(Circulation. 2000;101:1185.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Atrial Fibrillation Produced by Prolonged Rapid Atrial Pacing Is Associated With Heterogeneous Changes in Atrial Sympathetic Innervation
From the Krannert Institute of Cardiology (J.V.J., H.J.S., D.P.Z., J.E.O.), and the Department of Radiology (W.W., G.D.H.), Indiana University School of Medicine, Indianapolis.
Correspondence to Jeffrey Olgin, MD, Krannert Institute of Cardiology, Indiana University School of Medicine, 1111 W 10th St, Indianapolis, IN 46202. E-mail jolgin{at}iupui.edu
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Abstract |
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Background—Structural and electrophysiological changes of the atria occur with prolonged rapid rates; however, the effects of sustained atrial fibrillation (AF) on autonomic innervation of the atria are unknown. We hypothesized that electrophysiological remodeling from rapid atrial rates is accompanied by altered atrial autonomic innervation.
Methods and Results—Six dogs (paced group) underwent atrial pacing at 600 bpm; 9 dogs (control animals) were not paced. All paced dogs developed sustained AF by week 4 of pacing. All 15 animals underwent positron emission tomography imaging of the atria with [C-11] hydroxyephedrine (HED) to label sympathetic nerve terminals. HED retention in the atria was significantly greater in paced dogs compared with control animals (P=0.03). Tissue samples from the atrial appendages had a greater concentration of norepinephrine in paced animals than in control animals (P=0.01). The coefficient of variation of HED retention was also greater in paced animals (P=0.05) and was greater in the right atrium than in the left atrium (P=0.004). Epicardial activation maps of AF were obtained in the paced animals at baseline and with autonomic manipulation. Mean AF cycle length was longer in the right atrium (109.2±5 ms) than in the left atrium (85.8±5.5 ms) at baseline (P=0.005). AF cycle length did not vary significantly from baseline (97.6±13.4 ms) with stellate stimulation (100.5±6 ms) but lengthened with propranolol (107.5±6.1 ms, P=0.03).
Conclusions—Rapid rates of AF produce a heterogeneous increase in atrial sympathetic innervation. These changes parallel disparate effects of rapid pacing–induced AF on atrial electrophysiology.
Key Words: atrial fibrillation • electrophysiology • nervous system, autonomic • tomography • hydroxyephedrine
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Introduction |
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Perturbation of normal atrial electrophysiological properties by rapid atrial rates that promotes atrial fibrillation (AF) has been termed electrophysiological remodeling.1 Shortening of refractoriness has been described as a hallmark of electrophysiological remodeling.1 2 3 4 It has been proposed that other electrophysiological properties such as the spatial dispersion of atrial refractoriness and conduction velocity are also important elements of electrophysiological remodeling.5 6 An increased heterogeneity of atrial refractoriness has been found in animal models of AF6 7 8 and in humans with paroxysmal AF.9 Although the underlying cause of such an increase in heterogeneity of atrial refractoriness is unknown, alterations in sympathetic innervation have been implicated in ventricular arrhythmogenesis by producing spatial heterogeneity of electrophysiology.10 11 Recently we showed that heterogeneous atrial sympathetic denervation with epicardial phenol increases dispersion of atrial refractoriness and creates a substrate for sustained AF.12 Whether changes in sympathetic innervation occur during electrophysiological remodeling of the atria and the mechanism by which these changes could alter atrial electrophysiology is unknown. We used a rapid atrial–paced canine model of AF to test the hypothesis that rapid atrial rates are accompanied by altered sympathetic innervation.
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Methods |
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This study was approved by the Institutional Animal Care and Use Committee of Indiana University in accordance with the "Guide for Care and Use of Laboratory Animals" (NIH publication No. 86-23, revised 1985).
Long-Term Pacing
Fifteen mongrel dogs, each weighing 28 kg, were studied. Of
these, 9 dogs served as control animals and underwent no intervention
before the study. Six dogs (paced group) underwent transvenous
implantation of permanent atrial pacemakers. These animals underwent
anesthesia with isoflurane and volume-cycled ventilation.
An active fixation pacing lead was positioned in the right atrial
appendage to obtain an appropriate pacing threshold. A pulse generator
(Itrel, Medtronic) was connected to the lead and positioned in a
subcutaneous pocket over the dog’s right shoulder. After recovery, the
pacemakers were programmed "AOO" at 600 bpm, at 4 times
diastolic threshold. Pacemakers were interrogated weekly
for 6 weeks. At each interrogation, a 4-lead surface ECG was
recorded during temporary inhibition of pacing to determine the
underlying rhythm and mean ventricular rate. Threshold of
atrial capture was determined for dogs in sinus rhythm, and pacemaker
output was adjusted if necessary to ensure atrial capture.
Electrophysiological Study
After 6 weeks of pacing, during sustained atrial fibrillation
(AF), paced dogs underwent an open chest
electrophysiological study under general
anesthesia maintained with isoflurane. Arterial
blood pressure and cardiac rhythm were monitored during all studies. A
median sternotomy was performed, and the pericardium was opened to
cradle the heart. Both cervical vagi and thoracic ansae subclaviae
nerves were exposed and cut. Custom-made bipolar electrodes were
attached to the distal ends of the cut nerves for bilateral stimulation
with the use of a constant voltage stimulator (Grass Instruments).
Separate stimulators were used to stimulate bilateral vagi and ansae
subclaviae. The stimulators were programmed with a voltage and
frequency that was sufficient to obtain a 50% reduction in
ventricular rate during bilateral vagal stimulation and a
40% increase in ventricular rate during bilateral ansae
subclaviae stimulation.
A custom-built set of epicardial plaques was used to map atrial activation during AF. This set of 4 epicardial plaques had a total of 240 electrodes (5.6-mm interelectrode spacing) and covered the entire atrial epicardial surface. Two plaques were placed on the medial aspect of both the left and right atrial appendages and along Bachmann’s bundle in the transverse sinus (43 and 50 electrodes, respectively). A plaque with 77 electrodes was placed on the lateral aspect of the appendage and free wall of the right atrium and a plaque with 70 electrodes was placed on the lateral aspect of the appendage and free wall of the left atrium.
All unipolar recordings were made relative to a reference electrode in the inferior vena cava. Thirty-second epochs of AF were recorded at baseline, during vagal stimulation, and during stellate (ansae subclaviae) stimulation. Ventricular rate was allowed to return to baseline before and subsequent to stellate and vagal stimulation. Propranolol hydrochloride was then infused with an intravenous bolus dose of 0.2 mg/kg followed by infusion at 0.04 mg/kg per hour. Data were acquired with the use of a digital acquisition system at 1-kHz sampling frequency (Cardiomapp, Prucka Engineering). Postacquisition analysis was performed with the use of MATLAB (Math Works Inc) and C programming languages. Four-second epochs from each recording were analyzed. The first rapid deflection of each atrial electrogram was marked to time local atrial activation and the mean AF cycle length (AFCL) for each electrode determined. Timing of the QRS complex on the surface ECG was used to exclude ventricular electrograms. Mean AFCL was used to estimate atrial refractoriness at each electrode.13
Positron Emission Tomography
After 6 weeks of rapid atrial pacing, all animals in both groups
underwent positron emission tomography (PET) imaging to determine
sympathetic innervation. The feasibility and methods of using
[C-11]–labeled hydroxyephedrine (HED) to label atrial sympathetic
nerve terminals have been previously described by our
group.12 14 HED was injected intravenously and
arterial blood samples were drawn over a 30-minute period
to calculate the available blood pool of HED. Two minutes before
euthanasia, [F-18]–labeled microspheres of hydroxyapatite
(20- to 40-µm diameter) were injected into the left
ventricular cavity and a continuous blood sample was drawn
from the femoral artery at a predetermined rate to determine total
atrial blood flow by the reference sample technique.15 16
The [F-18]–labeled microspheres were used to determine
atrial perfusion to correct for regional variability in delivery of HED
to atrial tissue and partial volume effect caused by variable wall
thickness. The animal was euthanized with pentobarbital (1.2 g). The
atria were separated from the ventricles by cutting along the tricuspid
and mitral annuli. Left and right atrial cavities were filled with
gauze, and the entire atrium was placed in the imaging chamber of a
custom-built, high-resolution (3.2 mm, full width at half maximum)
PET scanner. An initial scan was performed immediately. Without moving
the heart, a second scan was performed 2 hours later. Because [C-11]
has a much shorter half-life (20 minutes) than [F-18] (110 minutes),
the second scan only imaged the distribution of the [F-18]–labeled
microspheres. Subtraction methods were used to generate
individual projection data sets for both [F-18] and [C-11].
Filtered backprojection image reconstruction algorithms were used
to generate tomographic images of the [C-11] and [F-18]
distribution. Individual tomographic slices of the atria were stacked
and linear interpolation was used to generate 3D image volumes for data
analysis.
PET Analysis
Qualitative differences in HED uptake were compared between
paced dogs and control dogs. For quantitative analysis of
regional differences in sympathetic innervation, the reconstructed
atrial images were divided into regions of interest. Each atrial image
was divided into 10 axial sections. Each axial section was divided into
13 predetermined regions of interest that included the right and left
atria and interatrial septum. Thus there were 130 regions of interest
for both atria combined. The HED retention fraction was calculated as
the ratio of the HED concentration in the tissue at the time the heart
was removed, divided by the integral of the HED concentration in the
blood from the time of injection until the heart was removed:
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Norepinephrine Content
Biopsy samples of atrial muscle (88±4 mg) were obtained
from the appendages of left and right atria. Samples were weighed and
stored at -70°C. Samples were subsequently thawed and
homogenized with 5 to 10 vol of 0.1N perchloric acid and
centrifuged for 15 minutes. The acid supernatant was diluted
with 1 mmol/L HCL. A radioenzymatic assay with purified
phenylethanolamine N-methyltransferase was used to determine
norepinephrine content of the
supernatant.17
Statistical Analysis
Values are presented as mean±SD. Two-way comparisons
were made with t tests, paired when appropriate. A value of
P=0.05 was considered significant.
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Results |
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By the fourth week of pacing, the underlying rhythm during temporary inhibition of pacing was sustained AF in all dogs (n=6) in the paced group. At 6 weeks, with pacemakers programmed off, all dogs remained in sustained atrial fibrillation during the electrophysiological study. Mean ventricular rate was similar (P=NS) in control (105±18 bpm) and paced animals (115±25 bpm). All control dogs maintained sinus rhythm throughout the study.
PET Images
An example of positron emission tomography (PET) images from a
control dog is shown in Figure 1A
, demonstrating increased [C-11]–labeled hydroxyephedrine (HED)
retention in the region of the sinus node and crista terminalis,
consistent with previously described increased sympathetic
innervation of the sinus node region.18 In all paced dogs,
extensive redistribution of HED retention was observed (Figure 1B).
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Quantitative Analysis
The mean HED retention fraction of both atria was significantly
greater (P=0.03) in paced dogs (0.877±0.36) than in control
dogs (0.223±0.10). This was also true of individual left atria [paced
(0.814±0.25) vs control (0.215±0.06), P=0.03] and right
atria [paced (0.922±0.45) vs control (0.205±0.08),
P=0.03] (Figure 2).
There was no significant difference in mean HED retention fraction
between left and right atria in control animals or paced dogs (Figure 2).
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The spatial variation of sympathetic innervation, measured by the
coefficient of variation of HED retention, was significantly greater in
the paced group (0.57±0.34) compared with control dogs (0.36±0.12,
P=0.05) (Figure 3).
Also, while the variability of sympathetic innervation was similar in
the left (0.32±0.03) and right (0.41±0.05) atria of control animals
(P=NS), in AF dogs the variability of sympathetic
innervation in the right atria (0.66±0.20) was significantly greater
than that of the left atria (0.39±0.03) (P=0.004) (Figure 3).
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Electrophysiological Studies
The effect of autonomic stimulation on mean atrial fibrillation
cycle length (AFCL) measured from all electrodes is shown in Figure 4. Mean AFCL at baseline was
97.6±13.4 ms. Vagal stimulation shortened mean AFCL to 85.3±11.6 ms
(P=0.09). Compared with baseline, stellate stimulation did
not result in significant change in overall mean AFCL (100.5±6.0 ms),
whereas infusion of propranolol resulted in a significant
lengthening of mean AFCL to 107.5±6.1 ms (P=0.03).
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Mean AFCL was also compared between the left and right atria at
baseline and with autonomic manipulation, as shown in Figure 5. At baseline, mean AFCL was
significantly shorter (P=0.0005) in the left atrium
(85.8±5.5 ms) than in the right atrium (109.2±5.0 ms). Vagal
stimulation shortened mean AFCL to a greater extent in the right than
in the left atrium and therefore resulted in similar mean AFCL in the
right (88.5±15.7 ms) and left (82.1±6.5 ms) atria (P=NS).
During stellate stimulation, similar to baseline state, mean AFCL
remained significantly longer in the right atria (112.2±7.5 ms) than
in the left atria (88.1±6.2 ms, P=0.009). Similarly, with
propranolol, mean AFCL remained significantly longer in the
right than in the left atria (P=0.005) (Figure 5).
Also with propranolol when compared with baseline, mean
AFCL was longer both in right atria (121.7±8.4 ms, P=0.02)
and left atria (91.4±4.9 ms, P=0.001).
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Dispersion of atrial refractoriness, as determined by the coefficient
of variation of AFCL, was measured during autonomic manipulation
(Table). For both atria combined, the coefficient
of variation of AFCL was unchanged from baseline with stellate
stimulation, vagal stimulation, or infusion of propranolol
(Table). The coefficient of variation of AFCL was also compared
between the left and right atria at baseline and during autonomic
manipulation. At baseline, the mean coefficient of variation of AFCL
was significantly greater in the right atrium than in the left atrium
(P=0.005) (Table). This finding of a greater
dispersion of AFCL in the right atrium than in the left atrium was also
observed with vagal stimulation (P=0.001) and stellate
stimulation (P=0.002) as well as during
propranolol infusion (P=0.006)
(Table).
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Norepinephrine Content
Tissue norepinephrine content of the atrial appendage
samples was significantly greater in the AF group (2.91±0.09 µg/mg
of tissue) compared with the control group (2.02±0.51 µg/mg of
tissue, P=0.01).
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Discussion |
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Major Findings
We found that rapid atrial pacing–induced AF in the dog results in both autonomic and electrophysiological remodeling of the atria. This was confirmed by PET imaging of atrial sympathetic nerve terminals as well the finding of increased tissue norepinephrine content. Autonomic remodeling was characterized by increased sympathetic innervation of the atria as well as increased heterogeneity of atrial sympathetic innervation. These autonomic findings correlated with electrophysiological changes in the atrium. Dispersion of AFCL was greater in the right atrium compared with the left atrium, which correlated with an increased heterogeneity of sympathetic innervation in the right atrium. Although stellate stimulation did not affect the mean duration of AFCL or the dispersion of AFCL, ß-receptor blockade lengthened mean AFCL significantly.
Role of Sympathetic Innervation in Electrical Remodeling and
AF
Altered autonomic function has long been implicated in the
pathogenesis of AF in animal models19 and
humans.20 Although increased vagal tone has been
demonstrated to cause AF in animals21 and
humans,20 the role of the sympathetic nervous system in AF
is less understood.21 22 23 Moreover, previous
investigations of the effect of sympathetic stimulation on atrial
refractoriness have found varied results.21 22 23 In humans,
an increased incidence of AF has been observed in states of increased
sympathetic activity.24 The mechanisms underlying the
provocation or sustenance of AF as the result of an altered sympathetic
state have not been clarified. Although our study has not demonstrated
a causal link to the sustenance of AF, we have demonstrated that
sympathetic remodeling occurs with the rapid rates of AF.
Previous studies have shown that autonomic blockade (ß-blockade and vagolysis with atropine) does not prevent a short-term decrease in atrial effective refractory period from rapid pacing in animals4 or humans.25 Wijffels et al26 have shown that propranolol or atropine have little effect on AFCL length during the first 7 days of sustained AF. This is in contrast to our study, which demonstrated an increase in AFCL after the infusion of propranolol after 6 weeks of rapid pacing induced sustained AF. Thus our study suggests that significant autonomic remodeling may occur only with more prolonged episodes of rapid rates.
We also hypothesized that heterogeneity of autonomic innervation promotes heterogeneity of atrial refractoriness. Normal atria exhibit a heterogeneous distribution of vagal and sympathetic innervation.18 21 27 An increased dispersion of atrial refractoriness has been observed in animal models of AF2 6 7 28 and humans with paroxysmal AF.9 Increased regional dispersion of AFCL appears to be an important independent determinant of electrophysiological remodeling and is observed even after shortening of atrial refractoriness caused by rapid pacing has stabilized.6 Whereas vagal stimulation results in regional differences in shortening of refractoriness, promoting both induction and sustenance of AF,21 23 27 sympathetic stimulation appears to have a less pronounced effect on the dispersion of atrial refractoriness, at least in autonomically decentralized animals.21 22 It is also of note that these studies were performed in normal animals in sinus rhythm.21 22 However, in recent studies we found that heterogeneous sympathetic denervation of the atria with the epicardial application of phenol in dogs resulted in increased heterogeneity of atrial refractoriness and a milieu for sustained AF.12 In the present study, we found that heterogeneity of sympathetic innervation increases with prolonged rapid rates. We also found that this sympathetic heterogeneity is spatially related to heterogeneity of atrial refractoriness (as reflected by AFCL).13
Autonomic Remodeling
To the best of our knowledge, the present study is the first
to assess changes in sympathetic innervation during the process of
electrophysiological remodeling and
sustained AF. HED is taken up by an energy-dependent uptake-1 mechanism
of postganglionic presynaptic sympathetic nerve terminals and is not
metabolized and thereby labels functioning sympathetic nerve
terminals.29 30 Extraneuronal HED retention is low and the
extraction of HED from blood to the neuronal axoplasm is
high.30 This suggests that the increase in HED retention
in paced dogs represents either an increased number of
sympathetic nerve terminals with an intact uptake-1 mechanism or an
upregulation of the uptake-1 mechanism. Because our technique corrected
for spatial variations in blood flow and myocardial blood flow was in
fact reduced in paced dogs, altered flow could not have accounted for
increased HED retention.16
The triggers and mechanisms underlying these autonomic changes are unknown. Recent findings of reduced atrial myocardial blood flow16 and histological similarities between chronically ischemic ventricular myocardium and atrial myocardium in sustained AF31 suggest the possibility of ischemia as a trigger. Myocardial infarction causes sympathetic denervation in the ventricle32 ; however, the effects of long-term ischemia on ventricular sympathetic innervation are unknown. In diabetic cardiac autonomic neuropathy, regional hyperinnervation (increased HED retention) can accompany sympathetic denervation.33 The structural myopathy of long-term AF also may play a role in these alterations, akin to ventricular sympathetic changes in nonischemic dilated cardiomyopathy.34
Electrophysiological Effects of Autonomic
Remodeling
The present study suggests significant
electrophysiological effects of sympathetic
activity in the electrically remodeled atrium. It is possible that
unopposed 
-adrenergic activity in the presence of ß-blockade with
propranolol in this model prolongs atrial refractoriness,
whereas "balanced" - and ß-adrenergic activity as the result
of stellate stimulation effects no net change in refractoriness, as in
the healthy canine atrium.21 Unfortunately, the
electrophysiological effects of
-adrenergic–blocking agents could not be assessed in the
present experiment because they affect the uptake of HED used for
sympathetic imaging.
Study Limitations
With the use of the above model, the exact time course of the
onset and development of changes in sympathetic innervation could not
be assessed because the technique of high-resolution atrial imaging in
dogs does not permit sequential in vivo studies. The effects of
-receptor blockade on autonomic remodeling could not be assessed in
this study because these drugs interfere with PET imaging with the use
of HED.35 This also precluded the assessment of the effect
of sympathomimetic agents such as epinephrine or dopamine on
atrial electrophysiology.35 Samples of tissue for
norepinephrine content were only obtained from the atrial
appendages to allow preservation of atrial architecture for PET
imaging. However, because changes in HED uptake were widespread, such
sampling may not have significantly biased our results.
Atrioventricular junction ablation and
ventricular pacing were not performed to control
ventricular rate out of concern that ablation at this site
would affect atrial innervation. However, ventricular rates
were not significantly different between paced dogs and control dogs;
furthermore, no animal developed congestive heart failure by clinical
or echocardiographic estimation.
Conclusions
"Autonomic remodeling" occurs during
electrophysiological remodeling of the
atria produced by rapid atrial pacing. The possible triggers for this
phenomenon and modalities of intervention in preventing their
electrophysiological impact during the
process of electrophysiological remodeling
need further investigation.
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Acknowledgments |
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This work was supported in part by the Herman C. Krannert Fund, a grant from the Indiana Heart Association, and grants HL-52323 (Dr Zipes, Dr Hutchins, and Dr Sih) and HL-03703 (Dr Olgin) from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The authors thank Drs David P. Henry and Judith A. Eudaly for measurement of tissue norepinephrine levels and Kerry Antonuccio and C.J. Arnett for technical assistance.
Received July 6, 1999; revision received September 17, 1999; accepted September 29, 1999.
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B. J.J.M. Brundel, R. H. Henning, H. H. Kampinga, I. C. Van Gelder, and H. J.G.M. Crijns Molecular mechanisms of remodeling in human atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 315 - 324. [Abstract] [Full Text] [PDF]
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