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.

[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.

High resolution 3-Dimensional imaging of the human cardiac conduction system from microanatomy to mathematical modeling.

Cardiac arrhythmias and conduction disturbances are accompanied by structural remodelling of the specialised cardiomyocytes known collectively as the cardiac conduction system. Here, using contrast enhanced micro-computed tomography, we present, in attitudinally appropriate fashion, the first 3-dimensional representations of the cardiac conduction system within the intact human heart. We show that cardiomyocyte orientation can be extracted from these datasets at spatial resolutions approaching the single cell. These data show that commonly accepted anatomical representations are oversimplified. We have incorporated the high-resolution anatomical data into mathematical simulations of cardiac electrical depolarisation. The data presented should have multidisciplinary impact. Since the rate of depolarisation is dictated by cardiac microstructure, and the precise orientation of the cardiomyocytes, our data should improve the fidelity of mathematical models. By showing the precise 3-dimensional relationships between the cardiac conduction system and surrounding structures, we provide new insights relevant to valvar replacement surgery and ablation therapies. We also offer a practical method for investigation of remodelling in disease, and thus, virtual pathology and archiving. Such data presented as 3D images or 3D printed models, will inform discussions between medical teams and their patients, and aid the education of medical and surgical trainees.

Morphological study of the atrioventricular conduction system and Purkinje fibers in yak.

We studied the morphology of the atrioventricular conduction system (AVCS) and Purkinje fibers of the yak. Light and transmission electron microscopy were used to study the histological features of AVCS. The distributional characteristics of the His-bundle, the left bundle branch (LBB), right bundle branch (RBB), and Purkinje fiber network of yak hearts were examined using gross dissection, ink injection, and ABS casting. The results showed that the atrioventricular node (AVN) of yak located in the right side of interatrial septum and had a flattened ovoid shape. The AVN of yak is composed of the slender, interweaving cells formed almost entirely of the transitional cells (T-cells). The His-bundle extended from the AVN, and split into left LBB and RBB at the crest of the interventricular septum. The LBB descended along the left side of interventricular septum. At approximately the upper 1/3 of the interventricular septum, the LBB typically divided into three branches. The RBB ran under the endocardium of the right side of interventricular septum, and extended to the base of septal papillary muscle, passed into the moderator band, crossed the right ventricular cavity to reach the base of anterior papillary muscle, and divided into four fascicles under the subendocardial layer. The Purkinje fibers in the ventricle formed a complex spatial network. The distributional and cellular component characteristics of the AVCS and Purkinje fibers ensured normal cardiac function.

About the specialized myocardial conducting tissue / Acerca del tejido miocárdico especializado de excitoconducción

The chronological succession of discoveries on the location and structure of the atrio-ventricular conducting system are described. The starting point of this system is located in the sinus atrial node, identified by the English scientists A. Keith and M. W. Flack in 1907. The atrioventricular conducting system was pointed out by the Swiss physician Wilhelm His Jr. in 1893. The atrioventricular node (AV) was first identified by the Japanese pathologist Sumao Tawara and his German professor Ludwig Aschoff in 1906. Likewise the structure and routes of the three internodal bundles are described. These bundles include: Bachmann's bundle (1916) connecting the right with the left atrium and the AV node; the middle Wenckebach's bundle (1910) and the posterior or Thorel's bundle (1910), extending from the region of the sinus atrial node towards the posterior margin of the AV node. Lastly, the ventricular left and right conduction systems are detailed. These include the main trunk and their peripheral subdivisions with respective networks. Regarding the controversial existence of the left middle subdivision, it can exist in animal and human hearts. Nevertheless, an intermediate left septal network of specialized fibers seems to act as a functional equivalent of this subdivision.

Se describe, en orden cronológico, la sucesión del descubrimiento de la localización y la estructura de los componentes del sistema de conducción auriculoventricular. El haz de conducción AV fue descrito por el médico suizo Wilhelm His Jr. en 1893. El punto de origen de dicho sistema se halla en el nodo sinoauricular, identificado por los ingleses A. Keith y M.W. Flack en 1907. El nodo auriculoventricular (AV) fue identificado por el patólogo japonés Sunao Tawara y su maestro, el alemán Ludwig Aschoff, en 1906. Asimismo se relatan la estructura y los recorridos de los 3 haces internodales: el anterior o de Bachmann (1916), que conecta la aurícula derecha con la izquierda y el nodo AV; el medio o haz de Wenckebach (1910) y el posterior o haz de Thórel (1910), que se dirige desde la región del nodo sinoauricular hacia la aurícula izquierda y el margen de atrás del nodo AV. Se presentan asimismo, de forma esquemática, los sistemas de conducción ventricular izquierdo y derecho, que comprenden el tronco principal y las subdivisiones periféricas con sus respectivas redes de Purkinje. Respecto a la controvertida existencia de un fascículo izquierdo medio, éste sí puede existir en corazones humanos y de animales. Pero la red septal intermedia de fibras especializadas parece ser un equivalente funcional de dicho fascículo.

Personalization of atrial anatomy and electrophysiology as a basis for clinical modeling of radio-frequency ablation of atrial fibrillation.

Multiscale cardiac modeling has made great advances over the last decade. Highly detailed atrial models were created and used for the investigation of initiation and perpetuation of atrial fibrillation. The next challenge is the use of personalized atrial models in clinical practice. In this study, a framework of simple and robust tools is presented, which enables the generation and validation of patient-specific anatomical and electrophysiological atrial models. Introduction of rule-based atrial fiber orientation produced a realistic excitation sequence and a better correlation to the measured electrocardiograms. Personalization of the global conduction velocity lead to a precise match of the measured P-wave duration. The use of a virtual cohort of nine patient and volunteer models averaged out possible model-specific errors. Intra-atrial excitation conduction was personalized manually from left atrial local activation time maps. Inclusion of LE-MRI data into the simulations revealed possible gaps in ablation lesions. A fast marching level set approach to compute atrial depolarization was extended to incorporate anisotropy and conduction velocity heterogeneities and reproduced the monodomain solution. The presented chain of tools is an important step towards the use of atrial models for the patient-specific AF diagnosis and ablation therapy planing.

Morphological remarks regarding the structure of conduction system in the right ventricle.

BACKGROUND: The knowledge of conduction system morphology has a vital significance in cardiology and cardiac surgery - it enables to interpret pathologies and choose treatment. This has been confirmed by numerous accounts, both in the context of e.g. atrial fibrillation ablations as well as treating septum defects. Due to diversity and changeability of conduction system structure and their clinical implications, its thorough analyses seem to bear special importance. AIM: To examine the structure of selected elements of conduction system present in the right ventricle (RV). METHODS: Elements of conduction system present in RV of 6 foetuses (from 12 to 32 weeks of foetus age), 6 children (from 1 day to 7-year-old) and 10 adults (from 37 to 79-year-old) were histologically examined. Cross sections of 10 moderator bands and 10 anterior papillary muscles of adult human hearts were made. Specimens including membranous and muscular parts of the septum along with diverging moderator band were taken from a group of foetus, child and adult hearts. Cuttings of 10 micron width were stained with Masson's method in Goldner's modification. On the basis of the sections of membranous and muscular parts of the septum, the continuities of the elements of the conduction system were analysed. RESULTS: It was observed that in most cases the right branch of His' bundle locates itself deep in the muscular tissue of the septum irrespective of age; it is clearly separate along its whole run and gradually penetrates the muscular tissue with its fibers. Hardly ever does the right branch of His' bundle locate itself on the surface, subendocardially, with a minimum penetration into the muscular tissue. Moreover, in most cases, elements of conduction system are present in moderator band. The main tissue constituting its stroma is above all muscular tissue and to a lesser extent, connective tissue. In addition to this, fat tissue in variable proportion was also observed. In cross sections of the moderator band a distinctively circumscribed stripe of fibers of the conduction system was found. However, one could also observe samples in which its identification was not possible. CONCLUSIONS: The right branch of His bundle within the muscular part of the septum in most cases is located intramuscularly irrespective of age. The results of analyses prove a relatively constant character of the presence of the conduction system within the moderator band.

Cardiac anatomy for the interventional arrhythmologist: I.terminology and fluoroscopic projections.

Cardiac anatomy is complex and its understanding is essential for the interventional arrhythmologist. The first difficulty is the terminology used to describe the location of sites of mapping and ablation. For many years, electrophysiologists have named these positions following the conventional electrocardiographical vocabulary, or the terminology used by surgeons performing arrhythmic surgery. This traditional nomenclature, however, failed to take note of the crucial principle of considering the location of the heart in the human body as viewed in its erect position. In other words, it had failed to use an attitudinally appropriate terminology. Almost 10 years ago, a new attitudinal nomenclature was proposed for the right and left atrioventricular junctions. In this first of a series of reviews of cardiac anatomy as seen by the interventional arrhythmologist, we discuss the role of attitudinally appropriate terminology, and relate this to the projections used for cardiac fluoroscopy, fluorography, and angiography. Throughout our series of reviews, we will illustrate the value of The Visible Human Slice and Surface Server in facilitating the understanding of the fluoroscopic anatomy. (PACE 2010; 497-507).

Aortic fat pad and atrial fibrillation: cardiac lymphatics revisited.

The lymphatics of the heart have not generated any broad or sustained interest among clinicians. Few publications on cardiac lymphatics are available, the anatomy is not routinely known and the true role of cardiac lymphatics remains doubtful. One important anatomical concept needing clarification is that of the lymphatic drainage of conduction tissue. The sinoatrial node lymphatic collector and right principal lymphatic trunk are both incorporated into the aortic fat pad of the ascending aorta and are the most frequently damaged lymphatic vessels during cardiac surgery. Thus, preservation of the aortic fat pad and its lymphatic collectors should reduce the incidence of new atrial fibrillation observed in patients after cardiac surgery. This review assesses current knowledge of cardiac lymphatics and shows their possible role in triggering arrhythmias in the postoperative period.

The tight junction protein CAR regulates cardiac conduction and cell-cell communication.

The Coxsackievirus-adenovirus receptor (CAR) is known for its role in virus uptake and as a protein of the tight junction. It is predominantly expressed in the developing brain and heart and reinduced upon cardiac remodeling in heart disease. So far, the physiological functions of CAR in the adult heart are largely unknown. We have generated a heart-specific inducible CAR knockout (KO) and found impaired electrical conduction between atrium and ventricle that increased with progressive loss of CAR. The underlying mechanism relates to the cross talk of tight and gap junctions with altered expression and localization of connexins that affect communication between CAR KO cardiomyocytes. Our results indicate that CAR is not only relevant for virus uptake and cardiac remodeling but also has a previously unknown function in the propagation of excitation from the atrium to the ventricle that could explain the association of arrhythmia and Coxsackievirus infection of the heart.

Epicardial and intramural excitation during ventricular pacing: effect of myocardial structure.

Published studies show that ventricular pacing in canine hearts produces three distinct patterns of epicardial excitation: elliptical isochrones near an epicardial pacing site, with asymmetric bulges; areas with high propagation velocity, up to 2 or 3 m/s and numerous breakthrough sites; and lower velocity areas (<1 m/s), where excitation moves across the epicardial projection of the septum. With increasing pacing depth, the magnitude of epicardial potential maxima becomes asymmetric. The electrophysiological mechanisms that generate the distinct patterns have not been fully elucidated. In this study, we investigated those mechanisms experimentally. Under pentobarbital anesthesia, epicardial and intramural excitation isochrone and potential maps have been recorded from 22 exposed or isolated dog hearts, by means of epicardial electrode arrays and transmural plunge electrodes. In five experiments, a ventricular cavity was perfused with diluted Lugol solution. The epicardial bulges result from electrotonic attraction from the helically shaped subepicardial portions of the wave front. The high-velocity patterns and the associated multiple breakthroughs are due to involvement of the Purkinje network. The low velocity at the septum crossing is due to the missing Purkinje involvement in that area. The asymmetric magnitude of the epicardial potential maxima and the shift of the breakthrough sites provoked by deep stimulation are a consequence of the epi-endocardial obliqueness of the intramural fibers. These results improve our understanding of intramural and epicardial propagation during premature ventricular contractions and paced beats. This can be useful for interpreting epicardial maps recorded at surgery or inversely computed from body surface ECGs.

Anisotropic wave propagation and apparent conductivity estimation in a fast electrophysiological model: application to XMR interventional imaging.

Cardiac arrhythmias are increasingly being treated using ablation procedures. Development of fast electrophysiological models and estimation of parameters related to conduction pathologies can aid in the investigation of better treatment strategies during Radio-frequency ablations. We present a fast electrophysiological model incorporating anisotropy of the cardiac tissue. A global-local estimation procedure is also outlined to estimate a hidden parameter (apparent electrical conductivity) present in the model. The proposed model is tested on synthetic and real data derived using XMR imaging. We demonstrate a qualitative match between the estimated conductivity parameter and possible pathology locations. This approach opens up possibilities to directly integrate modelling in the intervention room.

The autonomic nervous system of the human heart with special reference to its origin, course, and peripheral distribution.

A submacroscopic anatomical investigation of the entire autonomic cardiac nervous system, from origin to peripheral distribution, was performed by examining 36 sides of 18 adult human cadavers under a stereomicroscope. The following new results and points of discussion were obtained: (1) The superior cervical, the middle cervical, the vertebral, and the cervicothoracic (stellate) ganglia, composed of the inferior cervical and 1st thoracic ganglia, were mostly consistent among the specimens. (2) The superior, middle, and inferior cardiac nerves innervated the heart by simply following the descent of the great arteries. In contrast, the thoracic cardiac nerve in the posterior mediastinum followed a complex course because of the long distance to the middle mediastinum. (3) The actual course of the right thoracic cardiac nerve differed from that of the previous descriptions in that it ascended obliquely or ran transversely to the vertebrae, regardless of the intercostal vessels. Regarding the right thoracic cardiac nerve, two descending courses were observed: the descent of the right thoracic cardiac nerve via the azygos vein and right venous porta, and the descent of the recurrent right thoracic cardiac nerve via the aorta. (4) The cranial cardiac nerve and branch tended to distribute into the heart medially, and the caudal cardiac nerve and branch tended to distribute into the heart laterally. (5) The mixing positions (cardiac plexus) of the sympathetic cardiac nerve and the vagal cardiac branch, as well as the definitive morphology of brachial arteries with the recurrent laryngeal nerves, tended to differ on both sides. These new and detailed anatomical descriptions of the human autonomic cardiac nervous system may provide important clues regarding the morphogenesis of autonomic cardiac nerves in addition to contributing to the improvement of cardiac surgery.

How close are the phrenic nerves to cardiac structures? Implications for cardiac interventionalists.

BACKGROUND: Phrenic nerve injury is a recognized complication following cardiac intervention or surgery. With increasing use of transcatheter procedures to treat drug-refractory arrhythmias, clarification of the spatial relationships between the phrenic nerves and important cardiac structures is essential to reduce risks. METHODS AND RESULTS: We examined by gross dissection the courses of the right and left phrenic nerves in 19 cadavers. Measurements were made of the minimal and maximal distances of the nerves to the superior caval vein, superior cavoatrial junction, right pulmonary veins, and coronary veins. Histologic studies were carried out on tissues from six cavaders. Tracing the course of the right phrenic nerve revealed its close proximity to the superior caval vein (minimum 0.3 +/- 0.5 mm) and the right superior pulmonary vein (minimum 2.1 +/- 0.4 mm). The anterior wall of the right superior pulmonary vein was <2 mm from the right phrenic nerve in 32% of specimens. The left phrenic nerve passed over the obtuse cardiac margin and the left obtuse marginal vein and artery in 79% of specimens. In the remaining specimens, its course was anterosuperior, passing over the main stem of the left coronary artery or the anterior descending artery and great cardiac vein. CONCLUSIONS: The right phrenic nerve is at risk when ablations are carried out in the superior caval vein and the right superior pulmonary vein. The left phrenic nerve is vulnerable during lead implantation into the great cardiac and left obtuse marginal veins.

Transcriptional regulation of cardiac conduction system development: 2004 FASEB cardiac conduction system minimeeting, Washington, DC.

The development of the complex network of specialized cells that form the atrioventricular conduction system (AVCS) during cardiac morphogenesis occurs by progressive recruitment within a multipotent cardiomyogenic lineage. Understanding the molecular control of this developmental process has been the focus of recent research. Transcription factors representative of multiple subfamilies have been identified and include members of zinc-finger subfamilies (GATA4, GATA6 HF-1b), skeletal muscle transcription factors (MyoD), T-box genes (Tbx5), and also homeodomain transcription factors (Msx2 and Nkx2.5). Mutations in some of these transcription factors cause congenital heart disease and are associated with cardiac abnormalities, including deficits within the AVCS. Mouse models that closely phenocopy known human heart disease provide powerful tools for the study of molecular effectors of AVCS development. Indeed, investigations of the Nkx2.5 haploinsufficient mouse have shown that peripheral Purkinje fibers are significantly underrepresented. This piece of data corroborates our previous work showing in chick, mouse, and humans that Nkx2.5 is elevated in the differentiating AVCS relative to adjacent working ventricular myocardial tissues. Using the chick embryo as a model, we show that this elevation of Nkx2.5 is transient in the network of conduction cells comprising the peripheral Purkinje fiber system. Functional studies using defective adenoviral constructs, which disrupt the normal variation in level of this gene, result in perturbations of Purkinje fiber phenotype. Thus, the precise spatiotemporal regulation of Nkx2.5 levels during development may be required for the progressive emergence of gene expression patterns specific to differentiated Purkinje fiber cells.

Defects in cardiac conduction system lineages and malignant arrhythmias: developmental pathways and disease.

To unravel the complex disease phenotype of heart failure, we are utilizing an integrative approach employing genomics, physiology, and mouse genetics to identify nodal pathways for specific physiological end points such as myocyte stretch activation responses, contractility and electrical conduction. A new class of genetic pathways for cardiac sudden death and associated arrhythmias has been based on transcription factors that control conduction system lineages, including HF1b/SP4 and NKX2.5. Previous studies have established that HF1b plays a critical role in conduction system lineage formation and the loss of HF1b leads to a confused electrophysiological identity in Purkinje and ventricular cell lineages, resulting in cardiac sudden death and marked tachy and brady arrhythmias. Utilizing Hf1b and Nkx2.5 floxed alleles, we now have identified the primary pathways which link these transcription factors with cardiac arrythmogenesis. Mice which harbour a neural crest restricted knockout of HF1b display marked arrhythmogenesis and conduction system defects, implicating neural crest cues in conduction system development and disease. Mice which harbour a ventricular-restricted knockout of Nkx2.5 display completely normal conduction at birth, but a hypoplastic atrioventricular (AV) node. During maturation, progressive complete heart block ensues, associated with a selective dropout of distal AV nodal cell lineages at the boundaries of the penetrating His bundle. Single cell analyses examining individual nodal cells within AV node of ventricular restricted Nkx2.5 knockout mice clearly document a cell autonomous requirement for NKX2.5 within AV nodal lineages per se. Micro-electrophysiological AV nodal mapping indicates a selective conduction defect at the boundary of the distal AV node and His bundle. HF1b and NKX2.5 reflect new cardiac cell non-autonomous and autonomous pathways for conduction system lineage defects and associated cardiac arrythmogenesis.

The arterial blood supply of the conducting system in normal human hearts.

The distributing artery of the conducting system of the heart is occasionally injured in cardiac surgery. The aim of this study was to define the anatomic characteristics of the principal arterial source of the sinu-atrial node and atrioventricular node. Furthermore, the morphology of the tendon of Todaro was clarified. Thirty hearts were studied by gross anatomic methods, and the exact area of the conducting system was supported by histologic observations of four hearts. The sinu-atrial node was supplied by the right coronary artery more frequently (73% of cases) than by the left (3%), and in 23% of cases this node was supplied by both coronary arteries. The atrioventricular node was supplied by the right coronary artery (80% of cases) more than by the left (10%), and in 10% of the cases this node was supplied by both coronary arteries. The atrioventricular bundle branch arose from the right coronary artery in 10% of cases, the left coronary artery in 73%, and both coronary arteries in 17%. Most of the blood to the right bundle (the moderator band) was supplied by the interventricular septal branches of the anterior interventricular branch from the left coronary artery. Finally, all the arteries of the right bundle and left bundle were defined to be derived from left coronary arteries.

Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts.

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 His-Purkinje system.

Innervation of the heart and aorta of Manduca sexta.

Innervation of the heart and aorta of Manduca sexta was studied by using anatomic, neuronal tracing and immunocytochemical techniques. The study was undertaken to provide a foundation for investigating the neural mechanisms controlling cardiac reversal in adults. Lateral cardiac nerves were not found in the larval or adult heart. The larval heart and aorta seem to lack innervation, but a neurohemal system for the release of a cardioactive peptide is associated with the larval alary muscles. At adult metamorphosis, this neurohemal system regresses, and, at the same time, processes grow onto the anterior aorta. These processes seem to be neurohemal and originate from two pairs of neurosecretory cells located in the subesophageal ganglion. This system is immunoreactive to cardioactive peptides and may function, therefore, in hormonal modulation of the activity of the adult heart. Also during metamorphosis, synaptic innervation develops on the terminal heart chamber, and this innervation is from axons extending through the seventh and eighth dorsal nerves of the terminal abdominal ganglion. These axons originate from cells that have been identified as serial homologs of motor neuron-1 of other abdominal ganglia. These neurons are immunoreactive to a cardioactive peptide, and this peptide probably modulates the synaptic innervation of the terminal heart chamber. During metamorphosis, the target of the motor neurons-1 of the seventh and eighth segments becomes respecified from larval skeletal muscles to the terminal chamber of the adult heart.