(Circulation. 1995;91:2235-2244.)
© 1995 American Heart Association, Inc.
Articles |
Radiofrequency Catheter Ablation of the Atria Reduces Inducibility and Duration of Atrial Fibrillation in Dogs
Presented in part at the 15th Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology, Nashville, Tenn.
From the Krannert Institute of Cardiology, Department of Medicine (A.E., H.P.P., D.P.Z.), Indiana University School of Medicine and the Richard L. Roudebush Veterans Administration Medical Center, Department of Pathology (J.N.E.), Indianapolis, Ind.
Correspondence to Douglas P. Zipes, MD, Krannert Institute of Cardiology, 1111 W 10th St, Indianapolis, IN 46202-4800.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background The purpose of this study was to prevent induction of sustained atrial fibrillation (AF) by radiofrequency catheter ablation (RFCA) of the atria in an open-chest canine model.
Methods and Results In dogs randomized to acute studies, RFCA of the atria was performed after reproducible induction of sustained AF (lasting >30 minutes) with burst stimulation or premature atrial pacing and perpetuation by low level cervical vagal stimulation or IV infusion of methacholine. Additionally, in four dogs, the long-term effectiveness of RFCA was assessed 7 to 21 days after ablation. Continuous discrete transmural lesions were produced with radiofrequency energy pulses (20 to 40 W for 60 seconds) delivered to five atrial epicardial sites and endovascularly to the coronary sinus wall. RFCA electrically isolated regions of the atria that became dissociated from the nonisolated parts. Atrial RFCA markedly attenuated vagally induced shortening of effective refractory period (ERP) at both isolated and nonisolated test sites located in the left and right atria (P<.001, n=5). RFCA rendered noninducible sustained AF maintained by cervical vagal stimulation. The dose-response curve relating the dose of methacholine required to maintain AF was shifted down and to the right. AF was only inducible with high doses of methacholine. Atrial RFCA reduced the maximal sinus rate and prolonged the corrected sinus-node recovery time (P<.001, n=6). However, RFCA did not affect atrial contractile function, AV-nodal ERP, or AV-nodal or His-Purkinje conduction times. In dogs in the chronic group, normal sinus rhythm and normal AV conduction were preserved and AF was only inducible with a high dose of methacholine. No atrial perforations resulted.
Conclusions RFCA in open-chest dogs produces partial vagal denervation and reduces the inducibility of AF.
Key Words: fibrillation • vagus nerve • catheter ablation • radiofrequency • sinoatrial node
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Atrial fibrillation (AF) is one of the most prevalent cardiac arrhythmias; it affects
1.0% of the
population and is associated with significant clinical and public
health
implications.1 2 3 4 5 6 7
Ideal treatment should abolish the
detrimental effects of AF by restoring sinus rhythm with a synchronous
atrial kick8 and reducing the risk of thromboembolism.
Pharmacological therapy may not be successful for maintaining sinus
rhythm and may have proarrhythmic and other significant side
effects.9 10 11 12 If
pharmacological therapy fails, catheter
ablation of the His bundle with pacemaker implantation is often
performed to control the ventricular response rate, but the risk of
thromboembolism and compromised hemodynamics
remains.13 14 In selected cases, AF is treated surgically. One of the most promising surgical methods to treat AF is the maze procedure developed by Cox et al.15 The surgical-maze procedure divides the atrial myocardium to force atrial activation over a surgically determined route. The mass of tissue to be electrically activated in this atrial maze presumably is too small for multiple wavelets of reentry to sustain. The maze procedure restores normal sinus rhythm and AV synchrony with demonstrable atrial contractile function and reduces the risk of thromboembolism.
In the present study, we tested the effectiveness of epicardial application of radiofrequency energy to prevent the induction of AF in an open-chest canine model. The impetus to perform the present study was results from the surgical-maze procedure.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Surgical Preparation for Acute Study
For groups 1 through 4 and 6, 27 mongrel dogs of either sex weighing 25 to 35 kg each were anesthetized with pentobarbital 30 mg/kg IV. Additional doses were injected as needed to maintain anesthesia during the study. Dogs were ventilated with room air by use of a cuffed endotracheal tube and a constant volume–cycled respirator (model 607, Harvard Apparatus). A fluid-filled cannula was placed in the left femoral artery and connected to a transducer (Statham p-23Db, Gould) to monitor arterial blood pressure, and the left femoral vein was cannulated to infuse normal saline at 100 to 200 mL/h to replace spontaneous fluid losses. ECG lead II was monitored throughout the study. A His-bundle electrogram was recorded in all dogs with a 7F bipolar electrode catheter (USCI) introduced through the right carotid artery and advanced in a retrograde manner into the noncoronary cusp of the aortic valve. The signals were amplified, filtered between 30 and 1000 Hz, and recorded simultaneously on a recorder (model 2800, Gould Brush).
The chest was opened through a median sternotomy. The pericardium was opened and sewn to the chest wall to cradle the heart. Bipolar stainless-steel Teflon-coated wire electrodes were sutured to the right ventricular free wall to record the ventricular electrogram. An array of six stainless-steel electrodes embedded in an acrylic base with an interelectrode distance of 3 mm was sutured in the right atrial epicardium 1 to 2 cm inferior to the sinus node to record bipolar atrial electrograms and to pace the atrium. In 13 dogs, five plunge electrodes made from Teflon-coated wires, insulated except for their tips, were inserted in the right and left lateral atrial myocardium to a depth of 3 to 4 mm. These electrodes served as the cathodes for unipolar stimulation to determine the atrial refractory period. An anodal electrode was placed in the abdominal wall. A thermistor (model 430, series 400, Yellow Springs Instruments) was used to monitor epicardial temperature, which was maintained between 36° and 38°C by use of an operating-room table lamp.
Surgical Preparation for Chronic Study
For group 5, 4 mongrel
dogs were premedicated with antibiotics
(cefazoline 500 mg IM), heparinized with heparin 3000 U IV, and
anesthetized initially with sodium thiopental 30 mg/kg. Anesthesia was
maintained by ventilation with 1% to 3% isoflurane gas mixed with
oxygen at a rate of 1.0 to 2.0 L/min. By use of a sterile surgical
technique, a right and left lateral intercostal thoracotomy was
performed, the ribs and lungs were retracted, and the pericardium was
incised. Bilateral pericardial windows were created to expose the
atria. Serum electrolytes, pH, base excess, and blood gases were
monitored during the procedure and were repeated daily for 3 days after
surgery. Bipolar stainless-steel wire electrodes were sutured to the
atrial epicardium to pace the atria. Before radiofrequency catheter
ablation (RFCA) of the atria (described below), all dogs underwent
open-chest electrophysiological study to obtain baseline data. After
atrial RFCA, the chest was closed in layers and negative pressure was
reestablished in the pleural cavity. Antibiotics and heparin were
administered for 5 days after surgery, and analgesics were given as
needed.
Radiofrequency Energy Application
After reproducible
induction of sustained AF (duration >30
minutes) with atrial burst pacing (cycle length, 50 ms) or pacing with
multiple atrial extrastimuli at various coupling intervals and
perpetuation with either cervical vagal stimulation or infusion of
methacholine, radiofrequency energy was delivered through the
epicardium to the posterolateral right atrium, the anteromedial side of
the superior vena cava, both the right and left atrial appendages, and
the transverse sinus (Fig 1
, top) by means of 6F or 7F
catheters with hexapolar or octapolar multielectrode (interelectrode
distance, 3.4 mm; 3-mm rings with a 3-mm tip electrode) steerable tips
(EP Technologies). The catheter tips were positioned manually on the
epicardial surface of the atria under direct visualization to ensure
optimal tissue contact and energy delivery. Continuous unmodulated
radiofrequency current of 300 to 750 kHz with power output settings of
20 to 40 W was delivered from a radiofrequency generator (EP
Technologies) by means of the multielectrode catheter tips at each
ablation site. The radiofrequency generator measured root-mean-square
voltage and current and actual power output by use of the average value
of the product of voltage and current. This reflected the effective
heating power that was delivered to the tissue from the steerable
ablation catheter tip. Impedance was calculated as measured voltage
divided by measured current. Duration of radiofrequency power output
was programmable, and the number of radiofrequency applications was
counted automatically. Lesions were produced in the epicardium of the
atria at power-output settings of 30 to 40 W, with a duration of 60
seconds. Initially, an excessive rise in impedance often limited
radiofrequency power delivery during ablation. Since impedance rises
abruptly when temperatures at the electrode-tissue interface exceed
100°C,16 17 18 19
excessive heat formation was prevented by
flushing the catheter tip with small amounts of saline during
epicardial radiofrequency energy delivery. Cooling the tip reduced the
excessive rise of impedance and allowed delivery of larger amounts of
radiofrequency power.20 After epicardial atrial RFCA was
performed, a 6F catheter with a hexapolar multielectrode steerable tip
(EP Technologies) was introduced through the right external jugular
vein and advanced into the distal coronary sinus (Fig 1,
bottom). The
power output setting for the coronary sinus lesion was 10 to 20 W,
depending on the impedance level, and had a duration of 30 seconds. If
the measured tissue impedance was <50 
or >300 ,
radiofrequency
current flow was shut off with the built-in automatic shutoff feature
of the radiofrequency unit. The ablation catheters (EP Technologies)
simultaneously delivered the radiofrequency energy in a bipolar mode
through the three tip-electrode pairs to produce the coronary sinus
lesion. Epicardial atrial lesions were produced by simultaneously
delivering radiofrequency energy through the four tip-electrode pairs.
The energy was thus divided over the tip-electrode pairs and was not
delivered over only the distal electrode of the catheter. Since all
energy deliveries were bipolar, we did not use a backplate.
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Measurement of Effective Refractory Period
The atrial
effective refractory period (ERP) was determined at
each electrode site by the extrastimulus technique with a programmable
stimulator (Krannert Medical Engineering) and a constant current
isolator. Each atrial test site was driven with a 2-ms rectangular
stimulus that was twice the diastolic threshold and which was measured
during each intervention. A train of eight stimuli (S1) was
followed by a late premature stimulus (S2) that produced a
propagated response. The S1-S1 interval was 280
to 300 ms and was kept constant throughout the experiment. The atrial
responses to S1 and S2 were recorded in the
lead II ECG and from the bipolar atrial electrode and were displayed on
a storage oscilloscope. The S1-S2 interval was
shortened in 1-ms steps until S2 failed to produce a
propagated response. The ERP was defined as the longest
S1-S2 interval at which S2 failed
to produce a propagated response. The ERP was determined at least twice
at each electrode site. If the values differed by >1 ms, the data were
discarded and the determination was repeated. Since sustained AF may
affect atrial refractoriness, vagally induced ERP shortening was
measured at baseline, after a period of vagal stimulation, and after
resolution of vagally induced sustained AF before performing RFCA. The
atrial ERP alterations measured after resolution of vagally induced
sustained AF before ablation were used as control data to compare with
the ERP measurements that were obtained in the same fashion after RFCA.
Atrial ERPs were measured at both isolated and nonisolated atrial
sites.
AV-nodal ERP was determined by pacing the high right atrium with a train of eight stimuli (S1-S1 interval, 400 ms) followed by a late extrastimulus (S2) that produced a ventricular response. The S1-S2 interval initially was shortened by 5-ms steps and was shortened by 1-ms steps near the AV-nodal ERP. The longest S1-S2 interval at which S2 failed to produce a propagated ventricular response was considered to be the AV-nodal ERP.
Evaluation of Sinus-Node Automaticity and AV Conduction
Maximal heart rate (MHR) was determined by infusing graded doses
of isoproterenol (0.9 to 9.7 µg/min). Sinus-node recovery time (SNRT)
was determined by pacing the atria with a programmable stimulator
(Krannert Medical Engineering, Indianapolis, Ind) for 30 seconds at
progressively shorter drive-cycle lengths (400, 350, 300, and 250 ms)
with a unipolar electrode placed 1 cm inferior to the sinus node.
The longest time interval from the last paced atrial depolarization to
the first spontaneous sinus cycle was recorded as the SNRT. Corrected
SNRT (CSNRT) was determined by subtracting the mean sinus-cycle length
(SCL) measured before the beginning of atrial pacing from the
SNRT.
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To investigate AV conduction, conduction time in the AV node (AH interval) was measured from the earliest onset of rapid right atrial activity recorded on the His-bundle electrogram to the onset of the His-bundle potential during constant atrial pacing at a cycle length of 400 ms. His-Purkinje conduction time (HV interval) was measured from the onset of His-bundle deflection to the beginning of the first ventricular depolarization recorded on any lead during constant right atrial pacing at a cycle length of 400 ms. Five consecutive AH and HV intervals were measured and averaged to obtain final values.
Neural Stimulation
The dogs assigned to the acute studies
(groups 1 through 4 and
6) were all autonomically decentralized. Since group 5 consisted of
dogs for survival study, autonomic decentralization was not performed
in these dogs. In the dogs in the acute groups (groups 1 through 4 and
6), the heart was autonomically decentralized by isolating,
double-ligating, and transecting both cervical vagi and ansae
subclaviae as exited from the stellate ganglia. In dogs assigned to
group 1, both cervical vagi were stimulated through two Teflon-coated
wire electrodes embedded in the cardiac end of each vagal nerve.
Rectangular 4-ms pulses were delivered at a frequency of 8 to 20 Hz by
use of separate constant-current isolators driven by a programmable
stimulator (model SD-88, Grass Instrument Co). The current strength for
low-level vagal stimulation was 0.05 mA greater than that required to
produce sinus bradycardia (rate <75 beats per minute). The current
strength for high-level vagal stimulation was 0.05 mA greater than that
required to produce sinus arrest (>2 seconds) for the right vagus and
complete AV block for the left vagus. The conditions of neural
stimulation were kept constant in each experiment.
Histopathology of the Radiofrequency Lesions
All dogs were
killed at the end of each study in the
anesthetized state by excision of the heart. After the cardiac cavities
were washed with saline, myocardial tissue was preserved in neutralized
formaldehyde. After fixation, transmural tissue samples were taken from
normal atrial tissue and tissue encompassing ablation sites. Sections
were taken from the center of the lesion, fixed, and stained with
hematoxylin and eosin or Masson's trichrome stain for
histopathological examination. For each ablation site, assessment of
lesion size, transmural extent of necrosis, degree of inflammation, and
fibrosis were made from dogs in both the acute and chronic groups.
Experimental Protocols
Group 1: Effect of RFCA on
Inducibility of AF and on
Refractory-Period Response to Vagal Stimulation
In five dogs (group
1), reproducible sustained AF lasting >30
minutes was induced with rapid atrial pacing (pacing cycle length, 50
ms) or multiple premature atrial stimuli at various coupling
intervals21 22 23 24 25
and was maintained by low-level (right
vagus: 2 V, 4-ms duration, 8 Hz; left vagus: 3 V, 4-ms duration, 8 Hz)
cervical vagal stimulation. The stimulation parameters were kept
constant during each experiment. The procedure for atrial RFCA
(described above) was performed, and the inducibility of AF was
retested as in the baseline setting. Before and 30 minutes after
completion of the RFCA, atrial ERPs were determined at isolated atrial
sites, ie, atrial appendages and five different nonisolated left and
right atrial sites in the baseline setting and during low-level and
high-level (right vagus: 5 V, 4-ms duration, 20 Hz; left vagus: 7 V,
4-ms duration, 20 Hz) cervical vagal stimulation.
Group 2:
Effect of RFCA on Inducibility and Duration of AF During
Administration of Low and High Doses of Methacholine
In seven dogs
(group 2), the effects of administration of a low
dose (1.5 µg/kg per minute IV) and a high dose (3.6 µg/kg per
minute IV) of methacholine on the atrial ERP were examined to determine
whether the atrial myocardium was normally responsive after RFCA.
Inducibility of AF was tested with atrial burst pacing (cycle length,
50 ms) or extrastimulus pacing during administration of low and high
doses of methacholine before and after RFCA. Atrial ERP measurements
were obtained during continuous infusions of low and high doses of
methacholine before and after RFCA.
Group 3: Effect of RFCA
on the Dose of Methacholine Required to
Induce Sustained AF
In five dogs (group 3), we determined the relation
between the
dose of methacholine (0.2 to 6.5 µg/kg per minute IV) required to
promote sustained AF and the inducibility and duration of AF before and
after performing RFCA.
Group 4: Effect of RFCA on
Sinus-Node Automaticity and AV
Conduction
In six dogs (group 4), we assessed the effects of RFCA on
sinus-node automaticity and AV-nodal conduction by determining SNRT,
CSNRT, AH and HV intervals, and AV-nodal ERP before and after
ablation.
Group 5: Long-term Effectiveness of RFCA
In four dogs in the chronic group (group 5), short-term AF was
induced with rapid atrial pacing (pacing cycle length, 50 ms) or
multiple premature atrial stimuli at various coupling intervals and
perpetuated with a low dose of methacholine (1.5 µg/kg per minute).
Since these dogs were kept alive, we minimized the amount of
methacholine infused by stopping methacholine infusion after inducing
AF for >10 minutes. Sterile open-chest atrial RFCA was performed after
reproducible induction of sustained AF. Seven to 21 days later, all
dogs underwent open-chest electrophysiological testing, in which the
inducibility and duration of AF were retested during infusion of graded
doses of methacholine (0.2 to 6.5 µg/kg per minute). Multiple atrial
electrograms, a His-bundle electrogram, and an ECG of surface lead II
were recorded during normal sinus rhythm and during pacing from
isolated and nonisolated sites on the atria.
Group 6:
Effect of RFCA on Atrial Contractile Function and
Intra-atrial Conduction
In four dogs (group 6), cross-sectional and
pulsed-wave
Doppler echocardiographic examinations were performed before and after
RFCA to assess the transvalvular flow-velocity spectra across the
mitral and tricuspid valves before and after RFCA with a 2.5 MHz
transducer and a Toshiba (Sonolayer SSA 270A) or Hewlett Packard (Sonos
1500) cardiac ultrasound imaging system. The sample volume was placed
on the ventricular side at or near the tips of the mitral and tricuspid
valve leaflets; small adjustments were made to record optimal
transvalvular Doppler flow-velocity profiles in the apical four-chamber
view. Echocardiographic recordings and an ECG of surface lead II were
recorded on videotape, and video prints were obtained of optimal
recordings. Diastolic flow across the mitral and tricuspid valves
normally exhibits two peaks at slower sinus rates. However, the second
peak of the flow-velocity curve (A wave), which corresponds to atrial
contraction, is fused with the first peak (E wave) during normal sinus
rate (120 to 130 beats per minute) in dogs. The sinus rate was slowed
by 20% to 30% by vagal stimulation before and after atrial RFCA
during echocardiographic assessment of the presence of atrial
contraction (A wave).
To assess conduction across the radiofrequency lesions after RFCA, epicardial atrial electrograms were recorded from multiple sites on the right and left atrial appendages, low and high right atria, and left atrial free wall during sinus rhythm and pacing from the isolated regions, ie, the atrial appendages.
Data Analysis
Data are presented as mean±SD, except
for the
duration of AF, which is presented as median (minimum, maximum).
Comparisons within groups were done by paired t test,
whereas a group t test was used for comparisons between
groups. For comparisons among more than two groups, ANOVA was used. If
ANOVA was significant, then the least significant difference test for
multiple comparisons was used to define where the differences occurred.
Since the duration of AF was not distributed normally, comparisons
before and after ablation were made by the Wilcoxon signed rank test.
The methacholine dose-response curves before and after ablation were
compared by repeated-measures ANOVA. The interaction term from this
analysis indicates whether the dose-response curves are similar
before and after ablation.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Radiofrequency Energy Application
In group 1 dogs, the radiofrequency energy output was much higher than in dogs in the other experimental groups (Table 1
).
Because the incidence of excessive rise in impedance (>300 ) in the
first seconds of energy delivery was much greater in the group 1 dogs,
and because RFCA studies with atrial tissue samples showed that a lower
radiofrequency energy output setting and a longer exposure time (30 to
40 W, 60 seconds) reduced the incidence of excessive impedance rise and
still created transmural lesions, radiofrequency energy output was
reduced in subsequent studies in the other groups. This difference is
not reflected in Table 1, because exposure times <5 seconds
were not
included in the data analysis. Although the mean impedance level in
groups 2 through 6 was higher with the lower radiofrequency energy
output setting, the excessive rise in impedance (>300 ) was much
less than in group 1 dogs. Fig 2 shows a
representative recording of actual power output during coronary
sinus ablation (Fig 2, top) and during epicardial atrial
ablation (Fig 2, bottom). The RFCA procedure, ie, positioning
the catheters and
delivering the radiofrequency energy pulses, took 30 to 40
minutes.
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Effect of RFCA on Inducibility of AF and Refractory Period Response
to Vagal Stimulation: Group 1
Fig 3 shows that atrial
RFCA attenuated
vagally induced shortening of ERP at test sites in the right and left
atria during both low-level and high-level cervical vagal stimulations.
Test sites were both isolated, ie, atrial appendages, and nonisolated,
ie, free wall, portions of the atria. The magnitude of decrease in ERP
shortening at two left and three right atrial sites was most pronounced
with high-level vagal stimulation (right atrium 
ERP, 30.8±8.7 ms
before ablation versus 6.3±2.8 ms after ablation;
P=.004,
n=15 sites; left atrium ERP, 31.4±8.2 ms before ablation
versus
4.2±1.6 ms after ablation; P=.001, n=10 sites).
In
contrast, shortening of the ERP elicited by infusion of a low dose or a
high dose of methacholine remained unchanged after ablation at these
atrial test sites (P=.25 for the right side and
P=.19 for the left side by repeated-measures ANOVA for
ablation effect). Bilateral high-level cervical vagal stimulation that
caused sinus arrest or second degree or complete AV block before RFCA
was markedly attenuated after ablation.
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After epicardial atrial RFCA was performed, pacing induced atrial flutter in three dogs. After epicardial atrial ablations, endovascular application of radiofrequency energy through a hexapolar electrode configuration to the distal coronary sinus wall rendered atrial flutter noninducible in these dogs. Sustained AF became noninducible after ablation in all group 1 dogs. Only nonsustained AF was induced (duration, 5.6±4.1 minutes) after >10 minutes of concomitant high-level vagal stimulation and rapid atrial pacing at three times the diastolic threshold level.
Effects of RFCA on the Dose of Methacholine Necessary to Induce AF:
Groups 2, 3, and 5
In group 2 dogs, sustained AF became noninducible
after RFCA
during infusion of a low dose (1.5 µg/kg per minute) of methacholine
that induced sustained AF before ablation. AF was still inducible
during infusion of a high dose (3.6 µg/kg per minute) of methacholine
infusion.
To better quantify that relation, dose-response curves were
obtained in
group 3 and group 5 dogs (Fig 4). In these dogs, RFCA
shifted the dose-response curve relating the dose of methacholine
necessary to maintain AF down and to the right. At the lowest doses of
methacholine necessary to induce sustained AF, AF duration was
significantly reduced after ablation in dogs in both the acute and
chronic groups (P=.003, n=9). The inducibility and
duration
of AF after ablation were attenuated more markedly in group 5 (chronic)
dogs compared with dogs in groups 2 and 3 (acute). However, at higher
doses of methacholine (
3.6 µg/kg per minute for group 2 and 6.0
µg/kg per minute for group 5), AF duration remained unchanged after
ablation (Fig 4).
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) and after (
,
acute; 
, chronic) RFCA. All values are given as median (minimum,
maximum).One dog in group 2 had spontaneous paroxysms (>3 per hour) of AF with a mean duration of 8±3 minutes before ablation. After RFCA, no further paroxysms occurred. AF was also not inducible by infusion of a low dose of methacholine after ablation in this dog.
Effects of RFCA on Sinus-Node Function and AV Conduction: Group
4
Fig 5 shows the effects of the RFCA on sinus-node
function in group 4 dogs; spontaneous SCL remained unchanged, but the
MHR was attenuated after ablation (MHR, 17.6±7.7;
P<.001, n=6), whereas SNRT and CSNRT were significantly
prolonged after ablation (SNRT, 74±22 ms; CSNRT,
40.7±14.5 ms;
P<.001; n=6). AV-nodal ERP and AH and HV intervals were not
significantly affected (Table 2).
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Long-term Effectiveness of Atrial RFCA: Group 5
Nonsustained
AF was inducible in all group 5 dogs (n=4) in the
control state (duration, 11±32 seconds), and sustained AF (duration,
>10 minutes) was inducible with infusion of low doses of methacholine
(1.5 to 2.0 µg/kg per minute) before ablation. Seven to 21 days after
RFCA in all 4 dogs, AF was only inducible with high doses of
methacholine (6.0 µg/kg per minute, see Fig 4
). Sinus
rhythm was
preserved, and the PR interval remained unchanged 7 to 21 days after
ablation. His-bundle recordings during the acute follow-up
electrophysiological study 7 to 21 days after ablation showed normal AV
conduction. In 1 dog, sustained atrial flutter (cycle length, 315 ms)
with 1:1 AV conduction was inducible with rapid atrial pacing.
Histopathologic examination of the coronary sinus wall in this dog
showed a nontransmural lesion.
Effect of RFCA on Intra-atrial Conduction and Atrial Contractile
Function: Group 6
Pulsed-wave Doppler ultrasound imaging study (group
6, n=4) of the
flow across the mitral and tricuspid valves showed that atrial
contraction (A wave) was still present in all 4 dogs after RFCA
(Fig 6). Right and left AV synchrony was preserved after
ablation. Since the atrial contribution (A wave) during diastolic
filling of the ventricles depends on many factors, eg, preload and
afterload, we did not assess quantitative changes in atrial contractile
function. No mitral or tricuspid valve dysfunction was observed after
RFCA.
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Epicardial atrial electrograms after ablation from multiple
atrial
sites during sinus rhythm and pacing from the isolated portions of the
atria, ie, atrial appendages, showed no conduction across the lesions.
The electrical activity recorded from the atrial appendages was
dissociated from the rest of the atria (Fig 7).
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Histopathology of the Radiofrequency Lesions
Grossly, the
ablated areas were well-circumscribed contiguous
zones of discoloration that tended to be larger on the epicardial side
than on the endocardial side (Table 3). There was no
hemopericardium, perforation, or rupture. Microscopically, the lesions
consisted of distinct zones of coagulative necrosis bordered by zones
of inflammation and fibroblast proliferation extending from adjacent
normal tissues (Fig 8A). In the centers of the lesions,
the necrotic myocardial fibers remained "ghosts," lacking nuclei
and cross-striations (Fig 8B). The zones of proliferating
fibrous
tissue at the borders of the lesions contained numerous mononuclear
inflammatory cells and small blood vessels (Fig 8C).
Macroscopically, 1
to 2 cm of the distal part of the lesions showed a well-circumscribed
area of discoloration extending from the coronary sinus wall to the
surrounding fat tissue in the AV groove. Microscopically, the coronary
sinus and surrounding tissues also exhibited coagulative necrosis and a
thrombus was attached to the wall (Fig 8D). In dogs that were
killed
immediately after treatment, no lesions were visible.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Development of the RFCA Procedure
The RFCA procedure we used is based on atrial lesions produced by the surgical-maze procedure,26 but this procedure does not replicate the exact pattern or number of these surgical incisions. The impetus was to abolish the induction of AF in dogs while eliminating the need for cardiopulmonary bypass or extensive atriotomies and ultimately to develop a closed-chest approach.
Our initial attempts
focused on replication of all surgical-maze
lesions with RFCA. Attempting to replicate the surgical lesions in
close proximity to the sinus node affected the blood supply and the
functional integrity of this important structure, causing sinus arrest
or severe sinus bradycardia in some dogs. The surgical atrial incisions
are sharp, narrow lines, whereas the epicardial atrial radiofrequency
lesions are wider and may affect vascularization and innervation of the
surrounding tissue to a greater extent. Consequently, we eliminated the
lesions that produced sinus arrest but still could show that AF was
noninducible at low levels of vagal stimulation and infusion of low
doses of methacholine. This prompted us to develop an effective pattern
of atrial lines of conduction block with a minimum of radiofrequency
lesions. We did this by assessing inducibility of AF after performing
RFCA at each lesion site. The resultant RFCA procedure (Fig 1)
may
still reduce the mass of atrial myocardium that must be activated
sufficiently to prevent occurrence of sustained multiple wavelets of
reentry and thus abolish the inducibility of AF.
Major Findings
We demonstrated that our RFCA procedure
eliminated induction of AF
in dogs with atrial pacing and perpetuation of AF by use of either
low-level cervical vagal stimulation or infusion of low doses of
methacholine. The inducibility and duration of AF during high-level
vagal stimulation and infusion of high doses of methacholine were not
affected significantly by RFCA. It is likely that a high dose of
methacholine would induce AF owing to microreentry in virtually any
amount of atrial tissue.
The chronic studies indicate that the
procedure is safe and effective
for long-term prevention of induction of AF. Despite the fact that the
radiofrequency lesions were transmural, atrial-wall rupture or coronary
sinus perforation was not observed 7 to 21 days after ablation (Fig
8A
through 8D). Furthermore, we showed that sinus rhythm and AV-nodal
conduction were preserved and that inducibility of AF at low levels of
vagal stimulation and methacholine infusion was abolished. In one dog,
however, atrial flutter was inducible with rapid atrial pacing.
Histopathologic examination of this dog showed that radiofrequency
energy delivery to the coronary sinus did not produce a transmural
lesion, which corroborates the results of the surgical-maze procedure
by suggesting that transmural ablation of the coronary sinus wall is
essential to preventing induction of atrial flutter after
ablation.26
Vagal Denervation
Randall et al27 28
showed with selective
intrapericardial autonomic denervation of restricted portions of the
canine heart, by use of either phenol application or a surgical
ablation technique, that the vagal nerve fibers project to the heart by
traversing along the superior vena cava, over the right atrium, and
over the junction between the inferior vena cava and the inferior
atrial surface. As anticipated from their experiments, we showed that
the RFCA procedure attenuated the ERP shortening of nonisolated
portions of both right and left atrial myocardium induced by efferent
vagal nerve stimulation but did not affect the ERP response to
intravenous methacholine. Since the radiofrequency ablations created
contiguous transmural lesions, the vagal fibers projecting to the
isolated regions, ie, the atrial appendages, were also interrupted,
and, subsequently, the vagally induced atrial ERP shortening in
isolated regions was totally abolished after RFCA. These data indicate
that prejunctional vagal nerve fibers projecting to the atria are
interrupted by radiofrequency ablations without affecting
postjunctional responsiveness of the atrial myocardium to methacholine.
The duration of the atrial ERP is an important factor for the
vulnerability to
AF.21 22 23 24 25
Since vagotomy prolongs the ERP
of the atria or at least blunts its shortening, vagal denervation
induced by RFCA may play a role in the prevention of AF induction. The
surgical-maze procedure could produce a similar result. Intravenous
infusion of methacholine substantially reduces the atrial ERP and
potentiates the inducibility of AF. Importantly, however, RFCA still
made it more difficult for methacholine to induce AF, thus indicating
that, in addition to vagal interruption, the multiple lines of
interatrial conduction block probably directly affect the atria.
Sinus-Node Function, AV Conduction, and Hemodynamics
The
surgical-maze procedure maintains sinus-node function with
preserved AV conduction.15 26 30 However,
McLoughlin et
al29 have demonstrated that the surgical-maze procedure
causes acute sinus-node dysfunction that may improve spontaneously over
the months following the procedure. RFCA prolongs the sinus-node
recovery time and the corrected sinus-node recovery time and decreases
the maximal heart rate significantly, corroborating this previous study
by suggesting that interventions close to the sinus node or its blood
supply cause acute sinus-node dysfunction. We did not assess sinus-node
function in the chronic animal models, and future studies are needed to
establish whether this RFCA procedure affects sinus-node function over
the long term. AV-nodal and His-Purkinje conduction times were not
affected significantly by RFCA in dogs in the acute and chronic groups.
Pulsed-wave Doppler echocardiography showed that both right and left
atrial transport function was preserved after RFCA (Fig 6),
indicating
that ablation did not significantly affect atrial contractile
function.
Potential Advantages of RFCA Compared With Surgery
In centers
experienced with the technique, the surgical-maze
procedure has a success rate of 89% for permanently eliminating AF
without the need for antiarrhythmic medication and with restoration of
sinus initiated rhythm, AV synchrony, and preservation of atrial
booster-pump function.30 The surgical-maze procedure
requires an intricate pattern of atrial incisions and extensive
suturing to reestablish atrial integrity. The surgery is time consuming
and requires prolonged cardiopulmonary bypass. Cox et al30
have reported a 3.9% rate of occurrence of neurological events
(transient ischemic attacks or stroke) during or after surgery. These
ischemic neurological events may be related to prolonged
cardiopulmonary bypass and small air emboli during atriotomies. If the
open-chest RFCA procedure abolished induction of AF in humans, it would
eliminate the need for atriotomies and cardiopulmonary bypass.
Naturally, if atrial RFCA can be performed endocardially, surgery can
be eliminated altogether. That is the ultimate goal.
Consideration of the Experimental Model and Limitations of the
Study
In the present study, we examined the effects of the RFCA
procedure on the inducibility and duration of AF and on the
parasympathetic innervation of the atria in a canine model. As in many
previous studies, we used premature atrial pacing at different coupling
intervals and burst-pacing atrial stimulation to induce AF. In contrast
to the animal model used by Cox et al26 for the
surgical-maze procedure, either electrical cervical vagal stimulation
or infusion of methacholine was used to perpetuate AF. Despite
differences between the animal models, the results of the present
study show that the RFCA maze procedure reduced the ability to induce
AF in the dog. Prevention of induction of AF may depend on the atrial
lines of conduction block and vagal denervation produced by the RFCA
procedure. Although atrial contractile function is preserved, we do not
know whether RFCA increases the risk of thromboembolism, particularly
in the atrial appendages. Paroxysmal AF induced by enhanced vagal tone
is rare in humans, and, thus, it is possible that the observations of
this phenomenon in the present canine model may not be applicable.
This procedure also needs to be tested in dogs with self-perpetuating
AF induced by chronic rapid atrial pacing or by some other means. It is
important to remember that the dimensions of the canine atria are
smaller than those of the human atria, which may conceivably affect the
number of lesions required to prevent multiple wavelets of reentry from
sustaining in patients. Recently, however, Shyu et al31
demonstrated that chronic AF caused by mitral valve disease can be
eliminated surgically by creating a limited number of lesions that
compartmentalize the enlarged atria. The results of this latter
"compartment operation" corroborate our findings by suggesting
that creation of a limited number of lines of interatrial conduction
block can effectively abolish induction of AF.
|
Acknowledgments |
|---|
This work was supported in part by the Herman C. Krannert Fund; by grants HL-42370 and HL-07182 from the NIH, US Public Health Service; by the American Heart Association, Indiana Affiliate, Inc; and by EP Technologies. The authors thank Douglas Segar, MD, for the echocardiographic studies, Naomi Fineberg, PhD, for statistical analysis of the data, and Jacob Rohleder for technical assistance.
Received August 18, 1994; revision received November 1, 1994; accepted November 14, 1994.
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