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(Circulation. 1997;96:3710-3720.)
© 1997 American Heart Association, Inc.
Articles |
Electrical Remodeling due to Atrial Fibrillation in Chronically Instrumented Conscious Goats
Roles of Neurohumoral Changes, Ischemia, Atrial Stretch, and High Rate of Electrical Activation
From the Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
Correspondence to Prof Dr M.A. Allessie, Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background Recently, we developed a goat model of chronic atrial fibrillation (AF). Due to AF, the atrial effective refractory period (AERP) shortened and its physiological rate adaptation inversed, whereas the rate and stability of AF increased. The goal of the present study was to evaluate the role of (1) the autonomic nervous system, (2) ischemia, (3) stretch, (4) atrial natriuretic factor (ANF), and (5) rapid atrial pacing in this process of electrical remodeling.
Methods and Results Twenty-five goats were chronically instrumented with multiple epicardial atrial electrodes. Infusion of atropine (1.0 mg/kg; n=6) or propranolol (0.6 mg/kg; n=6) did not abolish the AF-induced shortening of AERP or interval (AFI). Blockade of K+ATP channels by glibenclamide (10 µmol/kg; n=6) slightly increased the AFI from 95±4 to 101±5 ms, but AFI remained considerably shorter than during acute AF (145 ms). Glibenclamide had no significant effect on AERP after electrical cardioversion of AF (69±14 versus 75±15 ms). Volume loading by 0.5 to 1.0 L of Hemaccel (n=12) did not shorten AERP. The median plasma level of ANF increased from 42 to 99 pg/mL after 1 to 4 weeks of AF (n=6), but ANF infusion (0.1 to 3.1 µg/min, n=4) did not shorten AERP. Rapid atrial pacing (24 to 48 hours; n=10) progressively shortened AERP from 134±10 to 105±6 ms and inversed its physiological rate adaptation.
Conclusions Electrical remodeling by AF is not mediated by changes in autonomic tone, ischemia, stretch, or ANF. The high rate of electrical activation itself provides the stimulus for the AF-induced changes in AERP.
Key Words: atrium • arrhythmia • fibrillation • remodeling • reentry
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Recently, we reported a study in chronically instrumented goats demonstrating that: "AF begets AF."1 Although initially, AF induced by burst pacing, terminated spontaneously within a few seconds, the repetitive induction of AF led to progressive prolongation of the duration of the induced paroxysms of AF. Within 1 to 3 weeks, this culminated in sustained AF lasting >24 hours. In addition, the rate of AF changed during the first week of maintained AF, increasing from
400 bpm during the first day to >600 bpm after 1 week. Programmed
electrical stimulation, which could be performed during the first days
when AF still terminated spontaneously, revealed a significant
shortening of the AERP. This shortening of the AERP was more pronounced
at slower than at faster heart rates (45% versus 23%), and the normal
physiological rate adaptation of refractoriness
became inversed. Instead of prolonging, now the AERP actually got
shorter at slower heart rates. This suggested that the finding that
"AF is begetting AF" was at least partly due to an AF-induced
shortening and maladaptation of the AERP. The goal of the present study was to elucidate the stimuli that are responsible for this process of AF-induced electrical remodeling. We evaluated the possible role of the ANS, ischemia, acute dilatation, and ANF. We also tested the hypothesis that the high rate of electrical activation per se was the trigger for the long-term shortening and inversed rate adaptation of the AERP by AF.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Goat Model of Chronic AF
Twenty-five goats weighing between 43 and 82 kg (mean, 57±9 kg) were used for this study. Animal handling was performed according to the guiding principles of the American Society of Physiology and approved by the Animal Investigation Committee of Maastricht University.
In Fig 1
, the most important
characteristics of the chronically instrumented goat model of AF are
given as described in greater detail in Wijffels et al.1
The goats were anaesthetized with 15 mg/kg thiopental (Nesdonal)
and ventilated with halothane (1% to 2%) and a 1:2 mixture of
O2 and N2O. A left intercostal thoracotomy was
made, and a Teflon felt strip (Bard) containing 15 unipolar silver
electrodes was sutured to Bachmann's bundle. Two smaller felt strips,
each containing six electrodes, were sutured to the lateral walls of
the right and left atria1 (Fig 1, top left). After closure
of the thorax, the electrode leads were tunneled subcutaneously to the
neck and exteriorized with a 30-pin connector (Lemosa). Three silver
plates (diameter, 25 mm) were left subcutaneously to serve as
grounding electrodes and to record an ECG. Postoperatively, the
animals received 0.01 mg/kg buprenorfine (Temgesic; Reckitt &
Colman) for 1 to 3 days. Gentamicin (3 mg/kg) and 1 g
sodium ampicillin (Pentrexyl; Bristol-Myers Squibb) were given IV
directly before surgery. After surgery, 1 g sodium ampicillin IM
was given.
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After 2 to 3 weeks after surgery, the goats were connected to an
external fibrillation pacemaker. This device was able to recognize the
spontaneous termination of AF. As soon as sinus rhythm was detected,
the pacemaker reinduced AF by delivering a 1-second burst of electrical
stimuli (50 Hz, four times diastolic threshold) (Fig 1
, top
right). In this way, the fibrillation pacemaker automatically
maintained AF for 24 hours a day for 7 days a week. A full description
of the pacemaker is given elsewhere.1
In Fig 1 (bottom left), the effect is shown of chronically maintained
AF on the duration of the AF episodes. When the pacemaker was switched
on (day 0), the induced paroxysms of AF were short lasting, and AF
terminated spontaneously within 5 seconds. However, the repetitive
induction of AF by the pacemaker led to a progressive increase in the
stability of AF, and in this case, AF became sustained (duration >24
hours) after 1 week of AF. The last episode of AF induced at day 10
continued for several weeks, after which AF was cardioverted. The right
atrial pressure of 2.6±1.1 mm Hg during sinus rhythm
increased to 5.8±3.3 mm Hg during chronic AF (n=7)
(P<.05).
Also in Fig 1 (bottom right), the effects of the first 24 hours of AF
on the AERP are shown. The top curve shows the normal
physiological rate adaptation of the AERP. Before
AF was induced, the AERP was 150 ms during slow pacing and shortened to
100 ms during fast pacing. After 6 hours of AF, the AERP during slow
pacing had shortened to 110 ms. During fast pacing, the shortening of
the AERP was less pronounced. However, after 24 hours of AF, the AERP
at the higher pacing rates had shortened. As a result, the normal rate
adaptation of the AERP was lost or even slightly reversed—in this
case, an AERP of 65 to 75 ms at high rates and <60 ms during pacing at
an interval of 400 ms.
Electrophysiological Measurements
Two weeks after implantation of the atrial electrodes and before
connection of the goats to the fibrillation pacemaker, a control
electrophysiological study was done. The
AERP was measured at both the right and left atrial appendage during
atrial pacing at various S1S1 pacing intervals
between 120 and 600 ms. A single premature stimulus (S2) of
four times diastolic threshold was interpolated after every
fifth S1S1 interval. The measurement of the
AERP was started with an S1S2 coupling interval
shorter than the AERP and incremented in steps of 1 ms. The shortest
S1S2 interval that resulted in a propagated
premature atrial response was taken as the AERP. This method of
measurement of the AERP is fast (usually taking <30 seconds) and
reliable because the steady state heart rate is not disturbed by the
measurement. The advantage of using an S2 stimulus strength
of four times threshold is that at this stimulus strength the
strength-interval curve is steep, which makes the measurement less
sensitive to variations in tissue excitability and applied current
intensity. The rate of AF was measured from a bipolar atrial
electrogram by counting the number of individual atrial complexes
during 15 seconds of AF. The ventricular response rate
during AF was measured from a precordial ECG.
Infusion of Atropine, Propranolol, and
Glibenclamide
Atropine and propranolol were administered both
before the induction of AF (with goats in sinus rhythm), after 1 to 3
days of AF, and after AF had become sustained. Atropine sulfate was
infused intravenously in cumulative doses of 0.1, 0.3, 0.6,
and 1.0 mg/kg in steps of 10 minutes. Propranolol
HCl (Inderal; Zeneca) was given in a similar way in cumulative dosages
of 0.1, 0.3, and 0.6 mg/kg. In 3 goats, both the sympathetic and
parasympathetic nervous systems were blocked by the combination of
propranolol (0.2 mg/kg) and atropine (0.2
mg/kg). In 5 goats with sustained AF, glibenclamide (Glyburide;
Sigma Chemical) was administered intravenously as a
5-minute bolus of 10 µmol/kg (4.94 mg/kg) to study
the effects on AFI. In 3 goats, the direct effect on AERP also was
measured during regular pacing (S1S1, 400 ms)
after cardioversion of sustained AF. Before infusion, glibenclamide was
freshly dissolved in NaOH and distilled water (1 mmol
glibenclamide, 17 mL of 0.1 N NaOH, 40 mL distilled water). In 3 of 5
goats, plasma levels of glibenclamide were determined by high-pressure
liquid chromatography analysis and
fluorescence detection.2 Venous blood samples were
collected in heparinized tubes and centrifuged with 3000 rpm at
4°C. The plasma was immediately stored at -20°C.
Acute Atrial Dilatation
In 12 goats, the effect of acute atrial dilatation was studied
by rapid infusion of a blood-expanding fluid (Hemaccel; Hoechst). The
infusion regimen was 0.5 L in 5 minutes, followed by another 0.5 L
after 10 minutes in 8 goats. In 8 goats, the changes in left atrial
diameter and/or right atrial pressure were monitored while the animals
were under anesthesia with propofol (Diprivan; Zeneca)
(bolus of 150 to 200 mg IV followed by infusion of 10 to 20
mg/min). The left atrial diameter was measured by
echocardiography in 7 goats using a parasternal
long-axis view with the animals positioned on their left side (Hewlett
Packard 77020-A system, 3.5-MHz transducer, M-mode). In 4 goats, the
right atrial pressure was measured with a Swan-Ganz catheter (Baxter)
inserted through an incision in the right jugular vein.
ANF
In 6 goats, plasma levels of ANF were monitored during the
development of chronic AF. Venous blood samples were taken from the
saphenous vein in cooled disposable tubes containing EDTA (2
mg/mL blood), immediately centrifuged at 4°C (3000
rpm), and stored at -20°C. The plasma concentration of ANF was
determined by radioimmunoassay (Nichols Institute
Diagnostics).3
In 4 control goats, ANF (
-human 1–28 ANF; Sigma Chemical) was
infused intravenously. As shown by Olsson et
al,4 administration of human ANF to conscious goats (1.5 to
2 µg/min) increased plasma ANF levels from 3±1 to 525±90
pmol/L and effectively increased natriuresis and attenuated
water intake in dehydrated animals. ANF was administered in the left
saphenous vein. Every 2 minutes, the infusion rate was increased by 0.1
µg/min until after 60 minutes, a cumulative dose of 100 µg
was given. The effective ANF plasma level was determined from venous
blood samples taken from the contralateral saphenous vein at 0, 15, 30,
45, and 60 minutes after the start of the infusion.
Effects of Long-term High-Rate Atrial Pacing
The effects of a long-term increase in the atrial pacing rate
were studied in 10 goats. First, the atria were paced during 1 to 3
days with a fixed pacing interval between 360 and 400 ms. After the
goats were hemodynamically adapted to atrial pacing,
the pacing rate was suddenly doubled (interval, 180 to 200 ms).
However, due to the presence of 2:1 AV block at this high atrial pacing
rate, the ventricular rate remained the same. The long-term
changes in AERP by prolonged rapid pacing were followed during 1 to 2
days, after which the pacemaker was switched back to its original
pacing interval of 360 to 400 ms. During the next 1 to 2 days, the time
course of the reversibility of the changes in AERP was studied.
Statistical Analysis
Data are presented as mean±SD. Statistical
analysis was performed with a paired Student's t
test. The probability values were corrected for multiple statistical
comparisons by multiplying with the number of comparisons
(Bonferroni's correction). In case of multiple measurements of a
single parameter in the same animals, a repeated-measures
ANOVA was used followed by a Bonferroni t test. A value of
P<.05 was considered be statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Effects of Atropine and Propranolol
To test the possibility that the AF-induced changes of the AERP were mediated by the ANS, the parasympathetic and sympathetic limbs of the ANS were blocked by continuous infusion of a stepwise increasing concentration of atropine or propranolol. In 6 goats, the effects on AERP were measured both during control (goat in sinus rhythm) and after a relatively short period (1 to 3 days) of maintained AF. In Fig 2
, representative examples of the effects of atropine
(left) and propranolol (right) are given. In both
experiments (different goats), the shortening of the AERP after 24
hours of AF can be clearly seen. The administration of atropine during
sinus rhythm (total dose, 1.0 mg/kg) slightly prolonged the AERP
during slow pacing (400-ms interval) (left). The fact that the
AF-induced shortening of atrial refractoriness was not abolished by
atropine means that the shortening of the AERP by AF was not mediated
by an increased vagal tone or a higher sensitivity of the atrial cells
for acetylcholine. Fig 2 (right) shows that infusion of
propranolol (total dose, 0.6 mg/kg) during sinus
rhythm slightly shortened the AERP at slow rates. After 24 hours of AF,
blockade of the ß-adrenergic system did not exert a significant
effect on the AERP.
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) and after (
) administration of atropine.
After 24 hours of AF (
), the AERP had shortened markedly at all
heart rates, and the rate adaptation was attenuated. After 24 hours of
AF, atropine prolonged the AERP still only slightly (
), and the
shortening by AF was not counteracted. Right, Blockade of the
ß-adrenergic system had no significant effect on the shortening of
the AERP by AF (different goat).
To evaluate the role of the ANS in sustained AF, the effects were
measured of atropine and propranolol on the mean AFI. The
ventricular response rate during AF (mean RR interval) was
monitored to study the effects on AV conduction. The infusion rate of
atropine and propranolol was increased every 10 minutes,
until a total dose of 1.0 mg/kg atropine and 0.6 mg/kg
propranolol was given. In Fig 3, the effects are shown of atropine
(left) and propranolol (right) on sustained AF. Both drugs
exerted a dose-dependent effect on AV conduction, with the mean RR
interval becoming shorter with atropine and longer with
propranolol. However, in this case, neither drug had a
clear effect on the AFI. On the average (n=6), atropine increased the
AFI and shortened the RR interval significantly at t=45 and 50 minutes
(P<.05, repeated measures ANOVA). Propranolol
did not significantly change AFI despite the fact that the RR interval
was already prolonged significantly after 15 minutes of infusion
(P<.05).
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In Table 1, the effects are given of
atropine and propranolol on the AERP and mean AFI for all
goats. During sinus rhythm and after 1 to 3 days of AF, atropine only
slightly increased AERP400 and AERP200, and
both the AERP400 and AERP200 remained shorter
than the values before AF was maintained (P<.05 and
P=.07). The mean AFI during sustained AF slightly lengthened
with atropine, from 93±8 ms to 99±5 ms (P<.05), whereas
the mean RR interval shortened from 462±71 to 351±137 ms
(P=.09). In 1 of 6 experiments, AF terminated 45 minutes
after infusion of atropine. In this case, the mean AFI had prolonged
from 84 to 101 ms. Propranolol had no clear effects on
AERP400 and AERP200 both during sinus rhythm
and after 1 to 3 days of AF. The lengthening of the mean AFI by
propranolol from 93±6 to 98±10 ms was not statistically
significant. The mean RR interval lengthened from 454±68 to 666±83 ms
(P<.01). Despite blockade of either the parasympathetic
limb of the ANS by atropine or the sympathetic limb by
propranolol, the mean interval of sustained AF remained
significantly shorter than during recent-onset AF (99±5 and 98±10
versus 148±13 ms) (P<.001). In 3 goats, the combination of
sympathetic and parasympathetic autonomic blockade was studied by
administration of propranolol (0.2 mg/kg) and
atropine (0.2 mg/kg). Similar to the effects of atropine and
propranolol alone, the combined sympathetic and
parasympathetic blockade did not result in a significant effect on the
mean AFI (108±4 versus 103±8 ms, P=NS).
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Atrial Ischemia and Administration of
Glibenclamide
In anesthetized dogs, induction of AF caused a twofold to
threefold increase in atrial perfusion and oxygen consumption of the
atrial myocardium.5 As a result, during AF the
reactive hyperemia response is substantially decreased. It
seems feasible that a further metabolic demand during AF,
for instance, during sympathetic stimulation, would lead to atrial
ischemia. It this case, opening of ATP-regulated potassium
channels might lead to a shortening of the action potential and atrial
refractory period. To test this hypothesis, we blocked the
ATP-regulated potassium channels by glibenclamide (10
µmol/kg IV) in 5 goats with sustained AF; in Fig 4, an example is given. Although after
infusion of glibenclamide the RR interval increased from 500 ms to
>600 ms, no effect could be seen on the AFI.
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At 5, 10, and 15 minutes after the bolus injection of glibenclamide, the average free plasma concentration was 1.2±0.1, 0.7±0.2, and 0.6±0.2 µmol/L (3 goats). These plasma levels were well within the effective range of glibenclamide of 0.1 to 1.5 µmol/L.6 On the average, at 10 minutes after the injection of glibenclamide, the mean AFI was slightly prolonged, from 95±4 to 101±5 ms (P<.05, repeated measures ANOVA). The lengthening of the average RR interval from 420±80 to 477±89 ms was not statistically significant. Blockade of the KATP channels thus did not abolish the AF-induced shortening of AFI. After glibenclamide, the mean AFI was still 101±5 ms compared with 145±11 ms during recent-onset AF (P<.001). In 3 goats with chronic AF, the effects of glibenclamide on AERP were directly measured after electrical cardioversion of AF. Glibenclamide had no significant effect on the AERP during pacing with a 400-ms interval (69±14 versus 74±15 ms).
Acute Atrial Dilatation
To determine whether atrial dilatation could be the cause of the
observed AF-induced shortening of AERP, in 12 normal goats that had
previously been in sinus rhythm, the vascular system was overfilled
with 0.5 to 1.0 L of a blood-expanding fluid. In Table 2, the effects of acute volume loading
are given. As expected, infusion of Hemaccel resulted in an increase in
atrial pressure and diameter. After infusion of 0.5 and 1.0 L of
Hemaccel, the right atrial pressure increased by 2.0±0.7
(P<.05) and 4.5±0.5 (P<.001) mm Hg. This
increase in pressure was comparable to the increase in right atrial
pressure seen during the development of chronic AF (from 2.6±1.1 to
5.8±3.3 mm Hg). The left atrial diameter increased from
45±4 mm during control to 48±4 (P<.001) and
47±2 mm, respectively. However, no shortening of AERP was found.
The average AERP measured at the right and left atria during pacing
with 300- to 350-ms interval was 163±21 and 164±21 ms during control,
171±21 and 166±19 ms after infusion of 0.5 L of Hemaccel, and 168±23
and 176±16 ms after 1.0 L (P=NS).
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ANF
In 6 goats, the level of ANF was determined from
peripheral venous blood samples collected during sinus
rhythm and after 1 to 2 days and 1 to 4 weeks of continuous AF. During
sinus rhythm, the median ANF plasma level was 42 pg/mL. After 1
to 2 days and 1 to 4 weeks of AF, the ANF plasma levels were 61
(P=NS) and 99 (P<.05) pg/mL,
respectively. To test the hypothesis that an increase in ANF plasma
levels was responsible for the shortening of AERP by AF, in 4 goats
-human 1–28 ANF was infused during 60 minutes at increasing dosages
of 0.1 to 3.1 µg/min; in Fig 5, an example is given. Although ANF infusion resulted in an increase in
plasma ANF from 165 to 550 pg/mL, no effects on AERP were seen.
The average ANF plasma levels before and after infusion (n=3) were
127±27 and 506±33 pg/mL (P<.001). AERP before and
after ANF infusion was 133±18 and 138±16 ms (P=NS).
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Long-term Effects of Rapid Atrial Pacing
In 10 goats, the effects was studied of prolonged rapid
pacing with a cycle length of 180 to 200 ms. Fig 6 gives a representative
example of the long-term effects of rapid pacing on the AERP. In this
example, the atria were paced with an interval of 180 ms associated
with 2:1 AV block. At the start of rapid pacing, the AERP was 120 ms
(top tracing). After 6 hours of maintained rapid pacing, the atrial
refractory period had shortened to 105 ms, and the early premature beat
was followed by three rapid repetitive responses (middle). After 24
hours of rapid pacing, the AERP was further shortened to 99 ms, and the
early premature stimulus now induced a short run of AF (bottom). In Fig 7, an example is given of the time course
of this long-term shortening of atrial refractoriness. First, the heart
was paced during 2 days with a fixed interval of 360 ms with 1:1 AV
conduction. During this time, the goat was allowed to adapt
hemodynamically to atrial pacing. Continuous pacing
with an interval of 360 ms slightly shortened the AERP from 165 to 155
ms. When the atrial pacing rate was suddenly doubled (t=0), the AERP
immediately shortened to 135 ms (physiological rate
adaptation). However, when the high pacing rate was maintained, the
AERP continued to shorten to 110 to 115 ms during the first 1 to 2
days. This long-term shortening of the AERP showed an exponential time
course. During the first 24 hours, the shortening was most pronounced,
whereas during the second day, the shortening was clearly less. During
the period of rapid pacing, the ventricular rate was not
changed due to the occurrence of 2:1 AV block. When after 2 days of
rapid atrial pacing the pacing rate was reduced again to a cycle length
of 360 ms (1:1 AV conduction), the AERP360 was 115 ms
compared with 155 ms before the 2 days of rapid pacing. This long-term
shortening of the AERP of 40 ms was completely reversible within 1 to 2
days of slow pacing.
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) (short-term rate adaptation).
When the high pacing rate was maintained for 2 days, the AERP further
shortened to 110 to 115 ms. This long-term adaptation to a higher
pacing rate occurred while the ventricular rate remained
unchanged (2:1 AV block). When after 2 days of rapid pacing the pacing
rate was slowed again (interval, 360 ms), the AERP prolonged again to
its original value.
In Fig 8, the rate adaptation of the AERP
is given both during slow pacing (360 ms) and after 2 days of rapid
pacing (interval, 180 ms) (same experiment as represented
by Fig 7). After 2 days of rapid pacing, the AERP had shortened
markedly at all pacing rates. Especially at the slower pacing rates,
the physiological rate adaptation was inverted;
instead of getting longer, the AERP became shorter at longer pacing
intervals. This resulted in a marked shortening of the AERP during
pacing with an S1S1 interval of 400 ms from 153
to 110 ms. Due to this maladaption of the refractory period to heart
rate, after 2 days of rapid pacing, the AERPs at high and low heart
rates were now about the same. The adaptation curve with the open
symbols was measured 2 days after the atria had been paced again at a
slow rate; as can be seen, the long-term effects of rapid pacing on
AERP were reversible within 2 days.
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In Table 3, the effects are given of
prolonged rapid atrial pacing on the AERP for 10 goats. During sinus
rhythm, the AERP at a pacing interval of 400 ms was 156±15 ms and
shortened to 137±5 at a pacing interval of 200 ms. After 1 to 2 days
of slow pacing, the AERP400 and AERP200 were
134±10 and 130±9 ms, respectively. It is remarkable that compared
with sinus rhythm, prolonged overdrive pacing
(S1S1, 360 to 400 ms) already shortened the
AERP and somewhat attenuated the physiological rate
adaptation; obviously, some degree of electrical remodeling already
occurs when sinus rhythm (100/min) is replaced by "slow" overdrive
atrial pacing (150/min). One day of rapid atrial pacing clearly
shortened the AERP400 from 134±10 to 105±8 ms
(P<.001). The AERP200 had also shortened from
130±9 to 110±8 ms (P<.001). After 2 days of rapid pacing,
the refractory period no longer showed a further statistically
significant shortening. The physiological
prolongation of the AERP in response to an acute slowing in heart rate
was completely abolished after 1 to 2 days of rapid pacing. The AERP
during pacing at the maximal rate actually had become slightly longer
compared with during slow pacing (108±7 versus 105±6 ms). As can be
seen from the last columns, all changes in AERP were completely
reversible within 1 to 2 days of slow pacing.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Recently, we reported that in chronically instrumented goats, the repetitive induction of AF resulted in a progressive shortening of atrial refractoriness and development of sustained AF.1 The present study was designed to evaluate whether the ANS, atrial ischemia, acute atrial stretch, ANF, or a high rate of atrial activation itself plays a role in this process of electrical remodeling.
ANS
Changes in the neurohumoral balance are important for both
induction and perpetuation of AF. In humans, Coumel et al7
distinguished two different types of AF based on the activity of the
ANS before the occurrence of AF. Experimental studies showed that the
administration of acetylcholine or a high vagal tone shortens the
refractory period and the wavelength of the atrial impulse, thereby
facilitating the induction of atrial
arrhythmias.8,9 The effects of an increase in
sympathetic activity are less clear. Sometimes, a shortening of atrial
refractoriness is found,9–12 whereas in other cases,
refractoriness prolongs.11,12 This discrepancy might be
explained by the fact that stimulation of ß-adrenergic receptors
enhances inward currents (Na+ or
Ca2+)13 as well as outward K+
currents.14 Quadbeck et al11 and Kass et
al12 showed that norepinephrine exerted a
biphasic effect on the APD. At low concentrations (10-7
mol/L), the action potential prolonged, whereas at higher
concentrations (>5 · 10-5 mol/L), the APD
shortened again. These studies suggest that it will depend on the
relative contribution of Na+, Ca2+, and
K+ channels and on the amount of sympathetic stimulation
whether the action potential, and hence the refractory period, shortens
or lengthens.
In the present study, we measured the effects of atropine and
propranolol on atrial refractoriness before and after
electrical remodeling by AF. Atropine and propranolol had
only minor effects on the AERP, both during normal sinus rhythm and
after AF had been maintained for 1 to 3 days. In all cases, the
shortening of the AERP by AF was preserved after blockade of either
limb of the ANS (Table 1). When atropine or propranolol was
given during chronic AF, the mean AF interval remained significantly
shorter than during recent-onset fibrillation (99±5 and 98±10 versus
148±13 ms). From these data, it might be concluded that the AF-induced
shortening of the atrial refractory period is not mediated by an
increase in parasympathetic or sympathetic activity or by a higher
sensitivity for neurotransmittors. However, because the ANS was blocked
only before and after completion of electrical remodeling, it cannot be
completely excluded that the ANS plays a role in the development of
long-term shortening of atrial refractoriness.
Atrial Ischemia and Blockade of the ATP-Regulated
K+ Channels
In anesthetized dogs, White et al5 studied the
acute effects of electrically induced AF on the balance between blood
supply and energy demand. AF caused a twofold to threefold increase in
atrial blood flow and oxygen consumption, with the resulting reduction
in the atrial flow reserve making it conceivable that a further
increase in metabolic demand during AF by sympathetic
stimulation could lead to atrial ischemia. The availability of
cavitary oxygen would not prevent the occurrence of ischemia in
at least the thicker parts of the atria. It has been shown that the
shortening of the action potential by ischemia is caused by
activation of an ATP-regulated K+ channel.15 To
test the hypothesis that the AF-induced shortening of refractoriness
was caused by atrial ischemia, we administered a blocker of the
ATP-regulated channel (glibenclamide) during sustained AF. We used a
high dose of glibenclamide (10 µmol/kg) compared with
other studies (0.6 to 6.0 µmol/kg),16,17
resulting in a free plasma concentration of 1.2 ± 0.1
µmol/L (assuming 99% binding to
plasmaproteins18). This concentration is well within the
effective range of 0.1 to 1.5 µmol/L used in vitro by
other investigators.6 The administration of glibenclamide
during sustained AF prolonged the AFI only slightly, from 95±4 to
101±5 ms (P<.05). This small increase in AF interval by
glibenclamide might be explained by the observation of Smallwood et
al17 that K+ATP channels can also
be slightly activated in the absence of ischemia.
However, this observation was made in ventricular
myocardium, and it is questionable whether these results
are applicable to atrial cells. The nonsignificant increase in RR
interval from 420±80 to 477±89 ms might be explained by a direct
effect on the refractory period of the AV node19 or by an
indirect effect on the ANS through an increase in systemic blood
pressure.20 Because the mean AFI remained clearly shorter
than during recent-onset AF (101±5 ms versus 145±11 ms,
P<.001), it may be concluded that
K+ATP channels are not responsible for the
AF-induced shortening of atrial refractory period and the increase in
rate of AF occurring during the first days of AF.
Atrial Dilatation and Effects of Acute Volume Loading
Several studies have shown a positive correlation between atrial
enlargement and the incidence of AF.21–24 Petersen et
al21 compared the left atrial size, as determined by
echocardiography, in patients in sinus rhythm with
that of patients with AF of "short" duration (<3 months) and
patients who had been in AF for 
1 year. The smallest atria were found
during sinus rhythm (38±6 mm); an intermediate size was found in
patients with AF of short duration (43±5 mm); and the largest
atria were found in patients in whom AF had existed for a long time
(49±5 mm). For many years, it has been discussed whether atrial
enlargement is the cause or a consequence of AF. The high incidence of
AF in the presence of mitral stenosis and/or mitral
insufficiency strongly suggests atrial dilatation to be a cause of
AF.22,23 In the Framingham Study, the presence of rheumatic
heart disease increased the risk ratio for the development of chronic
AF to 8.3 in men and 15.3 in women.25 Other evidence that
atrial stretch may cause an increased propensity for AF was provided by
animal studies in which AF was produced by mitral insufficiency or
acute volume expansion.26–28 Several studies have shown
that an inverse relationship exists between atrial size and the success
rate of cardioversion and maintenance of sinus
rhythm.24,29
Although this body of evidence leaves little doubt that atrial
enlargement is a cause of AF, other studies indicate that it also is a
result of it. In both humans and animals, it has been shown that the
atrial pressure and/or capillary wedge pressure rises acutely during
transition from sinus rhythm to AF.5,30,31 Sanfillipo et
al32 followed a group of 15 patients with lone AF with
normal atrial dimensions and no mitral valve or left
ventricular pathology. During a follow-up period of 12 to
28 ms (average, 20.6 ms), the diameter of the left and right atria
increased 10% to 15%, whereas the right and left atrial volumes
increased by 35% and 42%, respectively. Further support for atrial
enlargement as a result of AF is given by studies showing that after
successful cardioversion, the dimensions of the atria
decreased.33 From all these studies, it thus appears that
atrial dilatation can be the cause as well as the consequence of
AF.
There is a discrepancy in the literature about the effects of (acute)
atrial dilatation on the refractory period of the atrial
myocardium. In some studies, a shortening of the AERP or
monophasic action potential was found,27,28 whereas other
investigations reported no effect or a lengthening of the refractory
period.34–36 In the present study, we measured the
effects on the AERP of infusion of 0.5 to 1.0 L of Hemaccel. The right
atrial pressure rose with 4.5±0.5 mm Hg, whereas the diameter of
the left atrium increased by 4% to 7%. The atrial refractory period
of both right and left atria did not shorten but slightly prolonged,
although this effect was not statistically significant (Table 2). The
fact that in the goat an acute increase in atrial pressure did not
shorten the AERP suggests that the observed AF-induced shortening of
the atrial refractory period was not mediated by an increase in atrial
wall stress. However, this does not exclude that prolonged atrial
stretch, during days or weeks, may have a different effect. Recently,
Le Grand et al37 studied the effects of chronic atrial
dilatation on the human atrial APD. Although no significant differences
were found in atrial refractory period between dilated and nondilated
atria, action potentials recorded from dilated atria showed a
depressed or an absent plateau phase, and at slow pacing intervals the
APD at 50% and 90% repolarization was as much as 31% and 13%
shorter, respectively. Because the rate adaptation of the APD was
attenuated in the dilated atria, at higher pacing rates, the APD was
similar in the two groups.
ANF
It is well documented that the plasma level of ANF increases in
response to atrial tachyarrhythmias.38 This
was confirmed in our study in which the plasma level of ANF increased
from 42 to 99 pg/mL after 1 to 4 weeks of AF. The
electrophysiological effects of ANF were
recently reviewed by Clemo et al.39 ANF may exert an
electrophysiological effect either directly
on cardiac ionic channels or indirectly by modifying the ANS. Le Grand
et al40 studied the effects of ANF on L-type
Ca2+ currents (ICa) and
Ca2+-independent K+ currents
(Ito1) in isolated human atrial myocytes. They
found that both currents decreased under the influence of
ANF—ICa 38% and Ito1
22%. Although the effects of ANF on the APD were not determined,
another study from the same group37 showed that in myocytes
from dilated human atria, a similar depression of
ICa and Ito1 was
associated with a marked shortening of the action potential. The in
vivo electrophysiological effects of ANF in
dogs were studied by Stambler et al.41 Infusion of a low
dosage of ANF (0.015 µg · kg-1 ·
min-1) shortened the AERP and the duration of
MAPD90, but at higher dosages (0.15 and 0.60 µg ·
kg-1 · min-1), no shortening of AERP
was found. After vagal blockade (vagotomy plus atropine), low-dose ANF
prolonged AERP and MAPD90, whereas after combined vagal and
ß-adrenergic blockade (vagotomy plus atropine plus
propranolol), low-dose ANF no longer affected AERP and
MAPD90. From this study, it was concluded that the
shortening of AERP by ANF was mediated by the ANS.
In the present study, we determined the changes in ANF during maintained AF and infused ANF during sinus rhythm. Although after 1 to 4 weeks of AF, the ANF plasma level was significantly higher than during sinus rhythm, after 1 to 2 days of AF, when the AERP was already shortened, the ANF plasma level was not yet significantly increased. In addition, infusion of an increasing dosage of ANF during sinus rhythm did not shorten the AERP. These observations do not support that the AF-induced shortening of AERP is mediated through ANF, although they do not rule out that increased levels of ANF may play a role during the development of AF-induced electrical remodeling.
High Rate of Electrical Activation
Our present data suggest that the AF-induced shortening of the
AERP is a direct effect of the rate of electrical activation of the
atrial cells. Although "slow" overdrive pacing of sinus rhythm
during 1 to 2 days already resulted in some degree of electrical
remodeling, 24 hours of rapid atrial pacing (interval, 180 to 200 ms)
caused a considerable shortening of the AERP at all heart rates. At the
same time, the physiological rate adaptation of the
refractory period became attenuated or inversed. These effects of
prolonged rapid atrial pacing are strikingly similar to the changes in
AERP resulting from repetitive induction of AF.1 In both
cases, the shortening of atrial refractoriness was accompanied by an
increase in inducibility and stability of AF. In the rapid pacing
experiments, it is unlikely that hemodynamic changes
are involved in the remodeling process because the doubling of atrial
pacing rate was associated with 2:1 AV block and thus the
ventricular rate remained the same. Recently, Morillo et
al42 studied the effects of 6 weeks of rapid atrial pacing
(400 bpm) in dogs. After 6 weeks, the AERP had shortened by 15% and
episodes of AF lasting for >15 minutes could be induced in the
majority of animals. In this study, the time course of changes was not
measured. In our study, the most marked changes in AERP occurred during
the first 24 hours. As a result of rapid pacing, the AERP shortened an
average of 1 to 2 ms/h during the first day.
Short- and Long-term Rate Adaptation of the Refractory
Period
It is already known for a long time that the refractory
period adapts to acute changes in cycle
length.43 Although the duration of the refractory period is
predominantly determined by the immediately preceding
cycle,43 later studies have shown that after a sudden
change in heart rate, it may take several hundred beats before the
refractory period attains a new stable value.44,45 Our
present study shows that the adaptation of the atrial refractory
period after a change in heart rate continues for several days. There
are some indications that such a long-term adaptation of the refractory
period also occurs in the ventricles. In dogs, Vos et al46
have shown that after 6 weeks of bradycardia produced by total AV
block, the ventricular MAPD had increased by 4% to
24%.
Which Ionic Channels Are Responsible for AF-Induced Shortening
of AERP?
It has not been known which ionic channels are involved in the
long-term shortening of atrial refractoriness. Theoretically, the
action potential can be shortened by a decrease in inward current or an
increase in outward current. A study of Le Grand et al37
showed that in isolated cells from human dilated atria in which the APD
was shortened, the Ca2+ influx was markedly depressed.
Interestingly, like in AF, in these dilated atria, the shortening of
APD was less pronounced at higher than at lower heart rates and the
physiological rate adaptation of the action
potential thus was attenuated. Alternatively, the long-term shortening
of the atrial refractory period by AF or rapid pacing might be caused
by a change in expression of K+ channels. The inversed rate
adaptation of the refractory period during electrical remodeling may
give an important clue about the ionic channels involved in this
process. The transient outward current (Ito1) is
known to be partially inactivated at higher heart rates due
to its slow recovery from inactivation.47 An increase in
the density of these channels therefore would explain the phenomenon of
reversed rate adaptation. Giles and van Ginneken47 showed
that in isolated rabbit atrial myocytes, a decrease in pacing rate from
1 to 0.25 Hz shortened the APD due to an increase in the
4-amino-pyridine–sensitive Ito1. It remains
unclear whether upregulation of the Ito1 and/or
IK+ATP or downregulation of inward
Ca2+ currents is involved in the process of electrical
remodeling by AF.
Clinical Implications
Indirect evidence suggests that AF-induced electrical remodeling
may also occur in humans. Not only does paroxysmal AF frequently
deteriorate into chronic AF, but also the success rate of electrical
and pharmacological cardioversion diminishes when AF persists for a
longer period of time.48,49 Recently, direct evidence for
AF-induced electrical remodeling was found in humans.50,51
In these studies, it was shown that already short episodes of AF or
rapid atrial pacing shortened the atrial refractory period and
attenuated or even inversed its rate adaptation. Because the AF-induced
shortening of the atrial refractoriness increases the propensity for
AF, interventions inhibiting this process of electrical remodeling
might have clinical implications for a more effective treatment of
AF.
In the present study, the electrical remodeling by AF seemed not to be mediated by changes in autonomic tone, atrial ischemia, acute stretch, or ANF. Instead, the high rate of electrical activation itself seemed to be the stimulus for electrical remodeling. We do not know the cellular mechanisms responsible for this phenomenon; however, as shown recently by Tieleman et al,52 the process of electrical remodeling was delayed by verapamil, suggesting that the high Ca2+ influx associated with the high activation rate53 serves as an intracellular stimulus.
If the AF-induced shortening of atrial refractoriness is indeed due to changes in the function of a specific ion channel, drugs might be developed that target these channels and thus exert a specific antifibrillatory action by counteracting the AF-induced electrical remodeling.
Study Limitations
A limitation of the present study is that the possible stimuli
for electrical remodeling were not studied during the development of
shortening of atrial refractoriness. Theoretically, it is possible that
factors that trigger the long-term shortening of atrial refractoriness
are no longer operative after the remodeling process has been
completed. The design of our study using autonomic blockade, ANF, or
glibenclamide was primarily directed to answer the question whether the
AF-induced electrical remodeling, once it was established, was mediated
through ischemia or neurohumoral factors. Another limitation is
that we did not follow the changes in atrial diameter and pressure
during development of chronic AF and that only the effect of acute
atrial stretch on the AERP was evaluated. Our present study thus is
far from complete; in particular, the role of specific ion channels
needs to be further explored. Unfortunately, many selective channel
blockers are toxic and cannot be used in vivo. Future experiments using
isolated tissue or single cells isolated from fibrillating
myocardium will be needed to evaluate the involvement of
the various ion channels in the AF-induced long-term changes in the
repolarization phase of the action potential.
|
Selected Abbreviations and Acronyms |
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Acknowledgments |
|---|
This study was supported by Grant 900–516-318 from the Netherlands Organization for Scientific Research (NWO). The authors would like to thank J.J. van der Heyden and coworkers from the Department of Clinical Pharmacology and Toxicology (Academic Hospital Maastricht) for determining the plasma glibenclamide levels and Dr R.G. Tieleman from the Academic Hospital Groningen for determination of the ANF plasma levels.
Received June 3, 1997; revision received August 1, 1997; accepted August 5, 1997.
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References |
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T. Yamashita, Y. Murakawa, N. Hayami, E.-i. Fukui, Y. Kasaoka, M. Inoue, and M. Omata Short-Term Effects of Rapid Pacing on mRNA Level of Voltage-Dependent K+ Channels in Rat Atrium : Electrical Remodeling in Paroxysmal Atrial Tachycardia Circulation, April 25, 2000; 101(16): 2007 - 2014. [Abstract] [Full Text] [PDF]
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