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Cardiovascular Research 1999 44(2):344-355; doi:10.1016/S0008-6363(99)00201-1
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Role of the differential bombardment of atrial inputs to the atrioventricular node as a factor influencing ventricular rate during high atrial rate

Stéphane Garrigue1,*, Patrick J. Tchou and Todor N. Mazgalev

Department of Cardiology, Electrophysiology Section, The Cleveland Clinic Foundation, Cleveland, OH, USA

* Corresponding author. Correspondence address: Hôpital Cardiologique du Haut-Lévêque, 19, Avenue de Magellan, Clinical Cardiac Pacing and Electrophysiology Department, Pr. J. Clémenty and Pr. M. Haïssaguerre, 33600 Pessac, France. Tel.: +33-556-556-471; fax: +33-556-556-509 stgarrigue{at}aol.com

Received 27 January 1999; accepted 28 May 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objectives: The role of the atrial inputs for the conduction through the atrioventricular node (AVN) at slow rates and during reentrant tachycardia is well acknowledged, although still controversial. However, the relationship between the sequence and rate of atrial engagement of the AVN inputs and the resulting ventricular rate during high atrial rate remains unclear. This study provides quantitative description of complex AVN input—output correlations determining the ventricular rate during random high atrial rate. Methods and results: 12 rabbit heart preparations were used to evaluate the ventricular rate during programmed regular high atrial rate pacing or random pacing from eight atrial sites. Electrograms were recorded at the posterior (P) and anterior (A) AVN inputs, and at the bundle of His along with nodal cellular action potentials. Lorenz-plots and input—output-rate correlations were used to quantify the ventricular rate under different pacing protocols. Small alternations in the sequence of activation of P and A resulted in substantial changes of the organization of the intranodal cellular responses and the ventricular rate. The ventricular rate was shown to be significantly dependent on the site of high rate pacing (P<0.01) and on the resulting mean rate of inputs activation. Furthermore, the asymmetry between P- and A-bombardment was an important determinant, so that high ventricular rate was associated with large difference between the inputs’ rates and vice versa (P<0.05). Conclusions: The prevailing ventricular rate during high atrial rate is a complex dynamic parameter that depends not only on the global mean atrial rate but, in a major part, on the differential bombardment of the AVN inputs and on the site of initiation of the atrial wave fronts.

KEYWORDS A=anterior AVN input; also, electrograms recorded at this location; AA=interval measured between two consecutive electrograms at the A-input; AVN=atrioventricular node; HAR=high atrial rate; HH=interval measured between two consecutive His electrograms; P=posterior AVN input; also, electrograms recorded at this location; PP=interval measured between two consecutive electrograms at the P-input

This article is referred to in the Editorial by A.C. Rankin and A.J. Workman (pages 249–251) in this issue.


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Random high atrial rate (HAR) pacing has been identified as an irregular disorganized activity of the atria [1], although recent studies suggest that even during atrial fibrillation an appreciable amount of organization can result from the presence of stable reentrant circuits and fibrillatory conduction [2]. However, in the absence of advanced atrioventricular block, the ventricular response remains fully random [3,4] and dependent on the filtering by the atrioventricular node (AVN) [5,6].

The irregular ventricular rhythm observed during high atrial rate (such as atrial fibrillation) has been attributed to repetitive concealed anterograde conduction [7–9], electrotonic modulation of AVN propagation or pacemaker activity [10,11]. It has been suggested that the probability of AVN blockade should increase with an increase in the frequency of atrial impulses engaging the AVN [10,12]. In other words, the mean ventricular intervals might increase when the mean atrial intervals decrease. However, this simplified rule does not stress the fact that the ventricular rate is not only determined by the properties of the intranodal conduction but also by the rate and irregularity at the atrio-nodal inputs. It has been well established that the site of perinodal engagement and the input interactions are important determinants of AVN cellular action potential morphology and propagation sequence [13,14]. Furthermore, evidence from the clinical procedure known as nodal modification [15,16] suggests that lesions applied at the inputs, and not on the AVN, can produce ventricular rate slowing during irregular high atrial rate such as atrial fibrillation. Although the mechanism(s) underlying the success of this clinical procedure are still not well understood, one logical assumption is ablation-induced alteration in the balance between impulses entering the AVN via the posterior and anterior input sites. However, neither the role of the directional engagement nor the importance of the AVN inputs rates during high atrial rate have been previously investigated.

Therefore the aims of the present study were: (1) to evaluate the role of the pacing site on the differential bombardment of the AVN inputs during random HAR pacing, and (2) to quantify the relationship between the local anterior and posterior AVN inputs rates and the ventricular rate during the same pacing configuration.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Atrioventricular nodal preparation
The experimental set-up was similar to that previously reported [17], thus only a brief description is provided below. The experiments were performed in vitro on 12 hearts obtained from anesthetized New Zealand rabbits weighing 2 to 2.2 kg. All studies were performed in accordance with the existing policies and the Guide for the Care and Use of Laboratory Animals established by the National Institute of Health and were monitored by our Institutional Animal Care and Use Committee. After dissection and removal of the ventricles the right atrium was opened and the endocardial surface was exposed for subsequent superfusion (a photograph of a typical preparation is shown in Fig. 1A). Standard Tyrode solution oxygenated with 95% O2–5% CO2 was pumped at 35 ml/min in a thermostatically controlled glass chamber at 35.5°C and pH of 7.35±0.5. Stable electrophysiologic parameters were maintained over a period of 6–8 h.


Figure 1
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  		Fig. 1 (A) Photograph of the atrial-AVN preparation. The dashed lines indicate the triangle of Koch with the compact AVN (star). The arrows point to major anatomical landmarks: interatrial septum (IAS), right appendage with the musculae pectinatis (MP), superior and inferior vena cava (SVC, IVC), septal leaflet of the tricuspid valve (TrV), fossa ovalis (FO), crista terminalis (CrT), bundle of His. (B) Drawing indicating the positions of pacing (dots) and recording (arrows) electrodes. These were: HRA (high right atrium), MRA (middle right atrium), LRA (low right atrium), CrT (crista terminalis), HS (high septum), CSO (coronary sinus ostium), MS (middle septum), LS (low septum). P, A and His indicate the positions from which posterior and anterior AVN input and bundle of His electrograms were recorded, respectively.

 
2.2 Electrical stimulation and recordings
Electrical stimuli (2 ms, twice diastolic threshold) were applied at different sites (Fig. 1B, black circles). Bipolar electrodes recorded surface electrograms (Fig. 1B, arrows) at the posterior (P) and anterior (A) AVN inputs, and at the His-bundle.

Action potentials were recorded from compact AVN fibers using standard microelectrodes techniques [18] under microscopic control. The impalements were made in the central (compact) nodal region. The latter was identified by using anatomical landmarks, the action potential morphology and timing, as well as by the specific strong response to brief bursts of local postganglionic vagal stimulation, as previously described [19]. We used the action potential of nodal cells to illustrate the effect of the pattern of inputs activation on the morphology of the cellular response that could suggest interaction of multiple wave fronts.

After amplification and filtering (30–3000 Hz), all signals were displayed for monitoring on a storage oscilloscope (Tektronix, 2216). In addition, they were digitally recorded on tape (Vetter Digital, 4000A) for subsequent analysis with PC and AxoScope (Axon Instruments) and ORIGIN (Microcal) software.

2.3 Stimulation protocols
The preparations were beating spontaneously at the start of the experiment. The mean sinus cycle length was 363±21 ms. The basic paced cycle length was 300 ms and the mean basic conduction time between the P-site and the bundle of His was 77±6 ms. The preparations were paced at the basic rate during the initial 30–40 min period of adaptation and between the repetitive episodes of regular or random HAR pacing.

Four hearts were dedicated to recordings of AVN action potentials. Regular high rate atrial pacing at progressively shorter coupling intervals (300 to 130 ms) was applied at the P-AVN input, the A-AVN input or both. In the latter case the P and A inputs could be paced either simultaneously or with a fixed arbitrary phase-delay. The objective was to reproduce experimentally controlled high level of repetitive atrial bombardment at the anterior and posterior AVN inputs. Subsequently, random HAR pacing was applied in the right atrium to mimic irregular atrial rhythm.

Random HAR-pacing was provided by a customized software with coupling intervals in the range of 75–150 ms (mean cycle length: 113±18 ms). Each individual interval occurred with similar probability during long runs of random HAR. This model was comparable to the one previously described by Chorro et al. [1]. In order to evaluate the site-dependency of the AVN propagation, we repeated exactly the same random stimulation pattern multiple times from different atrial pacing sites. As explained below, the random HAR-pacing protocol permitted consistent comparisons between the pacing sites.

In eight preparations we carried out quantification of the relationship between the local rates of activation at the two major AVN inputs and the resulting ventricular rate. In each of these preparations we initiated consecutive runs of random HAR pacing from up to eight different sites. Four posterior and four anterior pacing sites were chosen (black circles in Fig. 1B). The pacing sites were activated in a random order in different preparations. The placing of the pacing electrodes was guided by anatomical landmarks (Fig. 1) with a precision of±1 mm. Stable basic conduction time between P and His was monitored in each preparation between the pacing runs. The protocol was terminated if this delay became unstable or prolonged by >5 ms. All eight pacing sites were tested in four preparations, six pacing sites in three, and four in one preparation.

In separate experiments [20] we established the reproducibility during random HAR pacing. Each of the relevant mean time intervals used in this study (PPmean, AAmean and HHmean, see definitions in Data Acquisition) was measured in two consecutive trials performed from the same pacing site and with the same stimulation sequence. Although the individual atrial events evoked in each trial were unique, the differences between the corresponding mean intervals (PPmean, AAmean and HHmean) in trial 1 and trial 2 did not exceed 3 ms. The intra-class correlation coefficients for the mean intervals ranged from 0.97 to 0.99. Thus, repetitive random HAR pacing episodes performed at the same pacing site resulted in the same statistical distribution (mean±standard deviation) of PP, AA and HH intervals confirming high degree of reproducibility.

2.4 Data acquisition
Activation times at the anterior and posterior AVN inputs, and at the bundle of His (arrows in Fig. 1B) were determined with 1-ms precision and used to define the consecutive AA, PP and HH intervals. Large number of consecutive HH intervals (or any other intervals) can be conveniently displayed for easy visualization in the format of Lorenz plots [21–23]. In this study (Figs. 3 and 4Go) each Lorenz plot data point has as an abscissa the ‘current’ measured HH interval (in ms) and as an ordinate the ‘next’ measured HH interval. For the subsequent data point the HH interval previously identified as ‘next’ becomes an abscissa, while the ordinate will be the HH interval that follows the ‘next’, etc. The result of this procedure is a ‘scatterogram’ that permits visualization and quantification of the irregularity of all HH intervals. Statistically, the degree of dispersion was determined by the scattering index (S[H])


Figure 3
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  		Fig. 3 Lorenz plots of the HH intervals corresponding to the panels in Fig. 2 and obtained from 20-s records. The plots permit fast visualization of the scattering of the HH intervals. In addition, each plot is quantitatively characterized by the mean±SD value of the HH intervals, the scattering index S[H] of the HH intervals distribution (see Methods) and the ratio N[P]/N[A] of the events observed at the posterior and anterior AVN inputs. Shortening of the pacing cycle length (CL) from 150 to 140 ms (B and C) increased the scattering index (25 to 40) but shortened the HHmean. In contrast, pacing at the same cycle length (140 ms) but from two atrial sites with a 30 ms delay between them (D) increased the HHmean and reduced the scattering index (40 to 22). See text for more details.

 

Figure 4
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  		Fig. 4 Computerized random high atrial rate pacing. Traces are organized as in Fig. 2. The inset shows the Lorenz plot obtained from a 20-s recording of HH intervals. Note the dynamically changing sequence of postero—anterior bombardment of the AVN inputs and the larger number of P-events (N[P]/N[A]=1.44). Multiple humps with low amplitude were frequent in the action potential trace (vertical arrows) underlining the highly inhomogeneous conduction through the compact node. As a result of this very complex conduction pattern, the scattering index S[H] was high.

 

Formula

where xi and yi are the current and next value of the measured intervals at the respective site H (i.e., His), n is the number of measured intervals, Formula and Formula are the coordinates of the scatterogram mean.

Coupling intervals at the anterior AVN input (AA) and posterior AVN input (PP) were given as mean (AAmean and PPmean)±standard deviation. Similarly, mean intervals (HHmean) were determined from the His responses. In addition, the ratio of the number of P and A impulses (N[P]/N[A]) was calculated to quantify the degree of differential input bombardment during random HAR pacing. This parameter also permitted us to quantify the degree of intra-atrial block between the anterior and posterior part of the right atrium.

In the microelectrode experiments measurements were made from 20-s recordings. In the remaining experiments the random HAR pacing was programmed so that each episode continued until 500 HH intervals were collected. A total of 54 episodes were analyzed in eight preparations.

2.5 Statistical analysis
The PP, AA and HH intervals were compared between the different pacing sites by using a multivariate repeated measurement analysis for each preparation. The level of the within-factor analysis was determined by the number of tested pacing sites in each preparation. In addition, post-hoc comparisons were performed to compare the pacing sites two by two for the three measured intervals (AA, PP and HH). Polynomial and linear correlation analyses were performed to determine the relationship between the number of atrial events and the value of the current HH interval during random HAR pacing. For comparisons between preparations, the non-parametrical exact Fisher test was used for qualitative variables. A value of P<0.05 was considered statistically significant.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 AVN conduction during high rate pacing: role of the anterior and posterior inputs
In the first part of the experiments with microelectrode recordings, pacing was applied at two atrial sites (the low septum and the crista terminalis) in order to evaluate the role of the timing between the posterior and anterior AVN inputs activations at fast rates (Fig. 2). In A–C and E, the pacing was performed only from the crista terminalis site with progressively shorter cycle length from 300 to 130 ms. In D and F, the low septum site was also paced and a fixed phase of 30 ms was maintained between the posterior and the anterior input for each coupling interval. In A, one-to-one atrial—His conduction was obtained with pacing from the crista terminalis at slow rate (300 ms). In contrast, at a cycle length of 150 ms (B), blocks distal to the impaled AVN fiber led to Wenckebach periodicity with irregular HH intervals. At a cycle length of 140 ms (C), in addition, occasional intra-atrial blocks were evident, resulting in a ‘missing’ A electrograms (star) and AVN action potentials. Here, it could be suggested that the AVN was engaged more frequently but less successfully from the posterior AVN input. D illustrates the same cycle length of 140 ms as in C, but with the low septum now independently paced 30 ms after the stimulus applied at the crista terminalis. As a result, one-to-one conduction was restored between the atrial and the cellular activation compared with C. At a cycle length of 130 ms (E) the conduction between the paced posterior AVN input and His was 2:1, and similar block was also present at both the anterior AVN input and the compact node action potential (stars). Finally, in F, the same cycle length of 130 ms as in E was accompanied by additional low septum stimuli 30 ms after the stimuli at the crista terminalis. This resulted in an increased rate of cellular depolarization. However, an alternation of the action potentials’ amplitude was evident, with each other action potential with decremental amplitude. This resulted in concealment that was evident from the prolonged delay of the conducted beats (112 versus 92 ms in E and F, respectively). Consequently, it could be suggested that bombarding the AVN at the same rate from both the anterior and posterior inputs was deleterious for the conduction compared with the same rate of bombardment from one input.


Figure 2
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  		Fig. 2 AVN input electrograms (P, A), action potentials and His electrograms recorded during pacing only from crista terminalis (A–C and E) or from crista terminalis and low septum (D, F). The pacing cycle length (CL) is indicated along with the P—A delay (in brackets, D, F). Each panel represents 1 s of recording (time-scale in A). See text for details.

 
The effect of the above manipulations in the sequence of input activation on the HH intervals was readily evident from the Lorenz plots shown in Fig. 3 (A–F correspond to the same panels in Fig. 2). Note the substantial change in the scatterogram between B and C produced by only 10-ms shortening of the cycle length. The latter resulted in reduction of the number of anterior impulses due to occasional intra-atrial blocks, so that N[P]/N[A] increased to 1.26. This predominant bombardment of the AVN from one side was associated with shortening of the mean HHmean interval (211±21 in C vs. 233±23 ms in B) and higher degree of scattering S[H] (40 vs. 25). Note further the changes produced by a fixed time delay between the posterior and the anterior AVN inputs (D). There was a prolongation of HHmean and reduction of S[H] (234±17 ms and 22, respectively).

The changes observed between E and F in Fig. 3 were less dramatic since the pattern of AVN conduction was a rather stable 2:1 Wenckebach periodicity. Nevertheless, despite the same ‘global’ atrial rate detected posteriorly in both cases (PP intervals of 130 ms), different HH interval distributions were observed depending on the number of anterior events (Fig. 3E and F). There were twice as many more anterior depolarizations in F than in E and, in addition, a longer and more variable atrial—His conduction delay was apparent when both inputs were activated (Fig. 2F).

While in the above experiments the phase between the activation of the AVN inputs could be controlled, this parameter was variable during random HAR pacing. In Fig. 4 random-rate pacing applied at the high right atrium (Fig. 1B) produced a disturbance in the atrial conduction. The exact relationship between the level of pacing irregularity and the resulting atrial disorganized activity remains unknown, but the electrograms recorded at both the posterior (P) and the anterior (A) AVN inputs became irregular and polymorphic, suggesting a very complex inputs contribution to the subsequent AVN propagation. The microelectrode was impaled in a fiber from the proximal compact node. Random and decremental (i.e. with a reduced amplitude) membrane depolarizations with a complex morphology were consistent finding in all four studied preparations. Multiple humps with low amplitude were frequently observed (vertical arrows). Although these partial depolarizations could be closely followed by His electrograms, the latter most likely resulted from propagation via alternative path(s); that is, the impaled fiber was intermittently either part of a conducting or of secondary (‘dead end’) pathways. The His-Lorenz plot (inset) showed that the random input activation resulted in a random distribution of HH intervals with a large scattering index (S[H]=48). Interestingly, note that similar mean HH intervals and scattering indexes were observed in Fig. 3C and Fig. 4 (inset). This was associated with a comparable N[P]/N[A] values in both cases (1.26 and 1.44, respectively).

These experiments indicated that complex irregular HH distributions could be observed during regular as well as during random high atrial rates. Here the number of anterior and posterior AVN input depolarizations played an important role in determining the inhomogeneity of transmission and the resulting ventricular rate.

3.2 Relationship between the ventricular rate and the differential bombardment of the AVN inputs during random high atrial rate pacing
In view of the above demonstrated complexity and unpredictability of the phase between the AVN inputs during random HAR (Fig. 4), in subsequent studies we limited the quantitative analysis to the relationship between the HH intervals and the mean events occurring at the AVN inputs. Several hypothesis were evaluated.

As previously explained, we initiated random HAR pacing from eight different atrial sites (see Fig. 1B). Exactly the same sequence of random atrial coupling intervals was delivered at each site. In the first hypothesis, we attempted to characterize possible correlation between each HH interval and the number of posterior and anterior AVN inputs events. We plotted each measured HH interval versus the total number of anterior and posterior AVN input impulses ([N(A)+N(P)]-events) that occurred during the same time-period, for each of the pacing sites. 27 000 HH data-points are shown in Fig. 5 (in each preparation: 500 HH data-pointsxnumber of tested pacing sites). The number of [N(A)+N(P)]-impulses reaching the AVN during the generation of a given HH interval varied from 0 to 14 (Fig. 5). The correlation analysis performed in each preparation suggested that the larger the number of AVN inputs events, the longer were the HH intervals (P<0.01).


Figure 5
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  		Fig. 5 Correlation between the HH intervals generated in each preparation during random high atrial rate pacing induced from different pacing sites, and the number of [N(A)+N(P)] atrial events that occurred during the generation of a given HH. The lines are the best fit and the coefficients of correlation r are shown in each panel. Even though the correlation coefficients revealed a significant relationship between the two variables (P<0.01), the scattering of the data cloud is large in every preparation. For instance, in preparation 1, four [N(A)+N(P)] events could result in HH intervals between 170 and 400 ms. Thus, the parameter [N(A)+N(P)] could not be the single determinant of the resulting HH intervals during high atrial rate. See text for details.

 
These data confirmed the previous studies of Moe and Abildskov [7] and later Chorro et al. [1]: the slowing of the ventricular rate during high atrial rate appeared dependent on the large number of atrial impulses engaging the AVN, in accordance with the hypothesis that high atrial bombardment leads to excessive annihilation of wave fronts and subsequent concealment [9]. However, the large scattering of many bins of [N(A)+N(P)]-events in the eight preparations (Fig. 5) pointed out the limitations of this simple hypothesis. For example, in preparation 6, a 300-ms HH interval could have been provided by [N(A)+N(P)]-events ranging from 2 to 7 (Fig. 5). Indeed, the correlation parameter r2 that reflects the direct effect of the [N(A)+N(P)]-events on the HH intervals ranged from 0.46 to 0.62 in different preparations (close relationship between the [N(A)+N(P)]-events and the corresponding HH would require values near 1). This suggested that some additional factor(s) should be considered when predicting the cycle length of the resulting HH intervals during random HAR pacing.

Accordingly, we decided to test the hypothesis that one such additional factor could be the dynamic difference between the mean rates of bombardment of each of the AVN inputs. Thus, we calculated the values of the mean intervals AAmean and PPmean, and determined their correlation with the value of HHmean. In particular, we paid attention to the absolute value of the difference [PPmean–AAmean]. Furthermore, we evaluated the importance of the site from which the HAR pacing was initiated.

Fig. 6 illustrates the juxtaposed mean intervals obtained in every preparation for each pacing site (see abbreviations in Fig. 1). Each panel contains three lines representing, for a given preparation, the mean anterior and posterior input intervals AAmean, PPmean, and the intervals HHmean. The following important observations were made

• First, AAmean, PPmean and HHmean were significantly different depending on the pacing site (P<0.01 for all but preparation 5 Table 1). In five preparations, the crista terminalis (CrT) pacing site provided the shortest HHmean (P<0.05, Table 1 and Fig. 6). In six preparations the coronary sinus ostium (CSO) pacing site provided the longest HHmean (P<0.05).
• Second, the difference [PPmean–AAmean] (i.e., the absolute difference between PPmean and AAmean during stimulation from a particular site) also significantly depended on the pacing site (P<0.01 for all but preparation 5, Table 1). Importantly, the shortest difference [PPmean–AAmean] was observed with pacing from the coronary sinus ostium in five preparations (Table 1), while the longest difference [PPmean–AAmean] was obtained in six preparations with pacing from the crista terminalis.
• Third, two specific functional relationships became evident. The first one was: Longest [PPmean–AAmean] associates with shortest HHmean. Consequently, the shortest HHmean was always (except for preparation 5) associated with a substantial difference [PPmean–AAmean] (the dark bars in Fig. 6). The second one was: Shortest [PPmean–AAmean] associates with longest HHmean. As a result, the longest mean HHmean was always associated with negligible difference [PPmean–AAmean] (the light bars in Fig. 6). Interestingly, the shortest HHmean was most frequently observed with stimulation from the CrT (Table 1, the boldface CrT-pairs), while the longest HHmean was most frequently observed with stimulation from the CSO (Table 1, the boldface CSO-pairs). When we included all pacing sites in the analysis, the global picture also revealed a significant reversed correlation between the HHmean and the [PPmean–AAmean] (r=–0.68, P=0.01).
• Fourth, each preparation had a specific pacing site from which the functional refractory period (i.e. the shortest measured HH interval) was obtained (Table 1). This observation indicated that the shortest HH interval obtained during HAR pacing from different sites depended not only on the inherent conduction properties of the AVN and the sequence of atrial stimulation. The site of HAR pacing directly influenced the pattern of engagement of the AVN inputs and this apparently affected the functional refractory period.


Figure 6
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  		Fig. 6 Mean intervals (HHmean, PPmean and AAmean) obtained in each of eight preparations during random high atrial rate pacing induced from up to eight pacing sites (shown as abbreviations on the abscissa; see the legend in Fig. 1) during the generation of 500 consecutive HH intervals. In all preparations, each pacing site resulted in substantially different HHmean, PPmean and AAmean. Light bars accentuate the AAmean and PPmean intervals related to the longest HHmean interval in each preparation, while the dark bars point out the AAmean and PPmean intervals related to the shortest HHmean interval. In most preparations the shortest HHmean was associated with large absolute difference [PPmean–AAmean] and vice versa. More details are discussed in the text.

 

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  		Table 1 Statistical analysis of differences and correlations between AA, PP and HH intervalsa

 
The above results suggested that larger difference between the mean intervals observed at the AVN inputs appeared related to the occurrence of shorter HHmean intervals. However, the correlation coefficients observed in individual preparations ranged from –0.18 in preparation 5 to –0.82 in preparation 8 (Table 1), pointing out the limited predictive power of the parameter [PPmean–AAmean]. For example, in preparation 5 (Fig. 6) the shortest HHmean was obtained when PPmean and AAmean were identical. However, notice that the latter intervals were long (>180 ms), indicating that both AVN inputs were bombarded at a relatively slow rate. We concluded, therefore, that the predictive power of the parameter [PPmean–AAmean] can be enhanced by considering also the individual values PPmean and AAmean. Fig. 7 illustrates this point. We plotted all 54 data points from Fig. 6 in a 3D format. The vertical axis represents the normalized HHmean, i.e. the difference between a given HHmean value and the shortest HHmean in the same preparation. One of the two horizontal axes represents the AAmean intervals while the second one represents the PPmean intervals. Thus, for each random HAR pacing run performed at a pacing site in a given preparation, one data point for the normalized HHmean has been plotted against the corresponding AAmean and PPmean values. The resulting complex surface contains three regions (open circles) that can be easily understood. Region 1 represented the cases when both PPmean and AAmean were very short (usually <120 ms) with negligible difference [PPmean–AAmean]. This resulted in the longest HHmean intervals. Region 2 represented the cases when one of the AVN input intervals (e.g., AAmean) was long (>150 ms), while the other was short (<110 ms), resulting in a large difference [PPmean–AAmean]. This was associated with the shortest HHmean intervals, occupying the darkest portions of the 3D-surface. Finally, region 3 represented the cases when both AAmean and PPmean intervals were long (>180 ms) but similar, thus resulting in a small difference [PPmean–AAmean]. The corresponding HHmean intervals were relatively short. Thus, short HHmean intervals were observed when high-rate bombardment was present at only one of the AVN inputs (e.g., short PPmean, but long AAmean as in region 2 of Fig. 7), or when both inputs were driven at relatively slow rate (as in region 3). In contrast, long HHmean were observed when both AVN inputs were engaged at fast rate, apparently leading to high level of AVN concealment and annihilation.


Figure 7
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  		Fig. 7 Three-dimensional presentation of the relationship between the PPmean and AAmean intervals (horizontal axes) and the normalized HHmean intervals (vertical axis) from all eight preparations. Exactly the same sequence of random high atrial rate pacing was applied at each pacing site (see Methods for details). The top right inset shows a posterior view of the same three-dimensional graph. Isochronal lines were drawn to delineate time values as shown on the right. Note the three areas indicated by circles. Area 1 includes the longest HHmean intervals. As seen, they were obtained with very short PPmean along with very short AAmean intervals. Area 2 (note two sub-regions) includes the shortest HHmean intervals. As seen, they resulted from either shortest AAmean along with longest PPmean intervals or vice versa. Area 3 represented another category of very short HHmean distribution (as areas 2) that resulted from the long but similar AAmean and PPmean intervals. See the text for discussion.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
4.1 Major findings
The results from these experimental studies demonstrated that the ventricular rate during high atrial rate depends in a complex way on several parameters that determine the activation of the atrial-AVN inputs. Our study established the importance of the mean rate of impulses at each input, as well as the difference between these rates. Furthermore, we demonstrated that the site of high rate atrial pacing may influence the ventricular responses for the same random sequence of pacing stimuli.

The role of the timing in the postero—anterior sequence of activation for the conduction through the AVN has been previously demonstrated in experiments employing single prematurities [24]. Thus, both summation and annihilation of impulses can be observed, producing enhanced or depressed conduction, respectively. The present data showed the sensitivity of the mean ventricular rate to changes of the timing of the AVN inputs (Figs. 2 and 3Go). The AVN cellular responses and the corresponding His-Lorenz plots differed not only when one of the inputs was not activated due to intra-atrial block (C and E), but also when the time-phase was altered (D and F). It is obvious that during high atrial rate pacing, the global mean atrial cycle length cannot characterize the difference in the number of impulses reaching the posterior and anterior AVN inputs. Thus, the way of arrival of atrial impulses at the AVN inputs appears to be an important factor that influences ventricular rate during irregular high atrial pacing. This fact may be extended to real atrial fibrillation, especially in cases characterized by a single focus [25,26].

4.2 Quantification of the input—output relationships during high atrial rate pacing
Although we limited the scope of this study to the evaluation of the average rates at the two major AVN inputs and their impact on the ventricular rate, several important correlations were discovered.

Stimulation paradigms that resulted in a small difference between the PPmean and AAmean intervals were associated with long HHmean (corresponding to slow ventricular rate) in the majority of preparations (Table 1, Fig. 6). In contrast, shortest HHmean (corresponding to fast ventricular rate) were seen when the PPmean and AAmean intervals differed substantially. An exception from this rule was noticed in the case of similar but long PPmean and AAmean, when the resulting HHmean were relatively short (Fig. 7).

Notably, the above observations were made using a pacing protocol that utilized random but exactly reproducible stimulation sequence. This implies that similar global high atrial rate may result in different mean ventricular rates depending on the differential rates at the two major (anterior and posterior) AVN inputs. Thus, similar rapid rates at both AVN inputs apparently produced higher probability for collision and annihilation as this configuration provided slower ventricular rate.

Long individual HH intervals were significantly correlated with a larger total number of co-existing atrial impulses at the AVN inputs (Fig. 5). The large number of impulses competing for a space in the congested AVN pathways may underlie a high degree of concealed conduction. While the latter conclusion has been established in the classic work of Moe and Abildskov [7] and was supported by our results (Fig. 5), our study adds an important additional feature. Namely, it was necessary to bombard both AVN inputs at a short cycle length in order to achieve ventricular rate slowing. However, if the rate at one of the inputs was slow, then the ventricular rate was relatively high (Fig. 7, area 2).

Thus, the results from these studies suggest that it is not the mean (global) atrial rate during atrial tachycardia and probably also during atrial fibrillation that slows the ventricles. Rather, it is the resulting high-rate of impulses reaching both AVN inputs that translates into a high degree of concealment and subsequent ventricular slowing. In contrast, blocks of atrial impulses toward one of the AVN inputs may compromise the filtering role of the AVN and result in higher ventricular rate.

4.3 Clinical relevance and limitations
The present results should be primarily considered as a contribution to the basic AVN electrophysiology. While some of the reported observations certainly reflect fundamental properties, caution should be exercised in applying them to explain cases of clinical atrial fibrillation.

It might be suggested that the present data observed with random high atrial rate pacing can be, to a certain degree, extrapolated to real atrial fibrillation as suggested by the report of Chorro et al. [1] However, we utilized a single-focus random high atrial rate pacing model which is related to a very particular form of atrial fibrillation [25,26]. Our purpose was to analyze the complex AVN bombardment during high atrial rate and not specifically during atrial fibrillation. Accordingly, our model was specifically designed for reliable and controlled evaluation of AVN bombardment by the same arrhythmic sequence arriving with a given predominant orientation. The real-life atrial fibrillation would most likely be associated with multiple wave fronts arriving into the AVN domain from different sites, thus creating a very complex activation pattern.

For example, it has been demonstrated that AVN modification during atrial fibrillation can result in ventricular rate slowing without specifically eliminating the slow or fast AVN pathway [15]. The outcome of such procedure remains unpredictable [16]. Based on the present data it may be suggested that successful ablation might change the dynamic interaction between both atrial inputs resulting in a higher level of concealed AVN conduction. This implies that successful modification procedure for ventricular rate control in atrial fibrillation should not necessarily result in elimination or damage to the slow pathway. Other studies [27,28] demonstrated that pacing from the coronary sinus prevents atrial fibrillation in some patients. This may be due to a more homogeneous atrial activation pattern as suggested by the similarly short PPmean and AAmean intervals observed in these experiments (Fig. 6, CSO-pacing). Although extrapolations from this rabbit heart model are unwarranted, the orientation of the atrial fibrillation-wave front(s) toward the AVN inputs deserves investigation. In particular, it would be of interest to determine not only the global mean atrial rate in patients with atrial fibrillation, but also the local rates at the posterior and anterior inputs of the AVN. Such data are so far completely missing from the clinical literature.

Time for primary review 29 days.


   Acknowledgements
 
Supported in part by grant 9807701 from AHA (Ohio Valley Affiliate).


   Notes
 
1 Dr. Garrigue has been Research Fellow at the Cleveland Clinic Foundation during these studies. Back


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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