© 1997 American Heart Association, Inc.
Articles |
Outward K+ Current Densities and Kv1.5 Expression Are Reduced in Chronic Human Atrial Fibrillation
From the Departments of Cardiology (D.R. Van W.) and Cardiothoracic Surgery (P.M.M.), The Cleveland (Ohio) Clinic Foundation; the Department of Molecular Biology and Pharmacology (A.L.P., J.M.N.), Washington University School of Medicine, St Louis, Mo; and the Department of Biochemistry and Cell Biology (J.S.T.), State University of New York at Stony Brook.
Correspondence to Jeanne M. Nerbonne, PhD, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. E-mail jnerbonn{at}pharmdec.wustl.edu
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Abstract |
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Abstract Chronic atrial fibrillation is associated with a shortening of the atrial action potential duration and atrial refractory period. To test the hypothesis that these changes are mediated by changes in the density of specific atrial K+ currents, we compared the density of K+ currents in left and right atrial myocytes and the density of delayed rectifier K+ channel
-subunit proteins (Kv1.5 and Kv2.1) in left
and right atrial appendages from patients (n=28) in normal sinus rhythm
with those from patients (n=15) in chronic atrial fibrillation (AF).
Contrary to our expectations, nystatin–perforated patch
recordings of whole-cell K+ currents revealed
significant reductions in both the inactivating
(ITO) and sustained
(IKsus) outward K+ current densities
in left and right atrial myocytes isolated from patients in chronic AF,
relative to the ITO and
IKsus densities in myocytes isolated from
patients in normal sinus rhythm. Quantitative Western blot
analysis revealed that although there was no change in the
expression of the Kv2.1 protein, the expression of Kv1.5 protein was
reduced by >50% in both the left and the right atrial appendages of
AF patients. The finding that Kv1.5 expression is reduced in parallel
with the reduction in delayed rectifier K+ current density
is consistent with recent suggestions that Kv1.5 underlies the
major component of the delayed rectifier K+ current in
human atrial myocytes, the ultrarapid delayed rectifier K+
current, IKur. The unexpected finding of reduced
voltage-gated outward K+ current densities in atrial
myocytes from AF patients demonstrates the need to further examine the
details of the electrophysiological
remodeling that occurs during AF to enable more effective and safer
therapeutic strategies to be developed.
Key Words: K+ channels • atrial fibrillation • Kv1.5 • Kv2.1 • action potential duration
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Atrial fibrillation is the most common chronic arrhythmia, present in 2% to 4% of the population over the age of 60. It is responsible for considerable patient discomfort, morbidity, and mortality.1 Acute episodes of AF2 and long-term persistent AF3 are both marked by significant shortening in the effective refractory period of the atrium, shortening of the atrial action potential duration, and an increased dispersion of refractoriness. Although the clinically observed changes have been well documented and even reproduced in animal models,4 the underlying cellular changes in the atrium are still very poorly understood.
Atrial repolarization and refractoriness are parameters
determined by the balance of inward Ca2+ and outward
K+ currents. A decrease in action potential duration and
effective refractory period during AF, therefore, would be expected to
reflect (1) increased outward K+ current densities, (2)
decreased inward Ca2+ current densities, or (3) increased
outward K+ current density together with a decreased inward
Ca2+ current density. As a beginning step to distinguish
among these possibilities, the present study was undertaken to
evaluate the impact of AF on the distribution and density of human
atrial K+ currents. Several recent articles have now
reported the normal distribution of human atrial K+ current
components in a relatively comprehensive fashion, describing
ITO,5 6
IKur,7 IKr,
and IKs.8 One of the primary
K+ currents involved in atrial repolarization is
IKur. This current has recently been suggested
to correspond to the expression of the Kv1.5 subunit,7
which has been cloned by several groups from human
atrium.9 10 Therefore, we also examined Kv1.5 protein
expression levels in membranes prepared from atrial appendages obtained
from patients in NSR, as well as from patients who have been in AF
until the time of surgery. The expression of another putative delayed
rectifier K+ channel subunit, Kv2.1, was also
probed.
A combination of electrophysiological and
biochemical techniques was used to quantify the density of atrial
K+ currents and the expression of specific delayed
rectifier K+ channel subunits (Kv1.5 and Kv2.1).
Contrary to our hypothesis, the
electrophysiological experiments revealed
that voltage-gated outward K+ current densities are
significantly reduced in myocytes isolated from patients in chronic AF
compared with the current densities in myocytes isolated from
age-matched control patients in NSR. In addition, we show that the
attenuation in K+ current density in myocytes from patients
in AF is accompanied by a marked reduction in the expression of Kv1.5
but not Kv2.1 protein, consistent with the previous suggestions
that Kv1.5 underlies the sustained component7 of the
outward K+ current, IKur, in human
atrial myocytes.
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Materials and Methods |
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Patients
Atrial appendages were obtained as surgical specimens from patients undergoing cardiac bypass or cardiac transplantation surgery by following procedures approved by the Institutional Review Board. Left and right atrial appendages were obtained from 15 patients in chronic AF (>1 month at the time of surgery) undergoing mitral valve repair and/or the Maze procedure.11 The AF population included 9 men and 6 women (mean age, 56±3 years) (Table
). Atrial appendages from two additional male
patients (ages 40 and 61 years) who had experienced frequent episodes
of PAF but were in NSR at the time of coronary bypass graft
surgery were also included in the electrophysiological study.
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Control data were obtained from left and right atrial appendages obtained from 28 patients in NSR at the time of surgery (18 males, 10 females; mean age, 57±2 years). This population included 17 patients undergoing routine cardiac bypass graft surgery, 6 transplant recipients (all with DCM), and 5 donors with nonfailing hearts with normal left ventricular function that were not used for transplantation because of the presence of underlying coronary artery disease or right ventricular contusions. All of the control patients were in NSR at the time of surgery. None of the bypass patients or nonfailing heart donors were on class III antiarrhythmic medications at the time of surgery; two of the transplant recipients were receiving amiodarone at the time of transplant. None of the control patients had a documented history of AF. The surgeries were performed between April 1995 and January 1997.
Atrial Myocyte Isolation Protocol
For both patient groups, atrial appendages were collected in
either blood or saline and brought to the laboratory within 5
minutes of surgical excision. The tissue was rinsed in a dissection
buffer containing (mmol/L) NaCl 140, KCl 5.4, MgCl2 1.2,
HEPES 5, glucose 5, and BDM 30, pH 7.0. The tissue was cut into small
chunks (<1 mm3) with scissors. Tissue chunks were
transferred to a 25-mL Erlenmeyer flask containing 10 mL of a
Ca2+-free buffer with a composition similar to that of the
dissection buffer, but lacking the BDM. The flask was placed in a water
bath (30°C to 32°C) mounted over a magnetic stirrer. The minced
tissue was washed three times for 4 minutes with the
Ca2+-free buffer, followed by 10 mL of dissection buffer
supplemented with 0.2% BSA, collagenase (Worthington type
II [144 U/mg], 1 mg/mL), and protease (Sigma type XXIV, 0.4 mg/mL).
After 45 minutes of exposure to enzymes, the supernatant was aspirated
from the tissue and discarded. Fresh collagenase solution
in dissection buffer (0.75 mg/mL, without protease) was added for an
additional 10 minutes. The tissue was then triturated, and the chunks
were allowed to settle. The digestion buffer was aspirated with a
transfer pipette and centrifuged for 1 minute at 300 rpm (
18
g). The resulting supernatant was then discarded, and the myocyte
pellet was resuspended in an incubation buffer containing (mmol/L) NaCl
118, KCl 4.8, MgCl2 1.2, CaCl2 0.5,
KH2PO4 1.2, glutamine 0.68, glucose 11,
pyruvate 5, and BDM 10, along with 1 µmol/L insulin, pH 7.2, and
1% BSA. The undigested tissue was placed in a fresh aliquot of
collagenase solution for further digestion. This procedure
was repeated three to five times, until the yield of viable myocytes
began to decrease. After the final collection, the pooled myocytes were
again centrifuged to remove residual
collagenase/protease and resuspended in fresh incubation
buffer. The myocytes were kept in a open plastic beaker under a 100%
O2 hood, at room temperature, until used, within 8 hours of
isolation. Yields from this procedure were in the range of 10% to 30%
for Ca2+-tolerant myocytes. Only well-striated, bleb-free,
rod-shaped myocytes were used in the
electrophysiological studies.
Perforated-Patch Whole-Cell Voltage- and Current-Clamp
Recordings
The nystatin–perforated patch technique13 was used
to avoid dialysis of cytosolic components and concomitant changes in
ionic currents. Sylgard (Dow-Corning) coated low-resistance electrodes
(2 to 4 M
, Corning 8161 glass; outer diameter, 1.65 mm; World
Precision Instruments) were used as previously
described.14 The composition of the pipette solution was
(mmol/L) potassium methanesulfonate 100, KCl 40, K2EGTA 5,
MgCl2 2, and HEPES 10, pH 7.4. Nystatin was added to the
pipette solution at a final concentration of 100 µg/mL, from a stock
solution made fresh daily. Once nystatin was added to the buffer, the
pipette solution was sonicated (30 seconds) and used within 3
hours.
Nystatin-free pipette solution was placed in the tip of the pipette by capillary action (3 to 4 seconds), and then nystatin-containing solution was backfilled in the pipette immediately before use. Junction potentials were nulled immediately before seal formation. After seal formation, increases in the capacitative response to a -10-mV step pulse (from a -50-mV holding potential) occur as nystatin perforates the patch. Cell capacitance and access resistance were checked throughout the experiment by tuning the patch-clamp amplifier with small square-wave voltage steps.
Only recordings from cells with low stable access resistance
(<20 M) and high seal resistance (>1G) were included in the
present study. Typical access resistance values were 9 to 12 M.
Electronic series resistance compensation (40% to 80%) was used to
minimize voltage errors. With peak currents typically 
1.6 nA, voltage
errors resulting from the uncompensated series resistance were
typically in the range 3 to 11 mV and were not corrected. No
corrections were made for the negligible leak currents in these
experiments. Data acquisition was performed with pClamp 6.0 software
controlling either an Axopatch 200A or Axopatch 1C amplifier (Axon
Instruments).
All experiments were performed on cells superfused with test solutions
in a 35-mm culture dish mounted in a thermal stage controller (Bioptech
T system), maintained at a temperature of 30°C to 33°C, and
gassed with 100% O2. Solutions for whole-cell experiments
were changed via a six-port gravity flow system. To keep the myocytes
in position, the culture dishes were coated with laminin (Upstate
Biotechnology, Inc; 6 µg per well) before use. The control bath
solution contained (mmol/L) NaCl 135, KCl 5, sodium HEPES 5, sodium
acetate 3, glucose 5, MgCl2 1, and CaCl2 1, pH
7.40. Nifedipine (2 µmol/L) was added to the bath
solution to suppress voltage-gated Ca2+ currents. A holding
potential of -50 mV was used to inactivate the
voltage-dependent Na+ current.
Data analysis was performed using either the Clampfit module of pClamp or Origin (Microcal Software). Outward K+ conductances were measured as the slope of the current density-voltage relationship between the potentials of +10 to +70 mV. The current-voltage curves of both ITO and IKsus were very linear (r>.98) over this range of potentials. Current densities were determined by dividing current amplitudes by the whole-cell capacitance. ITO was evaluated as the difference between the peak outward current density and the current at the end of a 450-millisecond voltage step (IKsus). IK1 conductances were measured in the same manner, as the slope of the IK1 density-voltage plot in the voltage range of -70 to -90 mV.
Western Blotting of Human Atrial Membranes
Membrane proteins from human atrial appendages were isolated
using a previously described method, developed, and used previously to
obtain membrane proteins from rat atrial and ventricular
tissue.15 Briefly, rapidly frozen (-80°C) samples of
human atrial appendages, obtained as described above, were
homogenized at 4°C in 10 vol of TE buffer containing
10 mmol/L Tris and 1 mmol/L EDTA, pH 7.4, using a Tekmar
Tissuemizer homogenizer. All solutions contained the
following protease inhibitors (mmol/L): iodoacetamide 1,
phenanthroline 1, benzamidine 1, and pefebloc 0.5, along with 4
µg/mL aprotinin and 2 µg/mL pepstatin. After
homogenization, nuclei and debris were pelleted by
centrifugation at 1000g for 10 minutes, and
the supernatant was retained. The pellet was resuspended in TE,
homogenized, and centrifuged again at
1000g for 10 minutes. The supernatants from both low-speed
spins were pooled and centrifuged at 40 000g for 10
minutes. Pellets were resuspended in TE containing 0.6 mol/L KI and
incubated on ice for 30 minutes. After centrifuging at
40 000g for an additional 10 minutes, the resulting pellets
were twice more resuspended in TE and centrifuged at
40 000g. The resulting pellets were then solubilized in TE
containing 2% Triton X-100 on ice for 1 hour. Insoluble material was
centrifuged at 17 000g for 10 minutes. The protein
content of each of the solubilized membrane preparations was determined
using a BioRad DC protein assay kit. Solubilized membrane fractions
were aliquoted and stored at -20°C until used.
Sample aliquots containing 25 µg protein were fractionated on 10% SDS-polyacrylamide gels and transferred to Hybond-PVDF membranes (Amersham Life Sciences). The membranes were immunoblotted using anti-Kv1.5 (1:100 final dilution)16 or anti-Kv2.1 (1:250 final dilution)17 antibodies. The membranes were washed in blocking buffer (PBS containing 0.2% I-block [Tropix] and 0.1% Tween-20) for 1 hour at room temperature and then incubated overnight at 4°C in primary antibody solution prepared in PBS containing 5% normal goat serum, 0.2% Triton X-100, and 0.1% NaN3. After incubation with the primary antibody, membranes were washed twice in blocking buffer for 10 minutes and subsequently incubated for 1 hour at room temperature in alkaline phosphatase–conjugated goat anti-rabbit IgG (Tropix) diluted 1:10 000 in blocking buffer. Membranes were then washed three times (15 minutes) in blocking buffer and twice (2 minutes) in assay buffer (Tropix, containing 0.1 mol/L diethanolamine and 1 mmol/L MgCl2). Membrane-bound secondary antibodies were detected using the CSPD (Tropix) chemiluminescent alkaline phosphatase substrate and exposed to Scientific Imaging Film (Kodak). Films were scanned with a Molecular Dynamics personal densitometer and quantified with Image Quant software (Molecular Dynamics).
To facilitate comparison of samples for quantification purposes, an
internal standard (10 ng rabbit IgG) was added to each membrane protein
sample before the SDS-PAGE. Because the primary antibodies were raised
in rabbits, the secondary antibody used for the Western blot
analysis was alkaline phosphatase–conjugated goat anti-rabbit
IgG; thus, this antibody detected both the primary antibody of interest
and the rabbit IgG. The densities of the K+ channel
-subunit bands and the rabbit IgG internal standard were corrected
for background, and the ratio of the K+ channel subunit
to the IgG was calculated for each sample.
Statistical Analyses
Differences between groups were evaluated using unpaired
Student's t test. Statistical tests were deemed to be
significant for values of P<.05. All results are
presented as mean±SEM.
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Results |
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Outward K+ Currents Are Reduced in Chronic AF
In Fig 1A
, raw K+ current records
from a myocyte isolated from the right atrial appendage of a
56-year-old man in NSR are displayed. In Fig 1B, similar current
records from a myocyte isolated from a nondilated right atrial
appendage from a 59-year-old woman in chronic AF for >3 years are
presented. Although the myocytes were of similar size (104 pF
in Fig 1A, 115 pF in Fig 1B), both the inactivating
(ITO) and sustained
(IKsus) outward K+ current
amplitudes were lower in the myocyte from the patient in AF.
Interestingly, the amplitudes of IK1, evoked
during a step to -90 mV, were similar in both cells.
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Similar electrophysiological
recordings were obtained from myocytes isolated from both the
left and right atria of patients who were either in NSR at the time of
surgery (n=28 patients) or who had been in chronic AF for at least 1
month at the time of surgery (n=11 patients). Current amplitudes were
measured in individual cells, and current densities were determined (as
described in "Materials and Methods") to normalize for
differences in myocyte size. The mean±SEM current density versus
voltage relations for ITO are shown in Fig 1C
, and the mean±SEM current density versus voltage relations for the
sustained outward current measured at the end of the voltage step
(IKsus) are shown in Fig 1D. Note that both
components of the outward K+ current are reduced in
myocytes isolated from both the left and right atria of patients in
AF.
Fig 2A shows IK1 traces from four
different left atrial myocytes isolated from the appendages of patients
in NSR at the time of surgery (top) and traces from four different left
atrial myocytes isolated from the atrial appendages of patients in
chronic AF (bottom). The cumulative mean±SEM current-voltage relations
for IK1 in all myocytes are plotted in Fig 2B.
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The Table summarizes the clinical characteristics and the drug
treatments of the AF patients. All but one of the patients in AF were
simultaneously undergoing mitral valve repair surgery, and
because of the underlying valvular disease, dilation of the
left atria was obvious on visual inspection. The right atria of these
patients, however, were not significantly different from those of the
control patients. In an effort to discriminate between the effects of
dilation and fibrillation on the K+ currents, the
electrophysiological data obtained from
myocytes isolated from the left and right atrial appendages were
analyzed separately.
For each myocyte, three K+ current components were
evaluated: ITO, the Ca2+-independent
transient outward current; IKsus, the sustained
outward K+ current; and IK1, the
inward rectifier K+ current. The amplitudes of each current
component in each cell were measured and normalized to cell size
(capacitance). No significant differences in mean capacitance values
(cell size) were evident between left and right atrial myocytes
isolated from patients in NSR or in AF. There are no differences in
ITO or IKsus (Fig 3B) densities between myocytes isolated from the left
versus the right atrial appendages of patients in NSR at the time of
surgery. The densities of ITO and
IKsus were, however, significantly reduced in
left and right atrial myocytes isolated from the atrial appendages of
patients in AF (Fig 3B). In these patients, ITO
was reduced (compared with control values) by 61% in myocytes isolated
from the left atrial appendage and by 66% in myocytes isolated from
right atrial appendages. Although the density of
ITO was reduced, there were no significant
differences in the kinetics or voltage dependences of
ITO activation or steady state inactivation in
atrial myocytes isolated from patients in NSR compared with those
isolated from patients in chronic AF. As is also evident in Fig 3B, compared with control values, IKsus was reduced
by 53% in the left atrial myocytes and by 44% in the right atrial
myocytes obtained from patients in AF.
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In contrast to the marked reductions in outward K+ current
densities, there was a significant increase (106%) in
IK1 density in myocytes isolated from the left
atrial appendages of patients in chronic AF (Fig 3C). The increased
IK1 density results in a significantly more
positive holding current (at -50 mV) in the left atrial myocytes of
chronic AF patients, relative to the left atrial control myocytes
(P<.01). Mean±SEM holding currents were 0.9±0.3 pA (n=10)
and -12.7±2 pA (n=14) for left atrial AF myocytes and left control
myocytes, respectively. These observations suggest that resting
membrane potentials may be more negative in left atrial myocytes from
patients in chronic AF. No significant differences were evident,
however, in IK1 densities or holding currents in
myocytes isolated from the right atrial appendages of patients in
chronic AF compared with the control patients (see
"Discussion").
Do the Observed Changes in K+ Current Density Simply
Reflect Atrial Myocyte Hypertrophy?
Because of concerns about the impact of atrial myocyte
hypertrophy (which underlies the observed atrial dilation
noted above) on the density of atrial K+ current
components, the density of each current component was evaluated as a
function of cell size (whole-cell membrane capacitance). In Fig 4, the conductance values for ITO
(Fig 4A), IKsus (Fig 4B), and
IK1 (Fig 4C) in individual cells are plotted
versus whole-cell membrane capacitance. Although there was a trend
toward smaller ITO and
IKsus densities in larger myocytes, it is
evident that the densities of both outward K+ current
components were lower in the myocytes isolated from the atrial
appendages of patients in AF across the entire range of capacitance
values. To further evaluate the effects of hypertrophy on
the measured current densities, the data from individual cell
measurements were subdivided into three groups: 19 to 75 pF, 76 to 125
pF, and >125 pF. When myocytes are grouped in this way, the
hypertrophy associated with AF is also evident. For
example, 5 (32%) of 19 myocytes from patients in chronic AF were >125
pF, whereas only 7 (13%) of 55 myocytes from patients in NSR were in
this group. Nevertheless, and as clearly illustrated in Fig 4, these
analyses revealed that the mean reductions in
ITO (Fig 4D) and IKsus
(Fig 4E) densities were similar for myocytes in all three groups (19 to
75 pF, 76 to 125 pF, and >125 pF).
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Interestingly, for IK1, the same general trend,
ie, lower current density in larger myocytes, is evident (Fig 4C). As
shown in Fig 3C, there was an increase in mean
IK1 density in the left, but not right, atrial
myocytes of AF patients. When the current densities were
analyzed as a function of myocyte size, it became clear that
the increase in IK1 density was only significant
in the smallest group (19 to 75 pF) of atrial myocytes (Fig 4F). The
significance of this observation is not clear.
Do Changes in K+ Current Density Precede Chronic
AF?
To determine whether the changes in K+ current density
occur as a result of chronic AF or whether they might be factors
precipitating the rhythm disturbance, we also evaluated
K+ current densities in two groups of patients who were in
NSR at the time of surgery but who had cardiac disease and an increased
risk for the development of AF. Comparison of results obtained in
atrial myocytes isolated from nonfailing hearts (the nonfailing donor
hearts and normal surgical patients undergoing bypass surgery) and the
atrial myocytes isolated from 6 patients with end-stage heart failure
(DCM) who received a heart transplant but who were in NSR at the time
of transplantation revealed no significant differences in
ITO, IKsus, or
IK1 densities (Fig 5A).
K+ current densities were also examined in myocytes from
two patients who had experienced periodic episodes of PAF but were in
NSR at the time of bypass surgery. Similar to the results in Fig 5A, these experiments revealed no significant differences in
ITO, IKsus, or
IK1 densities in PAF myocytes compared with
control myocytes (Fig 5B). Taken together, these results suggest that
the changes in K+ current densities described here reflect
the effects of chronic AF (see "Discussion").
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Kv1.5 Expression Is Reduced in Chronic AF
To determine if there were corresponding reductions in the
expression of voltage-gated K+ channel -subunit
proteins, Western blot analysis was performed on membrane
proteins prepared from the left and right atrial appendages isolated
from the same patient populations used for the
electrophysiological studies. Typical
Western blots with anti-Kv1.5 and anti-Kv2.1 K+ channel
-subunit–specific antibodies are presented in Fig 6A and 6B, respectively. To facilitate comparisons among
samples and between blots, the density of the specific K+
channel -subunit bands was determined relative to an internal
standard (rabbit IgG), as described in "Materials and
Methods."
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As illustrated in Fig 6, Kv1.5 and Kv2.1 are readily detected in
membrane preparations from left and right atrial appendages of patients
in NSR. Western blots of membrane proteins isolated from the left and
right atrial appendages of two patients are illustrated in the left
panels of Fig 6. The Kv1.5 and Kv2.1 bands and the internal standard
are indicated. In the blot of right atrial membrane proteins from one
of the patients, a prominent band at 80 kD is evident. The identity
of this band is not known. These figures show that the expression
levels of both Kv1.5 (Fig 6A) and Kv2.1 (Fig 6B) are indistinguishable
in the left and right atrial appendages of patients in NSR. Similar
results were obtained in experiments completed on atrial membrane
preparations from four other patients in NSR.
Western blots with the anti-Kv2.1 antibodies revealed that Kv2.1
expression in the left and right atrial appendages of two AF patients
was not significantly different from that of control patients (Fig 6B).
Quantitative analysis of the Western blots with the
anti-Kv2.1–specific antibody in membrane preparations from the left
and right atrial appendages of four other patients in AF confirmed
these results, and mean±SEM normalized data are presented in
Fig 7. For patients in AF, the mean density of Kv2.1,
determined relative to the standard, from either the left (n=6) or the
right (n=6) atrial appendages was not significantly different from that
for the control patients (n=6).
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In contrast to the results with Kv2.1, Kv1.5 expression levels were
clearly reduced in membranes prepared from the left and right atrial
appendages of patients in AF (Fig 6A). Similar to the control hearts,
however, there is no significant difference in Kv1.5 expression between
the left and right atrial appendages from AF patients. Western blots of
membrane proteins from the atrial appendages of two AF patients are
displayed in the right panels of Fig 6A. Similar results were also
obtained in Western blots performed on atrial appendage membrane
preparations from four other AF patients. Kv1.5 densities were
determined in all samples and normalized to the internal IgG standard;
mean±SEM normalized data are presented in Fig 7. The mean
density of Kv1.5 was reduced by 57% in the left atrial appendages
(n=6) and by 51% in the right atrial appendages (n=6) of patients in
chronic AF.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Outward K+ Currents Are Reduced in Chronic AF
In the chronic model of AF developed in goats by Allessie and colleagues,4 18 it was demonstrated that induction of AF for extended periods was directly responsible for the increased duration of subsequent episodes of fibrillation. In addition, within 1 week of pacing-induced fibrillation, AF was self-sustained in 10 of 11 animals. Over this 1-week period, the action potential duration and effective refractory period were decreased, and the median activation interval (F-F) was also reduced. The observed changes in all of these parameters were statistically significant and were fully reversible upon cardioversion and removal of the external pacing stimulus. These results led the authors to suggest that rapid electrophysiological remodeling occurs in AF as a direct result of the fibrillatory process. Recent studies in patients have shown that a rapid reduction in atrial effective refractory period is also associated with the initiation of AF in humans.2
Because the reductions in refractory period and action potential duration are associated with the onset and maintenance of chronic AF, we hypothesized that outward K+ current densities would be increased in atrial myocytes isolated from patients in chronic AF compared with myocytes isolated from patients in NSR. However, the results presented here clearly demonstrate that this hypothesis is incorrect. Rather, our results demonstrate that ITO and IKsus densities are significantly reduced in myocytes isolated from both the left and right atrial appendages of patients in chronic AF.
By comparing the K+ current densities of patients at
increased risk for the development of chronic AF with normal patients,
we have attempted to determine whether the observed reduction in
K+ current density in patients with chronic AF is a result
of the disease process or a pathological change that precedes the onset
of chronic AF. As demonstrated in Fig 5, there was no significant
difference in any of the K+ current densities in myocytes
isolated from patients with either DCM or PAF relative to myocytes
isolated from control patients. Importantly, from a clinical
perspective, both groups are at a significant risk for the development
of chronic AF. Thus, our results strongly suggest that it is the
chronic AF, per se, that causes the reduction in outward K+
current densities.
Effects of AF on Atrial K+ Currents Are Not Due to
Atrial Dilation or Hypertrophy
In the AF patient population studied here, substantial left atrial
dilation was present in nearly all of the AF patients (Table),
whereas there was no significant right atrial enlargement in most of
these patients. Le Grand et al19 demonstrated that outward
K+ current densities were reduced in myocytes isolated from
dilated (but not necessarily fibrillating) atria. In the present
study, it is evident (Fig 4) that an increase in atrial myocyte size
(capacitance) is correlated with a decreased density of all
K+ current (ITO,
IKsus, and IK1)
components examined. However, we note that ITO
and IKsus densities were reduced to a similar
degree in myocytes isolated from both the dilated left and normal-sized
right atrial appendages. In addition, significant reductions in
ITO and IKsus densities
were evident in all AF myocytes, regardless of cell size (Fig 4). Taken
together, these results suggest that significant reductions in
ITO and IKsus are a
direct result of chronic AF, per se, and are not simply the result of
atrial dilation and/or increase in myocyte size. Thus, it seems
apparent that chronic AF, in the absence of visually or
echocardiographically evident atrial dilation, is
associated with a reduction in outward K+ current density
similar to or greater than that caused by atrial dilation alone.
Interestingly, the reduction in IK1 density with increased myocyte size (capacitance) appears to be attenuated in left atrial myocytes isolated from patients in chronic AF. On average, IK1 density was 106% greater in left atrial myocytes from fibrillating atria (P<.01), whereas there was no significant difference in IK1 density in myocytes isolated from the right atrial appendages of patients in AF compared with those isolated from patients in NSR. An increased IK1 density may result in more negative resting potentials and earlier repolarization in the left atrial myocytes of chronic AF patients. To better understand the significance of this observation, further experiments aimed at determining and comparing resting membrane potentials and Ba2+-sensitive IK1 current densities in atrial myocytes isolated from both normal and chronic AF patients are warranted.
AF Is Associated With a Reduced Expression of Kv1.5, But Not Kv2.1,
Subunits
Western blot analysis of Kv2.1 -subunit
expression in atrial appendages from control patients in NSR and from
patients in chronic AF revealed that there was no significant
difference in the expression of Kv2.1 between these two patient groups.
This observation suggests that the observed reduction in
IKsus is not due to a loss of K+ channels
containing Kv2.1 subunits. The simplest interpretation of these
results is that Kv2.1 subunits may not contribute importantly to
the outward K+ currents in isolated human atrial myocytes.
In support of this hypothesis, we have found that very little
tetraethylammonium-sensitive current is
apparent in human atrial myocytes (authors' unpublished observation,
1996). The currents produced by heterologous expression of Kv2.1,
however, are tetraethylammonium
sensitive.20
It has been shown that IKur is a primary component of the human atrial delayed rectifier K+ current,21 and it has been suggested that Kv1.5 underlies this current.7 Consistent with the latter hypothesis, recent immunohistochemical studies have also demonstrated Kv1.5 protein expression in human atrium.10 Previous studies in other preparations have also shown that the expression of Kv1.5 can be modulated by a variety of influences, including glucocorticoids,22 thyrotropin-releasing hormone,16 and, intriguingly, membrane depolarization.23 Elevated extracellular K+ (50 mmol/L), for example, specifically suppressed Kv1.5 (but not Kv1.4 or Kv2.1) expression in cultured GH3 cells.23 These results were interpreted as suggesting that variations in membrane potential (or any changes in electrical activity) can regulate Kv1.5 expression.23
The results presented here demonstrate that Kv1.5 expression is
also reduced in the atria of patients in AF, by 57% and 51% in the
left and right atrial appendages, respectively. Interestingly, these
values closely parallel the reductions in IKsus
of 53% and 44% in the myocytes isolated from the left and right
atrial appendages, respectively, of patients in AF. Thus, the decrement
in IKsus closely paralleled the reduction of
Kv1.5 expression. This close correlation between the reduction in
delayed rectifier K+ current density and the reduction in
Kv1.5 expression supports the hypothesis that the Kv1.5 subunit
contributes importantly to the delayed rectifier K+ current
in human atria.7
The activation interval (FF interval, or the interval between subsequent activations of the atria) is substantially reduced in the fibrillating atria (typically <200 milliseconds24 versus 600 to 800 milliseconds [normal]). Thus, atrial myocytes from the fibrillating atria must be in a depolarized state for a greater fraction of the time. Indeed, monophasic action potential recordings from patients in AF frequently demonstrate incomplete repolarization.25 It seems reasonable to speculate, therefore, that the downregulation of Kv1.5 expression observed here results from the altered electrical activity of the atrium.
Effects of AF on Other K+ Currents
Even if the hypothesis that Kv1.5 underlies
IKur is correct,7 it is clear that
there are other currents that contribute to the total outward
K+ currents in human atrial myocytes.
IKr, for example, has been documented in human
atrial myocytes.26 Importantly, this current is the target
of all presently approved class III antiarrhythmic drugs.
H-erg has recently been identified as the genetic locus of
long QT227 and has been shown in heterologous expression
systems to produce currents that closely resemble
IKr,27 28 suggesting that
H-erg underlies IKr. It will be of
interest, therefore, to determine if IKr
densities and H-erg expression are also affected by AF.
Clearly, such studies will require the availability of specific
anti–H-erg antibodies.
The results presented here also revealed that the density of
ITO is significantly reduced in human atrial
myocytes isolated from patients in AF compared with age-matched control
patients in NSR (Figs 1 through 4). Recent studies have demonstrated
that Kv4.3 message levels are high in the human ventricle, leading to
the suggestion that Kv4.3 is a likely subunit contributing to
ITO in the human heart.29 Further
studies, aimed at confirming the presence of the Kv4.3 protein in human
atria and at examining the impact of AF on the expression of this
subunit, are clearly warranted. These experiments will require the
availability of specific (anti-Kv4.3) antibodies.
Implicit Role for a Reduction in Inward Ca2+
Current Density
In the studies of Le Grand et al19 on
electrophysiological changes in dilated
human atria, a greater reduction in Ca2+ current density
was detected (75%) relative to the reduction in outward K+
current density (60%). Changes in Ca2+ current density
could likely explain the shortenings in action potential duration and
effective refractory period that are observed during chronic AF.
Interestingly, Ca2+ channel blockers have been found to
prevent both the changes in effective refractory period30
and contractile dysfunction31 that accompany short
episodes of AF. This strongly suggests that Ca2+ overload
may be the proximal mechanism initiating both the changes in
Ca2+ current density and the eventual reduction in
K+ current density. Intriguingly, although we have shown
that there was no difference in K+ current density between
our control atrial myocytes isolated from nonfailing hearts and those
isolated from the explanted hearts of transplant recipients in NSR with
DCM, Ouadid et al32 demonstrated that atrial myocytes from
transplant recipients had significantly lower peak Ca2+
current densities (2±1 pA/pF) than did myocytes isolated from a
control population of bypass patients (12±4 pA/pF). Because patients
in heart failure have an increased incidence of AF, the present
study supports the hypothesis that a reduction in Ca2+
current density may be involved in the initiation and/or
maintenance of chronic AF. Clearly, studies focused on
examining human atrial myocyte Ca2+ current densities and
Ca2+ channel expression in patients with chronic AF and in
patients predisposed to develop AF would be of great interest.
Summary
AF is a complex multifaceted disorder. Although sometimes
tolerated for long periods, AF causes substantial discomfort and
significantly increases the risk of thromboembolic events. Although AF
can be induced briefly even in normal patients, there are clear
decreases in refractory period with sustained episodes of
AF.2 These long-term changes in refractory period are
likely to reflect the fibrillation-induced changes in the expression of
atrial ion channels. The present study has shown that chronic AF is
associated with a decreased outward K+ current density and
a reduced expression of Kv1.5 subunits. Our results suggest that
these changes are the result, rather than the cause, of the chronic
AF.
Drugs that block K+ channels (eg, sotalol, dofetilide, ibutilide) are now commonly used to treat patients in AF. Clinical studies have shown that these drugs are most effective in treating patients with recent onset AF (days to weeks). The present study suggests that this loss of efficacy may in part be explained by the overall reduction in outward K+ current, since an incremental suppression of a small repolarizing current may be less effective than when normal densities of repolarizing currents are present. Further studies aimed at identifying the components of the outward atrial K+ current that are reduced and the specific K+ channel subunits that are modulated by the presence of AF are also clearly warranted. Once this information is available, it may be possible to develop new therapeutic strategies for the treatment of AF that have fewer side effects than currently available therapies.
|
Selected Abbreviations and Acronyms |
|---|
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|
Acknowledgments |
|---|
This study was supported by grants from Procter and Gamble Pharmaceuticals (Dr Van Wagoner), the National Institutes of Health (Dr Nerbonne), and the Monsanto/Searle/Washington University Biomedical Research Program (Dr Nerbonne). This work was done during the tenure of an Established Investigatorship from the American Heart Association (Dr Trimmer). Thanks are extended to Peggy Kirian and Michelle Lamorgese for expert technical assistance. We gratefully acknowledge the efforts of Dr Robert W. Stewart and Dr Christine Moravec for coordinating the Research Transplant Team, as well as the assistance of Dr Delos Cosgrove, for providing generous access to surgical tissue.
Received June 21, 1996; accepted March 21, 1997.
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References |
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M. Duytschaever, Y. Blaauw, and M. Allessie Consequences of atrial electrical remodeling for the anti-arrhythmic action of class IC and class III drugs Cardiovasc Res, July 1, 2005; 67(1): 69 - 76. [Abstract] [Full Text] [PDF]
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 P. Ellinghaus, R. J. Scheubel, D. Dobrev, U. Ravens, J. Holtz, J. Huetter, U. Nielsch, and H. Morawietz Comparing the global mRNA expression profile of human atrial and ventricular myocardium with high-density oligonucleotide arrays J. Thorac. Cardiovasc. Surg., June 1, 2005; 129(6): 1383 - 1390. [Abstract] [Full Text] [PDF]
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H. Zhang, C. J. Garratt, J. Zhu, and A. V. Holden Role of up-regulation of IK1 in action potential shortening associated with atrial fibrillation in humans Cardiovasc Res, June 1, 2005; 66(3): 493 - 502. [Abstract] [Full Text] [PDF]
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G. F. Tomaselli Ventricularization of Atrial Gene Expression in the Fibrillating Heart? Circ. Res., May 13, 2005; 96(9): 923 - 924. [Full Text] [PDF]
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E. Deroubaix, T. Folliguet, C. Rucker-Martin, S. Dinanian, C. Boixel, P. Validire, P. Daniel, A. Capderou, and S. N. Hatem Moderate and chronic hemodynamic overload of sheep atria induces reversible cellular electrophysiologic abnormalities and atrial vulnerability J. Am. Coll. Cardiol., November 2, 2004; 44(9): 1918 - 1926. [Abstract] [Full Text] [PDF]
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E. Wettwer, O. Hala, T. Christ, J. F. Heubach, D. Dobrev, M. Knaut, A. Varro, and U. Ravens Role of IKur in Controlling Action Potential Shape and Contractility in the Human Atrium: Influence of Chronic Atrial Fibrillation Circulation, October 19, 2004; 110(16): 2299 - 2306. [Abstract] [Full Text] [PDF]
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Y. Blaauw, H. Gogelein, R.G. Tieleman, A. van Hunnik, U. Schotten, and M.A. Allessie "Early" Class III Drugs for the Treatment of Atrial Fibrillation: Efficacy and Atrial Selectivity of AVE0118 in Remodeled Atria of the Goat Circulation, September 28, 2004; 110(13): 1717 - 1724. [Abstract] [Full Text] [PDF]
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T.-J. Cha, J. R. Ehrlich, L. Zhang, and S. Nattel Atrial Ionic Remodeling Induced by Atrial Tachycardia in the Presence of Congestive Heart Failure Circulation, September 21, 2004; 110(12): 1520 - 1526. [Abstract] [Full Text] [PDF]
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L. Hove-Madsen, A. Llach, A. Bayes-Genis, S. Roura, E. R. Font, A. Aris, and J. Cinca Atrial Fibrillation Is Associated With Increased Spontaneous Calcium Release From the Sarcoplasmic Reticulum in Human Atrial Myocytes Circulation, September 14, 2004; 110(11): 1358 - 1363. [Abstract] [Full Text] [PDF]
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G. Lonardo, E. Cerbai, S. Casini, G. Giunti, M. Bonacchi, F. Battaglia, B. Fiorani, P. L. Stefano, G. Sani, and A. Mugelli Atrial natriuretic peptide modulates the hyperpolarization-activated current (If) in human atrial myocytes Cardiovasc Res, August 15, 2004; 63(3): 528 - 536. [Abstract] [Full Text] [PDF]
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S. G. Birnbaum, A. W. Varga, L.-L. Yuan, A. E. Anderson, J. D. Sweatt, and L. A. Schrader Structure and Function of Kv4-Family Transient Potassium Channels Physiol Rev, July 1, 2004; 84(3): 803 - 833. [Abstract] [Full Text] [PDF]
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I. Libbus, X. Wan, and D. S. Rosenbaum Electrotonic load triggers remodeling of repolarizing current Ito in ventricle Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1901 - H1909. [Abstract] [Full Text] [PDF]
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 S. Wasson, H. K. Reddy, and M. L. Dohrmann Current Perspectives of Electrical Remodeling and Its Therapeutic Implications Journal of Cardiovascular Pharmacology and Therapeutics, April 1, 2004; 9(2): 129 - 144. [Abstract] [PDF]
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Y. Xu, D. Tuteja, Z. Zhang, D. Xu, Y. Zhang, J. Rodriguez, L. Nie, H. R. Tuxson, J. N. Young, K. A. Glatter, et al. Molecular Identification and Functional Roles of a Ca2+-activated K+ Channel in Human and Mouse Hearts J. Biol. Chem., December 5, 2003; 278(49): 49085 - 49094. [Abstract] [Full Text] [PDF]
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A. E. Lomax, C. S. Kondo, and W. R. Giles Comparison of time- and voltage-dependent K+ currents in myocytes from left and right atria of adult mice Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1837 - H1848. [Abstract] [Full Text] [PDF]
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K. J Wirth, T. Paehler, B. Rosenstein, K. Knobloch, T. Maier, J. Frenzel, J. Brendel, A. E Busch, and M. Bleich Atrial effects of the novel K+-channel-blocker AVE0118 in anesthetized pigs Cardiovasc Res, November 1, 2003; 60(2): 298 - 306. [Abstract] [Full Text] [PDF]
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D. Fedida, J. Eldstrom, J. C. Hesketh, M. Lamorgese, L. Castel, D. F. Steele, and D. R. Van Wagoner Kv1.5 Is an Important Component of Repolarizing K+ Current in Canine Atrial Myocytes Circ. Res., October 17, 2003; 93(8): 744 - 751. [Abstract] [Full Text] [PDF]
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W. Dun, P. Chandra, P. Danilo Jr., M. R. Rosen, and P. A. Boyden Chronic atrial fibrillation does not further decrease outward currents. It increases them. Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1378 - H1384. [Abstract] [Full Text] [PDF]
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A. J Workman, K. A Kane, and A. C Rankin Characterisation of the Na, K pump current in atrial cells from patients with and without chronic atrial fibrillation Cardiovasc Res, September 1, 2003; 59(3): 593 - 602. [Abstract] [Full Text] [PDF]
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C. Valenzuela Pharmacological electrical remodelling in human atria induced by chronic {beta}-blockade Cardiovasc Res, June 1, 2003; 58(3): 498 - 500. [Full Text] [PDF]
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W. Dun, T. Yagi, M. R Rosen, and P. A Boyden Calcium and potassium currents in cells from adult and aged canine right atria Cardiovasc Res, June 1, 2003; 58(3): 526 - 534. [Abstract] [Full Text] [PDF]
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R. F. Bosch, C. R. Scherer, N. Rub, S. Wohrl, K. Steinmeyer, H. Haase, A. E. Busch, L. Seipel, and V. Kuhlkamp Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces ICa,L and Ito in rapid atrial pacing in rabbits J. Am. Coll. Cardiol., March 5, 2003; 41(5): 858 - 869. [Abstract] [Full Text] [PDF]
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M. Rubart and D. P. Zipes NO Hope for Patients With Atrial Fibrillation Circulation, November 26, 2002; 106(22): 2764 - 2766. [Full Text] [PDF]
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M. Allessie, J. Ausma, and U. Schotten Electrical, contractile and structural remodeling during atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 230 - 246. [Abstract] [Full Text] [PDF]
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R. F Bosch and S. Nattel Cellular electrophysiology of atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 259 - 269. [Full Text] [PDF]
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D. Dobrev, E. Wettwer, A. Kortner, M. Knaut, S. Schuler, and U. Ravens Human inward rectifier potassium channels in chronic and postoperative atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 397 - 404. [Abstract] [Full Text] [PDF]
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V. L.J.L Thijssen, H. M.W van der Velden, E. P van Ankeren, J. Ausma, M. A Allessie, M. Borgers, G. J.J.M van Eys, and H. J Jongsma Analysis of altered gene expression during sustained atrial fibrillation in the goat Cardiovasc Res, May 1, 2002; 54(2): 427 - 437. [Abstract] [Full Text] [PDF]
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N. N Petrashevskaya, I. Bodi, M. Rubio, J. D Molkentin, and A. Schwartz Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse Cardiovasc Res, April 1, 2002; 54(1): 117 - 132. [Abstract] [Full Text] [PDF]
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 D. Godreau, R. Vranckx, and S. N. Hatem Mechanisms of Action of Antiarrhythmic Agent Bertosamil on hKv1.5 Channels and Outward Potassium Current in Human Atrial Myocytes J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 612 - 620. [Abstract] [Full Text] [PDF]
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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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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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H. Li, W. Guo, H. Xu, R. Hood, A. T. Benedict, and J. M. Nerbonne Functional expression of a GFP-tagged Kv1.5 alpha -subunit in mouse ventricle Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1955 - H1967. [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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N. Decher, O. Uyguner, C. R Scherer, B. Karaman, M. Yuksel-Apak, A. E Busch, K. Steinmeyer, and B. Wollnik hKChIP2 is a functional modifier of hKv4.3 potassium channels: Cloning and expression of a short hKChIP2 splice variant Cardiovasc Res, November 1, 2001; 52(2): 255 - 264. [Abstract] [Full Text] [PDF]
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V. L.J.L. Thijssen, J. Ausma, and M. Borgers Structural remodelling during chronic atrial fibrillation: act of programmed cell survival Cardiovasc Res, October 1, 2001; 52(1): 14 - 24. [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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 H. T. Kurata, G. S. Soon, and D. Fedida Altered State Dependence of C-Type Inactivation in the Long and Short Forms of Human Kv1.5 J. Gen. Physiol., September 1, 2001; 118(3): 315 - 332. [Abstract] [Full Text] [PDF]
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 E. BERTAGLIA, D. D'ESTE, A. ZANOCCO, F. ZERBO, and P. PASCOTTO Effects of pretreatment with verapamil on early recurrences after electrical cardioversion of persistent atrial fibrillation: a randomised study Heart, May 1, 2001; 85(5): 578 - 580. [Full Text]
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T. González, M. Longobardo, R. Caballero, E. Delpón, J. Tamargo, and C. Valenzuela Effects of Bupivacaine and a Novel Local Anesthetic, IQB-9302, on Human Cardiac K+ Channels J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 573 - 583. [Abstract] [Full Text]
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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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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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C. Pandozi, L. Bianconi, L. Calo, A. Castro, F. Lamberti, M. C. Scianaro, G. Gentilucci, and M. Santini Postcardioversion atrial electrophysiologic changes induced by oral verapamil in patients with persistent atrial fibrillation J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2234 - 2241. [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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N. Zilberberg, N. Ilan, R. Gonzalez-Colaso, and S. A.N. Goldstein Opening and Closing of KcnkO Potassium Leak Channels Is Tightly Regulated J. Gen. Physiol., November 1, 2000; 116(5): 721 - 734. [Abstract] [Full Text] [PDF]
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Y.-G. Wang, M. B. Wagner, R. Kumar, W. N. Goolsby, and R. W. Joyner Fast pacing facilitates discontinuous action potential propagation between rabbit atrial cells Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2095 - H2103. [Abstract] [Full Text] [PDF]
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L. Yue, Z. Wang, H. Rindt, and S. Nattel Molecular evidence for a role of Shaw (Kv3) potassium channel subunits in potassium currents of dog atrium J. Physiol., September 15, 2000; 527(3): 467 - 478. [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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D. Dobrev, E. Wettwer, H. M. Himmel, A. Kortner, E. Kuhlisch, S. Schuler, W. Siffert, and U. Ravens G-Protein {beta}3-Subunit 825T Allele Is Associated With Enhanced Human Atrial Inward Rectifier Potassium Currents Circulation, August 8, 2000; 102(6): 692 - 697. [Abstract] [Full Text] [PDF]
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D. Li, P. Melnyk, J. Feng, Z. Wang, K. Petrecca, A. Shrier, and S. Nattel Effects of Experimental Heart Failure on Atrial Cellular and Ionic Electrophysiology Circulation, June 6, 2000; 101(22): 2631 - 2638. [Abstract] [Full Text] [PDF]
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J. M Nerbonne Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium J. Physiol., June 1, 2000; 525(2): 285 - 298. [Abstract] [Full Text] [PDF]
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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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S. K. Doshi and B. N. Singh Reviews: Pure Class III Antiarrhythmic Drugs: Focus on Dofetilide Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 237 - 247. [PDF]
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W. Guo, H. Xu, B. London, and J. M Nerbonne Molecular basis of transient outward K+ current diversity in mouse ventricular myocytes J. Physiol., December 15, 1999; 521(3): 587 - 599. [Abstract] [Full Text] [PDF]
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S. Tessier, P. Karczewski, E.-G. Krause, Y. Pansard, C. Acar, M. Lang-Lazdunski, J.-J. Mercadier, and S. N. Hatem Regulation of the Transient Outward K+ Current by Ca2+/Calmodulin-Dependent Protein Kinases II in Human Atrial Myocytes Circ. Res., October 29, 1999; 85(9): 810 - 819. [Abstract] [Full Text] [PDF]
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H. Xu, D. M. Barry, H. Li, S. Brunet, W. Guo, and J. M. Nerbonne Attenuation of the Slow Component of Delayed Rectification, Action Potential Prolongation, and Triggered Activity in Mice Expressing a Dominant-Negative Kv2 {alpha} Subunit Circ. Res., October 1, 1999; 85(7): 623 - 633. [Abstract] [Full Text] [PDF]
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