Cellular Biology |
From the Department of Physiology, Loyola University Medical Center, Maywood, Ill.
Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Medical Center, 2160 South First Ave, Maywood, IL 60153. E-mail dbers{at}luc.edu\\ © 2000 American Heart Association, Inc.
| Abstract |
|---|
|
|
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[Ca2+]i (simple
exponential), and the
[Ca2+]i
threshold of 424±58 nmol/L was sufficient to trigger an AP. Blocking
Na+-Ca2+ exchange
current (INa/Ca) by removal of
[Na]o and
[Ca2+]o (or with 5
mmol/L Ni2+) reduced cDADs by >90%, for
the same
[Ca2+]i. In
contrast, blockade of Ca2+-activated
Cl current
(ICl(Ca)) with 50 µmol/L
niflumate did not significantly alter cDADs. We conclude that DADs are
almost entirely due to INa/Ca,
not ICl(Ca) or
Ca2+-activated nonselective cation current.
To trigger an AP requires 30 to 40 µmol/L cytosolic
Ca2+ or a
[Ca2+]i transient
of 424 nmol/L. Current injection, simulating
Itis with different time
courses, revealed that faster
Itis require less charge for AP
triggering. Given that spontaneous SR Ca2+
release occurs in waves, which are slower than cDADs or fast
Itis, the true
[Ca2+]i
threshold for AP activation may be
3-fold higher in normal myocytes.
This provides a safety margin against arrhythmia in normal ventricular
myocytes.
Key Words: delayed afterdepolarization sarcoplasmic reticulum transient inward current Na+-Ca2+ exchanger arrhythmia
| Introduction |
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50% of those in ischemic HF are
initiated by nonreentrant
mechanisms.1 These
can arise from abnormal ventricular
automaticity2 or
triggered activity. The latter consists of either early
afterdepolarizations (EADs) occurring in the plateau phase of the
action potential (AP) or delayed afterdepolarizations (DADs), occurring
at repolarized membrane potentials (Em). Some
EADs may be attributable to reactivation of
Ca2+ channels, which can partially recover
during long APs, especially as
[Ca2+]i
declines.3 4 5 6 DADs, the focus in the present study, are generally thought to be initiated by spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) and a Ca2+-activated transient, depolarizing inward current (Iti).7 Three candidates for Iti are Na+-Ca2+ exchange current (INa/Ca), Ca2+-activated Cl current (ICl(Ca)), and Ca2+-activated nonselective cation current (INS(Ca)).8 9 10 Although there was early evidence implicating INS(Ca) as underlying Iti,8 more recent work has not supported a major role for INS(Ca) in Iti or DADs of ventricular myocytes, favoring instead key roles for ICl(Ca) and INa/Ca.6 9 11 12 13 14 In canine ventricular myocytes, Zygmunt et al9 attributed 60% of Iti to INa/Ca and 40% to ICl(Ca). The contributions of aforementioned currents to DAD generation may differ from those during an Iti (where Em is constant), because Em changes dynamically to alter the electrochemical driving force (most notably for ICl(Ca)) during DADs. One goal of the present study was to measure the relative contribution of INS(Ca), ICl(Ca), and INa/Ca to Ca2+-activated depolarizations, leading to triggered APs.
Increasing SR Ca2+ load increases spontaneous SR Ca2+ release15 and DAD amplitude toward threshold to trigger an AP, the precursor of triggered arrhythmias.16 Although DADs are generally accepted to be Ca2+-dependent,12 17 the relationship between SR Ca2+ release and DAD amplitude has not been measured, partly because the underlying Ca2+ transients are hard to control.
In the present study, we used caffeine-induced SR
Ca2+ release to simulate DADs with different
[Ca2+]i in a much
more controlled manner and measured the resulting depolarization. These
caffeine-induced DADs (cDADs) can be initiated at various SR
Ca2+ loads (eg, by changing frequency),
allowing us to measure the
[Ca2+]i dependence
of DADs and triggered APs over a broad range of
[Ca2+]is.
Spontaneous SR Ca2+ release typically occurs
in waves,17 less
synchronized than during application of caffeine or
excitation-contraction coupling. Therefore, we injected
Iti-like current and measured
membrane depolarization (
Em). These
pseudo-Itis mimic real
Itis but are
Ca2+-independent. The resulting
Em depends on other membrane properties such
as IK1, the major background
current that stabilizes resting Em.
IK1 is reduced in
HF,18 19
where arrhythmias are common.
The goals of the present study are to measure, for the first
time, (1) the quantitative relationship between the amount of SR
Ca2+ release and the amplitude of cDADs, (2)
the amount of SR Ca2+ release (and
Em) required to reach threshold for an AP, (3)
the specific contributions of different
Ca2+-activated currents that cause cDADs,
and (4) the effect of different
Iti kinetics on
Em and AP threshold in the absence of
[Ca2+]i changes.
The results provide the first quantitative data on the basis of DADs
and triggered APs in rabbit ventricular myocytes at
37°C.
| Materials and Methods |
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Cells were loaded at 22°C with indo 1 (acetoxymethylester, 30-minute exposure, 30-minute washout). Indo 1 was excited at 365±25 nm and emitted fluorescence was measured at 405±10 and 485±10 nm. The fluorescence ratio (R=F405/F485) was translated as [Ca2+]i=Kdß(R-Rmin)/(Rmax-R),22 where ß is the ratio of maximum to minimum F485 (4.4) and Kd was 844 nmol/L.23 Rmin is R at [Ca2+]i<<Kd and Rmax is R at saturating [Ca2+]i (0.768 and 8.45 respectively; in vivo).
Whole-cell, ruptured-patch current clamp was used to measure
Em in response to caffeine and current
injection. Electrodes (borosilicate) had resistance of 2 to 20 M
when filled with (mmol/L) potassium aspartate 120, KCl 8, NaCl 7, HEPES
10, MgCl2 1, Mg-ATP 5, Li-GTP 0.3,
K5-indo 1 0.05 (included to prevent indo 1
washout), pH 7.2 adjusted with KOH. Measurements were performed at
36±1°C. Signals were recorded with an Axopatch-1B amplifier (Axon
Instruments) and pClamp (6.03) software. A Grass S44 stimulator gated
the amplifier for current injection to activate APs. After membrane
rupture, capacitance was measured in voltage-clamp
mode.21 For
Em measurements, current-clamp mode was used,
and APs were triggered by a 1- to 5-ms 2-nA current
injection.
Normal Tyrodes (NT) superfusate contained (mmol/L) NaCl
140, KCl 4, glucose 10, HEPES 5, MgCl2 2,
CaCl2 2, pH 7.4 adjusted with NaOH at 37°C.
Caffeine (10 mmol/L in NT) was applied by fast solution switching to
release SR Ca2+. The SR
Ca2+ load was varied either by AP frequency,
rest interval, or partial reloading after a preceding caffeine
application. Similar SR Ca2+ loads were
attained for comparisons in the presence and absence of 50 µmol/L
niflumate (to block ICl(Ca)), 5
mmol/L Ni2+, or 0Na/0Ca solution (replacing
Na+ with Li+ and
Ca2+ with Mg2+ in
addition to 10 mmol/L EGTA to block
INa/Ca). These agents were
applied rapidly for
2 seconds before (and during) caffeine
application.
For testing Iti effects on Em (independent of [Ca2+]i), we applied synthetic current waveforms (dual exponential), with one chosen to match measured Iti in rabbit myocytes (Iti,slow). The injected artificial Iti was varied in amplitude (and kinetics) to define a cell-dependent threshold for triggering an AP. Data are shown as mean±SE, and statistical significance was considered for values of P<0.05 (Students t test or ANOVA).
| Results |
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[Ca2+]i and a
shortening of AP duration with increasing frequency. After the last
stimulated AP, triggering current was switched off and 10 mmol/L
caffeine was applied rapidly to induce Ca2+
transients and cDADs (right). With increasing frequency, the amplitude
of the caffeine-induced Ca2+ transient
increased, consistent with the expected increase in SR
Ca2+ load. For 1- to 3-Hz stimulation, the
cDADs remained subthreshold, but Em changed as
[Ca2+]i rose
(Figure 1
|
Figure 2A
shows the mean effect of frequency on cDAD and
[Ca2+]i
(subthreshold events only). Ca2+ transients
increased progressively with frequency, and cDAD amplitude also rose
with frequency from 6.6±0.8 mV at 0.5 Hz to 14.4±1.2 mV at 3 Hz. In
contrast, there was no frequency-dependent change in diastolic
[Ca2+]i (range:
154±16 nmol/L at 0.5 Hz to 169±16 nmol/L at 2 Hz;
P=0.873, ANOVA) or resting Em
(range: -76.4±0.6 mV at 1 Hz to -77.1±1.1 mV at 3 Hz;
P=0.934, ANOVA).
|
A wider range of subthreshold
Ca2+ transients and cDADs were obtained by
varying SR Ca2+ load by frequency and/or
number of conditioning APs. Cells with four or more subthreshold
[Ca2+]i-cDAD value
pairs were fit to a simple-exponential equation
(Figure 2B
). In 20 cells, the average
[Ca2+]i causing
a doubling of
Em was 88±8 nmol/L
[Ca2+]i for
subthreshold values.
In 12 cells, APs were triggered at higher
[Ca2+]i values.
Threshold was defined as the highest
[Ca2+]i that
failed to trigger an AP (424±58 nmol/L
[Ca2+]i at
Em=12.5±1.1 mV,
Figure 2B
; peak
[Ca2+]i=608±72
nmol/L and Em=-64.7±1.2 mV). The first
[Ca2+]i to
trigger an AP exceeded the threshold by 34±10 nmol/L
[Ca2+]i. Thus, the
true threshold
[Ca2+]i may be
slightly above our threshold, but within
34
nmol/L.
Separation of Inward Currents Contributing to
the Generation of DAD
Three different
Ca2+-activated currents
(INa/Ca,
ICl(Ca),
INS(Ca)) could contribute to
DADs. Using AP trains that produced comparable caffeine-induced
[Ca2+]i, we
evaluated the effect of abrupt block of these different currents on the
amplitude of subthreshold cDADs.
Figure 3A
shows that elimination of
INa/Ca by removal of both
extracellular substrates (2 seconds in 0Na/0Ca solution) nearly
abolished cDADs. Because [Cl] was
unchanged, ICl(Ca) should be
unaffected, and the replacement of Na+ with
Li+ also ensures that
INS(Ca) is fully
functional.25 The
half-time of
[Ca2+]i decline
during caffeine exposure is dramatically slowed in 0Na/0Ca solution
(from 120 ms to 1.7 seconds in
Figure 3A
). This is consistent with
INa/Ca being responsible for
>90% of [Ca2+]i
decline in
caffeine.20
Moreover, the slower
[Ca2+]i decline
ought to enhance other Ca2+-activated
currents (including ICl(Ca)),
but none was evident. Thus, cDADs seem to depend on
INa/Ca and not
ICl(Ca) or
INS(Ca).
|
Ni2+ (5 mmol/L) is also commonly
used to inhibit INa/Ca,
although it affects Ca2+ and some other
currents (but not
INS(Ca)26 ).
Ni2+ superfusion for 2 seconds before and
during caffeine application also blocked cDADs almost completely
(Figure 3B
) for a similar
[Ca2+]i. With 5
mmol/L Ni2+, the
[Ca2+]i decline is
slowed, but to a lesser extent (
3-fold versus >10-fold for 0Na/0Ca
solution). This indicates less complete block of
INa/Ca by 5 mmol/L
Ni2+ than by 0Na/0Ca solution.
Figure 4A
shows that blockade of
ICl(Ca) by inclusion of 50
µmol/L niflumate before and during caffeine application had only a
very small depressant effect on subthreshold cDADs (whereas
[Ca2+]i induced
by caffeine was virtually identical in both cases). The
Cl reversal potential
(ECl) under our experimental conditions (and
physiologically) is about -58 mV. Therefore, increased
Cl conductance at resting
Em would lead to an inward current. However, as
depolarization proceeds toward ECl (as in a
DAD), the driving force for Cl will
decrease considerably. This and the outward rectification of
ICl(Ca) may explain why
ICl(Ca) appears to contribute
so little to the cDAD, despite the presence of this current in rabbit
ventricular myocytes at
37°C.27 28
|
ICl(Ca) is thought
to contribute to early repolarization of the ventricular AP.
Figure 4A
(inset) shows that 50 µmol/L niflumate (as used
in the present study) inhibits early repolarization seen as diminished
notch in the AP. Niflumate also increased AP duration. These data
provide an internal positive control for niflumate effects on
ICl(Ca).
Figure 4B
summarizes the effect of 0Na/0Ca,
Ni2+, and niflumate on subthreshold cDADs.
0Na/0Ca solution and Ni2+ almost completely
inhibited cDADs (by 93% and 91%, respectively) for comparable
[Ca2+]i
(bottom). On the other hand, blockade of
ICl(Ca) with niflumate did not
decrease cDAD amplitude significantly (cDAD remained 97% of control)
for matching
[Ca2+]i. We
infer that INa/Ca is almost
entirely responsible for cDADs, and by extension DADs, in rabbit
ventricular myocytes.
Figure 5
shows that when a cDAD was sufficient to trigger an
AP, the AP could be completely blocked by 0Na/0Ca solution (where
Li+ can carry Na+
channel current). However, niflumate did not prevent the triggered AP
(although it decreased early repolarization). This confirms that the
key current for SR Ca2+ releasetriggered
APs is INa/Ca, not
ICl(Ca) or
INS(Ca).
|
Membrane Response to Current Injection at
Resting Membrane Potential
To test the Ca2+-independent
effects of Iti kinetics on
membrane depolarization in a controlled manner, we injected inward
currents mimicking Ca2+-activated
Iti of different amplitudes and
kinetics. We used three scalable current injection templates (see
Figure 6A
). The slowest
(Iti,slow) resembles a measured
Iti, which is produced by a
spontaneous [Ca2+]i
wave traveling through the cell. The faster time courses
(Iti,mid;
Iti,fast) resemble the kinetics
of Itis with greater
synchronization of SR Ca2+ release (as
induced by rapid caffeine application). These
pseudo-Itis allowed us to
simulate, in a controlled manner, the depolarizing impact expected
during Ca2+ waves where
INa/Ca (or
Iti) is more spread out in time
as [Ca2+]i rises
sequentially in different cellular regions.
|
Figure 6A
(top) shows the Em response
to these three inward current waveforms (for equal current integrals).
Current amplitude was varied over a broad range until an AP was
triggered.
Figure 6B
shows the relationship between integrated injected
current, normalized to cell capacitance, and
Em. Exponential fits yielded a doubling of
Em every 0.128 C/F for
Iti,fast (n=7), whereas the
Iti,slow required 0.416 C/F to
double
Em (n=17, see
Table
).
In addition, Iti,slow required
3 times as much charge as
Iti,fast for a given
Em. The average charge necessary to trigger
an AP also increased progressively from 0.47 C/F for
Iti,fast to 1.69 C/F for
Iti,slow
(Table
).
Threshold Em was slightly, but not
significantly, more positive in the case of
Iti,slow versus
Iti,fast (-59±1 versus
-63±3 mV).
|
The integrated
Iti,mid can be converted to an
equivalent Ca2+ flux via
INa/Ca. That is, 0.89 C/F
corresponds to INa/Ca
Ca2+ extrusion of 59.6 µmol/L cytosol
(assuming a surface-to-volume ratio of 6.44 pF/pL
cytosol),29
requiring SR Ca2+ release of
64 µmol/L
cytosol (assuming 93% of released Ca2+ is
extruded by
INa/Ca20 ).
Taking cytosolic Ca2+ buffering into
account,30
[Ca2+]i would be
raised by
428 nmol/L. This is in remarkable agreement with the
[Ca2+]i
threshold for triggering an AP via cDAD, on the basis of data in
Figure 2B
(424 nmol/L).
| Discussion |
|---|
|
|
|---|
Em at resting
Em.
Mechanism Underlying DADs:
Ca2+-Activated Currents
Several Ca2+-activated
currents have been proposed to participate in
Iti and DADs, namely
INa/Ca,
ICl(Ca) and
INS(Ca).7 10 27 31
Our data clearly indicate that in rabbit ventricular myocytes at
37°C, DADs are almost entirely attributable to
INa/Ca (>90%) with <10%
attributable to ICl(Ca) and no
evidence for contribution from
INS(Ca).
Many Iti studies use
voltage clamp, where Em is held constant. This
has an inherent mechanistic bias and may not properly estimate relative
current contributions to DADs (as measured in the present study). For
example, with ECl=-58 mV under physiological
conditions, an Em change from -78 to -68 mV
during a DAD would reduce the driving force for
ICl(Ca) by 50%, leading to
overestimation of the ICl(Ca)
contribution in a voltage-clamp experiment. In contrast,
ENa/Ca is
-30 mV at rest in rabbit, but as
[Ca2+]i rises,
ENa/Ca becomes more positive (eg, +10 mV)
greatly enhancing the driving force for inward
INa/Ca, more than offsetting
the
Em-induced reduction of
INa/Ca driving
force.24 Allosteric
activation of INa/Ca by
[Ca2+]i32
could further stimulate inward
INa/Ca.
In voltage-clamped rabbit ventricular myocytes, Zygmunt and
Gibbons27 showed the
existence of a strongly outward rectifying
ICl(Ca) in the absence of
INa/Ca at 22°C. They used
step depolarizations and excitation-contraction coupling to evoke
[Ca2+]i transients.
Because of the highly synchronized local SR
Ca2+ release, this would be especially
effective in activating Ca2+-dependent
currents. Laflamme and
Becker13 confirmed a
strongly outward rectifying
ICl(Ca) even during spontaneous
SR Ca2+ release in rabbit ventricular
myocytes with no evidence of
INS(Ca) (again with
INa/Ca blocked and at 22°C).
A marked increase of ICl(Ca)
can be seen at 35°C versus
25°C.28 These
characteristics of ICl(Ca) do
support its apparent contribution to
Ito in APs
(Figure 4A
), despite its minor role (<10%) in the
generation of DADs in our experiments
(Figure 4B
). These
studies13 27 28
did not find any indication of
INS(Ca) contributing to
Iti. In contrast, Wu and
Anderson33 observed
a residual oscillatory current after blockade of both
INa/Ca and
ICl(Ca), which was sensitive to
the removal of extracellular cations. Although
INS(Ca) may exist in rabbit
myocytes, we find no evidence for its participation in DADs. Our
findings are in contrast to a study by Szigeti et
al,14 who inferred
that ICl(Ca) was the dominant
Ca2+-dependent inward current in rabbit
ventricular, atrial, and Purkinje cells. In dog ventricular myocytes,
Iti appears to be carried
almost equally by INa/Ca
(
60%) and ICl(Ca)
(
40%).9 This
could be a species difference or due to their rapid SR
Ca2+ release. The highly synchronized SR
Ca2+ release would produce higher local
[Ca2+]i, which
could better activate ICl(Ca)
(apparent Kd=150 µmol/L
[Ca2+]i).34
On the basis of hysteresis loops of
[Ca2+]i versus
INa/Ca or
ICl(Ca), Trafford et
al35 inferred a
closer physical location of
ICl(Ca) to the ryanodine
receptor than for INa/Ca in
ferret myocytes.
Relationship of
[Ca2+]i Transient
and DAD
DADs are triggered depolarizations, seen in SR
Ca2+ overload, with spontaneous SR
Ca2+ release being the underlying event. In
the present study, we used more controlled caffeine-induced SR
Ca2+ release (cDADs) and sacrificed the
normal spontaneous nature of DADs. However, this control allowed
systematic quantitative analysis of the Ca2+
dependence of depolarization over a broad
[Ca2+]i range,
which cannot be achieved by spontaneous SR
Ca2+ release. This also provides SR
Ca2+ load data that would not be available
during propagating Ca2+ waves associated
with the spontaneous Ca2+ release of
Ca2+ overload. The trade-off we make for
these big advantages is that we must separately consider the impact on
Em of spreading out the
Ca2+-induced current in time (as in slower
Ca2+ waves). The current injection
experiments in
Figure 6
address this. That is, we cannot spread the
Ca2+ transient in time (in a controlled and
measured way), but we can do this with the resulting current (as pseudo
Itis) to simulate a
Ca2+ waveinduced DADs.
INa/Ca is
approximately linear as a function of
[Ca2+]i,36
but the amount of depolarization produced is nonlinear because of
interactions with other currents (eg,
IK1,
INa) and membrane properties.
However, we focus on the integrated Em response
because depolarization is the immediate cause of triggered APs due to
SR Ca2+ release. An exponential equation
describes well this Ca2+ dependence of
Em (with a doubling of DAD for every 88
nmol/L rise in
[Ca2+]i).
The threshold of SR Ca2+ release
that raises [Ca2+]i
by 424 nmol/L, equivalent to an integrated
INa/Ca of 0.89 C/F, is
sufficient to trigger an AP with a threshold Em
of -65±1 mV. This
[Ca2+]i requires
a total SR Ca2+ release of
50 to 60
µmol/L cytosol,
50% to 70% of the SR
Ca2+ load. It is likely that at least this
amount of Ca2+ is released during a
spontaneous Ca2+ release under
Ca2+-overload
conditions.12
However, several factors may limit this from triggering an AP in a
normal cell. First, spontaneous SR Ca2+
release normally occurs as a
wave,15 37
with [Ca2+]i not
rising synchronously and consequently leading to a slower rise in
Ca2+-activated currents. Taking this into
account
3 times more
[Ca2+]i may be
required to trigger an AP under these conditions (on the basis of
Figure 6
). Second, even if all the SR
Ca2+ is released during a wave, only 15% to
20% of the SR Ca2+ load is extruded from
the cell via
INa/Ca,12 38
because the SR can reaccumulate Ca2+ after
the release channels close (unlike in our cDADs, where caffeine is
present). This may limit the integrated
INa/Ca more than peak
INa/Ca but may nonetheless
reduce the efficacy of a DAD leading to a triggered AP. Thus, the
normal ventricular myocyte may have a reasonable safety margin of 3- to
4-fold against any SR Ca2+ release being
able to trigger an AP.
An additional safety factor in the whole heart is that
neighboring cells will act as current sinks, blunting the
Em effect for a given local
INa/Ca. However, cellular
changes that cause either more SR Ca2+
release or greater local depolarization for a given
[Ca2+]i increase
propensity for triggered arrhythmias. That is, there would be greater
chance for a cell cluster that is local enough, synchronous enough, and
large enough to overcome the 3-dimensional current sink problem and
trigger a propagating arrhythmia.
Possible Arrhythmogenic Role in HF
In HF, Na-Ca2+ exchange
protein and INa/Ca can be
doubled and IK1 is reduced by
up to
50%,2 18 19 39 40 41
and may overcome the safety factor above. That is, doubling
INa/Ca will double
Iti amplitude for any given SR
Ca2+ release and reduction of
IK1 by 50% will allow a given
Iti to be more effective in
depolarizing the cell toward threshold for a triggered AP. Although SR
Ca2+ load may be low in HF, adrenergic
activity may increase Ca2+ load, allowing
spontaneous Ca2+ release. Consequently, HF
may greatly increase the propensity for DADs to trigger APs, with
4-fold less
[Ca2+]i being
sufficient to trigger an AP (as seen in computer
models).41 Because
triggered arrhythmias cause the majority of sudden cardiac death in
nonischemic HF,1 it
would be of vital interest to measure the
[Ca2+]i
dependence of
Em and the threshold in HF to
test the above-mentioned working
hypothesis.
| Acknowledgments |
|---|
This work was supported by grants from the US Public Health Service (HL-30077, HL-64724) and the Deutsche Forschungsgemeinschaft (Schl 485/2-1). The authors thank Drs S.M. Pogwizd and K.S. Ginsburg for stimulating discussions during this work.
Received June 13, 2000; revision received August 18, 2000; accepted September 5, 2000.
| References |
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H. E. D. J. ter Keurs and P. A. Boyden Calcium and Arrhythmogenesis Physiol Rev, April 1, 2007; 87(2): 457 - 506. [Abstract] [Full Text] [PDF] |
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N. Ono, H. Hayashi, A. Kawase, S.-F. Lin, H. Li, J. N. Weiss, P.-S. Chen, and H. S. Karagueuzian Spontaneous atrial fibrillation initiated by triggered activity near the pulmonary veins in aged rats subjected to glycolytic inhibition Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H639 - H648. [Abstract] [Full Text] [PDF] |
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S. Fredj, N. Lindegger, K. J. Sampson, P. Carmeliet, and R. S. Kass Altered Na+ Channels Promote Pause-Induced Spontaneous Diastolic Activity in Long QT Syndrome Type 3 Myocytes Circ. Res., November 24, 2006; 99(11): 1225 - 1232. [Abstract] [Full Text] [PDF] |
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P. Coutu, D. Chartier, and S. Nattel Comparison of Ca2+-handling properties of canine pulmonary vein and left atrial cardiomyocytes Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2290 - H2300. [Abstract] [Full Text] [PDF] |
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