Physiologic Pacing for the Prevention and Treatment of Heart Failure A State-of-the-Art Review.

Permanent pacing from the right ventricular apex can reduce quality of life and increase the risk of heart failure and death. This review summarizes the milestones in the evolution of pacemakers towards "physiologic pacing" with biventricular pacing systems and lead implantation into the cardiac conduction system to synchronize cardiac contraction and relaxation. Both approaches aim to reproduce normal cardiac activation and help prevent and treat heart failure. This review introduces the basic concepts and clinical evidence and discusses practical uses of physiological pacing.

Revisiting the anatomy of the left ventricle in the light of knowledge of its development.

Despite centuries of investigation, certain aspects of left ventricular anatomy remain either controversial or uncertain. We make no claims to have resolved these issues, but our review, based on our current knowledge of development, hopefully identifies the issues requiring further investigation. When first formed, the left ventricle had only inlet and apical components. With the expansion of the atrioventricular canal, the developing ventricle cedes part of its inlet to the right ventricle whilst retaining the larger parts of the cushions dividing the atrioventricular canal. Further remodelling of the interventricular communication provides the ventricle with its outlet, with the aortic root being transferred to the left ventricle along with the newly formed myocardium supporting its leaflets. The definitive ventricle possesses inlet, apical and outlet parts. The inlet component is guarded by the mitral valve, with its leaflets, in the normal heart, supported by papillary muscles located infero-septally and supero-laterally. There is but a solitary zone of apposition between the leaflets, which we suggest are best described as being aortic and mural. The trabeculated component extends beyond the inlet to the apex and is confluent with the outlet part, which supports the aortic root. The leaflets of the aortic valve are supported in semilunar fashion within the root, with the ventricular cavity extending to the sinutubular junction. The myocardial-arterial junction, however, stops well short of the sinutubular junction, with myocardium found only at the bases of the sinuses, giving rise to the coronary arteries. We argue that the relationships between the various components should now be described using attitudinally appropriate terms rather than describing them as if the heart is removed from the body and positioned on its apex.

The clinical anatomy of the atrioventricular conduction axis.

It is axiomatic that the chances of achieving accurate capture of the conduction axis and its fascicles will be optimized by equally accurate knowledge of the relationship of the components to the recognizable cardiac landmarks, and we find it surprising that acknowledged experts should continue to use drawings that fall short in terms of anatomical accuracy. The accuracy achieved by Sunao Tawara (1906) in showing the location of the atrioventricular conduction axis is little short of astounding. Our purpose in bringing this to current attention is to question the need of the experts to have produced such inaccurate representations, since the findings of Tawara have been extensively endorsed in very recent years. The recent studies do no more than point to the amazing accuracy of the initial account of Tawara. At the same time, we draw attention to the findings described in the middle of the 20th century by Ivan Mahaim (1947). These observations have tended to be ignored in recent accounts. They are, perhaps, of equal significance to those seeking specifically to pace the left fascicles of the branching atrioventricular bundle.

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.

Vulnerability of the ventricular conduction axis during transcatheter aortic valvar implantation: A translational pathologic study.

The ventricular components of the conduction axis remain vulnerable following transcatheter aortic valvar replacement. We aimed to describe features which may be used accurately by interventionalists to predict the precise location of the conduction axis, hoping better to avoid conduction disturbances. We scanned eight normal adult heart specimens by 3T magnetic resonance, using the images to simulate histological sections in order accurately to place the conduction axis back within the heart. We then used histology, tested in two pediatric hearts, to prepare sections, validated by the magnetic resonance images, to reveal the key relationships between the conduction axis and the aortic root. The axis was shown to have a close relationship to the nadir of the right coronary leaflet, in particular when the aortic root was rotated in counterclockwise fashion. The axis was more vulnerable in the setting of a narrow inferoseptal recess, when the inferior margin of the membranous septum was above the plane of the virtual basal ring, and when minimal myocardium was supporting the right coronary sinus. The features identified in our study are in keeping with the original description provided by Tawara, but at variance with more recent accounts. They suggest that the vulnerability of the axis during transcatheter valvar replacement can potentially be inferred on the basis of knowledge of the position of the aortic root within the ventricular base. If validated by clinical studies, our findings may better permit avoidance of new-onset left bundle branch block following transcatheter aortic valvar replacement.

Miniseries 1-Part III: 'Behind the scenes' in the triangle of Koch.

AIMS: To take full advantage of the knowledge of cardiac anatomy, structures should be considered in their correct attitudinal orientation. Our aim was to discuss the triangle of Koch in an attitudinally appropriate fashion. METHODS AND RESULTS: We reviewed our material prepared by histological sectioning, along with computed tomographic datasets of human hearts. The triangle of Koch is the right atrial surface of the inferior pyramidal space, being bordered by the tendon of Todaro and the hinge of the septal leaflet of the tricuspid valve, with its base at the inferior cavotricuspid isthmus. The fibro-adipose tissues of the inferior pyramidal space separate the atrial wall from the crest of the muscular interventricular septum, thus producing an atrioventricular muscular sandwich. The overall area is better approached as a pyramid rather than a triangle. The apex of the inferior pyramidal space overlaps the infero-septal recess of the subaortic outflow tract, permitting the atrioventricular conduction axis to transition directly to the crest of the muscular ventricular septum. The compact atrioventricular node is formed at the apex of the pyramid by union of its inferior extensions, which represent the slow pathway, with the septal components formed in the buttress of the atrial septum, thus providing the fast pathway. CONCLUSIONS: To understand its various implications in current cardiological catheter interventions, the triangle of Koch must be considered in conjunction with the inferior pyramidal space and the infero-septal recess. It is better to consider the overall region in terms of a pyramidal area of interest.

Miniseries 1-Part IV: How frequent are fasciculo-ventricular connections in the normal heart?

AIMS: Seeking to account for accessory atrioventricular conduction potentially leading to ventricular pre-excitation, Mahaim in the mid-20th century had described pathways between the atrioventricular conduction axis and the muscular ventricular septum. We aimed to look for such 'paraspecific' connections in adult human hearts. METHODS AND RESULTS: We serially sectioned 21 hearts, covering the triangle of Koch and the aortic root, and assessing the atrioventricular node, the penetration of the conduction axis, and the bundle branches in our search for fasciculo-ventricular connections. We also calculated the length of the non-branching bundle, and if present the origin of the fasciculo-ventricular connections. The non-branching bundle was 3.6 ± 1.7 mmin length, varying from 1.7 mm to 7.2 mm. Fasciculo-ventricular connections were found in more than half of the hearts, making direct contact with the muscular septum at an average of 3.5 ± 1.7 mm from the origin of the left bundle branch, with the site of origin varying from 1.1 mm to 5.5 mm from the first fascicle of the left bundle branch. In three hearts, additional fasciculo-fascicular connections were observed in the left bundle branch. Two loops were small, but one loop extended over 9.5 mm. CONCLUSION: We endorse the finding of Mahaim that fasciculo-ventricular pathways exist in most human hearts. We presume the identified connections had the capability of producing ventricular pre-excitation. More studies are needed to determine the potential clinical manifestations.

Miniseries 2-Septal and paraseptal accessory pathways-Part IV: Inferior paraseptal accessory pathways-lessons from surgical and catheter ablation.

Surgeons and electrophysiologists performing accessory pathway ablation procedures have used the term 'posteroseptal' region. This area, however, is neither septal nor posterior, but paraseptal and inferior; paraseptal because it includes the fibro-adipose tissues filling the pyramidal space and not the muscular septum itself and inferior because it is part of the heart adjacent to the diaphragm. It should properly be described, therefore, as being inferior and paraseptal. Pathways in this region can be ablated at three areas, which we term right inferior, mid-inferior, and left inferior paraseptal. The right- and left inferior paraseptal pathways connect the right and left atrial vestibules with the right and left paraseptal segments of the parietal ventricular walls. The mid-inferior paraseptal pathways take a subepicardial course from the myocardial sleeves surrounding the coronary sinus and its tributaries. Our review addresses the evolution of the anatomical concept of the inferior paraseptal region derived from surgical and catheter ablation procedures. We also highlight the limitations of the 12-lead electrocardiogram in identifying, without catheter electrode mapping, which are the pathways that can be ablated without a coronary sinus, or left heart approach.

Miniseries 2-Septal and paraseptal accessory pathways-Part I: The anatomic basis for the understanding of para-Hisian accessory atrioventricular pathways.

AIMS: Although the anatomy of the atrioventricular conduction axis was well described over a century ago, the precise arrangement in the regions surrounding its transition from the atrioventricular node to the so-called bundle of His remain uncertain. We aimed to clarify these relationships. METHODS AND RESULTS: We have used our various datasets to examine the development and anatomical arrangement of the atrioventricular conduction axis, paying particular attention to the regions surrounding the point of penetration of the bundle of His. It is the areas directly adjacent to the transition of the atrioventricular conduction axis from the atrioventricular node to the non-branching atrioventricular bundle that constitute the para-Hisian areas. The atrioventricular conduction axis itself traverses the membranous part of the ventricular septum as it extends from the node to become the bundle, but the para-Hisian areas themselves are paraseptal. This is because they incorporate the fibrofatty tissues of the inferior pyramidal space and the superior atrioventricular groove. In this initial overarching review, we summarize the developmental and anatomical features of these areas along with the location and landmarks of the atrioventricular conduction axis. We emphasize the relationships between the inferior pyramidal space and the infero-septal recess of the subaortic outflow tract. The details are then explored in greater detail in the additional reviews provided within our miniseries. CONCLUSION: Our anatomical findings, described here, provide the basis for our concomitant clinical review of the so-called para-Hisian arrhythmias. The findings also provide the basis for understanding the other variants of ventricular pre-excitation.

Miniseries 2-Septal and paraseptal accessory pathways-Part III: Mid-paraseptal accessory pathways-revisiting bypass tracts crossing the pyramidal space.

The mid-paraseptal region corresponds to the portion of the pyramidal space whose right atrial aspect is known as the triangle of Koch. The superior area of this mid-paraseptal region is also para-Hisian, and is close to the compact atrioventricular node and the His bundle. The inferior sector of the mid-paraseptal area is unrelated to the normal atrioventricular conduction pathways. It is, therefore, a safe zone in which, if necessary, to perform catheter ablation. The middle part of the mid-paraseptal zone may, however, in some patients, house components of the compact atrioventricular node. This suggests the need for adopting a prudent attitude when considering catheter ablation in this area. The inferior extensions of the atrioventricular node, which may represent the substrate for the slow atrioventricular nodal pathway, take their course through the middle, and even the inferior, sectors of the mid-paraseptal region. In this review, we contend that the middle and inferior areas of the mid-paraseptal region correspond to what, in the past, was labelled by most groups as the 'midseptal' zone. We describe the electrocardiographic patterns observed during pre-excitation and orthodromic reciprocating tachycardia in patients with pathways ablated in the middle or inferior sectors of the region. We discuss the modification of the ventriculo-atrial conduction times during tachycardia after the development of bundle branch block aberrancy. We conclude that the so-called 'intermediate septal' pathways, as described in the era of surgical ablation, were insufficiently characterized. They should not be considered the surrogate of the 'midseptal' pathways defined using endocardial catheter electrode mapping.

Miniseries 2-Septal and paraseptal accessory pathways-Part II: Para-Hisian accessory pathways-so-called anteroseptal pathways revisited.

Surgeons, when dividing bypass tracts adjacent to the His bundle, considered them to be 'anteroseptal'. The area was subsequently recognized to be superior and paraseptal, although this description is not entirely accurate anatomically, and conveys little about the potential risk during catheter interventions. We now describe the area as being para-Hisian, and it harbours two types of accessory pathways. The first variant crosses the membranous septum to insert into the muscular ventricular septum without exiting the heart, and hence being truly septal. The second variant inserts distally in the paraseptal components of the supraventricular crest, and consequently is crestal. The site of ventricular insertion determines the electrocardiographic expression of pre-excitation during sinus rhythm, with the two types producing distinct patterns. In both instances, the QRS and the delta wave are positive in leads I, II, and aVF. In crestal pathways, however, the QRS is ≥ 140 ms, and exhibits an rS configuration in V1-2. The delta wave in V1-2 precedes by 20-50 ms the apparent onset of the QRS in I, II, III, and aVF. In the true septal pathways, the QRS complex occupies ∼120 ms, presenting a QS, W-shaped, morphology in V1-2. The delta wave has a simultaneous onset in all leads. Our proposed terminology facilitates the understanding of the electrocardiographic manifestations of both types of para-Hisian pathways during pre-excitation and orthodromic tachycardia, and informs on the level of risk during catheter ablation.

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

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

Miniseries 1-Part I: the Development of the atrioventricular conduction axis.

Despite years of research, many details of the formation of the atrioventricular conduction axis remain uncertain. In this study, we aimed to clarify the situation. We studied three-dimensional reconstructions of serial histological sections and episcopic datasets of human embryos, supplementing these findings with assessment of material housed at the Human Developmental Biological Resource. We also examined serially sectioned human foetal hearts between 10 and 30 weeks of gestation. The conduction axis originates from the primary interventricular ring, which is initially at right angles to the plane of the atrioventricular canal, with which it co-localizes in the lesser curvature of the heart loop. With rightward expansion of the atrioventricular canal, the primary ring bends rightward, encircling the newly forming right atrioventricular junction. Subsequent to remodelling of the outflow tract, part of the primary ring remains localized on the crest of the muscular ventricular septum. By 7 weeks, its atrioventricular part has extended perpendicular to the septal parts. The atrioventricular node is formed at the inferior transition between the ventricular and atrial parts, with the transition itself marking the site of the penetrating atrioventricular bundle. Only subsequent to muscularization of the true second atrial septum does it become possible to recognize the definitive node. The conversion of the developmental arrangement into the definitive situation as seen postnatally requires additional remodelling in the first month of foetal development, concomitant with formation of the inferior pyramidal space and the infero-septal recess of the subaortic outflow tract.

The atrioventricular conduction axis and the aortic root-Inferences for transcatheter replacement of the aortic valve.

Conduction problems still occur following transcatheter aortic valvar replacement. With this in mind, we have assessed the relationship of the conduction axis to the aortic root. We used serial histological sections, made perpendicular to the base of the triangle of Koch in nine hearts, and perpendicular to the aortic root in 11 hearts. We first defined the extent of the fibrous tissues forming the boundaries of an infero-septal recess of the subaortic outflow tract, found in all datasets but one. When the recess was present, the axis penetrated through its rightward wall, giving rise to the left bundle branch prior to entering the outflow tract. The axis itself was usually on the crest of the ventricular septum, but could be deviated leftward or rightward. Its proximity to the virtual basal plane reflected the angulation of the muscular septum. On average, the superior edge of the left bundle was within 3.3 mm of the hinge of the right coronary leaflet, with a range from 0.4 to 10.2 mm. The arrangement was markedly different in the case lacking an infero-septal recess. Our findings necessitated a redefinition of the right fibrous trigone and the central fibrous body. The atrioventricular conduction axis, having entered the aortic root, is usually closest at the hinge of the right coronary leaflet. Knowledge of the depth of the infero-septal recess, and the angulation of the muscular ventricular septal, may help to avoid conduction problems following transcatheter implantation of the aortic valve.

Spatial characterization of the tachycardia circuit of atrioventricular nodal re-entrant tachycardia.

AIMS: The exact circuit of atrioventricular nodal re-entrant tachycardia (AVNRT) remains elusive. To assess the location and dimensions of the AVNRT circuit. METHODS AND RESULTS: Both typical and atypical AVNRT were induced at electrophysiology study of 14 patients. We calculated the activation time of the fast and slow pathways, and consequently, the length of the slow pathway, by assuming an average conduction velocity of 0.04 mm/ms in the nodal area. The distance between the compact atrioventricular node and the slow pathway ablating electrode was measured on three-dimensionally reconstructed fluoroscopic images obtained in diastole and systole. We also measured the length of the histologically discrete right inferior nodal extension in 31 human hearts. The length of the slow pathway was calculated to be 10.8 ± 1.3 mm (range 8.2-12.8 mm). The distance from the node to the ablating electrode was measured in five patients 17.0 ± 1.6 mm (range 14.9-19.2 mm) and was consistently longer than the estimated length of the slow pathway (P < 0.001). The length of the right nodal inferior extension in histologic specimens was 8.1 ± 2.3 mm (range 5.3-13.7 mm). There were no statistically significant differences between these values and the calculated slow pathway lengths. CONCLUSION: Successful ablation affects the tachycardia circuit without necessarily abolishing slow conduction, probably by interrupting the circuit at the septal isthmus.

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.

Histological examination of the potential arrhythmic substrates in the setting of Ebstein's malformation.

Cardiac arrhythmias, notably Wolff-Parkinson-White syndrome, are known to represent a major issue in patients with Ebstein's malformation of the tricuspid valve. Abnormal conducting circuits, however, can also be produced by pathways extending either from the atrioventricular node or the ventricular components of the atrioventricular conduction axis, direct to the crest of the muscular ventricular septum. We hoped to provide further information on the potential presence of such pathways by investigations of six autopsied examples of Ebstein's malformation. All were studied by histological sectioning on the full extent of the atrioventricular conduction axis, with limited sectioning of the right atrioventricular junction supporting the inferior and antero-superior leaflets of the deformed tricuspid valve. We used the criteria established by Aschoff (Verhandlungen der Deutschen Gesellschaft für Pathologie, 14, 1910, 3) and Mönckeberg (Verhandlungen der Deutschen Gesellschaft für Pathologie, 14, 1910, 64) over a century ago to define abnormal connections across the atrioventricular junctions, as these definitions retain their validity for the identification of gross myocardial connections across the insulating tissues of the atrioventricular junctions. In one specimen, we found two discrete accessory myocardial connections across the parietal right atrioventricular junction. In all of the hearts, we found so-called nodoventricular connections, and in one heart we also observed a well-formed connection originating from the penetrating atrioventricular bundle. In addition to accessory myocardial connections across the parietal right atrioventricular junction, therefore, our histological findings demonstrate a potential role for direct connections between the atrioventricular conduction axis and the ventricular myocardium in the setting of Ebstein's malformation.

Re-evaluation of the structure of the atrioventricular node and its connections with the atrium.

AIMS: The anatomic substrates for atrioventricular nodal re-entry remain enigmatic, but require knowledge of the normal arrangement of the inputs and exist from the atrioventricular node. This knowledge is crucial to understand the phenomenon of atrioventricular nodal re-entry. METHODS AND RESULTS: We studied 20 human hearts with serial sections covering the entirety of the triangle of Koch and the cavotricuspid isthmus. We determined the location of the atrioventricular conduction axis and the connections between the specialized cardiomyocytes of the conduction axis and the adjacent working atrial myocardium. The atrioventricular node was found at the apex of the triangle of Koch, with entry of the conduction axis to the central fibrous body providing the criterion for distinction of the bundle of His. We found marked variation in the inferior extensions of the node, the shape of the node, the presence or absence of a connecting bridge within the myocardium of the cavotricuspid isthmus, the connections between the compact node and the myocardium of the atrial septum, the presence of transitional cardiomyocytes, and the 'last' connection between the working atrial myocardium and the conduction axis before it became the bundle of His. CONCLUSION: The observed variations of the inferior extensions, combined with the arrangement of the 'last' connections between the atrial myocardium and the conduction axis prior to its insulation as the bundle of His, provide compelling evidence to support the concept for atrioventricular nodal re-entry as advanced by Katritsis and Becker.

Interatrial block can occur in the absence of left atrial enlargement: New experimental model.

We present the surface electrocardiogram of an open-chest anesthetized healthy adult swine after direct application of ice at the transversus sinus of the pericardium where the Bachmann's region is located. Gradual and transient interatrial block (IAB) in the absence of structural atrial disease is described. This new experimental model demonstrated that IAB is an independent entity from left atrial enlargement.

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

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