisms, underlying anatomy, and associated physiology. We, therefore, begin this review by presenting the scope of the problem, outlining therapeutic options, and summarizing congenital heart disease-related conduction system anomalies associated with disorders of the sinus node and AV conduction system. Arrhythmias encountered in common forms of congenital heart disease are subsequently discussed. In so doing, we touch upon issues related to risk stratification for sudden death, implantable cardiac devices, catheter ablation, and adjuvant surgical therapy.     

Wolff-Parkinson-White syndrome with an unroofed coronary sinus without persistent left superior vena cava treated with catheter cryoablation

Coronary sinus anomalies are rare congenital defects which are usually coexistent with a persistent left superior vena cava and may be associated with cardiac arrhythmias. We report an unroofed coronary sinus without persistent left superior vena cava diagnosed during a catheter ablation procedure for Wolff-Parkinson-White syndrome. Diagnostic and therapeutic options and outcomes are discussed. This condition is of relevance to electrophysiologists performing catheter-based procedures, as well as cardiologists implanting coronary sinus pacing leads, who may encounter this anomaly in their practice.     

Hemodynamic Forces Regulate Developmental Patterning of Atrial Conduction

Anomalous action potential conduction through the atrial chambers of the heart can lead to severe cardiac arrhythmia. To date, however, little is known regarding the mechanisms that pattern proper atrial conduction during development. Here we demonstrate that atrial muscle functionally diversifies into at least two heterogeneous subtypes, thin-walled myocardium and rapidly conducting muscle bundles, during a developmental window just following cardiac looping. During this process, atrial muscle bundles become enriched for the fast conduction markers Cx40 and Nav1.5, similar to the precursors of the fast conduction Purkinje fiber network located within the trabeculae of the ventricles. In contrast to the ventricular trabeculae, however, atrial muscle bundles display an increased proliferation rate when compared to the surrounding myocardium. Interestingly, mechanical loading of the embryonic atrial muscle resulted in an induction of Cx40, Nav1.5 and the cell cycle marker Cyclin D1, while decreasing atrial pressure via in vivo ligation of the vitelline blood vessels results in decreased atrial conduction velocity. Taken together, these data establish a novel model for atrial conduction patterning, whereby hemodynamic stretch coordinately induces proliferation and fast conduction marker expression, which in turn promotes the formation of large diameter muscle bundles to serve as preferential routes of conduction.     

Apoptosis in cardiac development

Cell degeneration, as a phenomenon accompanying developmental processes, was originally described over a century ago. Apoptosis, a term introduced approximately three decades ago, has occupied investigators particularly with respect to cell and tissue kinetics, emphasizing its role in the disposal of supernumerary, malinstructed or damaged cells. Although apoptosis is mostly related to developmental processes, evidence has been gathered indicating that it may also perform other roles. In this review, which concentrates on cardiac development, we examine focal apoptosis and subsequent signal cascades in combination with timed morphogenetic events. Apoptosis mainly occurs in the non-myocardial compartment of the embryonic heart, a compartment that consists of cells derived from the endocardium, the epicardium and the neural crest. The last-mentioned population invades the outflow tract and the atrioventricular endocardial cushions. The signalling cascade seems to involve the activation of latent transforming growth factor beta, resulting in cardiomyocyte migration and subsequent myocardialization of the endocardial cushions. Aberrant apoptosis accompanies cardiac anomalies. Furthermore, an apoptotic population is found surrounding the developing conduction system. A possible role for differentiation is suggested.     

Development of electrical activity in cardiac myocyte aggregates derived from mouse embryonic stem cells

Embryonic stem cells differentiate into cardiac myocytes, repeating in vitro the structural and molecular changes associated with cardiac development. Currently, it is not clear whether the electrophysiological properties of the multicellular cardiac structure follow cardiac maturation as well. In long-term recordings of extracellular field potentials with microelectrode arrays consisting of 60 substrate-integrated electrodes, we examined the electrophysiological properties during the ongoing differentiation process. The beating frequency of the growing preparations increased from 1 to 5 Hz concomitant to a decrease of the action potential duration and action potential rise time. A developmental increase of the conduction velocity could be attributed to an increased expression of connexin43 gap junction channels. Whereas isoprenalin elicited a positive chronotropic response from the first day of spontaneous beating onward, a concentration-dependent negative chronotropic effect of carbachol only developed after approximately 4 days. The in vitro development of the three-dimensional cardiac preparation thus closely follows the development described for the mouse embryonic heart, making it an ideal model to monitor the differentiation of electrical activity in embryonic cardiomyocytes.     

Notch signaling plays a key role in cardiac cell differentiation

Results from lineage tracing studies indicate that precursor cells in the ventricles give rise to both cardiac muscle and conduction cells. Cardiac conduction cells are specialized cells responsible for orchestrating the rhythmic contractions of the heart. Here, we show that Notch signaling plays an important role in the differentiation of cardiac muscle and conduction cell lineages in the ventricles. Notch1 expression coincides with a conduction marker, HNK-1, at early stages. Misexpression of constitutively active Notch1 (NIC) in early heart tubes in chick exhibited multiple effects on cardiac cell differentiation. Cells expressing NIC had a significant decrease in expression of cardiac muscle markers, but an increase in expression of conduction cell markers, HNK-1, and SNAP-25. However, the expression of the conduction marker connexin 40 was inhibited. Loss-of-function study, using a dominant-negative form of Suppressor-of-Hairless, further supports that Notch1 signaling is important for the differentiation of these cardiac cell types. Functional studies show that the expression of constitutively active Notch1 resulted in abnormalities in ventricular conduction pathway patterns.     

Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.