University of Groningen
Atrial remodeling due to atrial tachycardia and heart failure
Schoonderwoerd, Bas Arjan
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ATRIAL
AND
VENTRICULAR ELECTRICAL REMODELING
Chapter 3
Rapid Pacing Results in Changes in Atrial
but not in Ventricular Refractoriness
Bas A. Schoonderwoerd, Isabelle C. van Gelder,
Robert G. Tieleman, Klaas J. Bel and Harry J.G.M. Crijns
From the Department of Cardiology, Thoraxcenter,
University Hospital Groningen, the Netherlands
Pacing Clin Electrophysiol 2002;25:287-290
47
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ABSTRACT
Background It is well known that atrial tachycardia causes atrial electrical remodeling,
characterized by shortening of atrial refractory periods (AERP) and loss of physiological
adaptation of AERP to rate. However, to date the nature and time course of changes in
ventricular refractory periods (VERP) caused by rapid rates are to be established.
Methods and Results After being instrumented with epicardial electrodes on both atria
and both ventricles nine goats were subjected to one week of rapid atrioventricular (AV)
pacing with a rate of 240 bpm and an AV delay of 100 ms. Pacing was only interrupted
for measurement of left and right AERP and VERP at three basic cycle lengths (BCL) of
400 ms, 300 ms and 200 ms during sinus rhythm in the conscious animal.
Left and right AERP decreased at all BCL, reaching minimum values after 3 days
(Right AERP at BCL of 400 ms, 96±16 ms after 3 days vs. 144±16 ms at baseline,
p<0.05). In contrast, both left and right VERP did not change at any BCL.
Conclusion This study demonstrates a difference between the atria and ventricles with
respect to tachycardia induced changes in refractoriness.
48
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VENTRICULAR ELECTRICAL REMODELING
INTRODUCTION
Since the observation that atrial fibrillation (AF) causes changes in atrial electrophysiology
that may favor the perpetuation of the arrhythmia, these processes have been subject of
great interest. It has been extensively demonstrated that both AF and atrial tachycardia
cause shortening of the atrial effective refractory period (AERP) and a loss or even reversal
of the physiological adaptation of the AERP to rate, both in animals1-5 as well as in
patients.6-9 These changes in AERP are part of a process known as atrial electrical
remodeling.
The data on changes in ventricular effective refractory periods (VERP) due to chronic
high ventricular rates, however, are scarce. In dogs, rapid ventricular pacing during 3-5
weeks results, besides congestive heart failure, in a prolongation of the VERP10 and the
ventricular action potential duration (APD),11,12 which is an index of ventricular
refractoriness. However, during chronic AF with high ventricular rates during 8 weeks
no changes in VERP were observed in goats.13 The electrophysiologic changes caused by
chronic rapid rates in both atria and ventricles have never been simultaneously
investigated. The aim of the present study therefore was to establish the nature and time
course of tachycardia induced changes in atrial and ventricular electrophysiology.
METHODS
Animal preparation
All experiments were performed in accordance with the Guidelines for Animal Research
and approved by the Ethics Committee on Animal Research of the University of Groningen.
For this study, we used 9 goats weighing between 32 kg and 61 kg (mean 47±10
kg). The animals underwent a right lateral thoracotomy and four custom-made felt
electrode arrays each containing 4 platinum electrodes were sutured on the right atrial
appendage, the left atrial appendage, the right ventricular lateral wall and the left
ventricular lateral wall, respectively. The electrode leads were tunneled subcutaneously
to the back of the neck where they were exteriorized and stored in a leather collar. The
animals received ampicillin 1000 mg prophylactically and once daily for 3 days after
surgery. After a recovery period of two weeks, the goats were placed in a cage (1,5 x 0.7 m),
with free access to food and water. The electrode wires were connected to a custommade cardiac stimulator and multi-channel recording unit. The cables were connected
to the ceiling with a balancing counterweight and a pulley to allow the goats free
movement in their cages.
49
CHAPTER 3
Measurement of effective refractory periods
AERP and VERP were measured from one pair of electrodes on each atrium and ventricle,
respectively, at three different basic cycle lengths (BCL) of 400, 300 and 200 ms. At
four times diastolic threshold, eight basic drive stimuli were followed by one single
premature stimulus. The S1S2 coupling interval was increased in steps of 5 ms, starting
from well within the refractory period. The longest S1S2 coupling interval that failed to
result in a propagated response was taken as the local effective refractory period (ERP).
If measurement of AERP induced a paroxysm of AF that did not spontaneously convert
within 30 minutes, flecainide (10 mg/kg) was given intravenously through a catheter in
the right external jugular vein. If sinus rhythm was not restored, this procedure was
repeated maximally 2 times. If induction of AF required administration of flecainide,
measurements were discontinued for at least 24 hours because of possible influence of
flecainide on the investigated parameters.
Atrioventricular sequential pacing
After a baseline study, the goats were subjected to rapid atrioventricular (AV) pacing
during 1 week. AV pacing was performed at the right atrium and right ventricle using
the other electrodes than those used for measurement of right AERP and VERP. The
animals were paced with a pacing cycle length of 250 ms (240 beats/min) with an AV
delay of 100 ms, using a biphasic pulse of 2 ms duration at twice diastolic threshold.
Pacing was only interrupted for measurement of atrial and ventricular ERP, at t= 4, 8,
12, 24, 30, 36, 48, 60 hours and 3 and 7 days. At random, 24-hour Holter registrations
were made during AV pacing to confirm continuous atrial and ventricular capture.
Statistical analysis
Data are reported as mean ± SD. Data were assessed on multiple predefined time points.
To analyze time series, a repeated measurements analysis was performed. Contrasts were
defined to obtain a subanalysis between time points. If data were not normally distributed,
logarithmic transformation was performed. All p-values are two-sided. To correct for
multiple comparisons, a Bonferroni correction was used. A p-value<0.05 was considered
statistically significant. SAS version 6.12 (Cary, NC) was used for all statistical evaluations.
RESULTS
Atrial effective refractory periods
The mean effective refractory periods, measured at three different BCL at the left and
right atrial sites are shown in Figure 1 (top panels). As expected, left and right AERP
decreased rapidly at all BCL and reached minimum values after three days. Thereafter,
50
ATRIAL
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VENTRICULAR ELECTRICAL REMODELING
left and right AERP remained shortened at a similar level until the end of the experiment. Additionally, a reversal of physiological adaptation of left and right AERP to rate
developed, characterized by short AERP at long BCL and vice versa (Figure 2).
Ventricular effective refractory periods
The mean effective refractory periods, measured at three different BCL at the left and
right ventricular sites are shown in Figure 1, bottom panels. In contrast to the observed
shortening of AERP, left and right VERP did not significantly change during the course
of the experiment. At all BCL VERP was not significantly different from baseline at any
time point. As a consequence, the physiological adaptation of the left and right VERP
to rate remained intact.
Right
AERP (ms)
160
Left
160
150
150
140
140
130
130
120
120
110
110
100
100
90
90
80
80
0
1
2
3
4
5
6
7
0
1
2
VERP (ms)
Time (days)
3
4
5
6
7
5
6
7
Time (days)
210
210
200
200
190
190
180
180
170
170
160
160
150
150
140
140
130
130
120
120
110
110
0
1
2
3
4
Time (days)
5
6
7
0
1
2
3
4
Time (days)
Figure 1. Time course of mean right (left panels) and left (right panels) atrial (top panels) and ventricular
(bottom panels) effective refractory periods during one week of rapid AV pacing, measured at basic cycle
lengths of 400ms ( , solid line), 300ms ( , dotted line) and 200ms (, dashed line). AERP and VERP indicate
atrial and ventricular effective refractory period, respectively.
51
CHAPTER 3
160
Mean Right AERP (ms)
150
T=0
140
130
120
*
*
110
100
*
T=4 hours
*
*
*
90
* T=1 day
* T=2 days
*
T=1 week
80
BCL = 200 ms
BCL = 300 ms
BCL = 400 ms
160
Mean Left AERP (ms)
150
140
130
120
*
110
*
*
*
BCL = 200 ms
BCL = 300 ms
100
90
*
T=0
T=4 hours
* T=1 day
* T=2 days
T=1 week
*
80
BCL = 400 ms
Figure 2. Mean right (top panel) and left (bottom panel) atrial effective refractory period (AERP) at three
different basic cycle lengths (BCL) at baseline, 4 hours, 1 day, 2 days and 1 week. Rapid pacing resulted in a
reversal of the physiologic adaptation of AERP to rate, characterized by a short AERP at longer BCL and vice
versa. *p<0.05 vs. baseline.
DISCUSSION
Main findings
This study shows a difference in the nature and time course of pacing induced electrical
remodeling between atria and ventricles. During the one week of the experiment AERP
decreased rapidly at all BCL. This shortening of AERP was more pronounced at longer
BCL than at shorter BCL which resulted in a reversal of physiologic adaptation of
AERP to rate in all goats. In contrast VERP did not change and the physiological
adaptation of VERP to rate remained intact in all goats.
52
ATRIAL
AND
VENTRICULAR ELECTRICAL REMODELING
The effects of tachycardia on atrial electrophysiology
The effects of AF1 or rapid atrial pacing2,3,5 on atrial electrophysiology have been
investigated in many recent studies. The array of tachycardia induced changes is known
as electrical remodeling and comprise a progressive shortening of AERP, a maladaptation
of the physiological adaptation of AERP to rate, a decreased atrial conduction velocity,14,15
an increased dispersion of atrial refractoriness16 and a depression of sinus node function.15
Thus, electrical remodeling, by shortening the atrial wavelength, creating dispersion of
refractoriness and suppressing the normal impulse formation, favors the initiation and
perpetuation of the atrial arrhythmia itself. These findings are considered to be important factors in the progressive nature of AF in patients, apart from a progressive underlying
heart disease. Evidence for AF induced electrical remodeling in humans was provided by
Franz et al who demonstrated shortening of atrial refractoriness as presented by the
atrial action potential duration (APD) after conversion to sinus rhythm in patients with
chronic AF or atrial flutter when compared to controls.6 Furthermore, rapid atrial pacing
in patients during ten minutes results in atrial electrical remodeling.7 In addition, it has
been demonstrated that AERP increases after restoration of sinus rhythm when compared
to values measured directly after cardioversion of chronic AF which suggests recovery
from AF induced atrial electrical remodeling.9,17 The present study shows the time course
in individual animals of atrial electrical remodeling during rapid atrial pacing. AERP
starts to decrease rapidly and reaches minimum values after 3 days. This shortening of
refractoriness is related to the high activation frequency and is in accordance with the
results of the above-mentioned studies on tachycardia induced atrial electrical remodeling.
The effects of tachycardia on ventricular electrophysiology
The effects of tachycardia on ventricular electrophysiology are less well established but
existing data are in contrast to the changes observed in atrial electrical remodeling.
Short-term ventricular pacing during one hour after a 1-week period of bradycardia
results in a prolongation of VERP in dogs.18 In humans, short-term (30 minutes) rapid
ventricular pacing or atrial pacing with a high ventricular response also results in a
prolongation of VERP.19 However, this prolongation does not occur until 15 minutes
after cessation of pacing. Experimental heart failure in dogs and pigs, caused by longterm rapid ventricular pacing during 4-5 weeks results in a prolongation of the VERP,
the ventricular APD and the QT interval,10,12,20-22 which are also well known features in
patients with congestive heart failure. On the other hand, chronic AF with high
ventricular rates during 4-8 weeks caused no changes in VERP in goats.13 In the present
study, VERP did not change during 1 week of rapid AV pacing. The prolongation of
VERP in the above-mentioned studies is related to the development of tachycardia
induced heart failure which did not occur in the present study. This study demonstrates
that there is no pure “frequency dependent” change of ventricular refractoriness.
Nevertheless, the observation that VERP remained unchanged does not imply that there
is no ventricular electrical remodeling on a cellular level. Possibly, there may be concur-
53
CHAPTER 3
rent down- or upregulation of depolarizing and repolarizing forces that could result in a
constant ventricular action potential duration.
ACKNOWLEDGEMENTS
Dr. Van Gelder is supported by grant 94.014 of the Netherlands Heart Foundation.
This study is supported by grant 96.121 of the Netherlands Heart Foundation. We
thank Corine P. Baljé-Volkers, MSc, from the Trial Coordination Center, University
Hospital Groningen, for the statistical analysis.
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