mechanism for lack of ventricular rate slowing in atrial fibrillation

www.elsevier.com/locate/cardioresCardiovascular Research 61 (2004) 45–55

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nloaded from

Atrioventricular nodal fast pathway modification: mechanism for lack of

ventricular rate slowing in atrial fibrillation

Youhua Zhanga, Saroja Bharatib, Rabi Sulaymanb, Kent A. Mowreya,Patrick J. Tchoua, Todor N. Mazgaleva,*

aDepartments of Cardiovascular Medicine and Molecular Cardiology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Research Building FF1-02,

Cleveland, OH 44195, USAbMaurice Lev Congenital Heart and Conduction System Center, The Heart Institute for Children, Hope Children’s Hospital, Oak Lawn, IL, USA

h
ttps://a
Received 18 September 2003; received in revised form 24 October 2003; accepted 27 October 2003

Time for primary review 29 days
cadem ic.oup.com
/cardiovascres/article/61/1/45/332331 by guest on 0

Abstract

Objectives: Atrioventricular node (AVN) modification is one of the alternatives for ventricular rate control in patients with drug refractory

atrial fibrillation (AF). However, the underlying mechanisms, and in particular the role of the dual pathway electrophysiology is not clear. By

using a novel index, His electrogram (HE) alternans, we have previously demonstrated in rabbits that both the slow (SP) and the fast

pathways (FP) are involved in AVN conduction during AF. This electrophysiological–morphological study was designed to address the role

of selective FP ablation on AVN conduction during AF. Methods and Results: In 12 rabbit AVN preparations dual pathway conduction was

confirmed by HE alternans during A1A2 pacing protocol, as well as during AF. On average 48% of the conducted beats during AF utilized

the FP. Selective FP ablation (n=12) guided by HE alternans resulted in only-SP conduction, with longer AVN conduction time at basic beats,

but without change of AVN effective refractory period (ERP). Interestingly, despite elimination of all FP-conducted beats during AF, the

selective FP ablation allowed previously concealed SP beats to be conducted, resulting in little net effect on the ventricular rate (average His–

His interval 199F10 ms before versus 201F13 ms after FP ablation, p>0.05). Morphological evidence indicated that FP ablation created

lesions within the transitional cells of the superior approaches at the junction between the central fibrous body and the AVN. However,

extension of FP ablation lesion into the compact AVN domain resulted in non-selective AVN modification and slowing of ventricular rate

during AF. Conclusions: Despite its longer ERP, FP is responsible for a substantial number of ventricular beats during AF. However,

selective FP ablation has a minor effect on ventricular rate. The most likely mechanism for this phenomenon is that FP ablation allows

previously concealed SP beats to be conducted. On the other hand, ventricular rate slowdown could be achieved if FP ablations caused

collateral damage in the compact node. This study highlights the usefulness of HE alternans as a novel tool to monitor dual pathway

conduction during AF and to guide AVN modification.

D 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
9 J uly 2022
Keywords: Atrial fibrillation; Ablation; Arrhythmia (mechanisms); AV-node; Conduction system; Supraventricular arrhythmia; Rabbit; Dual pathway

electrophysiology

1. Introduction

Atrioventricular node (AVN) modification (i.e. partial

impairment of conduction by ablation) has emerged as one

of the alternatives for ventricular rate control in patients with

drug-refractory atrial fibrillation (AF). Although it is being

0008-6363/$ - see front matter D 2003 European Society of Cardiology. Publishe

doi:10.1016/j.cardiores.2003.10.023

* Corresponding author. Tel.: +1-216-445-6637; fax: +1-216-445-

4168.

E-mail address: [email protected] (T.N. Mazgalev).

used clinically, the mechanisms underlying AVN modifica-

tion are not clear [1–4].

Since AVNmodification for rate control during AF targets

similar anatomical sites as the ablations of the fast pathway

(FP) and slow pathway (SP) in patients with AVN reentrant

tachycardia (AVNRT), it has been speculated that the mod-

ification procedures involve the dual pathway electrophysi-

ology [1–3,5]. Clinical practice has indicated that the anterior

septal (i.e. the FP) approach for AVN modification has lower

success rate and higher incidence of AVN block compared

with the posterior (i.e. the SP) approach, leading to empirical

d by Elsevier B.V. All rights reserved.

Y. Zhang et al. / Cardiovascular Research 61 (2004) 45–5546

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recommendation that AVN modification should target the SP

rather than the FP [1–3,5]. The mechanistic basis for such

conclusion remains unclear.

The simplest reasoning as to why FP-ablation is less

effective would be that propagation via FP might not be

functioning at all during AF due to its long effective refrac-

tory period (ERP). If so, FP-targeted modification should be

considered vain a-priori. Such a preposition, however, contra-

dicts clinical reports that in about one third of patients FP-

ablation did result in ventricular rate slowing during AF [5].

The difficulty to solve these uncertainties is due in large to the

fact that there is no available index to monitor dual pathway

electrophysiology during AF. In addition, both experimental

and clinical modifications of the FP during AF are guided by

anatomical landmarks and are performed without objective

quantification of the degree and selectivity of the procedure.

Moreover, it has never been shown conclusively whether the

procedure indeed modified the FP, or inflicted collateral

damage on the AVN itself.

The standard discontinuous conduction curve remains a

major index to reveal dual pathway electrophysiology in

patients with AVNRT [6]. Clinical studies in such patients

demonstrated that after successful SP-ablation and induction

of AF, the ventricular rate was slower [7,8]. It is obvious,

however, that the causal relationship between this outcome

and the SP-ablation remains circumstantial since the direct

involvement of either the SP or FP during AF could not be

objectively determined. The situation is evenmore difficult in

patients with permanent AF, where the AVN conduction

curve cannot be obtained.

Recently, we have demonstrated that a novel index, His

electrogram (HE) alternans, can be used to determine the

AVN conduction through FP or SP on a beat-by-beat basis

[9]. Specifically, at long coupling intervals the FP-wavefront

first reaches the superior domain of the His-bundle, resulting

in an earlier, high-amplitude superior HE (SHE) and a later,

low-amplitude inferior HE (IHE). In contrast, at short pre-

maturities the SP-wavefront first reaches the inferior domain

of the His-bundle, producing an opposite phenomenon with

earlier, high-amplitude IHE and a later, low-amplitude SHE.

By using the HE alternans we have demonstrated for the first

time in rabbits that both FP and SP were involved in AVN

conduction during AF [10].

We have observed that a significant portion of the con-

ducted beats during AF in the rabbit heart utilize the FP. In

fact, after selective SP-ablation all conducted beats propa-

gated exclusively via the FP [10]. Therefore, our simplest

working hypothesis was that selective FP-ablation, without

inflicting damage to the compact node, should be able to slow

the ventricular rate during AF. In order to help resolve the

contradictions between such hypothesis and the available

clinical observations, we performed the present electrophys-

iological–morphological study while utilizing the index of

HE alternans and addressed the following questions: (1)

What is the contribution of the FP to the AVN conduction

during AF? (2) Is it possible to selectively ablate the FP

without inflicting damage to the compact node? (3) What is

the impact of such successful selective FP-ablation on the

AVN conduction and ventricular rate during AF? (4) What is

the plausible mechanism for the observed outcome?

2. Methods

This study was approved by the Institutional Animal

Research Committee and is in compliance with the ‘‘Guide

for the Care and Use of Laboratory Animals’’ published

by the National Institutes of Health (Publication #85-23,

revised 1996).

2.1. Rabbit AVN preparations

The experiments were performed on 12 New Zealand

white rabbit atrial-AVN preparations that were instrumented

as previously described [9,10]. Briefly, after sodium pento-

barbital (50mg/kg) anesthesia, the heart was removed, placed

in a glass chamber, and superfused with oxygenated Tyrode’s

solution (in mmol/l: NaCl 128.5, KCl 4.7, CaCl2 1.3, MgCl21.05, NaHCO3 25, NaH2PO4 1.19, and glucose 11.1; pH 7.3–

7.4 at 36 jC; saturated with 95%O2/5%CO2; flow rate 35 ml/

min). After trimming, the final preparation contained the

triangle of Koch and the surrounding right atrial and ventric-

ular tissues [9,10] (photographs of AVN preparations are

shown in Figs. 5 and 6).

2.2. Electrical stimulation and recordings

Bipolar leads (0.2 mm spacing) were custom-made from

125-Am Ag-AgCl Teflon-isolated wire and used to record

atrial electrograms at the crista terminalis and interatrial

septum. Roving bipolar electrodes were used to obtain HE

as previously described [9,10]. Although the HE alternans is

present in both the SHE and IHE recordings in a comple-

mentary (opposite) fashion and both can be used to monitor

the His-bundle activation pattern, [9,10] we will use only the

IHE for simplicity of presentation. Bipolar, platinum–iridi-

um leads of similar design were used for atrial pacing (2 ms

duration, twice the diastolic threshold). All electrodes were

positioned with micromanipulators (WPI, M330). An 8-

channel, programmable stimulator (AMPI, Master-8) was

used for pacing. The recorded signals were amplified and

filtered at 50–3000 Hz (Axon Instruments, CyberAmp 380),

saved on tape (Vetter Digital, 4000A), and later analyzed by

AxoScope (Axon Instruments) at 200 As per sample per

channel.

2.3. Pacing protocol and definition of electrophysiological

terms

All preparations were first paced at a basic cycle length

(A1A1 interval) of 300 ms. The AVN conduction curve was

generated by interposing a premature stimulus A2 after every

Y. Zhang et al. / Cardiovascular Research 61 (2004) 45–55 47

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20th basic beat A1, and by progressively shortening the

A1A2 coupling interval in 5 ms steps until the occurrence

of AVN block. The resultant atrial-His conduction times

A2H2 were plotted versus A1A2 prematurities. AVN ERP

was defined as the longest A1A2 coupling interval at which

the A2 beat did not conduct to the His-bundle. AVN func-

tional refractory period (FRP) was determined as the shortest

observed His–His (H–H) interval.

AF was simulated by high-rate atrial pacing with

random coupling intervals (range 75–125 ms). The cus-

tom software permitted the same sequence of pacing

intervals to be generated repeatedly. During simulated

AF, 2000 H–H intervals were collected and measured

to determine the shortest, longest, and average values. The

above observations were made in control and repeated

after FP-targeted modifications.

Low and high amplitude IHE were defined as the two

distinct signal levels of HE recorded from the inferior

domain of the His-bundle. Thus, a low-IHE indicates a

beat conducted by FP and a high-IHE indicates a beat

conducted by SP [9,10].

2.4. FP-targeted modification of the AVN conduction

In the absence of clear criteria for identification of FP

location [11–13], we used miniature ( < 2 mm2) thermo-

electric probes to explore by localized cooling the tissue

in the superior AVN approaches [9,10]. Multiple positions

could be tested since the effect of cooling was prompt

and fully reversible. There were no effects on AVN

conduction when the cooling was delivered to the tissue

above the Eustachian ridge (see Figs. 5 and 6). Clear

effects were noted when cooling was delivered about 1–2

mm below the Eustachian ridge and 1–2 mm proximal to

the apex of the triangle of Koch. The probe’s position

was considered within the FP-domain when moderate

cooling (z 25 jC) resulted in prolongation of the con-

duction time of basic beats, but without a significant

change in the AVN ERP or the maximal observed AVN

delay [11]. Proper positioning was further confirmed by

the loss of all low-IHE (i.e. the FP-conduction signature)

at any coupling interval and during simulated AF. After

these explorations the cooling probe was removed and

replaced by an ablation unipolar electrode made of 125-

Am Teflon-isolated platinum–iridium wire and mounted

on micromanipulator.

Small, point-size permanent lesions were created by

delivering constant current pulse (30 mA, 0.5–1 s). We

attempted to achieve complete elimination of the FP-signa-

ture (i.e. the low-IHE), and such permanent functional block

of the FP-conduction was achieved in all 12 preparations

with 2.7F 0.9 ablations. This was confirmed by repeating

the pacing protocol with generation of conduction curves

and by recordings during simulated AF. In both cases only

high-IHE were present. In addition, the modified conduction

curve was shifted upward only in the range of long A1A2

prematurities, while the ERP and the maximum AVN

conduction times remained unchanged.

2.5. Extension of FP lesions into the compact node domain

This procedure was performed in order to test the

hypothesis that lesions intended to ablate selectively the

FP may result in ventricular rate slowing due to inadver-

tent damage to the compact node. In two of the 12

preparations, after an initial selective FP-ablation was

performed as explained above, we moved the ablation

electrode 1–1.5 mm inferiorly toward the compact nodal

domain. Ablation in this position retained the SP-pattern

of conduction established after the initial FP-ablation, but

in addition slowed the ventricular rate.

2.6. Morphological examination

After completion of the electrophysiological observa-

tions and ablations, the AV conduction system was

studied by serial sectioning. The sections were made

perpendicular to the endocardial surface and oriented, in

general, parallel to the AV conduction axis. As described

previously [14] sections were cut at 7-Am steps and each

10th section was retained. Alternate sections were stained

by hematoxylin–eosin or Weigert–van Gieson stains. In

this manner, the consecutive sections permitted examina-

tion of all major components of the conduction system,

including the inferior approaches, the AVN, the superior

approaches and the penetrating His-bundle. During the

examination of multiple sections, a special attention was

paid on determining the sites where the ablation proce-

dures had created lesions.

2.7. Statistical analysis

All data are expressed as meanF S.D. where appro-

priate. Comparisons before and after FP-ablation were

performed using paired Student’s t-test. A value of

P < 0.05 was required for statistical significance.

3. Results

3.1. Use of localized cooling to guide the FP-targeted

modification

As explained in Section 2, the probe was positioned

sequentially in several (typically 3–4) spots and progres-

sive cooling was applied. At the proper position, a graded

elimination of FP-conduction was achieved by cooling the

tip moderately in the range 35–25 jC. Fig. 1 illustrates

the observations in one heart during simulated AF. Note

that in control at 36 jC (A) the FP-conduction was

present, in this heart, in 60% of the beats (low-IHE, *).

Cooling to 31 jC (B) eliminated most of the low-IHE so

Fig. 1. Effects of cooling in the superior approaches to the AVN on HE alternans during AF. (A) Alternating high and low (*) IHE in control. (B) Cooling to 31

jC reduced the number of low-IHE (*). (C) Further cooling to 26 jC eliminated all low-IHE, resulting in SP-pattern of conduction with only high-IHE.

However, the progressive cooling did not slow heart rate (note that total number of beats did not change for same time interval). IHE, inferior HE; RA, right

atrium signal; S, seconds.


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that only 25% of all beats were conducted via the FP

(low-IHE, *). At 26 jC the FP signature was completely

eliminated and the conduction utilized exclusively the SP

(C, high-IHE). However, this progressive cooling did not

slow the heart rate. Note that the total number of

conducted beats in IHE trace did not change for the

same time interval, suggesting that elimination of low-

IHE was compensated by the appearance of ‘‘new’’,

previously not seen high-IHE. After exploration with the

Fig. 2. Effects of selective FP-ablation on HE alternans (A, B) and AVN conduc

A1A2 are shown before (A) and after (B) the ablation. The ablation eliminated

resulted in an upward shift of the conduction curve for long prematurities (open cir

the AVN ERP (95 ms in both cases, C).

cooling probe, ablation lesion was created at the same

spot to produce permanent FP-ablation, as explained

below.

3.2. FP-ablation effects on His-electrogram alternans and

AVN conduction curve

Fig. 2 shows one example of the effects of selective

FP-ablation on the AVN conduction curve and the IHE

tion curve (C). The IHE corresponding to each of the plotted prematurities

HE alternans seen in (A) and resulted in only high-IHE (B). The ablation

cles, C), without significant change at short prematurities, and did not affect

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Table 1

AVN electrophysiologic characteristics before and after selective FP-

ablation in 12 rabbit heart preparations during programmed pacing

Programmed

pacing

AVN BCT

(ms)

AVN ERP

(ms)

AVN FRP

(ms)

AVN MCT

(ms)

Before

FP-ablation

66F 10 104F 12 184F 15 158F 24

After

FP-ablation

85F 6 104F 10 183F 14 163F 19

P value < 0.001 >0.05 >0.05 >0.05

FP, fast pathway; AVN, atrioventricular nodal; BCT, basic conduction time;

ERP, effective refractory period; FRP, functional refractory period; MCT,

maximum conduction time.

Y. Zhang et al. / Cardiovascular

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corresponding to each A1A2 prematurity. In control

(panel A, and panel C-filled circles) the IHE indicated

that the transition between the FP and SP occurred at

A1A2 = 175 ms. The FP-ablation (panel B, and panel C-

open circles) eliminated HE alternans seen in control, so

that only high-IHE were recorded after the ablation (B)

indicating that only the SP was now operative at all

prematurities. The conduction curve (C-open circles)

showed an upward shift (prolonged AVN conduction

times) at basic beats and long prematurities, while the

maximum achievable conduction time and the AVN ERP

were not altered, suggesting an uninterrupted SP-conduc-

tion [11].

We were able to achieve selective FP-ablation in all 12

preparations. Table 1 summarizes the average results.

Note that FP-ablation prolonged the basic AVN conduc-

tion times, but did not change AVN ERP, AVN FRP, as

well as maximal AVN conduction times.

Fig. 3. Effects of selective FP-ablation on HE alternans and H–H interval duri

respectively, were present before ablation. After successful FP-ablation (B), only

seconds.

3.3. Selective FP-ablation and ventricular rate during

simulated AF

Fig. 3 shows one example of the effects of FP-ablation

on dual pathway conduction and ventricular rate during

simulated AF. Before ablation (panel A), both wavefronts

were participating in AVN conduction as evident from the

presence of high and low (stars) amplitude IHE. After

successful FP-ablation (panel B), only high-IHE was seen,

suggesting that functionally only SP-conduction remained.

Although the ablation eliminated HE alternans, it did not

prolong the average H–H intervals. As during the cooling

experiments (see above), the reduction in the number of

beats with FP-signature was compensated by the appear-

ance of new beats with SP-signature. Table 2 summarizes

the shortest, the average and the longest H–H intervals,

and the percentage of low- and high-IHE in 12 prepara-

tions before and after FP-ablation. The FP-ablation resulted

in an exclusive SP-conduction during simulated AF, but it

did not change the shortest and the average H–H intervals

(all P>0.05), although the longest H–H interval was

slightly increased.

It is usually assumed that the shortest H–H intervals

observed during AF are an estimation of the FRP of the

node [15]. Since the shortest H–H intervals remained

unchanged after selective FP-ablation, we concluded that

this functional characteristic of the AVN should be related to

conduction via the SP. Fig. 4 provides supportive evidence

from one experiment, and similar findings were obtained in

other experiments as well. In this case 1069 H–H intervals

(out of a total of 2000 consecutive beats) were designated as

SP-related since they terminated with a high-IHE. The

Research 61 (2004) 45–55 49

ng AF. In control (A), high and low (stars) IHE indicate that SP and FP,

SP-pattern (high-IHE) was documented. RA, right atrium electrogram; S,

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Table 2

H–H intervals (the shortest, the average and the longest) and the percentage

of beats with FP-conduction (low-amplitude IHE) and SP-conduction

(high-amplitude IHE) in 12 preparations before and after selective FP-

ablation during simulated AF

AF Shortest

H–H (ms)

Average

H–H (ms)

Longest

H–H (ms)

Low-IHE

(%)

High-IHE

(%)

Before

FP-ablation

152F 12 199F 10 366F 34 48F 25 52F 25

After

FP-ablation

155F 11 201F13 399F 48 0 100

P value >0.05 >0.05 < 0.05 < 0.001 < 0.001

H–H, His–His interval; IHE, inferior HE. The proportions of low-IHE and

high-IHE were determined as percent in 2000 consecutive beats.


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remaining H–H intervals were termed FP-related. Note that

in control (panel A) the shortest H–H were indeed SP-

related, while intervals terminating with a low-IHE were

longer. After selective FP-ablation (panel B) all 2000

intervals were SP-related. The shortest H–H (i.e. the AVN

FRP) did not change (157 ms in A, 157 ms in B). The

average H–H interval (which is directly linked to the

ventricular rate) also did not change (arrows, 208 ms in

A, 209 ms in B) since the FP-related intervals were

replaced, on average, by comparable in length SP-related

intervals.

3.4. Morphological findings after FP-ablation

Serial sections revealed that successful FP-ablation

created a lesion within the superior transitional cells at

the ‘‘bottle neck’’ between the central fibrous body and

Fig. 4. Distribution of 2000 consecutive H–H intervals before (A) and after (B) FP

as conducted by the fast pathway (FP) or slow pathway (SP). After selective FP-a

intervals.

AVN (Fig. 5). No substantial morphological damage was

evident in the compact node. This suggested that carefully

placed lesions in the anterior AVN approaches could

selectively eliminate the FP signature in the HE.

As previously explained in Section 2, in two prepara-

tions after successful selective FP-ablation an additional

lesion was created approximately 1–1.5 mm inferiorly

toward the compact node domain. In the preparation

illustrated in Fig. 6 (left) the selective FP-ablation was

first achieved with lesions 1 and 2. (Lesion 2 was needed

to eliminate few residual low-IHE observed after lesion

1). Morphological examination confirmed that these two

initial ablations were limited to the superior approaches,

similar to the observations made in Fig. 5. The additional

inferior lesion (point 3), however, inflicted partial damage

within the AVN compact region (Fig. 6, right). The

electrophysiological consequences of these morphological

alterations are illustrated in Figs. 7 and 8.

As seen from the conduction curve in Fig. 7, after the

initial FP-ablations (points 1, 2 in Fig. 6) the conduction

times prolonged at longer prematurities (open circles), but

there was no change of either the longest A2H2 intervals

or the ERP of the AVN. After the lesion at point 3 (Fig.

6), however, the ERP prolonged from 95 to 165 ms and

all conduction times also significantly prolonged (Fig. 7,

triangles). This suggested that, following selective FP-

ablation, the additional modification of the AVN inflicted

partial damage to the remaining functional SP.

This was further confirmed by the observations during

simulated AF (Fig. 8). Note that in control (panel A) one

could easily identify in the IHE trace the signatures of both

-ablation. Note that in control before FP-ablation (A), beats were classified

blation (B) all beats were conducted by SP. Arrows indicate the mean H–H

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Fig. 5. Photograph of a rabbit AVN preparation after successful FP-ablation (left). Morphological sections were made perpendicular to the endocardial surface

(as illustrated by the dashed parallelogram) and one low-power morphological slide at the ablation spot is shown on the right. The ablation spot was located 1.5

mm below the Eustachian Ridge and 2 mm proximal to the apex of triangle of Koch, and the lesion was within the superior transitional area. Multiple

sequential sections indicated that the compact node remained intact (note that the current section was made at the borders of the compact region, CN, located

closer to the CFB). AVN, atrioventricular node; CFB, central fibrous body; VS, ventricular septum; R and L, right and left atrial sites of the specimen,

respectively.


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the FP (low-IHE, stars) and the SP (high-IHE). After the

ablations in points 1 and 2 (Fig. 6), the IHE trace contained

only high amplitude electrograms (Fig. 8, panel B), indicat-

Fig. 6. Photograph of a rabbit AVN preparation (left) in which lesions 1 and 2 wer

added about 1 mm inferiorly towards the compact nodal region (CN, ellipse). The

the partial damage in the compact region. Same abbreviations are used as in Fig.

ing that the conduction to the bundle of His was now

utilizing only the SP. As previously discussed, the ventric-

ular rate remained virtually unchanged (average H–H= 234

e consecutively applied to achieve complete FP-ablation. Then lesion 3 was

right panel illustrates morphological slide from the vicinity of lesion 3. Note

5.

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Fig. 7. Effects of partial damage of compact node on AVN conduction curve

in the preparation illustrated in Fig. 6. Filled circles, conduction curve in the

intact preparation. Open circles, after selective FP-ablation with lesions 1

and 2 (see Fig. 6). Note that the ablation did not affect the conduction at

short prematurities (AVN ERP remained 95 ms as in control). Open

triangles, after addition of lesion 3 to partially damage the compact node

(see Fig. 6). Note the prolongation of AVN ERP to 165 ms, and the upward

shift of the entire curve.


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ms in panel A, vs. 231 ms in panel B). After lesion 3 (Fig. 6)

the IHE trace still contained only the SP-signature (Fig. 8,

panel C, high-IHE), but now the ventricular rate was

significantly slowed (average H–H= 334 ms).

Thus lesions placed in close proximity and inferiorly to

the sites of successful selective FP-ablation could inflict

collateral damage to parts of the compact node, and there-

fore, slow the ventricular rate as a result of an overall

nonselective FP plus SP modification.

Fig. 8. Effects of partial damage of compact node after selective FP-ablation on HE

6. (A) High and low (stars) IHE indicate that SP and FP, respectively, were presen

was documented, but the rate did not change. (C) After lesion 3 the rate was signif

4. Discussion

4.1. Major findings

This study confirmed the concept that FP- and SP-

wavefronts are functional entities that coexist during the

propagation of each conducted beat. At long prematurities

the FP-wavefront is leading, while the posterior SP-

wavefront remains concealed until FP is blocked (or

delayed) at shorter prematurities. During AF, the propa-

gated beats utilize either the SP or the FP. Selective FP-

ablation has no significant effect on H–H intervals, since

newly manifest SP beats maintain the ventricular rate

unchanged. This confirms that SP is a major determinant

of ventricular rate during AF, and explains why its

ablation produces consistent rate slowing [1,2,4,10]. The

present study has further demonstrated that HE alternans

provide an essential tool to monitor dual pathway con-

duction and guide AVN modification during AF.

4.2. HE alternans versus conduction curve in evaluation of

dual pathway conduction

Based on the changes in the AVN conduction curve after

SP or FP modifications, the concept that FP-conduction has

relatively short AV delays and blocks easier due to longer

ERP is well accepted [10,11,16,17]. However, especially in

the absence of conduction discontinuity (‘‘jump’’), [6,18]

one cannot determine with certainty at which prematurity

the transition from FP to SP takes place, and whether a

lesion results in full or partial ablation of the affected

conduction pathway.

alternans and H–H interval during AF in the preparation illustrated in Fig.

t before ablation. (B) After selective FP-ablation only SP-pattern (high-IHE)

icantly slowed, while the pattern of conduction remained SP (i.e. high-IHE).

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The HE alternans permitted to determine precisely the

prematurity at which transition from FP to SP occurred (Fig.

2) and to confirm that, once the FP was successfully

eliminated, the SP became manifest and sustained AVN

conduction at both long and short prematurities. Such was

the case illustrated in Fig. 6. In that preparation judging only

by the conduction curve lesion 1 would be deemed success-

ful. In fact successful elimination of the FP-wavefront was

achieved only after lesion 2 and the established SP-conduc-

tion was documented by high-IHE during both basic and

premature beats, and simulated AF (Fig. 8B). In this regard,

HE alternans were more sensitive tool than the conduction

curve to reveal the transition between the two wavefronts.

4.3. FP-targeted modification of AVN conduction during AF

Based on the HE alternans this study clearly demonstrated

that dual pathway conduction was present during simulated

AF (Figs. 1, 3, 8). This confirmed previous observations

[10]. Since a large portion of beats was conducted by FP

during AF, it was logical to speculate that selective FP-

ablation might have significant effect on ventricular rate. The

present results, however, did not support this expectation.

During simulated AF, successful FP-ablation resulted in

elimination of all low-IHE (Figs. 3, 8). However, there was

no significant change in either the average or the shortest H–

H intervals (Table 2). While the average H–H interval is a

direct measure of the ventricular rate, the shortest H–H

interval is thought to represent the FRP of the AVN during

AF [15].

The fact that the removal of the FP-conduction had such

negligible effects during AF may initially appear unexpect-

ed, in view of the fact that before ablation 48% of the

conducted beats were with FP-signature (i.e. low-IHE). This

apparent discrepancy can be explained if one assumes that

SP was actually present during every conducted beat.

However, successful conduction via the FP produced a

concealment of the delayed SP-wavefront, [19] which did

not reach the His-bundle. This was obvious during the

generation of the conduction curves (Fig. 2) when the FP-

ablation replaced all low-IHE with high-amplitude spikes

(i.e. SP-conduction). Similarly, during AF, the FP-ablation

simply revealed the presence of the previously concealed

SP-wavefront while the average rate of successful His-

bundle penetrations remained unchanged.

Anatomically the lesions that produced selective FP-

ablation were limited to quite a small area near the apex

of the triangle of Koch. Therefore, it is conceivable that

inadvertent damage to the compact AVN region could be

inflicted during the procedure. Partial injury of the compact

node would slow the ventricular rate [7]. We have done this

deliberately and confirmed that such morphological damage

of the SP results in slower ventricular rate during AF (Figs.

6–8). These results not only provide explanation for the

clinical observations that ablations using the AVN superior

septal approach for control of ventricular rate in AF have

minimal effect in most patients, but also provide explana-

tion that collateral damage of the compact node might be

responsible for rate slowing observed in a small portion of

patients [3,5].

4.4. Substrate of FP and functional model of dual pathway

electrophysiology during AF

The morphological evidence indicated that selective FP-

ablation created a lesion within the superior transitional cells

between the central fibrous body and the AVN. However,

the compact AVN remained intact (Fig. 5). These results are

consistent anatomically with a model of dual pathway

electrophysiology according to which the FP utilizes the

‘‘bottle neck’’ formed by the superior transitional cells

between the central fibrous body and the compact AVN

that reach the superior domain of the His-bundle [9].

According to such model, three basic scenarios could be

encountered during AF depending on the prematurity and/or

the organization of the atrial-AVN engagement (Fig. 9,

panels A–C). In Fig. 9A (for beats with longer coupling

intervals), the FP-wavefront (green) propagates through

transitional cells’ region ahead of the SP-wavefront (orange),

invades the superior domain of the His-bundle, and trans-

versely activates the inferior domain generating low-IHE. At

that time, the delayed SP still transverses the posterior nodal

extensions, encounters the refractory tail of the FP, and

remains concealed. Panel 9B illustrates the alternative situ-

ation (e.g. during shorter coupling intervals) when a beat is

propagated via the SP-wavefront (blue). Note the reversed

sequence of engagement of the His-bundle, with the inferior

domain depolarized longitudinally, resulting in a high-IHE

signal. Panel 9C illustrates a beat with excessive prematurity

for which the FP blocks due to its longer ERP, while the SP

is still capable of conduction and generates again high-IHE.

Panels A–C thus show how random engagement during AF

of the superior and inferior His domains by the FP and SP,

respectively, produces the characteristic alternating HE

(alternans) seen in Figs. 1, 3 and 8. Finally, panel 9D shows

the end-result of successful selective FP-ablation. Note that

now all beats are being conducted in the SP-domain with

high-IHE. The beats conducted by the FP before the ablation

(panel A, green) have been carried via the SP after the

ablation (panel D, orange).

The proposed model, although only intended for con-

ceptualization purposes, indicates that anatomical and func-

tional asymmetry of the atrial-nodal-His connection can

support dual pathway electrophysiology without requiring

the presence of specific isolated cable-like structures [19].

Recent experimental mapping studies support this view

[20,21].

4.5. Study implications and limitations

In addition to providing a deeper understanding of the

dual pathway AVN electrophysiology, our results may have

Fig. 9. Schematic functional model of dual pathway electrophysiology during AF. The AVN (dotted line) includes all nodal regions, and along with the superior

approaches (SA), inferior approaches (IA), and the bundle of His forms functional continuum. (A) A beat in which FP-conduction (green) is formed in the

transitional cell (TC) region of the SA and is first to reach the superior His-bundle. Transverse propagation into the inferior bundle produces low-IHE at the

recording electrode (black dotes). The SP-wavefront (orange), originating in the IA, is concealed before exiting AVN. (B) Reversed situation in a beat with a

leading SP-wavefront (blue) associated with high-IHE. (C) Beat with blocked FP-wavefront (curved dashed line) due to excessive prematurity. (D) Lesion (star)

within the superior transitional cells between central fibrous body (CFB) and the AVN (the ‘‘bottle neck’’ linking the SA to the superior His-bundle) forces all

beats to proceed through the AVN, and longitudinally along the inferior His-bundle (SP-conduction pattern with high-IHE). See text for further details.


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important implications with respect to the AVN modifica-

tion during AF. FP-ablation had minute effect in slowing

ventricular rate during AF. The most likely mechanism for

this phenomenon is that FP-ablation allows previously

concealed SP beats to be conducted. Slower rate could be

achieved only if ablations also caused collateral damage in

the compact nodal region (Figs. 6–8). The latter procedure

is obviously very risky, since inadvertent complete AVN

block can be easily produced. Therefore, the safer site for

application of the SP modification should be the posterior/

inferior approaches. We have previously demonstrated that

SP-ablation in this manner invariably resulted in slowing of

ventricular rate during AF while preserving the compact

nodal region intact [10].

It should be noted that while FP-ablation procedures in

this study were deemed successful based on the observed

functional responses, we could not be sure if the propaga-

tion in the FP-domain was fully interrupted. It could be

inferred from the model (Fig. 9) that elimination of the FP

signature in the His-recording would also be observed if the

wavefront were just sufficiently delayed relative to the SP.

This as well as our previous studies, [9,10] reiterate that

dual pathway electrophysiology is a normal, inherent prop-

erty of the AVN in rabbits. As we acknowledged before,

[10] although HE alternans have been demonstrated in

rabbits as well as in canines, [22] and most likely exist in

humans as well, [23,24] further clinical evidence is needed

in order to establish the existence of this novel index and its

usefulness in patients.

Acknowledgements

This study was supported in part by grant from NIH

(NHLBI RO1 HL60833).

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