© 1996 American Heart Association, Inc.
Articles |
Ionic Mechanism of Action Potential Prolongation in Ventricular Myocytes From Dogs With Pacing-Induced Heart Failure
From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Gordon F. Tomaselli, MD, 844 Ross Bldg, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. E-mail gtomasel@welchlink.welch.jhu.edu.
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Abstract |
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Abstract Membrane current abnormalities have been described in human heart failure. To determine whether similar current changes are observed in a large animal model of heart failure, we studied dogs with pacing-induced cardiomyopathy. Myocytes isolated from the midmyocardium of 13 dogs with heart failure induced by 3 to 4 weeks of rapid ventricular pacing and from 16 nonpaced control dogs did not differ in cell surface area or resting membrane potential. Nevertheless, action potential duration (APD) was significantly prolonged in myocytes isolated from failing ventricles (APD at 90% repolarization, 1097±73 milliseconds [failing hearts, n=30] versus 842±56 milliseconds [control hearts, n=25]; P<.05), and the prominent repolarizing notch in phase 1 was dramatically attenuated. Basal L-type Ca2+ current and whole-cell Na+ current did not differ in cells from failing and from control hearts, but significant differences in K+ currents were observed. The density of the inward rectifier K+ current (IK1) was reduced in cells from failing hearts at test potentials below -90 mV (at -150 mV, -19.1±2.2 pA/pF [failing hearts, n=18] versus -32.2±5.1 pA/pF [control hearts, n=15]; P<.05). The small outward current component of IK1 was also reduced in cells from failing hearts (at -60 mV, 1.7±0.2 pA/pF [failing hearts] versus 2.5±0.2 pA/pF [control hearts]; P<.05). The peak of the Ca2+-independent transient outward current (Ito) was dramatically reduced in myocytes isolated from failing hearts compared with nonfailing control hearts (at +80 mV, 7.0±0.9 pA/pF [failing hearts, n=20] versus 20.4±3.2 pA/pF [control hearts, n=15]; P<.001), while the steady state component was unchanged. There were no significant differences in Ito kinetics or single-channel conductance. A reduction in the number of functional Ito channels was demonstrated by nonstationary fluctuation analysis (0.4±0.03 channels per square micrometer [failing hearts, n=5] versus 1.2±0.1 channels per square micrometer [control hearts, n=3]; P<.001). Pharmacological reduction of Ito by 4-aminopyridine in control myocytes decreased the notch amplitude and prolonged the APD. Current clamp–release experiments in which current was injected for 8 milliseconds to reproduce the notch sufficed to shorten the APD significantly in cells from failing hearts. These data support the hypothesis that downregulation of Ito in pacing-induced heart failure is at least partially responsible for the action potential prolongation. Because the repolarization abnormalities mimic those in cells isolated from failing human ventricular myocardium, canine pacing-induced cardiomyopathy may provide insights into the development of repolarization abnormalities and the mechanisms of sudden death in patients with heart failure.
Key Words: action potential • heart failure • animal model • K+ current • transient outward current
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Sudden cardiac death, often the result of ventricular arrhythmias, accounts for up to 50% of deaths in patients with heart failure.1 Despite intensive investigation, the underlying pathogenesis of ventricular arrhythmias in heart failure is poorly understood.2 Myocardial cells and tissue isolated from failing animal and human hearts consistently reveal abnormalities in repolarization, independent of the mechanism of heart failure.3 4 5 6 7 Prolongation of the APD can predispose to dispersion of repolarization, leading to nonexcitable gap reentry.8 Long action potentials also favor the development of afterdepolarizations, which in turn can induce triggered arrhythmias.9
The membrane current abnormalities that underlie action potential prolongation in failing human myocytes have recently been described.6 Studies involving isolated myocytes from failing human hearts highlight the importance of K+ current downregulation in the action potential prolongation observed in heart failure. According to these studies, Ito is markedly reduced in cardiac myocytes isolated from patients with heart failure.6 Other studies have suggested a reduction in Ito from failing human myocytes limited to cells isolated from the subendocardium.10 Nonetheless, even this regional reduction in current density could predispose to cardiac arrhythmias.
Measurements of ionic current in human cellular studies rely on a single time point in the course of disease, usually terminal heart failure of several years' duration. The etiology of the myocardial failure, its duration, and medical treatment are varied and uncontrolled. In this regard, an animal model of heart failure characterized by malignant ventricular arrhythmias and sudden death would facilitate the investigation of the changes in the cardiac electrical properties.
The canine pacing-induced tachycardia model11 reliably reproduces the hemodynamic changes seen in human heart failure.12 13 14 15 We characterized the changes in the action potential in dogs with pacing-induced heart failure compared with nonpaced control dogs. The ionic currents underlying these changes in action potentials and the mechanism for the reduction in Ito density were investigated. In addition, we tested the idea that a reduction in Ito density suffices to produce the observed changes in action potential shape and duration.
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Canine Pacing-Induced Tachycardia Heart Failure Model
Thirteen adult mongrel dogs of either sex underwent sterile surgical preparations for hemodynamic measurements and pacemaker implantation as previously described.15 The dogs (20 to 30 kg) were sedated with sodium thiamylol, intubated, and anesthetized with 1% to 2% halothane. Oxygen saturation and expired CO2 were maintained within the physiological range throughout the procedure by continuous volume ventilation. A left lateral thoracotomy was performed, and two right ventricular free wall pacing wires were placed. A subcutaneous pocket was fashioned for the placement of a VVI pacemaker (Activitrax or Spectrax, Medtronics). A rapid pacing mode was maintained by permanently attaching a magnet to the posterior surface of the pacemaker pulse generator. Animals were allowed to recover fully from surgery for 1 to 2 days, after which pacing was initiated at 240 bpm for 3 to 4 weeks. Terminal heart failure for the purpose of this and previous studies is defined by symptoms of lethargy, loss of appetite, dyspnea, and/or ascites.12 15 Prior work from our laboratory reveals that dogs subjected to this pacing protocol consistently develop an elevated left ventricular end-diastolic pressure (>25 mm Hg), depressed dP/dtmax (<1700 mm Hg/s), and a delayed time constant of relaxation (>45 milliseconds). Hemodynamics recorded in an unselected subset of 6 of the failing dogs revealed a left ventricular end-diastolic pressure of 36±2.8 mm Hg, dP/dtmax of 1187±239 mm Hg/s, and
value of
69.7±9.4 milliseconds, consistent with severe myocardial
failure. The hearts were harvested at terminal heart failure with the
animals anesthetized as described above. The chest was opened
by a left lateral thoracotomy, and the chest cavity was flooded with
ice-cold saline. The great vessels were banded, and the
coronary arteries were perfused retrogradely with cold
cardioplegic solution containing (mmol/L) NaCl 110, KCl 16,
MgCl2 16, NaHCO3 10, and CaCl2 1,
pH 7.4, until diastolic cardiac arrest. The heart was
quickly excised and submerged in cold cardioplegic solution. The time
from tissue harvest to start of cell isolation was <15 minutes. To
obtain normal control cells, euthanasia was performed in 16 adult
mongrel dogs (20 to 30 kg) in the same manner but without prior
pacing.
Isolation of Ventricular Myocytes
Ventricular myocytes were
isolated as previously
described with minor modifications.16 The territory
perfused by the LAD from the aortic root to the apex was excised. This
myocardial segment was then perfused via the LAD at a rate of 15 mL/min
with the following solutions: 30 minutes with a nominally
Ca2+-free modified Tyrode's solution containing (mmol/L)
NaCl 138, KCl 4, MgCl2 1, glucose 10,
NaH2PO4 0.33, and HEPES 10, pH 7.3, followed by
40 minutes in the same solution with collagenase (type I,
178 U/mL, Worthington Biochemical Corp) and protease (type XIV, 0.12
mg/mL, Sigma Chemical Co). The enzyme solution (80 mL) was
recirculated. The myocardial segment was then washed for 15 minutes
with modified Tyrode's solution containing 200 µmol/L
Ca2+. All solutions were oxygenated with 100%
O2 and warmed to 37°C. To control for the previously
described transmyocardial variability of the
currents,10 17 all cells were isolated from the
central
third of the myocardial wall, excluding endocardial and epicardial
layers. At the end of perfusion, epicardial and subepicardial layers
were dissected and discarded, and small chunks of well-digested
midmyocardial tissue were taken from the area of the left
ventricular anterior free wall between the LAD and the
first diagonal branch. Ventricular cells were then
mechanically disaggregated, filtered through a nylon mesh, and stored
at room temperature in Tyrode's solution containing 2.0 mmol/L
Ca2+ until electrophysiological
study. Only Ca2+-tolerant cells with clear cross striations
and without spontaneous contraction or significant granulation (
20%
to 40% of those isolated in both control and failing hearts) were
selected for experiments.
Solutions
The experimental conditions were chosen to be
comparable to
those used in previous studies of human ventricular
myocytes.6 18 For action potential and total membrane
current recordings, the external solution contained (mmol/L)
NaCl 138, KCl 4, CaCl2 2.0, MgCl2 1, glucose
10, NaH2PO4 0.33, and HEPES 10, pH 7.3. For the
measurement of whole-cell K+ currents,
CdCl2 (0.3 mmol/L) was added to block Ca2+
currents. For the measurement of whole-cell Ca2+
currents, the external solution contained (mmol/L)
N-methyl-D-glucamine 140, CsCl 5,
CaCl2 2.0, MgCl2 0.5, glucose 10, HEPES 10, and
4-AP 5, pH 7.4. 4-AP was prepared fresh before each use.
Single-channel K+ currents were recorded in the
cell-attached configuration in a depolarizing bath solution
containing (mmol/L) KCl 140, NaCl 10, MgCl2 1, glucose 10,
HEPES 10, and EGTA 0.1, pH 7.4. The pipette solution for action
potential recordings contained (mmol/L) KCl 140, NaCl 5,
MgCl2 1, HEPES 10, EGTA 2, and Mg-ATP 4, pH 7.4. For
recording whole-cell K+ currents, the
patch-clamp electrodes contained (mmol/L) potassium glutamate 120,
KCl 10, MgCl2 2, HEPES 10, EGTA 5, Mg-ATP 2, QX 314 (ALMONE
Laboratories) 5, pH 7.2. The pipette solution used for
single-channel recording of Ito was identical
to the external solution used for action potential recordings.
For single-channel recordings of IK1,
patch-clamp electrodes contained (mmol/L) KCl 140, EDTA 0.1, and
HEPES 10, pH 7.4. For whole-cell Ca2+ current
recordings, patch-clamp electrodes contained (mmol/L) CsCl
125, TEA-Cl 20, HEPES 10, EGTA 10, and Mg-ATP 4, pH 7.3. Whole-cell
Na+ currents were recorded in symmetrical 5 mmol/L
Na+; the external solution contained (mmol/L) NaCl 5,
MgCl2 2, CsCl 5, TEA-Cl 125, and HEPES 20, pH 7.4 with
TEAOH, and the pipette solution contained (mmol/L) NaCl 5, CsF 145, and
HEPES 10, pH 7.2 with CsOH. Whole-cell Na+ currents
were recorded in symmetrical 5 mmol/L Na+; the external
solution contained (mmol/L) NaCl 5, MgCl2 2, CsCl 5, TEA-Cl
125, and HEPES 20, pH 7.4 with TEAOH, and the pipette solution
contained (mmol/L) NaCl 5, CsF 145, and HEPES 10, pH 7.2 with CsOH. All
chemicals were purchased from Sigma unless otherwise stated.
Electrophysiological
Recording Techniques
Both the whole-cell and cell-attached
configurations of
the patch-clamp technique were used.19 Myocytes were
transferred to the stage of an inverted microscope and superfused with
external solution at a rate of 1 to 2 mL/min. Action potential
recordings were performed at 37°C. All other experiments were
performed at room temperature (22°C to 23°C). Patch electrodes were
pulled from borosilicate glass and had 2- to 5-M
tip resistances for
whole-cell recordings and 12- to 15-M tip resistances
for single-channel recordings. Cell-attached patches
were formed with seal resistances of 20 to 100 G. Currents were
recorded using an Axopatch 200A patch-clamp amplifier (Axon
Instruments) interfaced with a personal computer. Voltage or current
control and data collection were performed using custom-written
software. Cell capacitance was calculated by integrating the area under
an uncompensated capacity transient elicited by a 20-mV depolarizing
test pulse from a holding potential of -80 mV. Series resistance
was then compensated as much as possible without ringing, typically
60% to 80%. Given the average series resistance of our electrodes,
the maximal uncompensated voltage error was <7 mV for the largest
currents studied here. Whole-cell currents were
low-pass–filtered at 2 kHz and digitized at 5 to 10 kHz via a
TL-1 or Digidata 1200 A/D (Axon Instruments) interface for off-line
analysis. The repetition interval was 5 seconds, unless
otherwise specified. The currents recorded for nonstationary
fluctuation analysis were filtered at 5 kHz. For
cell-attached single-channel currents, records were
filtered at 1 kHz and sampled at 5 kHz with a repetition interval of 5
seconds. Action potentials were recorded using an Axoclamp 2A
voltage-clamp amplifier and sampled at 0.2 kHz.
Data Analysis
The data were analyzed using custom-written
software. Leakage and capacity currents were subtracted from unitary
current records by fitting a smooth template, containing a sum of
exponentials, to null traces. Single-channel current amplitudes
were determined by amplitude histograms fitted by multiple gaussian
distributions (IK1) or by averaging the amplitudes of
well-resolved openings (Ito).
Leak-subtracted current records were idealized using a
half-height criterion,20 and idealized records
were used to construct ensemble-averaged currents. The number of
channels in a patch was estimated from the maximal stacking of the
unitary events in long runs (>200 sweeps). The peak open probability
was determined from the ensemble-averaged current using the
single-channel current amplitude and the estimated number of
channels in the patch.
Nonstationary fluctuation analysis was used to
estimate the
number (N) of functional Ito channels in the membrane. For
a homogeneous population of channels gating independently,
the mean macroscopic current (I) is defined as follows:
I=N·i·po. The macroscopic current variance
(
I2) is defined as follows:
I2=N·i2·po·[1-po],
where i is the single channel current amplitude and po
represents the open probability of the
channel.21 22 Variance was calculated by subtracting
pairs
of sequential current records to obtain the difference current,
squaring, and dividing by 2. The variance was then averaged over all
the records collected.23 Provided that I and
2 are determined for a range of open
probabilities, i and N can be estimated by a plot of variance versus
mean current fit by the following parabolic function:
I2=i·I-I2/N.24 25
The
currents plotted in the current-voltage relations were
determined from non–leak-subtracted records, with the
exception of Na+ current (Fig 3A
) and
IK1 (Fig 4B). For Na+ current,
capacity transients and leak currents
were subtracted using the P/4 method. In the case of
IK1, a linear leak component defined by a line
connecting the origin and the current at -80 mV was subtracted
from the net current values at each potential to facilitate the
analysis of the small outward component of IK1.
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, n=18) and control
hearts (
, n=15). At potentials between -90 mV and
-150 mV, IK1 current densities are significantly
reduced in myocytes from failing hearts compared with control myocytes
(P<.05). The steady state currents at potentials positive
to the K+ reversal potential are replotted in the inset on
a different scale. The asterisk at -60 mV indicates a significant
difference in the current density (P<.05).Pooled data are presented as mean±SEM unless otherwise stated. Statistical comparisons were made using Student's t test or ANOVA, with P<.05 considered to be significant. A Wilcoxon signed-rank test was used to compare the APD before and during the phase-1 current injection.
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Results |
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The surface area of the myocytes was estimated by the cell capacitance. The capacitance was comparable in cells isolated from failing (142±4.4 pF [n=91]) and control (146±4.4 pF [n=87]) hearts (P=NS). The resting membrane potential of cells isolated from control and failing ventricles was nearly identical (-82 mV; see Table 1
), suggesting that cells from
failing hearts were not systematically damaged by the cell isolation
procedure.
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Action Potential Changes in Heart Failure
Action potentials
recorded in cardiac myocytes from failing
hearts show significant changes in shape and duration compared with
control hearts. The action potential features from 7 dogs with
pacing-induced heart failure and 6 control dogs are summarized in
Table 1
. Control cells typically have a prominent notch in
phase 1,
which is markedly attenuated in the cells from failing hearts (Fig
1). The depth of the notch measured from the peak of the
overshoot to the voltage minimum before the plateau was significantly
decreased in cells from failing hearts. The diminutive notch is
followed by a significantly elevated maximum plateau potential in cells
from failing hearts. APD50 and APD90 were
significantly prolonged in cells from failing hearts (Fig 1).
The
average duration at 90% repolarization, under our recording
conditions, was >1 second in cells from failing hearts. The resting
membrane potential did not differ between the two groups.
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We next examined the ionic currents that underlie the heart failure–associated alterations in the action potential. Although the prolongation of the APD may be the result of changes in a number of currents active during the plateau phase, the reduction in the size of the notch in phase 1 suggests a decrease in Ito.6 17
L-Type Ca2+ Current
Robust L-type
Ca2+ currents were present in both
ventricular myocytes from failing and normal canine hearts
(Fig 2A). There was no difference in the peak L-type
Ca2+ current density (at +5 mV, -2.7±0.6
pA/pF
[failing hearts] versus -2.7±0.5 pA/pF [control
hearts];
P=NS). The current-voltage relation in the absence of
ß-adrenergic stimulation was not altered in cells isolated from
failing hearts compared with those from control hearts (Fig 2B,
circles), although the response to isoproterenol (1 µmol/L) was
blunted in myocytes from failing ventricles (Fig 2B,
triangles). The
mean peak L-type Ca2+ current density at +5 mV was
increased 74% in myocytes isolated from failing hearts compared with
111% in those from control hearts (P=NS). The tendency
toward reduced responsiveness to ß-adrenergic stimulation is
consistent with previous data in myocytes isolated from
patients with heart failure26 and may reflect
ß-receptor downregulation and/or distal changes in
ß-adrenergic signal transduction, consistent with the
severity of heart failure produced in this animal model.
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) compared with control myocytes
(
).
Na+ Current
Data from other
investigators27 concluded that
Na+ current is not altered in failing human myocytes. We
observed no significant difference in Na+ current measured
in cells isolated from the failing canine ventricle compared with
control cells. The currents activated at test potentials above
-50 mV and peaked at -25 mV (Fig 3A). The
peak current density did not differ between the two groups
(-12±7 pA/pF [control hearts, n=5] versus
-15±4 pA/pF
[failing hearts, n=3], Fig 3B). Steady state
inactivation was similar
in both groups, with a half-inactivation midpoint and slope factor
of -73±0.6 and 3.8±0.3 mV, respectively, in cells isolated
from
failing ventricles and -71±0.6 and 4.4±0.3 mV,
respectively, in
control cells (P=NS). The rate and voltage dependence of
whole-cell current decay were similar in both groups, and the
currents were almost completely inhibited by 20 µmol/L tetrodotoxin
(data not shown).
It does not appear that changes in depolarizing currents mediate the action potential prolongation in canine pacing-induced tachycardia. We next examined changes in K+ currents.
IK1
IK1 is important in maintaining the
resting membrane
potential and in shaping the contour of the action potential. Fig
4A illustrates representative
whole-cell currents in myocytes from failing and control hearts.
The density of IK1 in this preparation is similar to that
reported in human ventricular myocytes.6 Cells
from failing hearts exhibit a reduction in the current density at
negative potentials, which is confirmed by the pooled steady state
current-voltage relations. The curves diverge significantly between
test potentials of -90 to -150 mV (P<.05, Fig
4B). The relevant component of IK1 for
repolarization is
the outward current "hump" observed at potentials positive to the
K+ reversal potential. The peak outward component of
IK1 at -60 mV was significantly decreased in cells
from failing hearts (1.7±0.2 pA/pF) compared with control cells
(2.5±0.2 pA/pF, P<.05) (Fig 4B, inset).
Fig 5A shows representative
single-channel IK1 records from cells isolated from
failing and control hearts. Channel activity appears with voltage steps
negative to the K+ reversal potential (0 mV under these
ionic conditions). The open duration of the channels decreases
monotonically with more hyperpolarized voltage steps; subconductance
current levels were observed in both groups.
Representative single-channel current-voltage
relations demonstrate no difference in the IK1
single-channel conductance of cells from failing and control hearts
(Fig 5B). The average slope conductance for four control and
three
failing cells was 28.6±1.4 and 30.8±0.9 pS, respectively
(P=NS). Thus, the difference in IK1
whole-cell current density reflects either a decrease in open
probability, a modest reduction in channel number, or a change in the
frequency of substate openings.
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Ito
The attenuation of the prominent notch in
phase 1 of the action
potential of myocytes from failing hearts suggested a reduction in
Ito. Canine ventricular myocytes exhibit two
components of transient outward current: a Ca2+-independent
4-AP–sensitive current and a Ca2+-dependent
current.28 29 We focused on the former, which has
previously been shown to be decreased in failing human
ventricular myocytes,6 10 and refer to it
simply as Ito. The Ca2+-dependent component was
suppressed in the present study by the inclusion of 5 mmol/L EGTA
in the intracellular solutions.
Upon depolarization, control myocytes
exhibit a rapidly activating
Ito, which then decays to a nonzero steady state
current level (Fig 6A, left). Cells isolated from
failing canine hearts exhibit a dramatic decrease in this current (Fig
6A, right). Panels B and C of Fig 6 show the
current-voltage
relations of the peak and the steady state current components for 20
cells from failing hearts and for 15 control myocytes. Peak current
density measured at +80 mV was significantly reduced in the
failing myocytes (7.0±0.9 pA/pF [failing hearts] versus
20.4±3.2
pA/pF [control hearts], P<.001). In contrast to the peak
current, the steady state component was not significantly altered
(4.6±0.9 pA/pF [failing hearts] versus 3.2±0.6 pA/pF
[control
hearts], P=NS).
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The reduction in whole-cell
Ito could reflect a shift
in the voltage dependence of activation and/or inactivation.
Alternatively, maximal Ito conductance may be reduced. To
distinguish between the possibilities, we characterized the kinetics of
Ito in more detail. In the myocytes from both failing and
control hearts, Ito activated at test potentials of
-10 mV. The voltage dependence of activation was determined by
measurement of tail currents at -20 mV. Cells from failing hearts
and control myocytes had similar activation curves (Fig 7A).
The half-maximal activation voltages and slope
factors were 4.2±0.2 and 8.2±0.4 mV, respectively, for failing
myocytes and 7.1±0.3 and 11.6±0.4 mV, respectively, for control
myocytes (P=NS). Other gating properties of Ito
were also unchanged in cells from failing hearts. The voltage
dependence of steady state inactivation, assessed using a standard
two-pulse protocol, did not differ between the two groups
(half-inactivation voltages and slope factors of -33±0.4 and
5.5±0.3 mV, respectively, for failing cells versus -37±0.2
and
4.7±0.2 mV, respectively, for control cells). These steady state
gating parameters are comparable to those reported
previously for cardiac ventricular Ito in
several species.17 28 30 The time course
of inactivation
was determined by single-exponential fits to the whole-cell
current decay over a range of test voltages from +30 to +80 mV.
Pacing
tachycardia–induced heart failure did not affect the
time course of inactivation of Ito (Fig 7C). The
rates of
current decay in cells from failing hearts and in control cells
overlapped at all potentials. The recovery kinetics at -100 mV
were determined using a standard two-pulse protocol. Repriming in
cells from failing hearts and in control cells is biexponential;
neither the time constants nor the relative amplitudes of the
components differed significantly between the groups (Fig 7D).
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By exclusion, the reduction in macroscopic Ito
density in myocytes from failing hearts appears to reflect an
underlying decrease in maximal Ito conductance at the
whole-cell level. This could be due to alterations in channel
number, single-channel conductance, or open probability. Therefore,
we further examined the mechanism of the reduction in Ito
density using single-channel recording. Fig 8A shows
representative
single-channel current records at various test potentials (+40
to +80 mV) from a holding potential of -80 mV. The channels tend
to open at the beginning of the voltage step and rapidly
inactivate; openings late in the voltage steps are rare.
This single-channel gating pattern was similar in the myocytes from
failing hearts and in the control myocytes and was reflected in the
similar decay rate of the ensemble-averaged currents (Fig 8B).
The
whole-cell (WC) current decay at +80 mV was faithfully reproduced
by the ensemble-averaged (EA) current (EA, 55
milliseconds [failing hearts] and 50 milliseconds [control
hearts];
WC, 34 milliseconds [failing hearts] and 34
milliseconds [control hearts]). The ensemble averages, corrected for
channel number and represented as open probabilities, show
the same peak opening probability in myocytes from failing hearts and
in control myocytes (Fig 8B). The single-channel conductance of
Ito in myocytes from failing and control hearts is nearly
identical (Fig 8C). Differences between the conductance
measured in the
present study and in other
studies30 31 32 33 34
reflect
differences in recording conditions, species, or tissue of
origin. Previous recordings were from ferret,30
mouse,31 and rat34 ventricle and rabbit
atrium32 ; these are the first single-channel
Ito recordings from canine ventricular
myocytes.
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The absence of changes in single-channel current or unitary
open
probability suggest, by exclusion, that the number of functional
Ito channels is reduced. As a more direct means of
estimating number of functional channels in myocytes from failing and
control hearts, we used nonstationary fluctuation analysis of
whole-cell Ito. Fig 9 shows plots of
variance as a function of mean current in a normal cell (left) and in a
cell isolated from a failing ventricle (right). The peak of the
parabolic fit yields the number of functional channels, which is
obviously higher in the control cell. Pooled data from three control
and three cells from failing hearts are summarized in Table 2,
illustrating that channel density was significantly
reduced in myocytes from failing hearts.
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Can the Reduction of Ito Account for the Prolongation
of Action Potentials?
If the reduction in Ito that we
observed is sufficient
to produce prolongation of the action potential of myocytes from
failing hearts, pharmacological inhibition of Ito in a
control cell should result in action potential prolongation. Blockers
of K+ channels are not specific, but low concentrations of
4-AP preferentially inhibit Ito. Peak Ito
elicited by a voltage step to +60 mV is >50% blocked by 2 mmol/L 4-AP
and almost completely eliminated by 5 mmol/L, with a half-blocking
concentration (IC50) of 1.1 mmol/L (Fig 10A). Peak
Ito is inhibited over the entire
range of test voltages, with more pronounced block at positive
potentials (Fig 10B and 10C, right). The
records also confirm that
there is little effect on the maintained component of Ito.
To determine whether the drug was having an unanticipated effect on
currents other than Ito, we examined the effect of
4-AP on total membrane current over a wide range of voltages. Fig
10C
shows the result of such experiments in three control cells and three
myocytes from failing hearts. 4-AP had no effect on total membrane
current over the range of test potentials from -150 to +20 mV but
did reduce outward current at more positive voltages,
consistent with a predominant effect on Ito.
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), and five (
) mmol/L 4-AP in a control
cell. (right). B, A representative family of current
traces elicited by voltage steps of 500 milliseconds from 0 to +80 mV
in 20-mV increments from a holding potential of -80 mV in a
control cell without drug (left) and with 5 mmol/L 4-AP (right). The
horizontal lines to the left of the traces indicate the
zero-current level. C, Averaged current-voltage relation of
total membrane currents in control cells without drug (
We then
examined the effect of 4-AP on action potentials. Fig 11A
illustrates the action potential prolongation by
4-AP, with attenuation of the phase-1 notch and no change in the
resting membrane potential. These changes mimic faithfully the action
potential contour in failing myocytes. Fig 11B summarizes the
effects
of 4-AP on six control cells. The amplitude of the notch was
consistently reduced, and APD50 was significantly
increased. In the absence of a substantial effect of 4-AP on other
membrane currents, the present findings support the notion that the
reduced Ito in failing myocytes is important in the
prolongation of repolarization.
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If inhibiting Ito in normal
cells can reproduce the
failing action potential phenotype, it is logical to predict
that an action potential from a failing ventricular myocyte
may be normalized by simply reconstituting the electrical effect of
Ito. We addressed this question by injecting a brief
repolarizing current pulse during phase 1 of the action potential in
myocytes from failing hearts to mimic the effect of Ito. If
Ito is essential for setting the plateau potential and
indirectly influencing the trajectory of the remainder of the action
potential, artificially restoring the notch should shorten the APD. In
Fig 11C, a 250-pA repolarizing current pulse delivered for 8
milliseconds during phase 1 was sufficient to shorten the duration of
the action potential. This pulse represents an underestimate of
the current contribution of Ito during this phase of the
action potential. Nonetheless, in 9 of 10 cells in which the protocol
was attempted, APD50 and APD90 were shortened
(P<.02). Thus, APD in cells from failing hearts could be
effectively abbreviated by brief injections of repolarizing current
during phase 1 of the action potential.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and Methods Results Discussion References |
|---|
Action potential prolongation is a prominent feature of cardiac myocytes isolated from pacing tachycardia–induced heart failure in the dog. The changes include prolongation of both APD50 and APD90 and a dramatic attenuation of the notch in phase 1 without a significant change in the resting membrane potential. There is a concomitant reduction in Ito density with a significant reduction in channel number estimated from nonstationary fluctuation analysis. We also observed a reduction in IK1, which may be involved in the terminal phase of repolarization. Our findings are consistent with reports of heart failure–induced action potential lengthening in other species35 36 as well as those described in human cells isolated from failing hearts explanted at the time of cardiac transplantation.6 16
Significance of the Canine Pacing-Induced Heart Failure
Model
Congestive heart failure induced by rapid pacing in the dog
exhibits many mechanical and neurohumoral derangements reminiscent of
human heart failure. After 3 to 4 weeks of rapid
ventricular pacing, the animals exhibit marked contractile
depression, chronic chamber remodeling, and blunted ß-adrenergic
responsiveness.12 Neurohumoral activation is evident as a
substantial rise in plasma and myocardial norepinephrine
levels.37 Biochemical abnormalities in the
ß-adrenergic receptor–G protein–adenylyl cyclase pathway
resemble those in human heart failure.38 39
Therefore,
this model appears to reproduce the major mechanical, biochemical, and
clinical features of human heart failure. As an important first step in
determining the mechanism of repolarization abnormalities that develop
with heart failure and their relation to ventricular
tachyarrhythmias and sudden cardiac death, we have
characterized the cellular electrophysiology of this model. As we
sought to compare our results directly with those obtained in human
myocytes, the experimental conditions were designed to mimic those of
Beuckelmann et al6 and Näbauer et
al.18
Ito
Canine ventricular myocytes exhibit two
components of
the transient outward current28 29 : the
Ca2+-independent transient outward component (referred to
here as Ito) and a Ca2+-dependent
component (sometimes referred to as Ito2). The
Ca2+-dependent component of Ito is not active
under the present experimental conditions, given the presence of 5
mmol/L EGTA in the intracellular solutions. The density of
Ca2+-independent Ito was reduced by 66% in
cells from failing hearts compared with cells from control hearts (at
+80 mV). The voltage dependence of activation and inactivation curves
did not differ in ventricular myocytes from failing hearts
compared with those from nonfailing control hearts. The kinetics of
whole-cell current decay could be fit with a single exponential,
and the rates of decay did not change with the induction of heart
failure. Recovery of peak Ito at a
physiologically relevant voltage was
biexponential and did not differ in cells from failing hearts and cells
from control hearts. The absence of changes in single-channel
conductance and open probability left only a reduction in channel
number as an explanation for the reduction in the current density in
cells from failing hearts; this interpretation was confirmed by
nonstationary fluctuation analysis. The mechanism of the
reduction in functional channel number is still under investigation,
but the unchanged electrophysiological
properties of the residual current remaining in cells from failing
hearts argues against a posttranslational mechanism. Alternatively, a
reduction in transcription (or translation) of Ito genes
could reduce channel number. At present, these mechanisms remain
speculative; indeed, the prospects for elucidating these mechanisms are
rendered somewhat daunting, given the uncertain identity of the
molecular components of Ito.
Comparison With Human and Other Animal Data
Our data are
quite consistent with those reported in
similarly isolated human ventricular
myocytes.6 18 However, other laboratories have not
found a
significant difference in the current density of Ito in
cells from normal and failing human hearts.10 The cause of
this discrepancy is not known, but several possibilities exist. An
important difference may be the method of cell isolation. We used a
coronary perfusion technique similar to that described by
Beuckelmann et al16 rather than a chunk method and
observed a viable cell yield of 20% to 40% compared with a
considerably lower yield when the chunk method is used. The use of a
coronary artery for perfusion may limit cell damage during
isolation because of superior perfusion and oxygenation
of the tissue. In addition, we restricted our sampling to the
midmyocardium, a region of the myocardial wall with a
large Ito density. It is possible that
Ito in these "M" cells17 40
has a
fundamentally different response to myocardial failure than either the
endocardial or epicardial cells studied by Wettwer et
al.10 Species differences may also have significant
effects on the Ito density and its change in heart failure.
A complicating issue in all human studies, which is circumvented in the
present study, is the variability in the etiology, stage, and prior
treatment of the explanted hearts from which cells were isolated.
The transmural variability in Ito density has been well documented.10 17 41 Since our main goal was to compare electrical properties in the presence and absence of heart failure, we isolated cells from only one region of the heart, the midmyocardial layer (see "Materials and Methods"). We did not address possible regional changes or alterations in the transmyocardial Ito gradient that may occur in heart failure.
Other K+ Currents
IK1 may also
contribute to repolarization of
ventricular myocytes, at least at
near-diastolic potentials. We observed a 40% reduction
(at -150 mV) in the steady state current density of
IK1 in ventricular myocytes from failing canine
hearts compared with nonfailing control cells. However, the reduction
at very negative potentials will not influence the action potential
profile. Outward current through IK1 is observed at
voltages positive to the K+ reversal potential and is
likely to affect the terminal phase of the action potential. The small
but significant reduction in the outward IK1 component
observed in myocytes from failing hearts (Fig 4B, inset) could
account
for some of the prolongation of APD90 but is unlikely to
figure in the equally prominent abbreviation of APD50.
The delayed rectifier K+ current (rapidly and slowly activating components) has recently been described in canine ventricular myocytes. However, this current is present at a much lower density (0.4 to 0.9 pA/pF) in midmyocardial cells than is Ito.42 The change in the action potential contour in the present study suggested a downregulation of Ito. The delayed rectifier K+ current was never resolved under our experimental conditions; if present, it would form part of the "maintained component" of Ito, which was not altered in cells from failing hearts. Nevertheless, the fact that these currents were not specifically examined in the present study does not exclude the possibility that they may influence repolarization, particularly under more physiological conditions (37°C, no cell dialysis) than those used.
Significance of Reduced Ito in Heart Failure for
Alterations in APD
If the major change in cells from failing canine
ventricles is a
reduction in Ito, the obvious question is whether
this change in Ito suffices to explain the observed changes
in the action potential profile and duration. The main features of the
action potential of ventricular myocytes isolated from
failing hearts could indeed be reproduced by exposing myocytes from
normal hearts to 5 mmol/L 4-AP. Under our recording conditions,
this concentration of 4-AP affects only Ito. In fact, 4-AP
prolongs the action potential more dramatically in myocytes from
failing hearts than in normal myocytes (data not shown), implying that
myocytes from the failing heart are even more dependent on the residual
Ito for repolarization. We further demonstrated the
importance of Ito in ventricular repolarization
by restoring the action potential notch in myocardial cells from
failing hearts. Abbreviation of the APD was effected by artificially
recreating the phase-1 notch with a repolarizing current pulse
delivered during the first 8 milliseconds of the action potential.
These data suggest that Ito, despite its transient
nature, is important in determining the shape and duration of the
ventricular action potential.
Physiological and Clinical
Implications
Ito is prominent in normal canine
ventricular myocardium, but its
physiological role has not been fully defined. The
prominent notch found in myocytes that have been isolated from the
midmyocardium and the initial level of the plateau of
the action potential have been attributed to
Ito.6 17 18 The importance of
Ito
in the genesis of cardiac arrhythmias is suggested by its
reduction in arrhythmogenic substrates such as heart failure (Reference
6 and the present study), myocardial infarction,43
hypertrophy,44 and anoxia.45
Nevertheless, much remains to be learned regarding the mechanistic
links between the downregulation of Ito and the
pathogenesis of ventricular arrhythmias.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported by grants HL P50 52307 (SCOR in Sudden Cardiac Death) and RO1 HL-47511 (Dr Kass) from the National Institutes of Health; by an American Heart Association, Maryland Affiliate, Inc, Grant-in-Aid (Dr Tomaselli); and by fellowships from the National Institutes of Health T32 HL-07227 (Dr Pak), the Medical Research Council of Canada (Dr Chiamvimonvat), the American Heart Association, Maryland Affiliate, Inc (Dr Nuss), and the Deutsche Forschungsgemeinschaft (Dr Kääb). We are grateful to Richard S. Tunin for his expert technical assistance.
Received May 24, 1995; accepted October 17, 1995.
|
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P. A. Helm, L. Younes, M. F. Beg, D. B. Ennis, C. Leclercq, O. P. Faris, E. McVeigh, D. Kass, M. I. Miller, and R. L. Winslow Evidence of Structural Remodeling in the Dyssynchronous Failing Heart Circ. Res., January 6, 2006; 98(1): 125 - 132. [Abstract] [Full Text] [PDF]
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M. Shah, F. G. Akar, and G. F. Tomaselli Molecular Basis of Arrhythmias Circulation, October 18, 2005; 112(16): 2517 - 2529. [Abstract] [Full Text] [PDF]
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S. Saba, A. M. Janczewski, L. C. Baker, V. Shusterman, E. C. Gursoy, A. M. Feldman, G. Salama, C. F. McTiernan, and B. London Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-{alpha} Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1456 - H1467. [Abstract] [Full Text] [PDF]
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F. G. Akar, R. C. Wu, G. J. Juang, Y. Tian, M. Burysek, D. DiSilvestre, W. Xiong, A. A. Armoundas, and G. F. Tomaselli Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2887 - H2896. [Abstract] [Full Text] [PDF]
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J. Rose, A. A. Armoundas, Y. Tian, D. DiSilvestre, M. Burysek, V. Halperin, B. O'Rourke, D. A. Kass, E. Marban, and G. F. Tomaselli Molecular correlates of altered expression of potassium currents in failing rabbit myocardium Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2077 - H2087. [Abstract] [Full Text] [PDF]
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R. L Winslow, S. Cortassa, and J. L Greenstein Using models of the myocyte for functional interpretation of cardiac proteomic data J. Physiol., February 15, 2005; 563(1): 73 - 81. [Abstract] [Full Text] [PDF]
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E. Vanoli, S. Bacchini, S. Panigada, F. Pentimalli, and P. B Adamson Experimental models of heart failure Eur. Heart J. Suppl., November 1, 2004; 6(suppl_F): F7 - F15. [Abstract] [Full Text] [PDF]
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G. F. Tomaselli and D. P. Zipes What Causes Sudden Death in Heart Failure? Circ. Res., October 15, 2004; 95(8): 754 - 763. [Abstract] [Full Text] [PDF]
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F. G. Akar, D. D. Spragg, R. S. Tunin, D. A. Kass, and G. F. Tomaselli Mechanisms Underlying Conduction Slowing and Arrhythmogenesis in Nonischemic Dilated Cardiomyopathy Circ. Res., October 1, 2004; 95(7): 717 - 725. [Abstract] [Full Text] [PDF]
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S. Poelzing and D. S. Rosenbaum Altered connexin43 expression produces arrhythmia substrate in heart failure Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1762 - H1770. [Abstract] [Full Text] [PDF]
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C. M. Loughrey, G. L. Smith, and K. E. MacEachern Comparison of Ca2+ release and uptake characteristics of the sarcoplasmic reticulum in isolated horse and rabbit cardiomyocytes Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1149 - H1159. [Abstract] [Full Text] [PDF]
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Y. Wakisaka, S. Niwano, H. Niwano, J. Saito, T. Yoshida, S. Hirasawa, H. Kawada, and T. Izumi Structural and electrical ventricular remodeling in rat acute myocarditis and subsequent heart failure Cardiovasc Res, September 1, 2004; 63(4): 689 - 699. [Abstract] [Full Text] [PDF]
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A. Yatani, S.-J. Kim, R. K. Kudej, Q. Wang, C. Depre, K. Irie, E. G. Kranias, S. F. Vatner, and D. E. Vatner Insights into cardioprotection obtained from study of cellular Ca2+ handling in myocardium of true hibernating mammals Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2219 - H2228. [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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R. Cardinal, G. Rousseau, C. Bouchard, M. Vermeulen, J.-G. Latour, and P. L. Page Myocardial electrical alteration in canine preparations with combined chronic rapid pacing and progressive coronary artery occlusion Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1496 - H1506. [Abstract] [Full Text] [PDF]
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F. G. Akar, R. C. Wu, I. Deschenes, A. A. Armoundas, V. Piacentino III, S. R. Houser, and G. F. Tomaselli Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H602 - H609. [Abstract] [Full Text] [PDF]
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M. J Janse Electrophysiological changes in heart failure and their relationship to arrhythmogenesis Cardiovasc Res, February 1, 2004; 61(2): 208 - 217. [Abstract] [Full Text] [PDF]
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C. R. Weber, V. Piacentino III, S. R. Houser, and D. M. Bers Dynamic Regulation of Sodium/Calcium Exchange Function in Human Heart Failure Circulation, November 4, 2003; 108(18): 2224 - 2229. [Abstract] [Full Text] [PDF]
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F. G. Akar and D. S. Rosenbaum Transmural Electrophysiological Heterogeneities Underlying Arrhythmogenesis in Heart Failure Circ. Res., October 3, 2003; 93(7): 638 - 645. [Abstract] [Full Text] [PDF]
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D. D. Spragg, C. Leclercq, M. Loghmani, O. P. Faris, R. S. Tunin, D. DiSilvestre, E. R. McVeigh, G. F. Tomaselli, and D. A. Kass Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart Circulation, August 26, 2003; 108(8): 929 - 932. [Abstract] [Full Text] [PDF]
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A. A. Armoundas, I. A. Hobai, G. F. Tomaselli, R. L. Winslow, and B. O'Rourke Role of Sodium-Calcium Exchanger in Modulating the Action Potential of Ventricular Myocytes From Normal and Failing Hearts Circ. Res., July 11, 2003; 93(1): 46 - 53. [Abstract] [Full Text] [PDF]
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Y.-M. Cha, P. P. Dzeja, W. K. Shen, A. Jahangir, C. Y. T. Hart, A. Terzic, and M. M. Redfield Failing atrial myocardium: energetic deficits accompany structural remodeling and electrical instability Am J Physiol Heart Circ Physiol, April 1, 2003; 284 (4): H1313 - H1320. [Abstract] [Full Text] [PDF]
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S. M Pogwizd, K. R Sipido, F. Verdonck, and D. M Bers Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis Cardiovasc Res, March 15, 2003; 57(4): 887 - 896. [Full Text] [PDF]
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B. London, L. C. Baker, J. S. Lee, V. Shusterman, B.-R. Choi, T. Kubota, C. F. McTiernan, A. M. Feldman, and G. Salama Calcium-dependent arrhythmias in transgenic mice with heart failure Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H431 - H441. [Abstract] [Full Text] [PDF]
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C Ramakers, M.A Vos, P.A Doevendans, M Schoenmakers, Y.S Wu, S Scicchitano, A Iodice, G.P Thomas, C Antzelevitch, and R Dumaine Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of IKs in canine hypertrophied hearts Cardiovasc Res, February 1, 2003; 57(2): 486 - 496. [Abstract] [Full Text] [PDF]
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R. Sah, R. J Ramirez, G. Y Oudit, D. Gidrewicz, M. G Trivieri, C. Zobel, and P. H Backx Regulation of cardiac excitation-contraction coupling by action potential repolarization: role of the transient outward potassium current (Ito) J. Physiol., January 1, 2003; 546(1): 5 - 18. [Abstract] [Full Text] [PDF]
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T. J. Kamp and J.-Q. He L-Type Ca2+ Channels Gaining Respect in Heart Failure Circ. Res., September 20, 2002; 91(6): 451 - 453. [Full Text] [PDF]
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G.-R. Li, C.-P. Lau, A. Ducharme, J.-C. Tardif, and S. Nattel Transmural action potential and ionic current remodeling in ventricles of failing canine hearts Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1031 - H1041. [Abstract] [Full Text] [PDF]
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Y. Matsumoto, H. Aihara, R. Yamauchi-Kohno, Y. Reien, T. Ogura, H. Yabana, Y. Masuda, T. Sato, I. Komuro, and H. Nakaya Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters Circulation, July 30, 2002; 106(5): 613 - 619. [Abstract] [Full Text] [PDF]
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I. Deschenes, D. DiSilvestre, G. J. Juang, R. C. Wu, W. F. An, and G. F. Tomaselli Regulation of Kv4.3 Current by KChIP2 Splice Variants: A Component of Native Cardiac Ito? Circulation, July 23, 2002; 106(4): 423 - 429. [Abstract] [Full Text] [PDF]
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G. J. Rozanski and Z. Xu Glutathione and K+ channel remodeling in postinfarction rat heart Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2346 - H2355. [Abstract] [Full Text] [PDF]
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D. Lacroix, P. Gluais, C. Marquie, C. D'Hoinne, M. Adamantidis, and M. Bastide Repolarization abnormalities and their arrhythmogenic consequences in porcine tachycardia-induced cardiomyopathy Cardiovasc Res, April 1, 2002; 54(1): 42 - 50. [Abstract] [Full Text] [PDF]
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L.-M. Zhang, Z. Wang, and S. Nattel Effects of sustained beta -adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H880 - H889. [Abstract] [Full Text] [PDF]
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K. R Sipido, P. G.A Volders, M. A Vos, and F. Verdonck Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res, March 1, 2002; 53(4): 782 - 805. [Abstract] [Full Text] [PDF]
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R. Sah, R. J. Ramirez, and P. H. Backx Modulation of Ca2+ Release in Cardiac Myocytes by Changes in Repolarization Rate: Role of Phase-1 Action Potential Repolarization in Excitation-Contraction Coupling Circ. Res., February 8, 2002; 90(2): 165 - 173. [Abstract] [Full Text] [PDF]
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T. Watanabe, M. Yamaki, S. Yamauchi, O. Minamihaba, T. Miyashita, I. Kubota, and H. Tomoike Regional prolongation of ARI and altered restitution properties cause ventricular arrhythmia in heart failure Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H212 - H218. [Abstract] [Full Text] [PDF]
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B Huang, D Qin, and N El-Sherif Spatial alterations of Kv channels expression and K+ currents in post-MI remodeled rat heart Cardiovasc Res, November 1, 2001; 52(2): 246 - 254. [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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W. Han, D. Chartier, D. Li, and S. Nattel Ionic Remodeling of Cardiac Purkinje Cells by Congestive Heart Failure Circulation, October 23, 2001; 104(17): 2095 - 2100. [Abstract] [Full Text] [PDF]
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Z. Wang, W. Kutschke, K. E. Richardson, M. Karimi, and J. A. Hill Electrical Remodeling in Pressure-Overload Cardiac Hypertrophy: Role of Calcineurin Circulation, October 2, 2001; 104(14): 1657 - 1663. [Abstract] [Full Text] [PDF]
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S. Kaab and M. Nabauer Diversity of ion channel expression in health and disease Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K31 - K40. [Abstract] [PDF]
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R. F Gilmour Jr. Life out of balance: The sympathetic nervous system and cardiac arrhythmias Cardiovasc Res, September 1, 2001; 51(4): 625 - 626. [Full Text] [PDF]
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R. Sah, R. J Ramirez, R. Kaprielian, and P. H Backx Alterations in action potential profile enhance excitation-contraction coupling in rat cardiac myocytes J. Physiol., May 15, 2001; 533(1): 201 - 214. [Abstract] [Full Text] [PDF]
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D. Babuty and M. J Lab Mechanoelectric contributions to sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 270 - 279. [Full Text] [PDF]
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S. Demolombe, G. Lande, F. Charpentier, M. A van Roon, M. J.B van den Hoff, G. Toumaniantz, I. Baro, G. Guihard, N. Le Berre, A. Corbier, et al. Transgenic mice overexpressing human KvLQT1 dominant-negative isoform Part I: Phenotypic characterisation Cardiovasc Res, May 1, 2001; 50(2): 314 - 327. [Abstract] [Full Text] [PDF]
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I. A. Hobai and B. O'Rourke Decreased Sarcoplasmic Reticulum Calcium Content Is Responsible for Defective Excitation-Contraction Coupling in Canine Heart Failure Circulation, March 20, 2001; 103(11): 1577 - 1584. [Abstract] [Full Text] [PDF]
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J. Huang, J. M. Rogers, C. R. Killingsworth, G. P. Walcott, B. H. KenKnight, W. M. Smith, and R. E. Ideker Improvement of Defibrillation Efficacy and Quantification of Activation Patterns During Ventricular Fibrillation in a Canine Heart Failure Model Circulation, March 13, 2001; 103(10): 1473 - 1478. [Abstract] [Full Text] [PDF]
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J.-Q. He, M. W Conklin, J. D Foell, M. R Wolff, R. A Haworth, R. Coronado, and T. J Kamp Reduction in density of transverse tubules and L-type Ca2+ channels in canine tachycardia-induced heart failure Cardiovasc Res, February 1, 2001; 49(2): 298 - 307. [Abstract] [Full Text] [PDF]
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S. S. Chugh, S. B. Johnson, and D. L. Packer Altered response to ibutilide in a heart failure model Cardiovasc Res, January 1, 2001; 49(1): 94 - 102. [Abstract] [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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J. L. Greenstein, R. Wu, S. Po, G. F. Tomaselli, and R. L. Winslow Role of the Calcium-Independent Transient Outward Current Ito1 in Shaping Action Potential Morphology and Duration Circ. Res., November 24, 2000; 87(11): 1026 - 1033. [Abstract] [Full Text] [PDF]
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S. Nattel Acquired delayed rectifier channelopathies: how heart disease and antiarrhythmic drugs mimic potentially-lethal congenital cardiac disorders Cardiovasc Res, November 1, 2000; 48(2): 188 - 190. [Full Text] [PDF]
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Y. Tsuji, T. Opthof, K. Kamiya, K. Yasui, W. Liu, Z. Lu, and I. Kodama Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreases in calcium and transient outward currents in rabbit ventricle Cardiovasc Res, November 1, 2000; 48(2): 300 - 309. [Abstract] [Full Text] [PDF]
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