Development of the Cardiac Conduction System.

The electrical impulses that coordinate the sequential, rhythmic contractions of the atria and ventricles are initiated and tightly regulated by the specialized tissues of the cardiac conduction system. In the mature heart, these impulses are generated by the pacemaker cardiomyocytes of the sinoatrial node, propagated through the atria to the atrioventricular node where they are delayed and then rapidly propagated to the atrioventricular bundle, right and left bundle branches, and finally, the peripheral ventricular conduction system. Each of these specialized components arise by complex patterning events during embryonic development. This chapter addresses the origins and transcriptional networks and signaling pathways that drive the development and maintain the function of the cardiac conduction system.

Evidence for concealed fasciculo-ventricular connections as revealed by His bundle pacing.

BACKGROUND: It is almost 100 years ago since Mahaim described the so-called paraspecific connections between the ventricular conduction axis and the crest of the muscular ventricular septum, believing such pathways to be ubiquitous. These pathways, however, have yet to be considered as potential pathways for septal activation during His bundle pacing. MATERIALS: So as to explore the hypothesis that specialised septal pathways might provide the substrate for septal activation during His bundle pacing, we compared the findings from 22 serially sectioned histological datasets and 34 different individuals undergoing His bundle pacing. RESULTS: We found histologically specialised pathways connecting the branching component of the atrioventricular conduction axis with the crest of the muscular ventricular septum in almost four-fifths of the histological datasets. In 32 of 34 patients undergoing His bundle pacing, the QRS complex closely resembled published images of known conduction through fasciculo-ventricular pathways. In only two patients was a delta wave not seen at any pacing voltages. Capture of these connections varied according to pacing voltage, a finding which correlated with the distance of the pathways from the site of penetration of the ventricular conduction axis. Ventricular activation times remained normal in the presence of the delta wave at higher pacing voltage but were prolonged at lower voltages. CONCLUSIONS: Our histologic findings confirm fasciculo-ventricular connections, initially described by Mahaim as being paraspecific, are likely ubiquitous. Analysis of 12-lead electrocardiograms leads us to conclude that fasciculo-ventricular pathways, concealed during sinus rhythm, become manifest with His bundle pacing.

Transcriptional Patterning of the Ventricular Cardiac Conduction System.

RATIONALE: The heartbeat is organized by the cardiac conduction system (CCS), a specialized network of cardiomyocytes. Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the normal heartbeat. Distinct node versus VCS physiology has been recognized for more than a century, but the molecular basis of this regional patterning is not well understood. OBJECTIVE: To study the genetic and genomic mechanisms underlying node versus VCS distinction and investigate rhythm consequences of failed VCS patterning. METHODS AND RESULTS: Using mouse genetics, we found that the balance between T-box transcriptional activator, Tbx5, and T-box transcriptional repressor, Tbx3, determined the molecular and functional output of VCS myocytes. Adult VCS-specific removal of Tbx5 or overexpression of Tbx3 re-patterned the fast VCS into slow, nodal-like cells based on molecular and functional criteria. In these cases, gene expression profiling showed diminished expression of genes required for VCS-specific fast conduction but maintenance of expression of genes required for nodal slow conduction physiology. Action potentials of Tbx5-deficient VCS myocytes adopted nodal-specific characteristics, including increased action potential duration and cellular automaticity. Removal of Tbx5 in vivo precipitated inappropriate depolarizations in the atrioventricular (His)-bundle associated with lethal ventricular arrhythmias. TBX5 bound and directly activated cis-regulatory elements at fast conduction channel genes required for fast physiological characteristics of the VCS action potential, defining the identity of the adult VCS. CONCLUSIONS: The CCS is patterned entirely as a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network driven specifically in the VCS. Disruption of the fast VCS gene regulatory network allowed nodal physiology to emerge, providing a plausible molecular mechanism for some lethal ventricular arrhythmias.

Embryonic Tbx3+ cardiomyocytes form the mature cardiac conduction system by progressive fate restriction.

A small network of spontaneously active Tbx3+ cardiomyocytes forms the cardiac conduction system (CCS) in adults. Understanding the origin and mechanism of development of the CCS network are important steps towards disease modeling and the development of biological pacemakers to treat arrhythmias. We found that Tbx3 expression in the embryonic mouse heart is associated with automaticity. Genetic inducible fate mapping revealed that Tbx3+ cells in the early heart tube are fated to form the definitive CCS components, except the Purkinje fiber network. At mid-fetal stages, contribution of Tbx3+ cells was restricted to the definitive CCS. We identified a Tbx3+ population in the outflow tract of the early heart tube that formed the atrioventricular bundle. Whereas Tbx3+ cardiomyocytes also contributed to the adjacent Gja5+ atrial and ventricular chamber myocardium, embryonic Gja5+ chamber cardiomyocytes did not contribute to the Tbx3+ sinus node or to atrioventricular ring bundles. In conclusion, the CCS is established by progressive fate restriction of a Tbx3+ cell population in the early developing heart, which implicates Tbx3 as a useful tool for developing strategies to study and treat CCS diseases.

The membranous septum revisited: A glimpse of our anatomical past.

The so-called membranous septum is the fibrous component of the septal structures within the heart. It is relatively subtle in its appearance, but of considerable significance to the understanding of cardiac function and cardiac disease, both congenital and acquired. Surprisingly, its existence was seemingly unknown until the early decades of the 19th century. At this time, those writing in the English language described it as the "undefended space," recognizing its importance in the setting of its aneurysmal dilation, and as the site of septal defects. By the initial decade of the 20th century, it had come to be recognized as the landmark to the site of atrioventricular bundle. Over the first decade of the 21st century, its clinical significance has been emphasized in the context of transcutaneous replacement of the aortic valve. In this review, we describe our own recent investigations of this fibrous part of the septal structures. At the same time, we provide a glimpse of our anatomic past, explaining how its initial description relied on the observations of young physicians taking their first steps in the investigation of cardiac anatomy.

Risk Stratification for Arrhythmic Events in Patients With Asymptomatic Pre-Excitation: A Systematic Review for the 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

OBJECTIVE: To review the literature systematically to determine whether noninvasive or invasive risk stratification, such as with an electrophysiological study of patients with asymptomatic pre-excitation, reduces the risk of arrhythmic events and improves patient outcomes. METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (all January 1, 1970, through August 31, 2014) were searched for randomized controlled trials and cohort studies examining noninvasive or invasive risk stratification in patients with asymptomatic pre-excitation. Studies were rejected for low-quality design or the lack of an outcome, population, intervention, or comparator of interest or if they were written in a language other than English. RESULTS: Of 778 citations found, 9 studies met all the eligibility criteria and were included in this paper. Of the 9 studies, 1 had a dual design-a randomized controlled trial of ablation versus no ablation in 76 patients and an uncontrolled prospective cohort of 148 additional patients-and 8 were uncontrolled prospective cohort studies (n=1594). In studies reporting a mean age, the range was 32 to 50 years, and in studies reporting a median age, the range was 19 to 36 years. The majority of patients were male (range, 50% to 74%), and <10% had structural heart disease. In the randomized controlled trial component of the dual-design study, the 5-year Kaplan-Meier estimates of the incidence of arrhythmic events were 7% among patients who underwent ablation and 77% among patients who did not undergo ablation (relative risk reduction: 0.08; 95% confidence interval: 0.02 to 0.33; P<0.001). In the observational cohorts of asymptomatic patients who did not undergo catheter ablation (n=883, with follow-up ranging from 8 to 96 months), regular supraventricular tachycardia or benign atrial fibrillation (shortest RR interval >250 ms) developed in 0% to 16%, malignant atrial fibrillation (shortest RR interval ≤250 ms) in 0% to 9%, and ventricular fibrillation in 0% to 2%, most of whom were children in the last case. CONCLUSIONS: The existing evidence suggests risk stratification with an electrophysiological study of patients with asymptomatic pre-excitation may be beneficial, along with consideration of accessory-pathway ablation in those deemed to be at high risk of future arrhythmias. Given the limitations of the existing data, well-designed and well-conducted studies are needed.

Wilhelm His Junior and his bundle.

We have reviewed the evidence relative to the initial description of the penetrating atrioventricular bundle, seeking to determine whether Wilhelm His Junior is deserving of his eponym.

[Sick sinus node syndrome ¿Pacemaker or ablation? Case report]. / Síndrome del nodo sinusal enfermo ¿marcapaso o ablación? Reporte de caso.

The tachycardia-bradycardia syndrome is the most frequent form of presentation of Sick sinus node syndrome and is commonly characterized by episodes of paroxysmal atrial fibrillation followed by significant pauses, especially in older adult patients. Other frequently associated tachyarrhythmias are atrial tachycardia and atrial flutter. The association between orthodromic tachycardia and significant pauses in these patients is an unusual presentation. We present the case of an older adult with bradycardia-tachycardia syndrome and syncope, who presented with a hidden accessory pathway and who, after successful ablation of it, did not present syncope again.

The anatomical basis of third-degree atrioventricular block in dogs with atrioventricular valve endocardiosis.

The cardiac conduction system was examined histologically in 13 canine cases of atrioventricular (AV) valve endocardiosis with third-degree AV block. In all cases, gross examination revealed marked thickening and distortion of the base of the central fibrous body (CFB) and varying degrees of endocardial thickening of the upper portion of the ventricular septum (VS) as well as marked thickening of the mitral and tricuspid valve leaflets due to myxomatous degeneration. Microscopically, the thickened and distorted CFB had encased or trapped, either partly or totally, the underlying penetrating and branching portions of the AV bundle. The myxomatous and/or fibrofatty tissue, which had proliferated at the base of the extensive CFB, protruded into or encroached on the AV bundle, causing severe (51-75%) to very severe (76% or more) reduction of the conduction fibres. The upper portions of the left and right bundle branches were involved in the endocardial thickening due to degenerative and fibrotic changes at the uppermost VS; however, both bundle branches were much less severely affected than the AV bundle, the degree of reduction of the conduction fibres ranging from mild (25% or less) to moderate (26-50%). These observations suggest that the sites most vulnerable to lesions in the AV conduction system are the penetrating and branching portions of the AV bundle, which would represent the anatomical basis for third-degree AV block in canine cases of AV valve endocardiosis.

Anatomical study of the cardiac conduction system in swine hearts.

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

Histological Features of the Atrioventricular Conduction System in Cats with High-Grade Atrioventricular Block.

The histopathological features of the atrioventricular (AV) conduction system of nine cats with high-grade atrioventricular block (H-AVB) were compared with those of 22 cases of third-degree atrioventricular block (3-AVB). All nine H-AVB cats had experienced syncopal attacks of variable severity and had been diagnosed electrocardiographically. The AVB, which was permanent in all cases, had been observed for 15-1,981 days (average 663 days) before death. Histological examination of the AV conduction system revealed moderate (25-50%) or severe (>50%) loss of conduction fibres associated with fibrous replacement in the regions of the branching portion of the AV bundle and the upper portion of the left bundle branch in almost all of the H-AVB cases and in all the 3-AVB cases. Comparison of lesion severity in each region in the H-AVB and 3-AVB cases revealed that the branching portion of the AV bundle was less severely affected in the H-AVB cases. This finding might explain why the H-AVB cases had intermittent block of AV conduction while the 3-AVB cats had permanent block.

Ventricular versus atrial side ablation for treatment of atrioventricular accessory pathways: a randomized controlled clinical trial.

BACKGROUND: The earliest atrial (A)/ventricular (V) activation potentials, or fused A/V potentials, are commonly used as ablation targets for atrioventricular (AV) accessory pathways (APs). However, these targets can be achieved in a relatively wide area of the heart around AV rings at both atrial and ventricular sides. The aim of this study is to analyze the height of intracardiac A and V waves and their correlation to find the most appropriate side for successful delivery of radiofrequency energy, atrial or ventricular edge. METHODS: Ninety patients diagnosed with orthodromic AV re-entrant tachycardia (AVRT) or Wolff-Parkinson-White syndrome were enrolled. Local atrial/ventricular (A/V) amplitude potentials with the earliest activation or fused AV potentials were measured. Patients were randomly assigned into two groups with a 2:1 ratio. In group 1, ablation was done at the site where A was greater than V. In group 2, V was greater than A. Primary endpoint was success at first attempt, achieving antegrade AP conduction block, AV block during right ventricle pacing, or AVRT termination with no AP conduction. RESULTS: Fifty-one patients (56.7%) were male. Thirty patients had an ablation at an atrial site (A > V) and 60 at a ventricular site (V > A). Ablation was more successful at the ventricular site (87% vs 100%, P = 0.011). All 30 patients in the atrial arm and 71% of the ventricular group underwent ablation via the antegrade method. CONCLUSIONS: Success of catheter ablation of APs is higher where V > A (ventricular site of AP), indicating the priority of the ventricular edge of the mitral ring for a better outcome.

The Atrioventricular Conduction Axis and its Implications for Permanent Pacing.

Extensive knowledge of the anatomy of the atrioventricular conduction axis, and its branches, is key to the success of permanent physiological pacing, either by capturing the His bundle, the left bundle branch or the adjacent septal regions. The inter-individual variability of the axis plays an important role in underscoring the technical difficulties known to exist in achieving a stable position of the stimulating leads. In this review, the key anatomical features of the location of the axis relative to the triangle of Koch, the aortic root, the inferior pyramidal space and the inferoseptal recess are summarised. In keeping with the increasing number of implants aimed at targeting the environs of the left bundle branch, an extensive review of the known variability in the pattern of ramification of the left bundle branch from the axis is included. This permits the authors to summarise in a pragmatic fashion the most relevant aspects to be taken into account when seeking to successfully deploy a permanent pacing lead.

Variable Arrangement of the Atrioventricular Conduction Axis Within the Triangle of Koch: Implications for Permanent His Bundle Pacing.

OBJECTIVES: This study sought to describe, in detail, the angiographic, gross macroscopy, and histological dissection of the conduction axis in humans. BACKGROUND: The recent upsurge of interest in specific pacing of the atrioventricular conduction axis has emphasized the need for precise knowledge of the location of the atrial and penetrating components of the atrioventricular conduction axis. METHODS: A total of 41 human hearts were studied by serial histological sectioning and an additional 3 hearts by gross dissection. One of the hearts studied histologically was also dissected to show the location of the conduction axis prior to serial sectioning. The anatomical findings were then compared with the results of angiography undertaken in the catheter laboratory in 60 patients undergoing electrophysiological studies. RESULTS: Marked variation of the location of the transition from atrioventricular conduction axis to the penetrating atrioventricular bundle, or the bundle of His, relative to the landmarks of the triangle of Koch was observed. In just over one-half of both the specimens and the patients, the site of penetration was on the atrial aspect of the hinge of the septal leaflet of the tricuspid valve, with further variation noted relative to the apex of the triangle of Koch. Based on measurements of the histological sections, marked variation in the dimensions of the axis and its adjacency to the right-sided endocardium were also found. In almost three-fifths of hearts, an interventricular component of the fibrous membranous septum was not able to be identified. The significance of these findings to those who seek to perform selective pacing of the atrioventricular conduction axis are discussed. CONCLUSIONS: Marked variability of the location of the conduction axis within the triangle of Koch is reported. In three-fifths of hearts, the interventricular component of the fibrous membranous septum is nonexistent.

Transient complete heart block following catheter ablation of a left lateral accessory pathway.

A 16-year-old female with symptomatic Wolff-Parkinson-White (WPW) syndrome underwent catheter ablation of a left-sided lateral accessory pathway. The accessory pathway was eliminated with the first ablation lesion; however, the patient immediately developed complete heart block (CHB). At first, complete heart block was thought to be due to ablation of left atrial extension of the AV node, and pacemaker therapy was considered. However, careful ECG analysis revealed that the development of CHB was in fact due to bump injury to the AV node during transseptal catheterization. Conservative management allowed resolution of AV nodal conduction without need for a permanent pacemaker.

The 125th anniversary of the His bundle discovery.

In 1893, Wilhelm His Jr. was the first to describe the AV (atrioventricular) bundle of the vertebrate heart, which now bears his name. Moreover, prior to the turn of the century, W. His Jr. had proved the function of the AV bundle by transection experiments in animals, and had interpreted Adams Stokes disease as heart block due to pathological changes within the bundle. In this way, he was ahead of his time. While clinical interest was limited to the bundle as the location of an AV block in the first half of the 125 years, it has gained attractiveness since then as a target of diagnostic and therapeutic procedures. The introduction of His bundle electrography relaunched the interest in cardiac arrhythmias. Once the AV bundle could be localized clinically, its ablation, and in recent times its permanent stimulation, became options in the therapy of well-defined arrhythmia and conduction problems.