Bridge Between Anatomy And Physiology

Although the morphological structure of the AV node is very complex and has been the subject of long lasting debates¹, the electrophysiologists usually simplify the matter by identifying the general AV nodal area within the boundaries of the so-called triangle of Koch.² The latter, ambivalently endorsed,³ refers to the region demarcated by the attachment of the septal leaflet of the tricuspid valve (inferiorly), the ostium of the coronary sinus (posteriorly), and the Tendon of Todaro (superiorly). If there is one issue on which it appears an agreement has been reached, it is that precise borders of the AV node cannot be determined. Indeed, in its seminal monograph Tawara⁴ stressed that on the atrial side the transition between nodal and atrial tissue is so gradual "that no sharp boundary can be detected". Furthermore, Tawara found similar continuity between the nodal region and the opening of the coronary sinus, while others²;⁵ demonstrated that this latter area could behave as a pacemaker in special cases. Thus, the general region of the triangle of Koch contains multilayered and very complex morphological structures that anatomically and functionally form a continuum between the atrium and the bundle of His.

Although different authors usually use different nomenclature, the AV junctional area is most frequently described as encompassing transitional cells, specialized nodal cells (AV node), lower nodal cells, and the penetrating AV bundle (bundle of His).

The term "transitional cells" is used broadly to describe the approaches from the working atrial myocardium to the AV node. Most frequently recognized are the posterior (inferior) and anterior (superior) approaches.⁶ The posterior approaches serve as a bridge with the atrial myocardium at the coronary sinus ostium, while the anterior approaches merge with the AV node closer to the apex of the triangle of Koch. A third, middle group of transitional cells has also been identified^7,8 to account for the nodal connections with the septum and the left atrium. It should be stressed that even though the term transitional might imply incorrectly that the region is outside of the AV node proper, its functional importance for the impulse transmission cannot be overestimated.

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Figures 1a and 1b.

The "typical" AV nodal cells define the so-called midnodal, or compact node region. These are the cells forming a dense discoid-shaped network for which Tawara⁴ coined the term "Knoten" (meaning "node"), frequently used for description of the entire region. In addition to being closely packed together ("compact"), the midnodal cells are typically the smallest, have random orientation⁹, and contain few nexuses.¹⁰

Lower nodal cells start posteriorly as thin bundle of small cells that make scarce contacts with transitional cells. Closer to the compact node one can recognize larger individual bundles separated by fibrous tissue, and as the lower cells progress even more distally they form, without any sharp boundary, the penetrating AV bundle.

The above description has been originally proposed for the rabbit heart,⁷ although similar subdivisions have been employed to describe the AV junction in other species as well.^11-13 A major source of confusion in delineating the sub-regions of the nodal area is apparently related to the smooth transitions and the lack of clear morphological/histological features that would easily distinguish between transitional, mid-nodal, and lower nodal cells. The result is that different authors have used the term AV node differently. Accordingly, we are now embracing again as most appropriate the "old" definition of Tawara,⁴ according to which there is a clear "boundary at the site where this system penetrates into the membranous septum". With such simple and logical criterion, the insulated part of the pathway for atrioventricular conduction engulfed by the central fibrous body is best described as part of the penetrating atrioventricular bundle (bundle of His). In contrast, the AV node becomes an integral part of the atrial musculature. Like the penetrating bundle, the nodal cells are morphologically distinct interconnecting meshes set in a prominent fibrous matrix,¹ and can be traced from section to section. Unlike the penetrating bundle, the AV node and the transitional cells are not insulated from the surrounding atrial tissues.

It should be stressed that the arrangements described above, although generally similar, do differ between the species. This, in particular, refers to the so-called compact node in 2 of the most widely used experimental models. In the rabbit heart, the "compact node" is predominantly part of the insulated penetrating bundle portion of the axis. In contrast, in both dog and man, this densely packed region is part of the atrial component of the axis, and is not insulated by fibrous tissue from the atrial myocardium, although an envelope of histologically transitional cells is interposed between the cells of the packed region and the cells of the ordinary "working" myocardium. Therefore morphologists are particularly careful when using the term compact node.^6;14

Electrophysiologically Distinct Zones

Based on activation times during antero/retrograde propagation and on the action potential (AP) characteristics, the cells of the AV nodal region are frequently described as AN (atrio-nodal), N (nodal), and NH (nodal-His).¹⁵ There is no strict correspondence between these cellular types and the specific areas from which the responses are recorded. In general, the AN responses come from the cells in the transitional region and, as the name suggests, their action potentials are intermediate between the fast and brief atrial AP and the slower nodal responses. The AN cells are activated shortly after the atrial cells and the atrial-AN delay appears to be independent on the prematurity. The N cells, allegedly the "most typical" of the nodal cells, have slow rising and longer AP. Most importantly, they are highly sensitive to the prematurity, so that closely coupled AP (as during Wenckebach periodicity) exhibit decremental amplitude and upstroke, double-humped AP shape, as well as low-amplitude non-propagated local responses when block occurs. The NH cells are typically distal to the site of Wenckebach block and their AP are closer in appearance to the fast rising and long AP of the His bundle.¹⁶

Ionic Currents

Several studies have reported ionic currents recorded during voltage clamp on isolated AV nodal cells ^{16, 18, 19} or minute AV nodal tissues.²⁰ Although the action potentials recorded from isolated cells were also classified in AN, N, and NH subgroups,²¹ direct juxtaposition of these groups to the groups described in intact hearts (see above) is only approximate, since the isolation procedures are blind and do not permit to identify the specific region from which the isolated cell originates. Instead, the isolated cells were described based on their shape after isolation as ovoid or rod-shaped.²¹

While it is widely thought that the slow inward currents play a dominant role in the depolarization of the AV nodal cells, the precise details are still insufficient.²² The most detailed recent description of action potential and ionic currents recorded from isolated AV nodal cells²¹ concluded that AP morphologies observed in these cells were similar to those obtained previously from intracellular recordings of intact atrioventricular nodal preparations: ovoid cells had N- or NH- like action potential configurations, whereas rod- shaped cells had AN-like configurations. At shorter prematurities, the AP of the ovoid cells was characterized by a progressive decrease in overshoot potential, maximal upstroke velocity (Vmax) and action potential duration, as well as an increase in latency from stimulation. In rod-shaped cells, premature stimuli could induce new membrane responses before full preceding repolarization, whereas ovoid cells exhibited post- repolarization refractoriness. A hyperpolarization-activated inward current (I(f)) was described in the range between -60 and -90 mV in the ovoid cells, whereas in rod-shaped cells I(f) was 25 times smaller and activated at more negative potentials. A rapid inward current (INa) was found in all rod-shaped cells but in only 30% of ovoid cells. A transient outward current (I(to)) was found in almost all of rod- shaped cells and in half of ovoid cells. These results suggest that there are at least two distinct populations of isolated AV nodal cells with action potentials and ionic currents that may determine the complex electrophysiological properties observed in the intact AV node.

One of the major electrophysiological functions of the AV node is the generation of appropriate delay in the transmission of the atrial impulse. Where, how, and by which underlying mechanisms is the AV node delay generated remains not fully elucidated. It appears that in most cases the N region is the site of conduction block during incremental pacing.¹⁶;²³;²⁴ However, microelectrode studies on so-called 'concealed' conduction²⁵ demonstrated that during fast rates blocked impulses, resulting in local electrotonic humps of the cellular membrane potential, can migrate between the N and AN regions.

The determination of the precise contribution of different nodal regions in the conduction delay is difficult due to the lack of sharply defined boundaries between them. It has been reported that, of the total 100% of the atrio-ventricular delay, the atria itself is responsible for 20%.²³ The widely spread transitional region (AN type cells) may generate from 25% to 60% of the delay according to different sources. ²³;¹⁶;²⁴ The central midnodal region (N cells) accounts for 30% or more of the total delay depending on methodology used. Once the impulse reaches the NH region, the conduction proceeds promptly to the bundle of His, consuming only 5-10% of the total atrio-ventricular delay.

The conduction velocity is not constant in the entire AV nodal area. In small discrete specks of the N region it may take up to 60 ms to transverse longitudinally 1 mm, i.e., less than 2 cm/s. However, precise definition of the term conduction velocity as applied to the AV node is inherently difficult since the propagation is not cable-like. Thus, progressive vertical impalements with glass microelectrodes routinely demonstrate that the superficial cells of the transitional envelope fire 40 ms or more earlier than the N cells located only 100 microns or-so deeper. While it is certain that the activation of the node is inhomogeneous and multi-directional, the pattern of intranodal propagation is not known. Recent optical mapping studies added some valuable information,²⁶;²⁷ but inherent methodological limitations of currently available technologies do not permit this issue to be conclusively resolved.

Two general mechanisms have been proposed to explain how the AV node generates the conduction delay. According to the decremental driving force hypothesis²⁸ the properties of the AV nodal fibers along the pathway of propagation may change in such a way that the propagating "action potential becomes progressively less effective as a stimulus to the unexcited portion of the fiber ahead of it".²⁸ In contrast, the electrotonic transmission hypothesis assumes that the driving force is constant, but that inexcitable microscopic segments cause "stagnation between N and NH zones".²⁴ Since the interposed segments act just like a passive resistance-capacitor link, it takes some delay before the distal excitable tissue's membrane (e.g., the NH region during anterograde conduction) is brought to the threshold of excitation. The proponents of both hypotheses provide observations in support of these mechanisms. It may well be that the real-life scenario incorporates elements of both. Thus, short prematurities and fast rates result in decreased amplitude and distortions in the N-cells' AP that could fully account for the decremental component. On the other hand, the long refractoriness and low excitability of the N-cells,²⁹ along with the rather sharp change in electrophysiological source-sink relation at the border with the NH cells, may account for electrotonic transmission especially in critical conditions, such as Wenckebach periodicity.³⁰

The functional properties of the AV node transmission are determined using the "black box" approach, whereas the highly complex nodal structure is replaced by a simpler model that has atrial input(s), and the bundle of His as its output. Driving stimuli are applied at one or several atrial sites while the His electrogram is simultaneously recorded. The stimulus-to-His conduction times (S-H) are usually plotted as a function of the corresponding atrial coupling intervals (S-S): shortening of S-S invariably results in prolongation of S-H. (In a clinical set-up the S-H intervals are sometimes approximated by S-V, even though the assumption that H-V activation times are constant may not always be correct).

Click on image for legend and to enlarge.

Figure 2.

The simplest protocol used in both clinical and experimental studies³¹ consists of basic steady-state atrial pacing at 400 or 600 ms intervals (beats S1), that is periodically interrupted by the introduction of extrastimuli (S2). The coupling intervals of the latter vary from the basic S1S1 to S1S2 at which the S2 beat is blocked. The plotted conduction curve (S2H2 versus S1S2) is analyzed to evaluate its shape, as well as to extract 2 valuable parameters. The first is the effective refractory period (ERP), equal to the longest S1S2 resulting in AV nodal block. The second is the functional refractory period (FRP), equal to the shortest achievable H1H2 interval. The conduction curve, ERP, and FRP are highly sensitive to the imposed driving rate, the electrophysiological status of the node, the presence of drugs modulating the transmission (verapamil, neurotransmitters, etc.), as well as interventions such as RF ablation.

In addition to using 2 atrial rates (e.g., 400 and 600 ms), conduction curves are also generated with somewhat more complex protocols, in which a third beat S* is interposed between the basic S1 and the test S2 beats. Changing of the S1S* interval permits further important insights into the cycle-length dependent functional properties of the node. Yet another variation of the standard AV nodal conduction curve has been described in which the conduction times S2H2 are plotted not as a function of the atrial prematurity S1S2, but as a function of the preceding H1S2 interval.³² However, this only changes the format of data presentation and therefore does not reveal additional physiological functional properties of AV nodal transmission.³³

The concept of reentry excitation is pivotal in arrhythmogenesis and plays important role in AV nodal electrophysiology. It has been clear for a long time that, under conditions of impaired AV transmission, premature ventricular beats could travel to the atria and then re-emerge in the ventricles as reciprocal beats (ventricular echoes). Similarly, atrial beats can re-enter the AV node producing atrial echo-beats ³⁴. The so-called functional longitudinal dissociation of the AV node was introduced as the mechanism responsible for these phenomena. As the term implies, it was assumed that in norm, and even more so in the presence of conduction abnormalities, functionally distinct pathways are revealed in the nodal domain that permit the formation of a reentry loop. The latter permits an impulse to travel along one branch while its propagation in the other branch is blocked; the impulse then returns after an appropriate delay to the blocked side and invades it retrogradely to complete the reentrant circuit. Thus the prerequisites of slow conduction and a site of unidirectional block during AV nodal reentry are the same as during any other form of reentry. The major question then is what exactly is the substrate of the nodal reentrant loop?

Mendez and Moe³⁵ proposed that atrio-nodal connection utilizes 'alpha' and 'beta' pathways, that connect together in the distal node. Graphically and functionally this conforms to the rules of circular reentry loop and can explain many experimental observations. Isolated cable-like atrio-nodal connections were however never identified,¹ and currently the substrate of the reentrant loop is thought to be either entirely intranodal^36,37 or to be loosely represented by the inferior and superior approaches to the AV node.³⁸

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Figure 3.

The concept of AV node reentry is related, but not identical, to the so-called dual pathway electrophysiology.³⁹ Strictly speaking, the dual AV nodal pathways refer to the complex wavefronts that engage the triangle of Koch. Instead of propagating within a cable (like in the His-Purkinje system), the atrial beat enters the AV node proper from several directions, the most prominent of which are the posterior approaches (Crista terminalis), the superior septal approaches along the fosa ovalis, and the broad mid-septal approaches across the tendon of Todaro.¹ While not isolated from each other, these connections result in a functionally highly inhomogeneous atrio-nodal transition. Thus, during sinus rate (or long pacing coupling intervals) predominant is the wavefront formed along the anterior septal nodal input(s). It reaches the bundle of His first, generating the relatively brief basic conduction delay. In contrast, short-coupled extrastimuli are blocked in these anterior approaches allegedly due to relatively long refractoriness of the tissue and/or due to specific passive properties of the conducting fibers and their interconnections. Therefore, the short-coupled beats proceed along the posterior input approaches and, in general, require longer time to reach the bundle of His. Based on these properties and following a very simplified (and therefore approximate) morphological model, the posterior approaches are regarded as a domain of the so-called slow pathway, while the anterior septal input region hosts the fast pathway.

It is important to stress that the dual pathways are real electrophysiologic entities that characterize the normal AV node electrophysiology. Dual, or rather multiple atrio-nodal wavefronts have been visualized in optical studies.⁴⁰ The presence of dual pathways (electrophysiology) does not result inevitably in formation of a reentry loop and initiation of an atrial echo-beat or sustained atrioventricular nodal reentrant tachycardia (AVNRT). However, the dual pathways electrophysiology provides the natural substrate for the occurrence of such extranodal reentry events. Indeed, just as in the classical Mendez/Moe model,³⁵ short-coupled atrial stimulus may be blocked in the fast pathway (anterior septal input) while successfully propagating via the slow pathway (posterior input) toward the bundle of His. If this propagation is slow enough, the impulse may reenter the atrium retrogradely via the sufficiently recovered fast pathway, producing an echo-beat. The latter may then continue the same process leading to AVNRT.

In some clinical cases the AV nodal conduction curve provides very convenient visual illustration of the dual pathways electrophysiology.³¹ That is, instead of being a smooth semi-exponential function the conduction curve exhibits a characteristic S2H2 "jump" of 50 ms or more at some critical S1S2 prematurity. This is where the fast pathway propagation is blocked and the slow pathway "takes over" after substantially longer delay. However, such discontinuity of the conduction curve is not a needed pre-requisite for the occurrence of atrial echo beats or AVNRT. Both events can be observed along with 'smooth' conduction in both humans⁴¹ and experimental animals.⁴²

Despite the impressive amount of information concerning AV nodal conduction²², the role of the AV node in AF is poorly understood. In particular, the spatial and temporal pattern of the AV node engagement from the atria has not been sufficiently studied.^43,44 Once the excitation waves have entered the AV node, the prevailing hypothesis is that many of the bombarding atrial impulses are blocked (annihilated) within the AV node due to its inherent refractory properties.⁴⁵ The early observations of Engelmann⁴⁶ and later the expanded studies by Langendorf⁴⁷ described in detail a phenomenon when an impulse only partially penetrates the AV node, but still have an influence on the conduction of the subsequent beats. This so called "concealed conduction" is considered the major mechanism responsible for the relatively slow (compared to the atria) and irregular ventricular rate in AF.⁴⁸;⁴⁹

It has long been known that the pattern of atrial input engagement influences AV node conduction. Thus, high rate pacing initiated from the septum results in inferior conduction, compared to pacing from the crista terminalis (CrT).⁵⁰ The phasic relationship between the wave fronts reaching the anterior and posterior AV node inputs determines the conditions for summation or annihilation,⁵¹;⁵² producing stronger or weaker proximal driving force, respectively. However, the above observations have only been made at relatively slow and regular rates. There are only incomplete observations suggesting that the duality of the AV node inputs is also important during AF.⁵³

The clinical AV node modification procedures during AF are based on the principle of dual pathway AV node electrophysiology.³⁵ Although still controversial and not fully understood,⁵⁴;⁵⁵ these principles provide strong mechanistic basis for the understanding and the clinical cure of the AVNRT and for modification of the AV node during AF.

Recent experimental studies confirmed that both the slow pathway and the fast pathway are present during AF⁵⁶ even though the majority of impulses appear to utilize the former. Successful selective ablation of the slow pathway results in fast pathway transmission and a substantial reduction of the ventricular rate during AF. Mechanistically this results from the elimination of a major route of atrio-nodal conduction during AF. In contrast, ablation localized at the apex of the triangle of Koch (targeting the fats pathway conduction) has little effect on the ventricular rate. The most likely explanation is that a beat conducted during AF via the fast pathway is always accompanied by a closely timed impulse propagating via the slow pathway. Therefore elimination of the fast pathway beats only helps reveal the previously concealed slow pathway beats leaving the ventricular rate unchanged.

Autonomic Control

The dromotropic effects of the vagus on atrioventricular conduction are classic and have been studied for a long time.⁵⁷ Experimentally, vagally induced depression of AV nodal conduction can be produced by stimulation of the cervical vagi⁵⁸ or of their projections in the special epicardial "fat pads".⁵⁹;⁶⁰ The so-called inferior vena cava-left atrium fat pad⁶¹ contains vagal fibers that almost exclusively innervate the AV node. Their stimulation depresses AV nodal conduction without any effect on the sinus node. Similar effects were demonstrated with stimulation of the nerve endings in the triangle of Koch, by using endocardial stimulation.^62-64 The latter technique, called postganglionic vagal stimulation (PGVS), has been extensively used^65-68 to determine the cellular mechanisms of the AV nodal vagal control. It has been established that short PGVS bursts mimic the effects of natural vagal discharges triggered by the baroreceptor reflexes⁶⁹. The resulting release of minute quantities of acetylcholine hyperpolarized the cellular membrane of the Ca++-dependent cells of the compact AV node⁶⁵, increased their threshold of excitation, and resulted in depressed AP amplitudes and prolonged conduction time.⁶⁶ PGVS produced only moderate effects on cells in other AV node regions.⁷⁰

Recently, experimental^71,72 and clinical^73,74 studies used the utility of vagal nerve stimulation to selectively suppress AV nodal transmission during fast atrial rates (as in atrial fibrillation), providing a new tool for ventricular rate control and improved hemodynamics.(Figure 4)

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Figure 4.

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