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Objectives: The purpose of this study was to characterize the pattern of atrial remodeling seen with human aging., Background: Atrial fibrillation (AF) occurs in 3% to 4% of the population over 65 years of age. It is associated with thromboembolic complications, worsening heart failure, and increased mortality, yet the electrical and structural remodeling that occurs with human aging remains unknown., Methods: Thirteen patients (66.4 +/- 1.7 years) > or =60 years (group A), 13 patients (50 +/- 2.1 years) age 31 to 59 years (group B), and 15 patients (24.7 +/- 1.0 years) < or =30 years (group C) underwent conventional electrophysiologic studies and electroanatomic mapping. We measured atrial refractoriness (ERP) at the distal coronary sinus (CS); low and high lateral right atrium (LRA) and the high septal right atrium at 600, 500, and 400 ms; maximum corrected sinus node recovery time (CSNRT); P-wave duration (PWD); conduction time (CT) along the CS and LRA; and discrete double potentials (DP) along the crista., Results: Aging was associated with an increase in atrial ERP, prolonged CT along the CS, increased PWD and CSNRT. There was no significant change in dispersion of refractoriness or rate adaptation. Electroanatomic mapping revealed diffuse areas of low voltage with regional conduction slowing. Both techniques demonstrated a greater number of DPs and fractionated signals along the crista terminalis with aging., Conclusions: Aging is associated with regional conduction slowing, anatomically determined conduction delay at the crista, and structural changes that include areas of low voltage. In addition, impairment of sinus node function and an increase in atrial ERP occurred with aging. This electrical and structural remodeling may explain the increased propensity to AF with aging.

Optical mapping of electrical activity from the surface of the heart is a powerful tool for studying complex arrhythmias. However, a limitation of traditional optical mapping is that the mapped region is restricted to the field of view of the sensor, which makes it difficult to track electrical waves as they drift in and out of view. To address this, we developed an optical system that panoramically maps epicardial electrical activity in three dimensions. The system was engineered to accomodate hearts comparable in size to human hearts. It is comprised of a surface scanner that measures epicardial geometry and a panoramic fluorescence imaging system that records electrical activity. Custom software texture maps the electrical data onto a reconstructed epicardial surface. The result is a high resolution, spatially contiguous, mapping dataset. In addition, the three-dimensional positions of the recording sites are known, making it possible to accurately measure parameters that require geometric information, such as propagation velocity. In this paper, we describe the system and demonstrate it by mapping a swine heart.

Objective: The aim of this work was to target a vital reporter gene in the mouse cardiac conduction system (CS) to distinguish this tissue from the surrounding myocardium in the adult heart., Methods: A transgenic mouse line has been created in which EGFP is expressed under the control of the Cx40 gene. Correlative investigations associating EGFP imaging and electrophysiological techniques were carried out on the adult heart and isolated cardiomyocytes., Results: In the heart of the Cx40(EGFP/+) mice, EGFP signal was seen in the coronary arteries, the atria, the atrioventricular (AV) node and the His-Purkinje system. The latter was found to be structurally and functionally asymmetrical. The anatomical asymmetry was apparent in both the number of strands or fasciculi making up the His bundle branches (BBs) (1 strand on the right, 20 or so on the left), and the density (low on the right, high on the left) of the network of Purkinje fibers (PFs) that extends over the ventricular wall surfaces. The profiles of the electrical activation patterns recorded on the right and left flanks of the septum were also asymmetrical, mirroring the architecture of the branches. EGFP made it easy to identify the Purkinje cells in populations of dissociated cardiomyocytes and they were investigated using the patch-clamp technique. The hyperpolarization-activated current (If) was recorded in all spontaneously active Purkinje cells., Conclusions: This investigation provides positive evidence of the asymmetry of the His-Purkinje system of the adult mouse, and the first patch-clamp recording data on murine cardiac Purkinje cells. This mouse model opens up new perspectives for investigating the contribution of specific genes to the morphology and function of the His-Purkinje system.

The presence of left ventricular bands has drawn attention to their possible clinical importance, though there are no concrete data to support their role in serious clinical diseases. We have investigated the incidence, location, microscopic and macroscopic structure of left ventricular bands in the human and animals. We examined 100 hearts: 28 human and 72 animal (dog, goat, sheep). Left ventricular bands were present in 13 of 28 (46%) human hearts and 62 of 72 (86%) animal hearts. The bands usually extended from the interventricular septum to the free walls in human hearts and from the papillary muscles to the interventricular septum in animal hearts. They were composed of muscle tissue in various proportions in human and dog hearts, and of connective and conductive tissue in sheep and goat hearts.

Objective: Previous studies have used acetylcholinesterase (AChE) histochemistry to identify cholinergic nerves in the heart, but this enzyme is not a selective marker for cholinergic neurons. This study maps cholinergic innervation of guinea pig heart using a new antibody to the human high-affinity choline transporter (CHT), which is present only in cholinergic nerves., Methods: Immunohistochemistry was used to localize CHTs in frozen and paraffin sections of heart and whole mount preparations of atrial ganglionated nerve plexus. AChE-positive nerve fibers were identified in sections from separate hearts for comparison., Results: Control experiments established that the antibody to human CHT selectively labeled cholinergic neurons in the guinea pig. CHT-immunoreactive nerve fibers and AChE-positive nerves were very abundant in the sinus and AV nodes, bundle of His, and bundle branches. Both markers also delineated a distinct nerve tract in the posterior wall of the right atrium. AChE-positive nerve fibers were more abundant than CHT-immunoreactive nerves in working atrial and ventricular myocardium. CHT-immunoreactive nerves were rarely observed in left ventricular free wall. Both markers were associated with numerous parasympathetic ganglia that were distributed along the posterior atrial walls and within the interatrial septum, including the region of the AV node., Conclusions: Comparison of labeling patterns for CHT and AChE suggests that AChE histochemistry overestimates the density of cholinergic innervation in the heart. The distribution of CHT-immunoreactive nerve fibers and parasympathetic ganglia in the guinea pig heart suggests that heart rate, conduction velocity, and automaticity are precisely regulated by cholinergic innervation. In contrast, the paucity of CHT-immunoreactive nerve fibers in left ventricular myocardium implies that vagal efferent input has little or no direct influence on ventricular contractile function in the guinea pig.

Stimulation of myocardium by either a native pacemaker or an artificial stimulus requires the initiation of a self-propagating wave of depolarization originating from the site of initial activation. In the present study we perform artificial stimulation at a site of focal discharge with the aim to compare the two mechanisms of impulse formation. High resolution epicardial mapping in senescent rat hearts provided examples of focal discharge during sinus rhythm at a single epicardial breakthrough (BKT) point emerging from an isolated Purkinje-ventricular muscle junction (PMJ) site. Stimulation was also performed at the same BKT point and potential distributions recorded during spontaneous and artificial stimulation were compared. During excitation latency, the negative potential pattern was elongated perpendicularly to fiber direction at both pacing and BKT point, in agreement with virtual cathode membrane polarization predicted by the bidomain model during point stimulation. During impulse initiation, activation wave fronts were initially circular around pacing site or BKT point and then elongated along local fiber direction. The similarity between impulse initiation during focal discharge and point stimulation in cardiac muscle suggests that high resolution pace mapping studies can help to elucidate the mechanism of abnormal impulse formation.

Introduction and Objectives: The recent introduction of navigation systems has made substantial improvements in cardiac electrophysiological mapping. We present our experience with non-fluoroscopic electroanatomical mapping in patients with atrial tachycardias., Patients and Method: We studied 24 consecutive patients with atrial tachycardias (10 of whom had undergone previous radiofrequency ablation which failed). In all patients we performed electroanatomical mapping of the atria with the CARTO system, which combines electrophysiological and spatial information and allows visualization of atrial activation in a three-dimensional anatomical reconstruction of the atrial cavity. Mapping was performed during tachycardia (22 patients) or in sinus rhythm (2 patients), using a left atrial approach in 12 patients. Cooled-tip ablation was performed in 3 patients., Results: Three-dimensional mapping distinguished clearly and rapidly between reentrant (9 patients) and focal mechanisms (15 patients). Radiofrequency catheter ablation was aimed at the critical isthmus of conduction (voltage maps) in patients with macroreentrant tachycardias. For focal tachycardias the catheter was re-navigated within the target area (activation maps) to the earliest focus of ectopic impulses. Acute success was obtained in 19 patients (79.2%), with early recurrence in 2 of them. Fluoroscopy time was 60 (21 min)., Conclusions: Visualization of atrial activation in a three-dimensional reconstruction of the atria with the CARTO electroanatomical mapping system facilitated the integration of electrophysiological and anatomical information in patients with atrial tachycardias. This technique is potentially helpful in ensuring successful treatment of the substrate of tachycardia in this selected group of patients.

The aim of the present study was to elucidate both the topography and architecture of the rat intrinsic cardiac nerve plexus, as this species becomes a frequent mammalian model for electrophysiological investigations of the intracardiac nervous system. Fifteen adult rats were examined employing histochemistry for acetylcholinesterase to visualize the intracardiac nerve plexus in hearts. Extracardiac nerves entering the rat heart were found amid aorta and pulmonary trunk as well as along both right and left cranial veins. The nerves from the arterial part of the heart hilum extended directly to the ventricles but the nerves from the venous part of the hilum interconnected among themselves forming a nerve plexus of the cardiac hilum on the heart base. Within the rat epicardium, intrinsic nerves clustered into six routes by which they selectively projected to different rat heart regions. Ventral wall of the ventricles was supplied by three neural subplexuses, dorsal ventricular wall--by one subplexus; each atrium received nerves from two distinct subplexuses. In conclusion, this morphological study demonstrates that rat intracardiac nerve plexus compounds to anatomical scheme of the same plexus in human, therefore rat is a usable model for electrophysiological experiments of the intracardiac nervous system.

Objective: To delineate the electrophysiological properties of transseptal conduction from the left to the right atrium in patients with paroxysmal atrial fibrillation (AF)., Design and Results: Right atrial mapping using the electroanatomic mapping technique was performed at 111 +/- 16 sites in 16 patients with paroxysmal AF during pacing from distal coronary sinus (CS). A single transseptal breakthrough near the CS ostium was observed in all patients. The activation time from the pacing site to the earliest septal activation site was 47 +/- 13 ms. The total septal activation time (68 +/- 16 ms) was markedly longer but the total right atrial activation time (118 +/- 17 ms) was similar to that in patients without AF in a previous observation., Conclusion: During distal CS pacing, a preferential site of transseptal conduction near the CS ostium was demonstrated in patients with paroxysmal AF. This has clinical implications when surgical dissection or catheter ablation is considered to eliminate interatrial connection in patients with AF.

In a recent paper, we described the behavior of the cardiac electric near-field, E, parallel to the tissue surface during continuous conduction. We found that the tip of E describes a vector-loop during depolarization with the peak field, E, pointing opposite to the direction of propagation, phiI(m). Experimentally recorded loop morphologies of E, however, frequently showed significant deviations from the theoretically predicted behavior. We hypothesized that this variety of morphologies might be caused by conduction obstacles at a microscopic size scale. This study examines the influence of obstacles on the morphology of vector loops of E and whether the peak of distorted loops remains a reliable indicator for the direction of propagation. We used a computer model of a sheet of cardiac tissue with a central conduction obstacle immersed in an unbounded volume conductor. We studied the loop morphologies of E and the differences between the intracellularly determined direction of propagation, phiI(m), and the direction of E, phiE. Distortions of the vector loop were morphologically similar to those observed experimentally. Differences between phiI(m) and phiE were less than 18 degrees at all observation sites. The obstacle led to deformations of the loop morphology, particularly during the initial and terminal phases, and to a lesser degree near the instant of E. We concluded that E is a reliable indicator of phiI(m).

Concomitant with the development of catheter ablation techniques for the treatment of atrial arrhythmias, there has been renewed interest in the morphologic arrangement of the cardiac conduction system. The first descriptions of the anatomy of the nodes and atrioventricular conduction system appeared nearly 100 years ago. Since then the subject has been controversial, possibly because of the early researchers' imprecise knowledge of histology. The components and structure of the specific conduction system in humans are similar to those found in commonly used laboratory animals. The conduction system is composed of specialized myocytes. Its atrial components, the sinus node and the atrioventricular node, are in contact with atrial myocardium. The His bundle penetrates the right fibrous trigone, then divides into two specialized ventricular bundle branches (right and left), which also are surrounded by a fibrous sheath that separates the specialized myocytes from the ordinary myocardium. Only at the distal ramifications of the bundle branches do the fibrous sheaths disappear, allowing continuity with the ventricular myocardium. Knowledge of the specialized myocardium can help in the development of potentially useful therapies for some forms of cardiac arrhythmia.

The study was designed to determine the three-dimensional organization of the rat intrinsic cardiac neural plexus (ICNP) and to ascertain whether the rat heart undergoes a decrease in neuronal number with aging as has been reported for other mammalian species, including human. Juvenile (3-4 weeks of age, n = 14) and adult (more than 2 months of age, n = 23) animals were examined using enzyme histochemistry for acetylcholinesterase in order to visualize the ICNP in total hearts. The number of intrinsic cardiac neurons was estimated by counting nerve cells in serial sections of the atrial pieces stained with cresyl fast violet. The total number of intrinsic cardiac neurons in old rats was 6576 +/- 317. The juvenile animals contained significantly fewer such neurons, only 5009 +/- 332. Approximately 70% of all intracardiac neurons were amassed within the heart hilum, while 30% of the neurons were distributed epicardially. Within the interatrial septum, only 11 +/- 11 neurons were identified in the juvenile and 6 +/- 4 neurons in old rats. Extrinsic nerves entered the rat heart in both the arterial and venous parts of the cardiac hilum. The nerves from the arterial part of the cardiac hilum extended directly to the ventricles but the nerves from the venous part of the hilum formed a particular nerve plexus of the cardiac hilum on the heart base. Within the rat epicardium, intrinsic nerves clustered into six routes by which they selectively projected to different atrial and/or ventricular regions. In conclusion, this study provides a detailed description of the three-dimensional organization of the rat ICNP and contradicts the decrease in neuronal number with aging in the rat heart.

A modified technique of heart dissection is proposed to prevent the damage to the conducting system.

Introduction: Cavotricuspid isthmus (CTI) topography includes ridges, pouches, recesses, and trabeculations. These features may limit the success of radiofrequency ablation (RFA) of typical atrial flutter (AFL). The aim of this study was to assess the utility of phased-array intracardiac echocardiography (ICE) for imaging the CTI and monitoring RFA of AFL., Methods and Results: Fifteen patients (mean age 64 +/- 9 years) underwent ICE assessment (imaging frequency 7.5-10 MHz) before and after RFA of AFL. The ICE catheter was positioned at the inferior vena cava-right atrial junction and the following parameters were measured: (1) CTI length from the tricuspid valve to the eustachian ridge; (2) extent of CTI pouching; and (3) thickness pre/post RFA of the anterior, mid, and posterior CTI. CTI length was 35 +/- 6 mm at end-ventricular systole but shorter (30 +/- 6 mm) and more pouched at end-ventricular diastole (P = 0.02). A pouch or recess was seen in 11 of 15 patients (mean depth 6 +/- 2 mm). The septal CTI was more pouched than the lateral CTI, but the latter had more prominent trabeculations. Trabeculations were seen in 10 of 15 patients, and at these locations the CTI was 4.6 +/- 1 mm thick. Anterior, mid, and posterior CTI thickness pre-RFA was 4.1 +/- 0.8, 3.3 +/- 0.5, and 2.7 +/- 0.9 mm, respectively (P < 0.001 by analysis of variance). ICE guided RFA away from unfavorable CTI features (recesses/thick trabeculations). RFA applications created discrete CTI lesions that coalesced, forming diffuse CTI swelling. Post-RFA thickness was as follows: anterior 4.8 +/- 0.8 mm (P = NS vs pre); mid 3.8 +/- 0.8 mm (P = 0.05 vs pre); and posterior 3.8 +/- 0.8 mm (P = 0.02 vs pre)., Conclusion: Phased-array ICE permits novel real-time CTI imaging with excellent endocardial resolution and may facilitate RFA of AFL.

We present a finite element (FE) derived finite difference (FD) technique for solving cardiac activation problems over deforming geometries using a bidomain framework. The geometry of the solution domain is defined by a FE mesh and over these FEs a high resolution FD mesh is generated. The difference points are located at regular intervals in the normalized material space within each of the FEs. The bidomain equations are then transformed to the embedded FD mesh which provides a solution space that is both regular and orthogonal. The solution points move in physical space with any deformation of the solution domain, but the equations are set up in such a way that the solution is invariant as it is constructed in material space. The derivation of this new solution technique is presented along with a series of examples that demonstrate the accuracy of this bidomain framework.

Background: Conduction velocity (CV) around the tricuspid valve annulus (TVA) during type 1 atrial flutter (AFL) has been shown to be slowest in the tricuspid valve-inferior vena cava (TV-IVC) isthmus, compared to the septal or free wall segments of the TVA. However, fiber orientation in the triangle-of-Koch suggests that the inferior septum and medial TV-IVC isthmus should be the most slowly conducting segments around the TVA., Methods: To test this hypothesis we evaluated CV around the TVA during type 1 atrial flutter in 11 patients, using an electro-anatomical mapping system (Carto). CV was first calculated in 4 segments around the TVA including the TV-IVC isthmus, lateral free wall, superior free wall and septum, and then calculated in 8 segments around the TVA including medial (MI) and lateral isthmus (LI), inferior (IL) and superior lateral (SL) free wall, lateral (LS) and medial superior (MS) free wall, and superior (SS) and inferior septum (IS). Statistical comparison of CV from these multiple segments was made by one-way analysis of variance., Results: Measured in 4 segments around the TVA, mean CV (m/sec) in the TV-IVC isthmus (0.81 +/- 0.23) and the septum (0.93 +/- 0.18) was significantly slower than CV in the lateral free wall (1.16 +/- 0.23) and superior free wall (1.10 +/- 0.20), and CV in the TV-IVC isthmus was significantly slower than in the septum (p < 0.05). However, when analyzed in 8 segments, mean CV in the MI (0.56 +/- 0.16) and IS (0.59 +/- 0.24) was significantly (p < 0.05) slower than in all other segments including the LI (1.06 +/- 0.46), IL (1.17 +/- 0.40), SL (1.15 +/- 0.40), LS (1.04 +/- 0.25), MS (1.15 +/- 0.28), and SS (1.26 +/- 0.36) segments., Conclusions: Consistent with previous reports, CV around the TVA during type 1 AFL was slowest in the TV-IVC isthmus, compared to the septum, superior and lateral free wall regions. However, when the TVA was further subdivided into 8 segments, CV in the MI and IS segments was significantly slower than in all other segments around the TVA. These observations more precisely define the regions of slow conduction in human type 1 AFL, and are consistent with the known anisotropy and slow conduction in the Triangle of Koch.

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.

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.

The neural markers, protein gene product 9.5 (PGP 9.5), neurofilaments (NF) and glutamate receptors (GluRs) were visualized by immunohistochemistry in the monkey heart. PGP 9.5 showed the greatest affinity for intramural ganglia cells and nerve fibres. Structural components of the conducting system were also stained, particularly the bundle of His, AV node and Purkinje fibres. Anti-NF 200 and NF 160 showed strong, preferential affinity to nerve fibres and ganglia throughout the heart. Further studies concentrated on the presence and the distribution of glutamate receptors: NMDAR 1, GluR 1, GluR 2/3, GluR 5/6/7, mGluR 2/3, and mGluR 5. Positive immunoreactivity of GluRs was evident in nerve terminals within the atrium, myocardium, intramural ganglia and elements of the conducting system. The intensity of the stain varied for each antibody according to the anatomical distribution within neural structures and conducting system. The specificity of immunolabelling was confirmed by absorption studies with each corresponding peptide. There is preferential affinity to and differential distribution of staining with PGP 9.5, NFs and several subtypes of GluRs in the various components of the cardiac conducting system in adult monkeys. The expression of specific neural markers and glutamate receptors common to nerve fibers and ganglia cells is consistent to our previous report in rodents. These expressions suggests that such structures in the heart share common characteristics with a variety of neural tissues and hence are potential targets for neurotoxins. Furthermore, the strong affinity and specific distribution of several subtypes of GluRs in the monkey heart fosters our view that these receptors may be able to influence the physiology and pathophysiology of cardiac rhythm and excitation. Hence as in the brain, the GluRs may be involved in the mediation of excitatory effects in the heart.

Although we soon will be marking the 100th anniversary of the discovery of the atrioventricular (AV) node, the mysteries of this most complex of all parts of the conduction system of the heart remain. We are still battling controversies related to the precise morphology of the AV node and its atrial approaches. We are still debating the exact reentrant pathways of the AV nodal reentrant tachycardia. We are still uncertain if the so-called dual AV nodal electrophysiology encompasses two or more pathways, and what exactly makes these pathways in the absence of distinct insulated cables between the atrium and the AV node. It may be just surprising, in view of the above limitations, that current level of knowledge has nevertheless made possible some of the most spectacular successes in the modern cardiac electrophysiology. Thus, the cases of typical AVNRT are cured with a very high rate of success by radiofrequency ablations, increasing the quality of life of thousands of patients. AV nodal modifications are being performed to slow the ventricular rate during atrial fibrillation, although more progress is needed in this endeavor. The goal of the present review is to outline the major anatomic and electrophysiologic efforts in understanding the mechanisms underlying the dual pathway AV nodal propagation and to trace some novel approaches that promise to widen the horizon of the experimental and clinical fields.

During cardiac development the heart tube loops and is septated into a four-chambered structure. The initial peristaltic contraction of the primitive myocardium is replaced by a system of working myocardium and a myocardial-derived central and peripheral conduction system. The genes guiding this differentiation process are still under investigation and it has yet to be decided whether we are dealing with a recruitment or a specification model. We have shown that the complicated looping process of the heart tube brings together the essential parts of the sinoatrial and primary ring myocardium, that are the embryonic precursors of the definitive conduction system. From our studies it is evident that during development there are sinoatrial tracts that run between the sinoatrial and the atrioventricular node as well as tracts surrounding the pulmonary veins and the coronary sinus. Furthermore, we show that both in the chicken and mouse embryo neural crest cells reach the confinement of the central conduction system through the inflow and outflow tract. For the Purkinje system there is a close approximation with the epicardium-derived cells. We postulate that both extracardiac-derived cell types have an influence on the differentiation of the definitive conduction system.

We review here the evolution and development of the earliest components of the cardiac pacemaking and conduction system (PCS) and the turnover or persistence of such cells into old age in the adult vertebrate heart. Heart rate is paced by upstream foci of cardiac muscle near the future sinoatrial junction even before contraction begins. As the tubular heart loops, directional blood flow is maintained through coordinated sphincter function in the forming atrioventricular (AV) canal and outflow segments. Propagation of initially peristaltoid contraction along and between these segments appears to be influenced by physical conditioning and orientation of inner muscle layers as well as by their slow relaxation; all characteristic of definitive conduction tissue. As classical elements of the mature conduction system emerge, such inner 'contour fibres' maintain muscular and electrical continuity between atrial and ventricular compartments. Elements of such primordial architecture are visible also in histological and optical electrical study of fish and frog hearts. In the maturing chick heart, cells within core conducting tissues retain early thymidine labels from the tubular heart stage into adult life, dividing only slowly, if at all. Preliminary evidence from mammals suggest similar function and kinetics for these 'oldest, toughest' cells in the hearts of all vertebrates.

The system responsible for initiation and propagation of the heartbeat became understood within the 20th century. Thus, it was Tawara (in 1906) who clarified the arrangement of the specialized muscular axis responsible for atrioventricular conduction, while Keith & Flack (in 1907) published the first account of the sinus node. Tawara's findings provide robust anatomic criteria for distinction of postnatal conduction pathways. Such pathways should be composed of cells which are histologically discrete, which can be traced from section to section in the histological series, and which are insulated by fibrous sheaths from the adjacent working myocardium. The cells making up the sinus and atrioventricular nodes fulfil the first two of these criteria, whilst those making up the ventricular conduction pathways fulfil all three criteria. The sinus node is found subepicardially within the terminal groove. The atrioventricular node, surrounded by its zones of transitional cells, is at the apex of the triangle of Koch. The penetrating bundle is sandwiched between the fibrous and muscular parts of the ventricular septum, with the bundle branches descending on either side of the septum. Other than nodal remnants found within the tricuspid vestibule, them are no other histologically discrete tracts to be found within the atrial myocardium.

The cardiac conduction system (CCS) is a network of cells responsible for the rhythmic and coordinated excitation of the heart. Components of the murine conduction system, including the peripheral Purkinje fibres, are morphologically indistinguishable from surrounding cardiomyocytes and there exists a paucity of molecular markers to specifically identify these cells. Recently, we identified a line of transgenic mice in which the lacZ reporter gene is expressed within the embryonic CCS beginning at 8.25 days post-conception (dpc); its expression appears to delineate the full extent of the CCS, including the distal Purkinje fibre network, throughout all subsequent stages of development. Moreover, using the highly sensitive technique of optical mapping of electrical activity in embryonic murine hearts, we provided evidence for functional specialization of components of the CCS as early as 10.5 dpc. Here, we summarize these findings and describe our initial efforts utilizing the CCS-lacZ mice to identify novel factors that promote CCS specialization.

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.

Although knowledge of its existence has barely exceeded one century, the anatomic pathway for conduction of the cardiac impulse from atria to ventricles has been the source of much controversy, controversy that continues to the present day. This article describes how attention to the original descriptions, along with adherence for sensible definitions for the histological distinction of conduction tissues, could have defused many of these disagreements. One of the problems with the initial descriptions was that they were written in German. Even this is no longer a problem, since the major text devoted to the topic has recently been translated into English, and is now available for all to study. This key work was the monograph produced by Sunao Tawara, a Japanese pathologist who studied in the first decade of the 20th century in the laboratory of Ludwig Aschoff. Tawara showed that the atrial impulse was conducted to the ventricular myocardium by a solitary pathway of specialized myocardium. He likened this pathway to a tree, with its roots in the base of the atrial septum, and its branches straddling the crest of the muscular ventricular septum. Significantly, he showed that the pathway became insulated as it crossed from atrial to ventricular musculatures, and suggested that the point at which the muscle became engulfed in fibrous tissue should be taken as the boundary between the "knoten," or atrioventricular node, and the penetrating bundle described earlier by Wilhelm His. The authors' findings are entirely compatible with the account given by Tawara. Like Tawara, they recognize atrial transitional cells, a compact node, the penetrating bundle, and the ventricular conduction pathways as the segments of the conduction axis which can be considered to represent the specialized atrioventricular junction.

Investigations of the electrophysiology of crustacean cardiac ganglia over the last half-century are reviewed for their contributions to elucidating the cellular mechanisms and interactions by which a small (as few as nine cells) neuronal network accomplishes extremely reliable, rhythmical, patterned activation of muscular activity-in this case, beating of the neurogenic heart. This ganglion is thus a model for pacemaking and central pattern generation. Favorable anatomy has permitted voltage- and space-clamp analyses of voltage-dependent ionic currents that endow each neuron with the intrinsic ability to respond with rhythmical, patterned impulse activity to nonpatterned stimulation. The crustacean soma and initial axon segment do not support impulse generation but integrate input from stretch-sensitive dendrites and electrotonic and chemically mediated synapses on axonal processes in neuropils. The soma and initial axon produce a depolarization-activated, calcium-mediated, sustained potential, the "driver potential," so-called because it drives a train of impulses at the "trigger zone" of the axon. Extreme reliability results from redundancy and the electrotonic coupling and synaptic interaction among all the neurons. Complex modulation by central nervous system inputs and by neurohormones to adjust heart pumping to physiological demands has long been demonstrated, but much remains to be learned about the cellular and molecular mechanisms of action. The continuing relevance of the crustacean cardiac ganglion as a relatively simple model for pacemaking and central pattern generation is confirmed by the rapidly widening documentation of intrinsic potentials such as plateau potentials in neurons of all major animal groups. The suite of ionic currents (a slowly inactivating calcium current and various potassium currents, with variations) observed for the crustacean cardiac ganglion have been implicated in or proven to underlie a majority of the intrinsic potentials of neurons involved in pattern generation.

Introduction: Better understanding of atrial propagation during sinus rhythm (SR) in normal hearts under the most normal physiologic conditions may be propaedeutic to pathophysiologic studies of complex atrial arrhythmias. In this study, qualitative and quantitative analyses of sinus impulse propagation in both atria were performed by electroanatomic mapping in patients with no organic heart disease who were undergoing an electrophysiologic procedure., Methods and Results: Seven patients (5 men and 2 women; age 37 +/- 11 years) undergoing ablation of a left-sided accessory pathway were considered. Associated heart disease and coexisting atrial arrhythmias were excluded. After obtaining informed consent, electroanatomic mapping of both atria was performed during SR using a nonfluoroscopic system in the postablation phase. Mapping was accomplished in all patients with no complications. Qualitative analysis showed that sinus impulse propagation gives a reproducible activation pattern with minor individual variations. During interatrial propagation, two breakthroughs (anterior and posterior) in the left atrium are observed in the majority of cases. The anterior breakthrough, which reflects conduction over Bachmann's bundle, is predominant and shows a peculiar "preexcitation-like" endocardial activation pattern. Quantitative analysis showed minimal individual variations of propagation time intervals. Atria are activated simultaneously for 65% +/- 9% of the duration of the atrial systolic time interval., Conclusion: In normal humans, electroanatomic mapping of SR identifies a typical and reproducible propagation pattern during SR. Bachmann's bundle plays the most important role in interatrial propagation. Atria are activated simultaneously by sinus impulse for a relevant portion of the systolic time interval.

The intrinsic cardiac nervous system is known to be important both in the prevention and treatment of risky heart diseases. The present study was designed to determine the topography and 3-dimensional architecture of the intrinsic nervous system in the canine heart highlighting the differences of this system in dogs and humans. The morphology of the intrinsic cardiac neural plexus was revealed with a histochemical method using acetylcholinesterase in whole hearts of 18 mongrel dogs and examined with the aid of dissecting stereoscopic and contact microscopes. The present study identified 13 locations between the canine ascending aorta and pulmonary trunk, around the pulmonary veins, and on every side of the superior vena cava, through which mediastinal cardiac nerves accessed the canine heart. Intrinsic nerves from these locations extended within the canine epicardium by seven neuronal subplexuses. Intrinsic nerves and ganglia were found to be widely distributed in topographically consistent atrial and ventricular regions. In general, the canine right atrium, including the sinoatrial node, was innervated by two subplexuses, the wall of the left atrium by three, and the right and left ventricles by two subplexuses. Depending on the age of the animal, the number of intrinsic ganglia per one canine heart might range from 400 up to 1,500. By taking into account the ganglion size and potential approximate number of neurons residing inside a ganglion of a certain size, it was estimated that on average about 80,000 intrinsic neurons are associated with the canine heart. A comparative analysis of the morphological patterns of the canine and human intrinsic cardiac neural plexuses showed that the topographies of these plexuses may be considered as quite similar, but the structural and quantitative differences of the intrinsic cardiac neural subplexuses between dogs and humans are significant., (Copyright 2003 S. Karger AG, Basel)

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., (Copyright 2001 Wiley-Liss, Inc.)

The study of the dissemination of the electric impulse throughout the ventricular myocardium, which gave rise to the current theories, was performed without taking into consideration the complex architecture of the cardiac muscle elucidated by more recent researchers. We propose a novel hypothesis based on the special macroscopic structure of the heart, the anisotropic electric and mechanical behavior of the myocardium, the characteristics of the intercellular matrix and its very special collagen scaffolding, chemical composition, and biochemistry. The unique properties of the intercellular matrix would make it especially suited to function, in conjunction with the specialized conducting system (His-Purkinje system), as an efficient anisotropic conductor for the spread of electric activation in the heart, and to allow an optimal sequence of excitation-contraction coupling that results in the coordination of effective myocardial contraction in birds and mammals of the most varied known heart rates., (Copyright 2001 by W.B. Saunders Company)

In order to study the changes in the pattern of autonomic innervation of the human cardiac conduction system in relation to age, the innervation of the conduction system of 24 human hearts (the age of the individuals ranged from newborn to 80 years), freshly obtained at autopsy, was evaluated by a combination of immunofluorescence and histochemical techniques. The pattern of distribution and density of nerves exhibiting immunoreactivity against protein gene product 9.5 (PGP), a general neural marker, dopamine beta-hydroxylase (DBH) and tyrosine hydroxylase (TH), indicators for presumptive sympathetic neural tissue, and those demonstrating positive acetylcholinesterase (AChE) activity, were studied. All these nerves showed a similar pattern of distribution and developmental changes. The density of innervation, assessed semiquantitatively, was highest in the sinus node, and exhibited a decreasing gradient through the atrioventricular node, penetrating and branching bundle, to the bundle branches. Other than a paucity of those showing AChE activity, nerves were present in substantial quantities in infancy. They then increased in density to a maximum in childhood, at which time the adult pattern was achieved and then gradually decreased in density in the elders to a level similar to or slightly less than that in infancy. In contrast, only scattered AChE-positive nerves were found in the sinus and atrioventricular nodes, but were absent from the bundle branches of the infant heart, whereas these conduction tissues themselves possessing a substantial amount of pseudocholinesterase. During maturation into adulthood, however, the conduction tissues gradually lost their content of pseudocholinesterase but acquired a rich supply of AChE-positive nerves, comparable in density to those of DBH and TH nerves. The decline in density of AChE-positive nerves in the conduction tissues in the elders was also similar to those of DBH and TH nerves. Our findings of initial sympathetic dominance in the neural supply to the human cardiac conduction system in infancy, and its gradual transition into a sympathetic and parasympathetic codominance in adulthood, correlate well with the physiologic alterations known to occur in cardiac rate during postnatal development. The finding of reduction in density of innervation of the conduction tissue with ageing is also in agreement with clinical and electrophysiological findings such as age-associated reduction in cardiac response to parasympathetic stimulation. Finally, our findings also support the hypothesis that, in addition to the para-arterial route, the parafascicular route of extension along the conduction tissue constitutes another pathway for the innervation of the conduction system of the human heart during development., (Copyright 2001 Wiley-Liss, Inc.)

The aim of this study was to evaluate the efficacy and safety of the anatomic linear approach in selective AVN slow pathway ablation, in comparison to the widely used electrogram mapping focal approach. It remains undetermined whether or not anatomic linear ablation has a greater potential for eliminating slow pathway conduction than does focal ablation. Fifty consecutive patients (21 men, 29 women, age 56 +/- 14 years) with common type AVNRT were randomly assigned to the linear approach (25 patients) or local electrogram mapping approach (25 patients). A linear lesion was created between the tricuspid annulus, at the midlevel of the coronary sinus (CS) ostium, and the anterior aspect of the CS infundibulum. In 22 (88%) patients in the linear group, the AVNRT was successfully eliminated by 1.5 +/- 0.8 linear RF applications without any complications. All 25 patients in the focal group satisfied the endpoint criteria after 3.8 +/- 2.4 focal RF deliveries. The success rate did not significantly differ between the two groups. Out of the 22 patients with a successful outcome in the linear group, 17 (77%) attained complete abolition of the slow pathway conduction, whereas this was observed in only eight (32%) patients in the focal group (P < 0.005). The session time was significantly shorter in the linear group. Recurrence of the tachycardia was not documented in any patient during a mean follow-up of 18 +/- 8 months except one with residual slow pathway conduction in the focal ablation group. In conclusion, the anatomic linear approach can be performed safely and possesses a greater potential for slow pathway interruption compared to the electrogram mapping focal approach.

The remarkable success of radiofrequency ablation in recent decades in curing atrioventricular nodal reentrant tachycardias has intensified efforts to provide a solid theoretical basis for understanding the mechanisms of atrioventricular transmission. These efforts, which were made by both anatomists and electrophysiologists, frequently resulted in seemingly controversial observations. Quantitatively and qualitatively, our understanding of the mysteries of propagation through the inhomogeneous and extremely complex atrioventricular conduction axis is much deeper than it was at the beginning of the past century. We must go back to the initial sources, nonetheless, in an attempt to provide a common ground for evaluating the morphological and electrophysiological principles of junctional arrhythmias. In this review, we provide an account of the initial descriptions, which still provide an appropriate foundation for interpreting recent electrophysiological findings.

Knowledge of the conduction system of the heart was greatly advanced by Tawara's work carried out in Aschoff's laboratory in Marburg at the beginning of this century. In his monograph, The Conduction System of the Mammalian Heart, published in 1906, Tawara indicated that the treelike structure of specific muscle fibers comprising the atrioventricular node, His bundle, bundle branches, and Purkinje fibers served as the pathway for atrioventricular conduction of excitation in the mammalian heart. From his own anatomic and histological findings of the conduction system, he assumed precisely that the conduction velocity of excitation in the system, except in the atrioventricular node, would be fast and that contraction as the result of excitation would take place at the various sites of the ventricles almost simultaneously. According to Tawara, a long pathway to each contracting unit and a fast conduction velocity of excitation would be a prerequisite for the effective contraction of the ventricles. Tawara's findings and assumptions provided Einthoven the theoretical basis for interpreting the electrocardiogram, resulting in rapid popularization of electrocardiography. This century has witnessed the rapid progress of cardiology, including cardiac pacing and its related sciences. This progress has its roots in the discovery of the conduction system and the development of electrocardiography that took place almost in the same period at the beginning of this century. Tawara's pioneering work on the conduction system still serves as an invaluable reference for basic and clinical research.

The capability of bats to have heart rates fewer than 10 beats/min during hibernation and greater than 700 beats/min during flight surprises biologists and cardiologists. Cardioacceleration of hibernating bats is considered to be a function of their intracardiac nervous system. In the present study we investigated the morphology of the heart innervation of ten M. daubentoni and four E. serotinus bats during their natural hibernation in order to determine which intracardiac structures may be involved in cardioacceleration during their short-term (in av. 15-30 min) arousal from hibernation. The primary conclusions were as follows: (1) The innervation pattern of bats differs from many mammals in that bats have: (a) a subepicardiac nerve plexus which is vastly developed and contains a large number of intrinsic ganglia on both atria and ventricles, and (b) very small diameter axons within the unmyelinated nerve fibres, from 0.15 to 0.7 microm. (2) During hibernation an intercellular space of the sinoatrial node of M. daubentoni bats was in part filled with a cottony substance which can presumably be considered to be a temporary barrier between the conductive cardiomyocytes and nerve fibres. (3) In the hibernating bats, the acetylcholine vesicles were aggregated in the synaptic bulbs away from the presynaptic membrane. Possibly, the aggregation of the acetylcholine vesicles is capable of modifying cholinergic influences on the heart activity of hibernating bats. (4) The dense cores of catecholamine synaptic vesicles within, adrenergic axon terminals were seldomly observed in hibernating bats. Therefore, catecholamines probably do not play a crucial role in the cardioacceleration of hibernating bats.

In this article, we focus on the nurse's role as caregiver and patient advocate for individuals requiring cardiac pacing. The history of cardiac pacing, new trends, indications for pacing, pacemaker dysfunction and complications, types of pacing, and nursing considerations will be discussed.

Introduction: Junctional rhythm usually is considered a sensitive but nonspecific marker of successful ablation of the slow pathway in AV nodal reentrant tachycardia. Nevertheless, this junctional rhythm has been little studied, and its relations to recognized predictors of successful radiofrequency (RF) application were never established in any study., Methods and Results: Thirty-nine patients underwent RF ablation of the slow pathway for AV nodal reentrant tachycardia. Ninety RF applications were delivered, and each ablation site was determined using three different fluoroscopic projections. Six anatomic zones were defined from low posterior septum to the site of distal His-bundle recording (P1, P2, M1, M2, A1, and A2). Characteristics of junctional rhythm during RF applications were analyzed. Atrial electrogram characteristics at the ablation sites also were studied. All patients had successful slow pathway ablation, without any complication. The ablation sites were located as follows: 41 at P1, 26 at P2, 20 at M1, and 3 in M2. Forty RF applications were successful: 14 of 41 attempts at P1, 7 of 26 at P2, 16 of 20 at M1, and 3 of 3 at M2. Mid-septal ablation site (M1 and M2) was associated with higher occurrence of junctional rhythm (P < 0.0001), earlier first junctional beat (P = 0.008), and earlier occurrence of the longest junctional burst (P = 0.03) compared with posterior ablation site (P1 and P2). The combination of a mid-septal ablation site and a first junctional beat occurring < or = 3 seconds after onset of RF application identified successful RF application with 100% accuracy. Using multivariate analysis, the ablation site, duration of atrial electrogram (including slow pathway potential when present), and occurrence of junctional rhythm were independent predictors of success., Conclusion: Successful slow pathway ablation depends on many factors. Junctional rhythm characteristics are related to the site of RF delivery and can be helpful in assessing successful slow pathway ablation.