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© 1999 American Heart Association, Inc.
Cellular Biology |
Atrial L-Type Ca2+ Currents and Human Atrial Fibrillation
From the Department of Cardiology (D.R.V.W., M.L.) and Kaufman Center for Heart Failure and Department of Cardiothoracic Surgery (P.M.M.), The Cleveland Clinic Foundation, Cleveland, Ohio; Department of Biochemistry (A.L.P., S.S.R.), Purdue University, West Lafayette, Ind; and Department of Molecular Biology and Pharmacology (J.M.N.), Washington University School of Medicine, St. Louis, Mo.
Correspondence to David R. Van Wagoner, PhD, Dept of Cardiology, FF10, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail vanwagd{at}ccf.org
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Abstract |
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Abstract—Chronic atrial fibrillation (AF) is characterized by decreased atrial contractility, shortened action potential duration, and decreased accommodation of action potential duration to changes in activation rate. Studies on experimental animal models of AF implicate a reduction in L-type Ca2+ current (ICa) density in these changes. To evaluate the effect of AF on human ICa, we compared ICa in atrial myocytes isolated from 42 patients in normal sinus rhythm at the time of cardiac surgery with that of 11 chronic AF patients. ICa was significantly reduced in the myocytes of patients with chronic AF (mean -3.35±0.5 pA/pF versus -9.13±1.0 pA/pF in the controls), with no difference between groups in the voltage dependence of activation or steady-state inactivation. Although ICa was lower in myocytes from the chronic AF patients, their response to maximal ß-adrenergic stimulation was not impaired. Postoperative AF frequently follows cardiac surgery. Half of the patients in the control group (19/38) of this study experienced postoperative AF. Whereas chronic AF is characterized by reduced atrial ICa, the patients with the greatest ICa had an increased incidence of postoperative AF, independent of patient age or diagnosis. This observation is consistent with the concept that calcium overload may be an important factor in the initiation of AF. The reduction in functional ICa density in myocytes from the atria of chronic AF patients may thus be an adaptive response to the arrhythmia-induced calcium overload.
Key Words: atrial fibrillation • postoperative atrial fibrillation • Ca2+ channel • ß-adrenergic antagonist • cardiac surgery
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Atrial fibrillation (AF) is the most common chronic arrhythmia, afflicting nearly 2 million Americans.1 In spite of a growing recognition of its prevalence and associated morbidity and mortality, the mechanisms involved in the initiation, maintenance, and termination of AF remain poorly understood. Altered action potential characteristics (decreased response to verapamil and decreased resting potential) were noted in microelectrode recordings from diseased and fibrillating atrial tissue in 1976.2 More than a decade ago, a shortening of the effective refractory period and diminished adaptation to changes in rate were demonstrated in patients vulnerable to the development of AF.3 In microelectrode recordings from atrial tissue removed from chronic AF patients, a later study demonstrated a similar loss of rate adaptation and concomitant shortening of atrial action potential duration.4 In 1995, Wijffels et al5 demonstrated that initiation of AF in electrically stimulated goat atria caused consistent and relatively rapid electrophysiological changes. This pivotal study rekindled scientific interest in identifying the mechanisms involved in the initiation of AF, as well as the mechanisms responsible for the adaptation of the atria to the high-rate rhythm.
To evaluate the cellular mechanism(s) responsible for these changes, we previously evaluated the hypothesis that an increased density of repolarizing K+ currents in the atrial myocytes of chronic AF patients could explain the reported electrophysiological changes.6 In contrast to this hypothesis, the densities of both the transient and sustained outward K+ currents were found to be significantly reduced in myocytes from chronic AF patients, combined with a decreased expression of the Kv1.5 K+ channel protein. To explain this result, we inferred that the reduction in action potential duration was most likely the result of a simultaneous greater reduction in the density of voltage-dependent L-type Ca2+ current (ICa). A reduction in ICa has been documented in the rapidly paced canine atria.7
Since the publication of our initial results, several studies have reported that the electrophysiological remodeling accompanying episodes of AF could be prevented by pretreatment with calcium channel blockers,8 9 suggesting that calcium overload was a critical factor in the electrophysiological remodeling process. Calcium overload might initiate the changes in gene expression that eventually lead to a downregulation of atrial K+ and Ca2+ current densities.
In the rapidly paced canine atria model of AF, there has been shown to be both a decrement in functional ICa and a decrease in the number of dihydropyridine binding sites.10 In recent studies on patients with AF, it has been demonstrated that both mRNA11 12 and protein12 for the L-type Ca2+ channel are reduced in patients with established AF. However, there has been no systematic evaluation of the functional L-type Ca2+ current density in patients with AF. The goal of the present study was to directly evaluate and compare the density of ICa in myocytes from patients in normal sinus rhythm with that of myocytes from chronic AF patients undergoing the Maze procedure for surgical treatment of the arrhythmia. Because of the implicit link between calcium overload and the initiation of electrophysiological remodeling, we also sought to analyze the relationship between preoperative ICa and the subsequent development of postoperative AF.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patient Population
Atrial myocytes in the present study were isolated from the atrial appendage of 3 distinct patient groups: (1) patients in normal sinus rhythm undergoing first-time coronary artery bypass graft and/or valve repair surgery (n=40); (2) nonfailing hearts from unmatched organ donors in normal sinus rhythm (n=3); and (3) chronic AF patients undergoing the Maze III surgery (n=14). The study protocol was approved by the Cleveland Clinic Foundation Institutional Review Board. Experiments were performed from January 1997 to May 1999.
Tissue from group 1 patients was excised from the tip of the right
atrial appendage at the time of bypass cannulation, placed in saline,
and taken to the laboratory. Similarly, atrial appendages from group 3
patients were excised, placed in saline, and brought to the laboratory.
Hearts from group 2 patients were perfused with cardioplegia before
removal, chilled, and returned to the laboratory (within 
1 hour of
explant). Clinical characteristics of the control patients (groups 1
and 2) are summarized in Table 1
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along with a notation about their subsequent status with respect to the
development of postoperative AF. Clinical characteristics of the
chronic AF patients are summarized in Table 2.
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Atrial Myocyte Isolation Protocol
Atrial myocytes were dissociated using the protocol previously
described,6 with one change in the composition of the
dissection buffer (DB). The DB in the present study contained
(mmol/L) sucrose 134, NaCl 35, NaHCO3 25,
Na2HPO4 16, KCl 4.75,
KH2PO4 1.2, HEPES 10, and
glucose 10 (pH 7.4) with NaOH. The myocytes were kept
oxygenated at room temperature until used, within 8 hours
of isolation. Yields were in the range of 10% to 40% for viable
calcium-tolerant myocytes. Only well-striated, rod-shaped myocytes were
used in the electrophysiological
studies.
Conventional Whole-Cell Patch-Clamp Technique
Conventional (ruptured patch) recording techniques were
used to measure whole-cell ICa. The pipette
solution contained (mmol/L) CsCl 125,
tetraethylammonium chloride (TEA-Cl) 20,
MgATP 5, creatine phosphate 3.6, EGTA 10, and HEPES 10 (pH 7.2) with
CsOH. The bath solution contained (mmol/L) TEA-Cl 157,
CaCl2 1, MgCl2 0.5, and
HEPES 10 (pH 7.4) with CsOH. The junction potential with these
solutions was 7.5 mV (calculated using Axoscope, version 1.1, Axon
Instruments) and was not corrected.
Data were acquired using a Pentium computer that controlled data acquisition hardware and software (pClamp 6.03+, Axon Instruments) connected to either Axopatch 1C or Axopatch 200 amplifiers (Axon Instruments). Currents were filtered at 2 kHz and sampled at 4 to 10 kHz. A holding potential of -50 mV was used to inactivate Na+ current. ICa was elicited with step depolarization protocols, using test potentials in the range of -40 to +30 mV. ICa densities were computed by dividing current amplitudes by the whole-cell capacitance. Peak Ca2+ current density refers to ICa density at the peak of the current-voltage (I-V) curve.
Voltage-Clamp Recordings
Myocytes were superfused with test solutions in a 35-mm
culture dish mounted in a thermal stage controller (Bioptech 
T
system), maintained at 35°C, and gassed with 100%
O2. Solutions were changed via a 6-port gravity
flow system. Patch pipettes were prepared from Corning 8161 glass
(WPI), and the shanks were covered with Sylgard. Tips were
fire-polished immediately before use to an access resistance of 2 to 3
M
, when filled with the pipette solution. After patch rupture,
series resistance values were in the range of 4 to 8 M and were
electronically compensated (30% to 80%) to minimize voltage-clamp
errors, while maintaining stable recordings. Recordings
were begun after 4 to 5 minutes of dialysis, after the
Ca2+ current amplitudes and access resistance had
stabilized. When using the above solutions, the rundown of
ICa was negligible (<5%) over the time
course of the experiments (<20 minutes).
Current-Clamp Recordings
Action potentials were recorded from a subset of the
myocytes, to clarify the functional effect of the changes in
ICa. Action potentials were recorded
using conventional whole-cell recording conditions, with a
pipette solution containing (mmol/L) KCl 140, MgATP 4, creatine
phosphate 4, sodium pyruvate 3, MgCl2 1, and
50 µmol/L EGTA (pH 7.2) with KOH. The bath solution for these
experiments contained (mmol/L) NaCl 140, sodium acetate 3, KCl 5, HEPES
5, glucose 5, MgCl2 1, and
CaCl2 2 (pH 7.4) with NaOH. Action potentials
were recorded at cycle lengths of 2, 1, 0.5, 0.4, and 0.3 seconds,
under constant flow conditions, at a temperature of 35°C. At least 12
steady-state action potentials were recorded at each cycle length.
These were averaged, and action potential amplitude and duration (50%
and 90% repolarization [APD50 and
APD90, respectively]) were measured from the
averaged traces.
Statistical Analysis
All data summaries are presented as mean±SEM.
Statistical differences were evaluated using appropriate t
tests (paired or unpaired). Differences were deemed to be significant
for values of P<0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Assessment of ICa Density
Our initial goal was to compare the ICa density of atrial myocytes from the patients in normal sinus rhythm with that of the patients in chronic AF. We measured ICa in a total of 86 myocytes isolated from the atria of 42 patients in normal sinus rhythm and 28 myocytes isolated from the atria of 11 patients (patients 1 through 11, Table 2
) in chronic AF. The age of the
patient populations was not different: the mean age of the patients in
normal sinus rhythm was 63.8±2 years, whereas the mean age of the
patients undergoing the Maze procedure was 61.4±3.5 years. The
voltage-clamp protocol is shown in Figure 1A. Figure 1 also illustrates
representative current traces from right atrial
myocytes isolated from either a patient in normal sinus rhythm (Figure 1B)
or a patient in chronic AF for 10 years (Figure 1C).
Mean I-V relations for all of the myocytes in the
present study are plotted in Figure 1D. Myocytes from the
patients in normal sinus rhythm had a significantly greater peak
ICa density (-9.13±1.0 pA/pF, n=86) than
those in chronic AF (-3.35±0.5 pA/pF, n=28, P<0.002). The
potential at which ICa was greatest was
somewhat variable (either 0 or +10 mV) from myocyte to myocyte.
However, there was no systematic difference in the voltage dependence
of activation of ICa between groups.
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To determine whether changes in the availability of
Ca2+ channels could account for the differences
in peak ICa, we analyzed the
steady-state inactivation characteristics in a series of myocytes from
both groups (Figure 2). The voltage-clamp
protocol for these experiments is shown in Figure 2A. Raw
current traces from a representative control myocyte
are shown in Figure 2B and from an AF myocyte in Figure 2C. The summary in Figure 2D shows that chronic AF,
although lowering the peak ICa density, had
no effect on the steady-state inactivation characteristics of
ICa in the human atrial myocytes studied.
Thus, the reduction in ICa is most likely
due to a decrease in the number of functionally available channels,
rather than to a modification of their voltage dependence.
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Relationship Between Myocyte Capacitance and
ICa
The mean capacitance of the AF myocytes studied was greater than
that of the control myocytes (control 67.6±2.9 pF, n=86, versus AF
90.4±8.3 pF, n=28; P<0.01). In Figure 3, peak ICa
amplitude (Figure 3A) and density (Figure 3B) for each
myocyte are plotted as a function of myocyte size (capacitance). These
plots illustrate that both the peak ICa
amplitude and density were inversely related to myocyte size. This
trend was observed in myocytes from both groups of patients.
Importantly, however, these plots demonstrate that the reduction in
ICa in the myocytes from the chronic AF
patients occurred in all myocytes, regardless of capacitance. To
emphasize this, Figure 3C plots the current density for control
and AF myocytes for small (<60 pF), medium (60 to 100 pF), and large
(>100 pF) atrial myocytes. The ICa density
was significantly lower in the myocytes isolated from the AF patients,
relative to the controls, in each capacitance range.
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Responses to ß-Adrenergic Stimulation
The adrenergic sensitivity of patients with heart failure is
reduced.13 14 To assess whether chronic AF is similarly
characterized by a diminished response to ß-adrenergic stimulation,
the response of individual myocytes to maximal ß-adrenergic
stimulation (1 µmol/L isoproterenol) was assessed in a subgroup
of myocytes from both the patients in normal sinus rhythm and those in
chronic AF. Figure 4 plots the mean±SEM
peak ICa densities for these myocytes.
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Isoproterenol significantly increased ICa in myocytes from both the control patients (-6.6±1.4 pA/pF to -16.1±2.3 pA/pF, n=15 myocytes, from 7 patients) and the chronic AF patients (-2.6±0.6 pA/pF to -8.9±2.1 pA/pF, n=11 myocytes, from 4 patients). However, the relative response to maximal ß-adrenergic stimulation (1 µmol/L isoproterenol) was greater (unpaired t test, P<0.05) in the myocytes isolated from chronic AF patients (4.3±0.7-fold increase, n=12) compared with patients in normal sinus rhythm (2.8±0.3-fold increase, n=15). This difference remained significant (unpaired t test, P<0.01) when the comparison was made by patient means (normal sinus rhythm 2.5±0.3 fold, n=7 patients, versus chronic AF 4.5±0.6 fold, n=4 patients).
Effect of Chronic AF on Action Potential Duration
Action potentials are recorded using
physiological ion concentrations in both the
pipette solution and the bath solution. Because
ICa is recorded under conditions in
which K+ currents are strongly suppressed (CsCl
in the pipette, TEA in the bath), it is not possible to quantitatively
assess ICa in the same myocytes from which
action potentials are recorded. To qualitatively evaluate the
effect of the observed changes in ICa on
the atrial action potential, action potentials were recorded from
right atrial myocytes from patients in normal sinus rhythm and from
patients in chronic AF. Figure 5A plots
representative action potentials recorded over a
range of cycle lengths from a myocyte isolated from a 26-year-old
patient in normal sinus rhythm. A clear, cycle length–dependent
variation of action potential duration is evident. To illustrate the
effect of a reduction in ICa, Figure 5B shows action potentials from the same myocyte recorded at
the same cycle lengths in the presence of 10 µmol/L
nifedipine. Figure 5C plots the action potential
duration at APD50 and
APD90. In contrast, Figure 5D and Figure 5E shows action potentials recorded from atrial myocytes
from 2 different chronic AF patients. Little cycle length–dependent
change in action potential duration was evident, except at a 300-ms
cycle length. Mean±SEM data for the APD90 and
APD50 values of 5 myocytes isolated from 5
chronic AF patients are plotted in Figure 5F. Myocytes from
chronic AF patients were characterized by shorter
APD90 values, with less variation as a function
of cycle length than the control myocyte in Figure 5A.
APD50 values were also flatter across the range
of cycle lengths tested.
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Relation of ICa to the Occurrence of
Postoperative AF
After cardiac surgery, many patients develop AF in the
postoperative recovery period (typically 2 to 5 days after surgery). To
determine whether the preoperative ICa was
correlated with the occurrence of postoperative AF, we analyzed
the control patient ICa recordings
on the basis of the occurrence of postoperative AF during the
in-hospital recovery period. Table 1 lists the clinical
characteristics of the control patients and indicates whether the
patient experienced postoperative AF. Half (19/38) of the surgical
patients experienced postoperative AF. Figure 6A shows that there was no significant
difference in either myocyte capacitance or the age between the patient
groups, separated by postoperative AF occurrence. Figure 6B
shows the mean±SEM current density–voltage relations for the patients
who experienced postoperative AF (•) versus those that did not (
).
There was no difference in the voltage dependence of
ICa between groups, but the current density
was significantly lower (P<0.01) in those patients who did
not experience postoperative AF (peak ICa
-5.96±0.6 pA/pF, n=37) versus those who did (-12.6±2.1 pA/pF,
n=35).
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Figure 6C plots the peak ICa density
values of each myocyte, with symbols indicating the presence (•) or
absence () of postoperative AF. Although there was a great deal of
overlap at low ICa densities, the myocytes
with the greatest ICa were isolated from
patients who experienced postoperative AF. To account for the fact that
different numbers of myocytes were studied per patient, we further
analyzed the data by comparing the mean
ICa densities for each patient. Figure 6D shows that analysis of the data by patient means
yielded the same result. The mean ICa of
the patients who did not experience postoperative AF (-6.12±0.9
pA/pF, n=19) was significantly lower compared with patients who did
(-10.3±1.9 pA/pF, n=19; P<0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study demonstrates that atrial myocytes isolated from chronic AF patients have a significantly lower ICa density than myocytes isolated from patients in normal sinus rhythm (Figure 2
). The mean reduction
in peak ICa (-3.35 versus -9.13 pA/pF)
was 63%. This is similar to the reduction that we previously detected
in the transient outward K+ current (60%) and
somewhat greater than the reduction in the sustained outward
K+ current (50%) in myocytes from the same
patient populations.6 Figure 2 shows that,
although the ICa density was reduced, there
was no change in the voltage dependence of activation or steady-state
inactivation of ICa in the myocytes
isolated from chronic AF patients.
We previously showed that the reduction in outward
K+ current density was present only in those
patients in whom AF was persistent.6 Patients with
paroxysmal AF or dilated cardiomyopathy had normal
outward K+ current densities. In the present
study, Figure 3 demonstrates that, although
ICa was consistently low in chronic
AF patients, there was a significant overlap with many of the patients
in normal sinus rhythm who also had low ICa
densities. Thus, whereas a low ICa density
is characteristic of myocytes from patients with chronic fibrillation,
it is possible for patients to have myocytes with low
ICa density in the absence of AF.
Our results are consistent with the observation of Le Grand et
al,15 who demonstrated a significant reduction in inward
Ca2+ and outward K+ current
densities in the myocytes of patients with dilated (but not necessarily
fibrillating) atria. The presence of very large myocytes in the AF
patient population (Figure 3A or 3B) is consistent with
the presence of atrial dilation. However, we clearly demonstrate that
the reduction in ICa density is not solely
due to a shift in myocyte size (Figure 3C). Both the
ICa amplitudes and current densities were
reduced in the chronic AF patients, regardless of myocyte size.
Most of the chronic AF patients in the present study were undergoing mitral valve repair. Mitral regurgitation increases left atrial pressure and can directly cause significant left atrial dilation, in the absence of AF. However, the changes in ICa that we detected are not solely due to atrial dilation as a result of valvular disease. Two of the chronic AF patients (8 and 10) had no underlying valvular disease. The left atria of these patients were only modestly dilated (4.9 and 4.3 cm; normal left atrial dimension is 2 to 4 cm), and the mean ICa density of these patients (-2.9 pA/pF and -3.3 pA/pF) was indistinguishable from that of those AF patients with valvular heart disease. Thus, it is likely that both atrial dilation and AF have a similar effect on atrial ICa.
Whereas heart failure is characterized by diminished adrenergic
responsiveness, the present study shows that chronic AF does not
diminish the ICa response to a maximal
ß-adrenergic stimulus. As shown in Figure 4, the response to
maximal ß-adrenergic stimulation was somewhat enhanced in the
myocytes from the chronic AF patients. Neither the mechanistic basis
for this response nor its significance is clear at this time. One might
speculate that a greater fraction of the Ca2+
channels in the atrial myocytes from the chronic AF patients may be
unavailable under basal conditions but can be recruited in the presence
of adrenergic stimulation (perhaps as a result of altered
phosphorylation status of the L-type
Ca2+ channels). In any case, this result
demonstrates that chronic AF does not result in a functional
downregulation of all membrane proteins or signal transduction
pathways.
In 1976, Hordof et al2 demonstrated that the plateau of action potentials recorded from atrial tissue of normal patients, but not those with AF, was attenuated in response to verapamil. Boutjdir et al4 demonstrated that action potentials recorded from atrial tissue isolated from patients with chronic AF had a shorter duration (APD90) and refractory period than tissue isolated from patients in normal sinus rhythm. The mechanisms responsible for these changes were not identified.
In rapidly paced canine atria, a significant reduction in the density
of ICa has been reported, similarly
resulting in an abbreviated action potential and decreased
accommodation to changes in rate.7 In that study,
superfusion of control myocytes with nifedipine (10
µmol/L) largely mimicked the changes observed after rapid atrial
pacing. We have shown that nifedipine has the same effect
on normal human atrial action potentials (Figure 5A through 5C)
and that similar reductions in action potential duration and
rate-dependent modulation of duration occur in atrial myocytes isolated
from patients with chronic AF (Figure 5D through 5F). Our action
potential recordings (Figure 5) are qualitatively
similar to those recorded by Hordof et al2 and
Boutjdir el al4 from intact, excised atrial tissue. Thus,
in combination with the finding of decreased
ICa density in the atrial myocytes from
chronic AF patients, our study supports the evolving concept that
ICa is a critical component of the normal
cycle length–dependent modulation of atrial action potential
duration.16 17
Time Course of Human Atrial Electrophysiological
Remodeling
It is now evident that AF causes
electrophysiological remodeling of the
atria. Studies have demonstrated that these changes are rapid and are
at least initially reversible.18 In addition to
electrophysiological remodeling, there is
also evidence for structural remodeling of the atria after prolonged
periods of AF.19 In humans, structural changes may be due
to both the underlying cardiac disease (eg, valvular problems,
atherosclerosis, or cardiomyopathy)
and the direct effects of the fibrillatory rhythm. Patients in the
present study had AF for a long time, with a minimum duration of 3
years (Table 2). Given the duration of AF in the patients in the
present study, no information about the time course of changes in
ICa can be determined. Studies based on
animal experiments in either fibrillating goats5 20
or rapidly paced canine atria7 suggest that significant
electrophysiological remodeling can occur
within a week of high-rate atrial activity.
Two recent biochemical studies on tissue isolated from patients with
chronic AF both show that significant downregulation of mRNA levels for
the L-type Ca2+ channel was detectable after only
6 months of persistent AF.11 21 Evidence from both an
animal model of AF10 and patients undergoing Maze
surgery12 suggests that mRNA changes result in reduced
expression of the 
1 subunit of the L-type
Ca2+ channel. Our study complements these results
and directly demonstrates that there is a significant (63%) reduction
in the density of ICa in atrial myocytes
isolated from patients with chronic AF. This decrement in
ICa is likely to contribute to the changes
in action potential morphology and to the loss of adaptation of action
potential duration as a function of activation rate that are
characteristic of recordings from chronic AF patients and from
those patients vulnerable to arrhythmia induction.
Structural Remodeling
In addition to electrophysiological
remodeling, chronic AF is also associated with structural changes in
the atria. In atrial tissue from many of the patients studied, there
was a significant accumulation of fatty deposits in the atria and a
loss of the trabeculation of the left atria. These changes
may have a significant effect on the pathways of atrial excitation and
the tendency to maintain AF. We have not yet begun to quantitatively
assess the structural remodeling, but we note that it was quite
variable from patient to patient. It could not be easily correlated
with the duration of chronic AF, the age of the patient, or the
presence of valvular regurgitation. Thus,
regardless of the time course of the
electrophysiological remodeling, it is
likely that once a patient is restored to sinus rhythm, the time
required for structural remodeling of the atria (if it is even
possible) will vary greatly and will likely be much slower than the
electrophysiological remodeling of the
individual atrial myocytes. These considerations reinforce the concept
that early intervention in terminating AF may be desirable.
Postoperative AF
AF in the postoperative period is a common complication of cardiac
surgery, occurring in 30% to 60% of all patients. Postoperative AF
increases the risk of embolic events and stroke to the patient. It also
increases the length of stay and, thus, the costs associated with being
in the hospital.22 The causes of postoperative AF are not
well understood and may be mechanistically different from nonsurgically
induced AF, reflecting, in part, the response to a variety of
intraoperative and/or postoperative factors associated with the overall
surgical trauma. In the present study, the incidence of
postoperative AF was 50%. When comparing those patients in the
present study who did and who did not experience postoperative AF,
we found that myocytes in both groups were of similar size and that the
patients who experienced postoperative AF tended to be older but were
not significantly different in age (Figure 6A). We initially
anticipated that patients with a lower ICa
would be more likely to sustain reentrant activity, owing to a
predicted shorter wavelength. On the contrary, our results revealed
(Figure 6B) a positive correlation between
ICa measured at the time of surgery and the
occurrence of postoperative AF. As demonstrated in Figure 6C, the myocytes with the greatest ICa were all
from patients who experienced postoperative AF. By averaging the mean
ICa densities for all myocytes from each
patient (Figure 6D), we reduced the possibility that sampling
bias from a few patients shifted the means artificially. This
analysis yielded the same result. In view of the significant
overlap in the Ca2+ current density data for most
patients, we suggest that the preoperative Ca2+
current density is an additional factor (but clearly not the only
factor) that modulates the propensity of the patient to develop
postoperative AF after cardiac surgery.
It has recently been demonstrated that administration of calcium
channel blockers before the initiation of AF can blunt or prevent the
electrophysiological remodeling that
accompanies AF.8 9 Calcium overload has also been
suggested to be an important factor in the initiation of
arrhythmias.23 The postoperative setting is one of
high sympathetic tone.24 As shown in Figure 4, catecholamines significantly increase calcium influx
through L-type Ca2+ channels. Thus, we speculate
that patients suffering from postoperative AF (with greatest
ICa) may be more easily subjected to atrial
calcium overload. Conversely, we speculate that patients with lower
basal ICa may have a lower risk of calcium
overload, potentially reducing their incidence of afterdepolarizations
that could trigger abnormal activity, premature atrial contractions, or
the activation of latent atrial pacemakers.25
Finally, many of the patients in the present study had been
administered beta-blocker therapy preoperatively (Table 1).
Postoperative beta-blocker therapy (which would blunt the
catecholamine effects on ICa)
has been shown to significantly reduce the incidence of postoperative
AF.26
Summary/Implications
Calcium influx via L-type Ca2+ channels
plays a crucial role in atrial excitation-contraction coupling. Atrial
mechanical function is impaired in chronic AF patients and returns
slowly (and only partially) after the Maze procedure (as assessed with
echocardiography).27 Atrial mechanical
function, as well as the amplitude of the cytosolic calcium transient,
is also impaired in a canine model of AF.28 We suggest
that the electrophysiological remodeling
that develops during chronic AF, resulting in significantly decreased
ICa, is likely to contribute to the
impairment of atrial mechanical function.
In contrast to the effects of chronic AF, some surgical patients in normal sinus rhythm with greater ICa may be predisposed to the development of postoperative AF. We suggest that calcium overload may contribute to the arrhythmogenesis in this setting, in response to the high sympathetic tone in the postoperative setting. For patients who have good cardiac function, prophylactic maintenance of these patients with beta-blocker therapy during the postoperative period would thus be logical and unlikely to present significant risk. In contrast, treatment of these patients with digoxin (for ventricular rate control after AF has appeared) seems counterintuitive, because it would further exacerbate the calcium overload of the atria. A combination of beta-blockers and/or calcium channel blockers (to slow the ventricular rate) would be a more logical treatment.
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Acknowledgments |
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This project was directly supported by grants from the NIH to Dr Van Wagoner (RO1-HL57262) and to Dr Pond (F32-HL09987). We thank Margaret Kirian and Beth Arakaki for their expert technical assistance. In addition, we gratefully acknowledge the cooperation of the surgeons in the Department of Cardiothoracic Surgery (Drs Delos Cosgrove, Marc Gillinov, Bruce Lytle, Jose Navia, and Nicholas Smedira) for providing access to the surgical tissue that made this study possible. Thanks also to Drs Patrick Tchou, Mina Chung, and Cynthia Carnes for helpful discussions.
Received March 25, 1999; accepted July 9, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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F. Yoshihara, T. Nishikimi, Y. Sasako, J. Hino, J. Kobayashi, K. Minatoya, K. Bando, Y. Kosakai, T. Horio, S.-i. Suga, et al. Plasma atrial natriuretic peptide concentration inversely correlates with left atrial collagen volume fraction in patients with atrial fibrillation: Plasma ANP as a possible biochemical marker to predict the outcome of the maze procedure J. Am. Coll. Cardiol., January 16, 2002; 39(2): 288 - 294. [Abstract] [Full Text] [PDF]
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U. Schotten, M. Greiser, D. Benke, K. Buerkel, B. Ehrenteidt, C. Stellbrink, J. F Vazquez-Jimenez, F. Schoendube, P. Hanrath, and M. Allessie Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort Cardiovasc Res, January 1, 2002; 53(1): 192 - 201. [Abstract] [Full Text] [PDF]
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D. Dobrev, E. Graf, E. Wettwer, H. M. Himmel, O. Hala, C. Doerfel, T. Christ, S. Schuler, and U. Ravens Molecular Basis of Downregulation of G-Protein-Coupled Inward Rectifying K+ Current (IK,ACh) in Chronic Human Atrial Fibrillation: Decrease in GIRK4 mRNA Correlates With Reduced IK,ACh and Muscarinic Receptor-Mediated Shortening of Action Potentials Circulation, November 20, 2001; 104(21): 2551 - 2557. [Abstract] [Full Text] [PDF]
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A. J Workman, K. A Kane, and A. C Rankin The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation Cardiovasc Res, November 1, 2001; 52(2): 226 - 235. [Abstract] [Full Text] [PDF]
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C. A. Carnes, M. K. Chung, T. Nakayama, H. Nakayama, R. S. Baliga, S. Piao, A. Kanderian, S. Pavia, R. L. Hamlin, P. M. McCarthy, et al. Ascorbate Attenuates Atrial Pacing-Induced Peroxynitrite Formation and Electrical Remodeling and Decreases the Incidence of Postoperative Atrial Fibrillation Circ. Res., September 14, 2001; 89 (6): e32 - e38. [Abstract] [Full Text] [PDF]
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L. Polontchouk, J.-A. Haefliger, B. Ebelt, T. Schaefer, D. Stuhlmann, U. Mehlhorn, F. Kuhn-Regnier, E. R. De Vivie, and S. Dhein Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria J. Am. Coll. Cardiol., September 1, 2001; 38(3): 883 - 891. [Abstract] [Full Text] [PDF]
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C. Boixel, S. Dinanian, L. Lang-Lazdunski, J.-J. Mercadier, and S. N. Hatem Characterization of effects of endothelin-1 on the L-type Ca2+ current in human atrial myocytes Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H764 - H773. [Abstract] [Full Text] [PDF]
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C Pandozi and M Santini Update on atrial remodelling owing to rate. Does atrial fibrillation always 'beget' atrial fibrillation? Eur. Heart J., April 1, 2001; 22(7): 541 - 553. [PDF]
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B. J. J. M. Brundel, I. C. Van Gelder, R. H. Henning, A. E. Tuinenburg, M. Wietses, J. G. Grandjean, A. A. M. Wilde, W. H. Van Gilst, and H. J. G. M. Crijns Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K+ channels J. Am. Coll. Cardiol., March 1, 2001; 37(3): 926 - 932. [Abstract] [Full Text] [PDF]
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H. Sun, D. Chartier, N. Leblanc, and S. Nattel Intracellular calcium changes and tachycardia-induced contractile dysfunction in canine atrial myocytes Cardiovasc Res, March 1, 2001; 49(4): 751 - 761. [Abstract] [Full Text] [PDF]
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B. J. J. M. Brundel, I. C. Van Gelder, R. H. Henning, R. G. Tieleman, A. E. Tuinenburg, M. Wietses, J. G. Grandjean, W. H. Van Gilst, and H. J. G. M. Crijns Ion Channel Remodeling Is Related to Intraoperative Atrial Effective Refractory Periods in Patients With Paroxysmal and Persistent Atrial Fibrillation Circulation, February 6, 2001; 103(5): 684 - 690. [Abstract] [Full Text] [PDF]
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U. Schotten, J. Ausma, C. Stellbrink, I. Sabatschus, M. Vogel, D. Frechen, F. Schoendube, P. Hanrath, and M. A. Allessie Cellular Mechanisms of Depressed Atrial Contractility in Patients With Chronic Atrial Fibrillation Circulation, February 6, 2001; 103(5): 691 - 698. [Abstract] [Full Text] [PDF]
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M. A. Allessie, P. A. Boyden, A. J. Camm, A. G. Kleber, M. J. Lab, M. J. Legato, M. R. Rosen, P. J. Schwartz, P. M. Spooner, D. R. Van Wagoner, et al. Pathophysiology and Prevention of Atrial Fibrillation Circulation, February 6, 2001; 103(5): 769 - 777. [Full Text] [PDF]
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F. Lombardi, A. Colombo, B. Basilico, R. Ravaglia, M. Garbin, D. Vergani, P. M. Battezzati, and C. Fiorentini Heart rate variability and early recurrence of atrial fibrillation after electrical cardioversion J. Am. Coll. Cardiol., January 1, 2001; 37(1): 157 - 162. [Abstract] [Full Text] [PDF]
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T. J. Kamp and J. W. Hell Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C Circ. Res., December 8, 2000; 87(12): 1095 - 1102. [Abstract] [Full Text] [PDF]
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 C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities Pharmacol. Rev., December 1, 2000; 52(4): 557 - 594. [Abstract] [Full Text] [PDF]
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S. Nattel and D. Li Ionic Remodeling in the Heart : Pathophysiological Significance and New Therapeutic Opportunities for Atrial Fibrillation Circ. Res., September 15, 2000; 87(6): 440 - 447. [Abstract] [Full Text] [PDF]
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 C.J. Garratt and S.P. Fynn Atrial electrical remodelling and atrial fibrillation QJM, September 1, 2000; 93(9): 563 - 565. [Full Text] [PDF]
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S. Nattel Ionic Determinants of Atrial Fibrillation and Ca2+ Channel Abnormalities : Cause, Consequence, or Innocent Bystander? Circ. Res., September 3, 1999; 85(5): 473 - 476. [Full Text] [PDF]
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C. Boixel, W. Gonzalez, L. Louedec, and S. N. Hatem Mechanisms of L-Type Ca2+ Current Downregulation in Rat Atrial Myocytes During Heart Failure Circ. Res., September 28, 2001; 89(7): 607 - 613. [Abstract] [Full Text] [PDF]
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M. K. Chung, D. O. Martin, D. Sprecher, O. Wazni, A. Kanderian, C. A. Carnes, J. A. Bauer, P. J. Tchou, M. J. Niebauer, A. Natale, et al. C-Reactive Protein Elevation in Patients With Atrial Arrhythmias: Inflammatory Mechanisms and Persistence of Atrial Fibrillation Circulation, December 11, 2001; 104(24): 2886 - 2891. [Abstract] [Full Text] [PDF]
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