A “drop” in the atrioventricular conduction curve and dual-pathway electrophysiology

Abstract

Background

Atrioventricular (AV) conduction time is rate-dependent. As the atrial coupling interval (A1A2) shortens, AV conduction time (A2H2) prolongs. Thus, the AV conduction curve, plotted using A1A2 vs A2H2, is usually “smooth” and “monotonic”. A “jump” in the curve is the current clinical criterion of dual-pathway electrophysiology, whereas a “gap” in the curve has also been described.

Objective

This study described a new phenomenon, a “drop” in the AV conduction curve. The potential relationship between a drop in the AV conduction curve and the dual-pathway electrophysiology was also examined.

Methods

Overall, 81 experimental records from rabbit AV nodal preparations containing the following data were analyzed: (1) had at least 1 AV conduction curve and (2) had a recording of His electrogram alternans (a validated new index of dual-pathway conduction). Most cases had intracellular action potential recordings from the AV nodal fibers.

Results

Of the 81 preparations, 3 (3.7%) showed a drop in the AV conduction curve. The drops (at A1A2 = 115 ± 35 ms) always occurred after fast pathway to slow pathway (SP) transition (at 148 ± 7 ms). The drops showed an SP-fast pathway pattern in 2 of the 3 preparations and an SP-SP pattern in the remaining 1 preparation. The drops were associated with and most likely caused by the formation of intranodal/nodal–atrial reentry and its subsequent conduction.

Conclusion

A new phenomenon, a drop in the AV conduction curve, has been demonstrated in this study. A drop is likely caused by the formation of intranodal/nodal–atrial reentry and its subsequent conduction.

Key Findings.

• ▪A new phenomenon, a drop in the atrioventricular (AV) conduction curve, has been demonstrated in this study.
• ▪The drops in the AV conduction curve always occurr after fast pathway (FP) to slow pathway (SP) transition.
• ▪The beats resulting in drops in the AV conduction curve show either an SP-FP pattern or an SP-SP pattern of AV conduction.
• ▪The drops are associated with and most likely caused by the formation of intranodal/nodal–atrial reentry and its subsequent conduction.

Introduction

The atrioventricular (AV) conduction curve, plotted using the atrial coupling interval (A1A2) vs the AV conduction time (atrial-His interval or A2H2), is used to describe the relationship between the atrial rates and the AV conduction times.1, 2, 3 It is a practical tool to evaluate the conduction properties of the AV node. The AV conduction time, the time needed for atrial electrical impulses conducted to the ventricles, is rate-dependent. As the atrial rate increases (A1A2 shortens), the AV conduction time (A2H2) prolongs until the AV nodal block occurs. Normally, A2H2 prolongs in an exponential manner as the A1A2 gradually shortens.^4,5 Thus, the “normal” AV conduction curve is usually “smooth” and “monotonic”.

A discontinuous AV conduction curve or a curve showing a “jump” or “jumps,” defined as a large increase in A2H2 (≥ 50 ms) when A1A2 shortens by 10 ms, is the current clinical criterion of AV nodal dual-pathway electrophysiology.^1,2 It assumes that a switch from the fast pathway (FP) to the slow pathway (SP) conduction leads to a large increase in the AV conduction time. However, this assumption may be incorrect because our recent evidence has shown that a jump in the AV conduction curve is not caused by a switch from FP to SP conduction.⁶ Another known anomaly in the AV conduction curve is the “gap” phenomenon, defined as the AV conduction block observed for a range of A1A2 while successful conduction was seen with both longer and shorter atrial intervals.^7,8 Classically the gap phenomenon has been explained to occur “when the effective refractory period (ERP) of a distal site is longer than the functional refractory period of a proximal site and when closely coupled stimuli are delayed enough at the proximal site to allow distal site recovery”.⁸ The gap could happen at sites of atrial–nodal, nodal, nodal-His, or His-ventricular.^7,8 It has also been suggested that the functional interaction of FP and SP could be the electrophysiological mechanism underlying the conduction gap in the AV node.⁷

In this study, we described a new phenomenon in the AV conduction curve. Contrary to a “jump” in the AV conduction curve, in some cases we found a “drop” in the AV conduction curve. A “drop” is defined as a decrease in the AV conduction time when the atrial coupling interval shortens. This is opposite to what is expected. To the best of our knowledge, a “drop” in the AV conduction curve has not been specifically described in the literature. In addition, we have also examined the potential relationship between a drop in the AV conduction curve and the AV node dual-pathway electrophysiology.

Methods

Study design

This study was conducted by reviewing and analyzing our previous experimental records obtained from rabbit AV node preparations since the discovery and validation of a novel index of dual-pathway electrophysiology, known as the His electrogram (HE) alternans,^1,9, 10, 11, 12, 13, 14 first reported in 2001.⁹ Recording of HE alternans permits monitoring of AV node dual-pathway conduction on a beat by beat basis (details will be described later). Experiments were included in the analysis if the following criteria were met: (1) data were collected during programmed (A1A2 or A1A2A3) atrial pacing and an AV nodal conduction curve could be generated, and (2) recordings of HE alternans. Intracellular action potential (AP) recordings from various AV nodal fibers had also been performed in most of these preparations. There were 81 experiments that met the criteria and were included in the analysis. Note that most experiments were conducted at the Cleveland Clinic during Dr. Zhang’s employment there,⁶ and specific data generated from these same rabbit preparations had been used in our previous publications.9, 10, 11, 12, 13, 14 The results presented in this report are new and have not been previously published. The use of animals was approved by the Institutional Animal Care and Use Committee and follows the “Guide for the Care and Use of Laboratory Animals” (NIH Publication No. 85-23, Revised 1996).

In vitro rabbit AV node preparations

Experiments were conducted on atrial-AV node preparations from adult New Zealand white rabbits of both sexes, as previously described.9, 10, 11, 12, 13, 14 Briefly, after sodium pentobarbital (50 mg/kg) anesthesia and opening of the chest, the heart was removed and placed in a standard oxygenated Tyrode’s solution saturated with 95% O₂ and 5% CO₂ at a flow rate of 35 mL/min. After trimming, the AV node preparation contained the triangle of Koch and the surrounding right atrial and ventricular tissues.

Recording of HE alternans to monitor AV node dual-pathway conduction

Over the years we have discovered and validated HE alternans as a novel index of AV node dual-pathway electrophysiology.^1,9, 10, 11, 12, 13, 14 In this study HE alternans was recorded to monitor dual-pathway conduction, as previously reported.9, 10, 11, 12, 13, 14 Briefly, HE recorded from the superior His bundle domain (superior HE [SHE]) is high in amplitude during FP conduction and the amplitude becomes low during SP conduction. In contrast, HE recorded from the inferior His bundle domain (inferior HE [IHE]) is always from low amplitude during FP conduction to high amplitude during SP conduction. Besides the amplitude changes, there are also timing changes between corresponding SHE and IHE during dual-pathway conduction. During FP conduction, the SHE is leading the corresponding IHE. The sequence is reversed during SP conduction.⁹ Thus both SHE and IHE can be used to monitor dual-pathway conduction. Although both SHE and IHE were recorded in the early experiments,^9,10 for convenience only 1 HE (typically IHE) was recorded in later experiments.

Electrical recordings and stimulation protocols

As described previously,9, 10, 11, 12, 13, 14 custom-made bipolar electrodes (0.2 mm spacing) were used to record atrial electrograms and for atrial pacing. Roving bipolar electrodes were used to record the superior and inferior HE. All electrodes were positioned with micromanipulators (M330, WPI, Sarasota, FL). An 8-channel, programmable stimulator (Master-8, AMPI, Jerusalem, Israel) was used for pacing. The electrical signals were amplified, filtered at 30–3000 Hz (CyberAmp 380, Axon Instruments, Union City, CA), recorded, and analyzed by AxoScope (Axon Instruments).

Intracellular APs from AV nodal fibers were recorded using standard glass microelectrodes. As we have reported previously,¹⁴ AP from fibers in the superior nodal domain typically shows 2 wavefronts at a short A1A2. The first wavefront is produced by the antegrade FP wavefront and the second is generated by the “retrograde” SP wavefront. AP from fibers in the inferior nodal domain usually does not show 2 wave fronts.

Programmed atrial pacing protocol (A1A2) was used in most preparations, with a basic cycle length (A1A1) of 300 ms. An A1A2A3 pacing protocol was utilized in a dozen preparations from which multiple conduction curves were available. A standard AV nodal conduction curve was generated by interposing a premature stimulus A2 (or A3) after every 20th basic beat A1. The premature coupling interval A1A2 (or A2A3) was progressively shortened (in steps of 10–5 ms) until the AV block occurred. The AV nodal ERP was defined as the longest A1A2 which failed to conduct by the AV node.

Definition of a “drop” in the AV conduction curve

A “drop” in the AV conduction curve is defined as a decrease in the AV conduction time (A2H2) when the atrial coupling interval (A1A2) is shortened, opposite to what is expected.

Results

A drop in the AV conduction curve and the transition from FP to SP conduction

Of the 81 preparations, 3 (3.7%) showed a drop in the AV conduction curve (Figure 1). In all 3 preparations, the transition from FP to SP conduction occurred before the beat resulting in a drop. In other words, the drop always occurred after the transition from FP to SP conduction, at the end portion of the conduction curve (at the short A1A2 region on the left side of the curve, Figure 1). On average, the transition from FP to SP conduction occurred at prematurity of 148 ± 7 ms vs the drop at 115 ± 35 ms, whereas the AV nodal ERP was 110 ± 26 ms in these 3 preparations. Note that the drop was reproducible in 2 of the 3 preparations when either the AV conduction curve was repeated or AP recordings were obtained with A1A2 pacing. In the remaining 1 preparation, the drop was present during taking the conduction curve. Because the pacing protocol was applied only once, it was uncertain whether the drop could be reproduced in this preparation.

Figure 1.

Atrioventricular (AV) conduction curve showing a drop and the transition from fast pathway (FP) to slow pathway (SP) conduction seen in 3 preparations (A, B, C). The AV conduction curve was plotted using the atrial premature coupling interval (A1A2) in the abscissa and the atrial-His interval (A2H2), representing the AV conduction time, in the ordinate. The transition from FP to SP conduction judged by the His electrogram (HE) alternans is indicated, as well as the drop (red arrow). Note that a drop always occurred later (at shorter A1A2) than the FP to SP transition in all 3 preparations.

The beat resulting in a drop and dual-pathway conduction

Because the transition from FP to SP conduction already occurred before the drop, the beat immediately before the drop was always conducted by the SP. At the beat resulting in a drop, the HE showed an SP-FP pattern in 2 of the 3 preparations (Figure 2A and 2B) and an SP-SP pattern in the remaining 1 preparation (Figure 2C). Note that here we used “FP pattern or SP pattern” instead of FP conduction or SP conduction to indicate the fact that the atrial premature beat (A2) resulting in a drop most likely failed to directly conduct to the His bundle; instead, the premature A2 beat induced an intranodal or nodal–atrial reentry and subsequently the reentrant beat conducted to the His bundle, as will be explained later.

Figure 2.

Beats with a drop and His electrogram (HE) alternans seen in 3 preparations (A, B, C). Atrial electrograms from interatrial septum (IAS), crista terminalis (CrT) together with the inferior His electrogram (IHE) recording at the premature beat preceding the drop (black traces), with the drop (red traces), and the overlapped traces of the 2 beats are shown in each preparation (A, B, C). The atrial echo beat induced by the premature beat is marked with “e”. There were 2 preparations with a drop resulted in a fast pathway (FP) pattern (A, B) and 1 preparation showing a slow pathway (SP) pattern (C).

A drop in the AV conduction curve is likely caused by the formation of intranodal or nodal–atrial reentry and its subsequent conduction

As already stated, in 2 of the 3 preparations the beat resulting in a drop showed an SP-FP pattern, that is, the beat before the drop was conducted by the SP (high IHE, Figure 2A and 2B), and the beat resulting in a drop showed an FP pattern (low IHE) of His bundle activation. Given that the FP had already failed long before the drop, the reappearance of FP conduction at an even shorter prematurity cannot be due to the “normal” FP conduction. The beat resulting in a drop with the FP pattern of His bundle activation was likely because of the formation of reentry (intranodal/nodal–atrial) and its subsequent conduction. The concept is supported by the evidence shown in Figure 3. In this case, the AP was recorded from a cell located in the superior nodal domain near the interatrial septum (IAS). Note that as A1A2 gradually shortens, the AP recordings showed an early, decremental FP wavefront (1) and the emergence of a later “retrograde” SP wavefront (2), which was associated with an atrial echo beat and SP conduction (high IHE). At the beat resulting in a drop, as expected the first FP wavefront further diminished due to further shortening of the prematurity. However, at this A2 beat the second wavefront occurred much earlier, indicating a different reentry (from previous retrograde SP wavefront) had been formed. This was also reflected by the early-occurring atrial echo beat. Note that in this beat the reentry activated only the IAS, not crista terminalis. Thus, the FP pattern of His bundle activation is likely caused by the newly formed reentry and its subsequent conduction to the superior His bundle, resulting in an FP pattern of His bundle activation. Thus, the drop in the AV conduction curve is most likely because of the formation of a reentry and its subsequent conduction, rather than a direct conduction to the His bundle by the A2 beat.

Figure 3.

Panel A shows simultaneously recorded atrial electrograms from interatrial septum (IAS), crista terminalis (CrT), and nodal cellular action potentials (AP) from a fiber in the superior nodal domain, together with the inferior His electrogram (IHE) during shortening of atrial prematurity A1A2. The numbers at AP traces indicate the corresponding A1A2 (Color matched). Note the presence of an early, decremental wavefront (1, arrow) and a late wavefront (2) at A2 beat as A1A2 gradually shortened. At the beat resulting in a drop (A1A2 = 75 ms, green traces), the first wavefront decreased further as expected, however, the second wavefront occurred much earlier, together with the atrial echo beat on IAS trace, no atrial activation on CrT trace. The His bundle activation showed a low IHE (FP pattern). To better illustrate these changes, panel B shows only 2 episodes: the episode before the drop (black traces) and the episode resulting in a drop (red traces), and the overlapped traces of these 2 episodes. Note that at the beat before the drop (A1A2 = 80 ms), the timing of HE and the second wavefront were almost at the same time, but at the beat resulting in a drop (A1A2 = 75 ms), the second wavefront AP occurred much earlier than the HE.

In the remaining 1 preparation, the beat resulting in a drop showed an SP-SP pattern of His bundle activation (Figure 2C). No AP recording was available when the drop occurred in this preparation. We have shown that intranodal or nodal–atrial reentry could occur in all preparations at short prematurity after the FP to SP transition, and some reentries could be intranodal, without atrial echo beat.⁶ Figure 4 shows an example that His bundle activation was due to the formation of intranodal reentry and its subsequent conduction, without an atrial echo beat. Thus, similar to what has already been described; it is possible that the A2 beat resulted in an intranodal reentry, which then conducted to the inferior His bundle, resulting in an SP pattern of His bundle activation.

Figure 4.

An example that formation of intranodal reentry likely resulted in His bundle activation. Note that in this case, superior His electrogram (SHE) was recorded. The recordings were taken at the same A1A2 = 130 ms. The A2 beat resulted in AV block in 1 episode (black traces). The action potential (AP) recording was from a fiber in the center of the node near the inferior nodal domain and showed a small local response, without His bundle activation. In another episode with the same A1A2 (red traces), however, there was His bundle activation (low SHE, slow pathway pattern). The AP recording showed an identical initial local response but followed by an additional activation (arrow), indicating an intranodal reentry occurred, but without atrial echo beat. The overlapped signals of these 2 beats are also shown.

Discussion

Major findings

In this study, we reported a new phenomenon, a drop in the AV conduction curve. This phenomenon is relatively rare, seen only in 3 of 81 (about 4%) rabbit AV node preparations. A drop in the AV conduction curve always occurred after the transition from FP to SP conduction. We have also provided evidence suggesting that a drop in the AV conduction curve is likely caused by the formation of an intranodal or nodal–atrial reentry and its subsequent conduction, rather than direct conduction by the atrial premature beat to the His bundle. Because we have shown recently that the formation of intranodal or nodal–atrial reentry and its subsequent conduction is the underlying mechanism for a jump in the AV conduction curve,⁶ it seems that a drop in the AV conduction curve and a jump in the AV conduction curve share the same mechanism of formation of intranodal or nodal–atrial reentry and its subsequent conduction. They are just different manifestations of the same mechanism.

AV node dual-pathway electrophysiology, formation of reentry, and the AV conduction curve

AV node dual-pathway electrophysiology was initially believed a pathology, existing only in patients with AV nodal reentrant tachycardia (AVNRT).^1,2 It has been recognized that dual pathways, as defined by a jump in the AV conduction curve, can be found in subjects without AVNRT,^1,2,15 whereas patients with AVNRT could display a smooth curve (without a jump).¹⁶ Thus, a smooth curve does not rule out the existence of dual pathways.^1,2 By using the new index of dual-pathway electrophysiology (HE alternans), we have demonstrated that dual-pathway electrophysiology exists in all preparations.¹ In fact, dual-pathway electrophysiology is a normal inherent property of the AV node conduction.¹⁷

We have shown that at slow heart rates, the AV conduction starts at the IAS boundary of the node (superior nodal domain) and spreads toward the tricuspid annulus side (inferior nodal domain) in a direction perpendicular to the AV axis.^14,17 Such activation results in an early, superior input into the superior His bundle (ie, FP conduction).^14,17 As A1A2 shortens, the FP wavefront gradually withdraws from the inferior nodal domain, this allows the SP wavefront formed at the crista terminalis end of the node to propagate through the inferior nodal domain to activate the inferior His bundle (ie, SP conduction).^14,17 The SP wavefront could also invade retrogradely into the superior nodal domain, resulting in reentry, that is, the premature beat activated the superior nodal domain twice: first by the antegrade FP wavefront, and then by the retrograde SP wavefront.^14,17 One of such examples is shown in Figure 3. Although reentry formation could be demonstrated in all preparations, normally no AVNRT was seen.^6,14 In other words, reentry formation (concealed intranodal reentry or with atrial echo beat) can be demonstrated in all preparations, but sustained AVNRT is very rare.

As to the AV conduction curve, indeed at basic beats and long A1A2, AV conduction utilized the FP. When A1A2 gradually shortened, it gradually transitioned to SP conduction, as expected.^10,11,17 However, at very short A1A2 near the end of the curve, complex reentry could form. Thus, a short atrial premature beat (A2) could fail to conduct directly to the His bundle, but instead, it could form a reentry (intranodal or nodal–atrial), and the reentrant beat could subsequently conduct to the His bundle.⁶ If the atrial-His interval were measured in this case, it would be an artificial/misinterpreted time/event, or pseudo-interval.⁶ This kind of pseudo-interval could be manifested as a sudden increase in the AV conduction time (a jump in the AV conduction curve) in most cases because of an increased path to the His bundle, as we have demonstrated recently.⁶ However, in rare cases a shortening of the “apparent” AV conduction time (a drop) might also be possible, as shown in the current study. We have to acknowledge that based on a few AP recordings, our data could not illustrate the exact reentrant circuits. However, they did provide evidence indicating that the formation of intranodal or nodal–atrial reentry was associated with the drop in the conduction curve (Figures 2 and 3). The shortening of the “apparent” AV delay could happen, at least in theory, when the reentrant circuit involved perinodal atrial tissue, and then conduction could go through the anterior “shortcut” connecting the IAS and the superior His bundle fibers, as shown in Figure 5A—reentry with FP pattern, similar to the FP conduction.¹⁷ A similar structure (the last atrial–nodal connection) has been described in human hearts as well.^18,19 Another possibility is that the formation of intranodal reentry, by producing a longer delay in the proximal site, could lead to better recovery of distal tissue and thus faster conduction to the His bundle, as shown in Figure 5B—reentry with SP pattern. This mechanism is similar to the classic explanation of the gap phenomenon,⁸ that conduction delay in the proximal site could allow recovery of the distal tissues, thus, enhancing conduction in the distal portion. It seems that both “a jump” and “a drop” in the AV conduction curve could share the same mechanism of reentry formation and its subsequent conduction. They are just different manifestations depending on the conduction time needed from the reentrant circuit conducted to the His bundle, most likely affected by the reentrant circuit location, size, etc.

Figure 5.

Schematic illustrations showing hypothetical mechanisms that formation of intranodal/nodal–atrial reentry could result in a drop in the AV conduction curve. The electrical excitation sequence and functional dissociation (superior nodal–His bundle domain in blue, and inferior nodal–His bundle domain in red) are shown. For a detailed illustration of fast pathway (FP) conduction and slow pathway (SP) conduction, please refer to our recent article by Ma S and colleagues.¹⁷ Here we only illustrate the potential reentries that could lead to a drop in the AV conduction curve. A. at short A1A2, the normal FP conduction was blocked (curved green arrow in the superior nodal domain). The SP also failed to directly conduct to the His bundle (curved yellow arrow) but instead formed a nodal–atrial reentry and activated interatrial septum (IAS). The IAS excitation could then be conducted to the superior His bundle domain (blue arrow) through the “shortcut” located at the anterior/superior nodal region, resulting in an FP pattern of His bundle activation. B. another example of reentry formation resulting in a drop in the AV conduction curve. At short A1A2, the normal FP conduction was blocked (curved green arrow in the superior nodal domain), and the SP also failed to directly conduct to the His bundle (curved yellow arrow). However, it formed an intranodal reentry. The slow conduction in the proximal site (curved yellow arrow) in the inferior nodal domain and the reentry formation allow distal tissue to recover, thus, enhancing the conduction in the distal tissue and activating the inferior His bundle domain (black arrow), resulting in an SP pattern of His bundle activation. AVN = atrioventricular node; CFB = central fibrous body; CrT = crista terminalis; CS = coronary sinus; TrV = tricuspid valve.

Limitations

We acknowledge that this is a retrospective study. AP recording was not obtained in all preparations. Despite that AP recordings provided evidence that the formation of intranodal/nodal–atrial reentry was associated with the “drop” in the AV conduction curve, the exact reentrant circuit could not be determined with only a few AP recordings. Future experiments with high-density mapping systems might provide new insights into the reentry circuits. In addition, in most preparations, only A1A2 pacing protocol was applied. Since it has been reported that using A1A2A3 pacing protocol could reveal more jumps in the AV conduction curve,²⁰ it remains to be studied whether A1A2A3 protocol could reveal more drops in the AV conduction curve.

The “drop” phenomenon has not been specifically reported in patients yet. Despite the anatomical similarities in the AV node in rabbits and humans, interspecies differences exist.^21,22

Thus, systemic evaluation in patients is needed to determine the existence and incidence of this phenomenon in patients.

Conclusion

A new phenomenon, a drop in the AV conduction curve has been demonstrated in this study. A drop in the AV conduction curve always occurred after the transition from FP to SP conduction at short A1A2, near the end of the AV conduction curve. The beat with a drop could show either FP or SP pattern of His bundle activation. It is likely that a drop in the AV conduction curve is caused by the formation of intranodal/nodal–atrial reentry and its subsequent conduction to the His bundle, rather than a direct conduction by the atrial premature beat.