© 2000 American Heart Association, Inc.
Integrative Physiology |
Functional Consequences of Elimination of Ito, f and Ito, s
Early Afterdepolarizations, Atrioventricular Block, and Ventricular Arrhythmias in Mice Lacking Kv1.4 and Expressing a Dominant-Negative Kv4 
Subunit
From the Department of Molecular Biology and Pharmacology (W.G., H.L., J.M.N.), Washington University School of Medicine, St. Louis, Mo, and Cardiovascular Institute (B.L.), University of Pittsburgh Medical Center, Pittsburgh, Pa.
Correspondence to Dr Jeanne M. Nerbonne, Department of Molecular Biology and Pharmacology, Campus Box 8103, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110. E-mail: jnerbonn{at}pcg.wustl.edu
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Abstract |
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Abstract—It was recently reported that the slow transient outward K+ current, Ito, s, that is evident in mouse left ventricular septal cells is eliminated in mice with a targeted deletion of the Kv1.4 gene (Kv1.4-/-). The rapidly inactivating transient outward K+ current, Ito, f, in contrast, is selectively eliminated in ventricular myocytes isolated from transgenic mice expressing a dominant-negative Kv4
subunit, Kv4.2W362F.
Expression of Kv4.2W362F results in marked prolongation of action
potentials and QT intervals. In addition, a slow transient outward
K+ current, that is similar to
Ito, s in wild-type mouse left
ventricular septal cells, is evident in all
Kv4.2W362F-expressing (left and right) ventricular cells.
To test directly the hypothesis that upregulation of Kv1.4 subunit
underlies the appearance of this slow transient outward K+
current in Kv4.2W362F-expressing ventricular cells and to
explore the functional consequences of elimination of
Ito, f and
Ito, s, mice expressing Kv4.2W362F in the
Kv1.4-/- background (Kv4.2W362FxKv1.4-/-)
were generated. Histological and
echocardiographic studies revealed no evidence of
structural abnormalities or contractile dysfunction in
Kv4.2W362FxKv1.4-/- mouse hearts.
Electrophysiological recordings from the
majority (
80%) of cells isolated from the right
ventricle and left ventricular apex of
Kv4.2W362FxKv1.4-/- animals demonstrated that both
Ito, f and
Ito, s are eliminated; action potentials
are prolonged significantly; and, in some cells, early
afterdepolarizations were observed. In addition, in vivo telemetric ECG
recordings from Kv4.2W362FxKv1.4-/- animals
revealed marked QT prolongation, atrioventricular
block, and ventricular tachycardia. These
observations demonstrate that upregulation of Kv1.4 contributes to the
electrical remodeling evident in the ventricles of
Kv4.2W362F-expressing mice and that elimination of both
Ito, f and
Ito, s has dramatic functional
consequences. (Circ Res. 2000;87:73-79.)
Key Words: transient outward K+ currents • early afterdepolarization • atrioventricular block • ventricular arrhythmia
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Introduction |
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Two types of voltage-gated K+ channel currents, transient outward K+ currents (Ito) and delayed rectifier K+ currents (IK), have been distinguished in most cardiac cell types.1 2 These are broad classifications, and it is now clear that there are at least 2 types of Ito, referred to as Ito, f and Ito, s, and multiple components of IK, including IKr, IKs, and IKur.1 2 3 4 5 6 7 8 The relative expression levels of Ito, f, Ito, s, IKr, IKs, and IKur vary in different cell types and regions3 4 5 6 7 8 and contribute to the regional heterogeneity in action potential waveforms evident in the mammalian heart.9 In addition, numerous studies have demonstrated that the individual components of Ito and IK are differentially regulated during normal heart development and in a variety of cardiovascular disease states.10 11 12 13 Attenuation of Ito in the hypertrophied heart, for example, likely contributes to action potential prolongation and to the generation or propagation of arrhythmias.11 12 There is, therefore, considerable interest in defining the molecular correlates of cardiac Ito and IK, as well as in determining the functional roles of these channels in the physiology and pathophysiology of the heart.
Ito, f is expressed in a number of cardiac cell types, and the biophysical properties of Ito, f are similar in that activation, inactivation, and recovery from inactivation are all rapid.1 2 3 4 5 6 Recently, a distinct Ito, s has also been identified in a number of cardiac cell types.3 4 5 6 Ito, s differs from Ito, f in that the rates of inactivation and recovery are significantly slower.3 4 5 6 In addition, Ito, f is blocked by nanomolar concentrations of the Heteropoda toxins, whereas Ito, s is unaffected by these toxins.4 5 Ito, f and Ito, s are also differentially distributed in the ventricles; Ito, f density, for example, is high in left ventricular epicardial (human3 and ferret4 ) and apical (mouse5 ) cells, whereas Ito, s is expressed in left ventricular endocardial (human3 and ferret4 ) and septal (mouse5 and rat6 ) cells. The differential expression of Ito, f and Ito, s contributes to regional heterogeneities in ventricular repolarization.9
Recently, it was reported that Ito, f is
eliminated in all ventricular and atrial myocytes isolated
from transgenic mice expressing a dominant-negative Kv4 subunit,
Kv4.2W362F, thereby directly demonstrating that Kv4 subunits
underlie mouse
Ito, f.14 15 Although
action potentials and QT intervals are markedly prolonged in
Kv4.2W362F-expressing transgenic animals, these animals do not display
spontaneous atrial or ventricular
arrhythmias.14 15 In ventricular
myocytes isolated from mice with a targeted deletion of the Kv1.4 gene
(Kv1.4-/-),16 in contrast,
Ito, s is selectively
eliminated.17 Whole-cell voltage-clamp
recordings also revealed the presence of a slow transient
outward K+ current in Kv4.2W362F-expressing mouse
left ventricular apex (LVA) cells that is similar to
Ito, s in wild-type mouse left
ventricular septum (LVS) cells.17 This
observation suggested that electrical remodeling occurs in the LVA when
Ito, f is eliminated, an effect that may
underlie the finding that Kv4.2W362F-expressing animals are not
arrhythmogenic. In addition, Kv1.4 protein expression is increased in
Kv4.2W362F-expressing ventricles,17 suggesting that
upregulation of Kv1.4 contributes to the electrical remodeling in
Kv4.2W362F transgenic animals. The experiments here were undertaken to
test this hypothesis directly by crossing Kv4.2W362F transgenic
mice with Kv1.4-/- mice to generate
Kv4.2W362Fx Kv1.4-/- animals.
Electrophysiological recordings revealed
that the slow transient outward K+ current
(Ito, s), evident in all
Kv4.2W362F-expressing ventricular cells, is undetectable in
the majority (80%) of the
Kv4.2W362FxKv1.4-/- cells. In addition, action
potentials are markedly prolonged and early afterdepolarizations are
evident in Kv4.2W362FxKv1.4-/-
ventricular myocytes. In vivo telemetric ECG
recordings revealed increased incidence of
atrioventricular block and ventricular
tachycardia in the
Kv4.2W362FxKv1.4-/- mice, although there is no
evidence of structural abnormalities or contractile dysfunction in the
hearts of these animals.
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Materials and Methods |
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An expanded online Materials and Methods section containing details of the generation of the Kv4.2W362FxKv1.4-/- mice, reverse transcriptase–polymerase chain reaction (RT-PCR), Western blot analysis, histological and echocardiographic assessments, and electrophysiological recordings are available at http://www.circresaha.org. Animals used in the present study were handled in accordance with guidelines published in the Guide for the Care and Use of Laboratory Animals (US National Institutes of Health).
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Results |
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Kv1.4 Expression in Wild-Type, Kv4.2W362F- Expressing, and Kv4.2W362FxKv1.4-/- Mice
As illustrated in Figure 1A
, RT-PCR
analysis revealed that the Kv1.4 mRNA is readily detected in
the LVA and LVS of adult wild-type and Kv4.2W362F-expressing mice. As
expected, no Kv1.4 message is detected in LVA or LVS of the
Kv1.4-/- animals. Western blot analysis
of fractionated LVA and LVS membrane proteins (50 µg) prepared from
wild-type animals revealed that the 97-kDa Kv1.4 protein is readily
detected in both samples, although the protein appears to be more
abundant in LVS (Figure 1B). Expression of the Kv4.2W362F
transgene results in a marked increase in Kv1.4 protein expression in
LVA (Figure 1B). No Kv1.4 protein is detected in LVA and LVS of
Kv4.2W362FxKv1.4-/- mice (Figure 1B).
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Phenotypic Analysis of
Kv4.2W362FxKv1.4-/- Mice
On gross examination, there were no obvious differences noted when
adult wild-type, Kv4.2W362F-expressing, and
Kv4.2W362FxKv1.4-/- mice (Figure 2A) or the hearts isolated from these
animals (Figure 2B) were compared. Mean±SEM heart
weight-to-body weight ratios (mg/g), for example, were 3.9±0.2 for
adult wild-type (n=6), 3.8±0.4 for Kv4.2W362F-expressing (n=4), and
4.1±0.2 for Kv4.2W362FxKv1.4-/- (n=5)
animals, respectively. As illustrated in Figures 2C through 2H,
longitudinal hematoxylin and eosin–stained paraffin sections of hearts
isolated from
Kv4.2W362FxKv1.4-/-
animals are indistinguishable from those prepared from wild-type and
Kv4.2W362F-expressing hearts, and there was no evidence of fibrosis or
myofibrillar disarray. In addition, echocardiographic
assessment (M mode) revealed no evidence of left
ventricular hypertrophy, chamber dilation, or
contractile dysfunction in the Kv4.2W362F-expressing, the
Kv4.2W362FxKv1.4-/-, or the
Kv1.4-/- animals (see Table 1
online; available at http://www.circresaha.org). These observations are
in sharp contrast to the findings recently reported by Wickenden et
al18 in transgenic mice expressing a truncation mutant of
Kv4.2 subunit (Kv4.2N) that functions as a dominant negative. In
addition to attenuation of Ito, f, Kv4.2N
expression results in dilated cardiomyopathy in
adult animals.18 The fact that there is no evidence
of structural abnormalities or contractile dysfunction in the
Kv4.2W362F-expressing and/or the
Kv4.2W362FxKv1.4-/- animals suggests that the
dramatic phenotype seen in the Kv4.2N-expressing mice is
unrelated to the loss of Ito, f (see
Discussion).
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Ito, s Is Eliminated in
Kv4.2W362FxKv1.4-/- Mouse Ventricular Myocytes
To assess the functional consequences of the expression of
Kv4.2W362F and the deletion of Kv1.4, whole-cell voltage-clamp
recordings were obtained from myocytes isolated from the right
ventricular free wall (RV), LVA, and LVS of adult
Kv4.2W362FxKv1.4-/- animals and compared with
those from wild-type and Kv4.2W362F-expressing animals. As illustrated
in Figure 3A, peak outward
K+ current densities recorded at room
temperature from wild-type RV and LVA cells are markedly higher than
those of LVS cells. In addition, in RV and LVA cells, the decay phases
of the outward K+ currents evoked during 4-second
depolarizations were well fitted by the sum of 2 exponentials,
consistent with the expression of
Ito, f,
IK, slow, and the steady-state
noninactivating current
(ISS).5 17 19 20 21
Ito, s is not detectable in either RV or
LVA cells. As reported previously,5 17 in the
majority (80%) of wild-type LVS cells (Figure 3A), the decay
phases of outward K+ currents were well described
by the sum of 3 exponentials, reflecting the presence of
Ito, f,
Ito, s, IK,
slow, and ISS.
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Similar to the findings in left ventricular
myocytes,14 17 peak outward K+
currents are reduced and Ito, f is
selectively eliminated in RV cells isolated from the
Kv4.2W362F-expressing animals (Figure 3B
). As in LVA
cells,17 analysis of the decay phases of the
outward currents recorded (at room temperature) from
Kv4.2W362F-expressing RV cells also revealed the presence of a slow
transient outward K+ current with
decay (at +40 mV) of 214±29 ms (n=14). The
kinetic and pharmacological properties of this slow transient outward
K+ current in Kv4.2W362F-expressing RV and LVA
cells are indistinguishable, and both are similar to
Ito, s in wild-type LVS
cells.5 17 Because Kv1.4 has been shown to underlie
Ito, s in mouse LVS
cells,17 these observations suggested that Kv1.4
upregulation underlies the appearance of this current in
Kv4.2W362F-expressing RV and LVA cells. To test this hypothesis
directly, the Kv4.2W362F-expressing animals were crossed with the
Kv1.4-/- animals to produce mice expressing the
Kv4.2W362F transgene in the Kv1.4-/-
background. Whole-cell voltage-clamp recordings revealed that
peak outward K+ current densities are
substantially lower in RV, LVA, and LVS cells isolated from
Kv4.2W362Fx Kv1.4-/- mice, compared with the
currents recorded from Kv4.2W362F-expressing or wild-type cells
(see Table 2 online; available at http://www.circresaha.org). In
addition, as is evident in Figure 3C, the waveforms and the
densities of the depolarization-activated outward
K+ currents in
Kv4.2W362FxKv1.4-/- RV, LVA, and LVS cells are
remarkably similar. In all LVS cells (n=18) and in the majority of RV
(13 of 16) and LVA (23 of 28) cells studied, the decay phases of the
outward currents were well described by a single exponential with a
mean±SEM decay (at +40 mV) of 1308±63 ms
(n=54), consistent with the expression of
IK, slow and
ISS. The densities of
IK, slow and
ISS in Kv4.2W362Fx
Kv1.4-/- cells are not significantly different
from those in wild-type and Kv4.2W362F-expressing cells (see Table 2
online; available at http://www.circresaha.org).
Although results similar to those illustrated in Figure 3C were
obtained in the majority (80%) of Kv4.2W362Fx
Kv1.4-/- RV and LVA cells examined, a slow
transient outward K+ current
(decay=202±31 ms at +40 mV) was evident in 3
(of the 16) RV and in 5 (of the 28) LVA cells. The mean±SEM densities
of this current in these (RV and LVA) cells were 8.4±2.7 pA/pF and
10.9±2.1 pA/pF (at +40 mV), respectively. These findings suggest that
a distinct Kv subunit (other than Kv1.4) is upregulated either in
some (20%) Kv4.2W362F-expressing RV and LVA cells or,
alternatively, in a subset of RV and LVA cells in
Kv4.2W362FxKv1.4-/- animals (see
Discussion).
Outward K+ Current Waveforms in Mouse
Ventricular Myocytes at Physiological
Temperature
To facilitate comparison of the single-cell
electrophysiological data with the findings
in intact animals (see below), depolarization-activated outward
K+ currents were further examined at
physiological temperature. As illustrated in Figure 4A, when whole-cell recordings
were obtained at 35°C, the rates of outward current decay in
wild-type LVA cells are markedly accelerated compared with currents
recorded at 25°C (Figure 4C). The decay phases of the
outward K+ currents recorded at 35°C in
wild-type LVA cells are also well described by the sum of 2
exponentials with mean±SEM decay (at +40 mV)
of 30±3 ms for Ito, f and 337±29 ms for
IK, slow (n=10), values that are 2 to 3
times faster than those determined at 25°C. In addition, the
contribution of IK, slow to the peak
outward K+ currents is increased at 35°C. The
increased IK, slow is further evident in
experiments in which cells were exposed to 50 µmol/L
4-aminopyridine (4-AP), a concentration shown previously to
selectively attenuate
IK, slow.5 17 19 20 21 As
illustrated in Figure 4A, exposure of wild-type LVA cells to
50 µmol/L 4-AP at 35°C essentially eliminates
IK, slow. The density of 50 µmol/L
4-AP–sensitive currents (IK, slow) at
35°C (Figure 4B) is significantly higher than at 25°C
(Figure 4D). In addition, in some wild-type LVA cells examined
at room temperature, Ito, f is also
partially blocked by 50 µmol/L 4-AP (Figure 4D). The
ratio of current densities (at +40 mV) in wild-type LVA cells is, on
average, 4.5:4.5:1 for Ito, f,
IK, slow, and
ISS, respectively, at 35°C, compared with
6:3:1 at room temperature.
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Whole-cell voltage-clamp recordings were also obtained at
35°C from LVA cells isolated from Kv4.2W362F-expressing and
Kv4.2W362FxKv1.4-/- animals and were compared
with those routinely recorded at 25°C. As with the wild-type
cells, the main differences between the records obtained at these 2
recording temperatures are that the rates of outward
K+ current decay are greater at 35°C than at
25°C and that IK, slow densities are
increased significantly at 35°C (Figure 4). Importantly, at
35°C, as at 25°C, no Ito, s was
detected in the majority (8 of 10) of Kv4.2W362Fx
Kv1.4-/- (LVA) cells when
IK, slow was selectively blocked by
50 µmol/L 4-AP (Figures 4A and 4C).
Action Potentials Are Prolonged and Early Afterdepolarizations Are
Evident in Kv4.2W362FxKv1.4-/- Ventricular
Myocytes
To determine the effects of elimination of (the upregulated)
Ito, s and Ito, f
on action potential waveforms in Kv4.2W362FxKv1.4-/-
LVA cells, current-clamp recordings in these cells were
examined and compared with those recorded from wild-type and
Kv4.2W362F-expressing animals. Experiments were completed at 25°C and
35°C, as well as at different pacing rates. As illustrated in Figure 5, action potentials recorded at
35°C are significantly briefer than those recorded at 25°C. In
addition, at both 25°C and 35°C, action potentials recorded at
1 Hz from Kv4.2W362Fx Kv1.4-/- LVA cells (Figure 5C) are substantially broader than those recorded from
wild-type (Figure 5A) or Kv4.2W362F-expressing (Figure 5B) LVA cells. When action potentials were examined at higher
stimulation frequencies, ie, at 3 Hz (25°C) or at 10 Hz (35°C), the
action potential prolongation evident in
Kv4.2W362FxKv1.4-/- LVA cells was even more
pronounced (Table). Interestingly, early afterdepolarizations were
observed in 3 of 15 and 3 of 12
Kv4.2W362FxKv1.4-/- LVA cells recorded at
1 and 3 Hz, respectively, at 25°C (Figure 5C), whereas early
afterdepolarizations have never been observed in wild-type (n=41) or in
Kv4.2W362F-expressing (n=29) LVA cells.
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Marked QT Prolongation, Atrioventricular Block, and
Ventricular Tachycardia in
Kv4.2W362FxKv1.4-/- Mice
To determine the functional consequences of elimination of
Ito, f and Ito, s,
in vivo telemetric ECG recordings were obtained from
Kv4.2W362FxKv1.4-/- animals. As is evident in
Figure 6A, in adult wild-type mice, much
of the ventricular repolarization process (J junction–S-T
segment–T wave complex) is truncated as a large transient repolarizing
wave that appears as an r' wave at the end of QRS
wave. As reported previously,14 QT intervals are
longer in Kv4.2W362F-expressing animals (Figure 6C) than in
wild-type animals. In contrast, QT intervals in the
Kv1.4-/- animals (Figure 6B) are not
significantly different from those in controls. As is also evident,
there is a marked prolongation of the QT intervals, a significant
decrease in the amplitude, and a pronounced widening and slowing of the
transient repolarizing wave in the
Kv4.2W362FxKv1.4-/- animals (Figure 6D). In all animals, QT intervals were correlated with heart
rates, and QT intervals in the
Kv4.2W362FxKv1.4-/- mice are longer than those
of the Kv4.2W362F-expressing animals over a wide range of heart rates
(Figure 6E). When QT intervals were corrected for heart rate
(QTc), the differences between Kv4.2W362Fx
Kv1.4-/- and Kv4.2W362F transgenic animals
remained highly significant (Figure 6F). In contrast to the
effects on QT (QTc) intervals, no differences in PR intervals were
observed in wild-type (33.7±0.9 ms, n=6),
Kv1.4-/- (33.1±0.8 ms, n=6),
Kv4.2W362F-expressing (32.9±0.3 ms, n=5), or Kv4.2W362Fx
Kv1.4-/- (34.3±0.7 ms, n=5) animals.
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), Kv1.4-/- (
),
Kv4.2W362F-expressing (•), and Kv4.2W362FxKv1.4-/-
(
) animals (n=5 to 6) are plotted as a function of
heart rate in panel E. Average QT intervals and heart rates in each
3-minute recording episode were determined, and each point is
represented. In all animals, QT intervals are correlated
with heart rates, and the difference between Kv4.2W362F-expressing and
Kv4.2W362FxKv1.4-/- mice is evident over a wide range of
heart rates. F, QTc intervals for each animal were obtained by
averaging the measured QTc intervals in a total of 21 to 22 episodes.
QTc intervals in Kv4.2W362F-expressing and
Kv4.2W362FxKv1.4-/- animals are significantly
(*P<0.001) longer than in either wild-type or
Kv1.4-/- animals. In addition, QTc intervals are
significantly (#P<0.001) longer in
Kv4.2W362FxKv1.4-/- animals than in
Kv4.2W362F-expressing animals.
In addition to the pronounced effect on QT (QTc) intervals, other
ECG abnormalities were observed in the
Kv4.2W362FxKv1.4-/- animals. Mobitz type I
second-degree atrioventricular block (Figure 7A), for example, was detected in
telemetric ECG recordings from 4 of the 5
Kv4.2W362FxKv1.4-/- animals and was evident in
several recording episodes (4 of 21, 5 of 22, 5 of 21, or 7 of
22 episodes) in each animal. High-degree
atrioventricular block with multiple sequential dropped
beats (Figure 7B) was also observed in 2 of these 5 animals and
was evident in 2 of 21 and 3 of 22 episodes recorded, respectively.
In contrast to these observations, there was no evidence of
atrioventricular block in any of the wild-type (n=6) or
Kv1.4-/- (n=6) mice monitored. In 2 of the 5
Kv4.2W362F-expressing mice, Mobitz type I second-degree
atrioventricular block was detected and was only seen
in 2 of 22 recording episodes in each animal. In addition,
ventricular tachycardia was observed in (2
of 22 and 3 of 22 episodes recorded from) 2 of the 5
Kv4.2W362FxKv1.4-/- animals (Figure 7C). In this example, the arrhythmia may reflect isorhythmic
dissociation given that the R-R interval does not change significantly.
No evidence of spontaneous ventricular arrhythmias
has ever been obtained in wild-type, Kv1.4-/-,
or Kv4.2W362F-expressing mice.
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Discussion |
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Upregulation of Kv1.4 Underlies the Electrical Remodeling in Kv4.2W362F Transgenic Mice
The goals of the experiments here were to test directly the hypothesis that upregulation of Kv1.4 underlies the electrical remodeling evident in Kv4.2W362F-expressing ventricular myocytes and to examine the functional consequences of elimination of Ito, f and Ito, s. The whole-cell voltage-clamp data revealed that the slow transient outward K+ current, Ito, s, seen in all Kv4.2W362F-expressing RV and LVA cells is selectively eliminated in the majority (
80%) of Kv4.2W362Fx Kv1.4-/- RV
and LVA cells studied, whereas IK, slow
and ISS densities in these cells were
indistinguishable from those of wild-type and Kv4.2W362F-expressing
cells. These results demonstrate the functional role of Kv1.4 in the
upregulation of Ito, s in
Kv4.2W362F-expressing animals. Nevertheless, a slow transient outward
K+ current is evident in a small subset
(20%) of RV and LVA cells from the Kv4.2W362Fx
Kv1.4-/- mice. Because
Ito, s is not detectable in
Kv1.4-/- LVS cells, we concluded that Kv1.4
underlies Ito, s in all wild-type
ventricular myocytes.17 The finding of a
slow transient outward K+ current in a subset of
ventricular cells from
Kv4.2W362FxKv1.4-/- animals, however, suggests
that other K+ channel subunits contribute to
the generation of Ito, s in
Kv4.2W362FxKv1.4-/- animals as well, perhaps,
as in Kv4.2W362F-expressing animals. Because heterologous expression of
Kv1.7 as well as Kv3 subunits also reveals transient outward
K+ currents,22 23 it is
possible that these subunits contribute to the slow transient outward
K+ current remaining in a subset of
Kv4.2W362FxKv1.4-/- ventricular
cells. Experiments aimed at testing this hypothesis will clearly be of
interest.
Kv4.2W362F-Expressing and Kv4.2W362FxKv1.4-/-
Animals Are Phenotypically Normal
It has recently been reported that
myocardium-specific expression of an N-terminal fragment of
Kv4.2 subunit (Kv4.2N) results in dilated
cardiomyopathy in adult mice.18 These
observations prompted us to explore in detail the phenotypic
consequences of Kv4.2W362F expression alone, as well as Kv4.2W362F in
the Kv1.4-/- background.
Histological and echocardiographic
studies revealed no evidence of left ventricular
hypertrophy, chamber dilation, or contractile dysfunction
in Kv4.2W362F-expressing or
Kv4.2W362FxKv1.4-/- animals. With respect to
structure and function, therefore, the experiments completed here
demonstrate that the Kv4.2W362F-expressing animals (which lack
Ito, f) and the
Kv4.2W362FxKv1.4-/- animals (which lack both
Ito, f and
Ito, s) are phenotypically normal; only
the electrical properties of the hearts of these animals are affected.
These findings suggest that the dilated
cardiomyopathy seen in the Kv4.2N-expressing
transgenic animals does not reflect the attenuation of
Ito, f, as previously
suggested.18 There are certainly other possible
interpretations of the rather profound effects of Kv4.2N expression
reported by Wickenden et al,18 including a direct toxic
effect of the Kv4.2N transgene. It is of interest to note here also
that Ito, s and the expression level of
Kv1.4 are upregulated in a variety of
cardiovascular disease states, such as myocardial
infarction.24 The findings that the hearts of
Kv4.2W362F-expressing (in which Kv1.4 is upregulated),
Kv1.4-/-, and
Kv4.2W362FxKv1.4-/- (both of which lack Kv1.4)
mice are indistinguishable from wild-type animals, however, clearly
demonstrate that changes in Kv1.4 expression in mice do not cause and
need not be associated with pathology.
Functional Consequences of Elimination of
Ito, f and
Ito, s
Consistent with the absence of
Ito, f and
Ito, s, action potentials recorded
from Kv4.2W362FxKv1.4-/-
ventricular cells are prolonged significantly relative to
action potentials in wild-type and Kv4.2W362F-expressing
ventricular cells. In addition, early afterdepolarizations
were observed in some of the
Kv4.2W362FxKv1.4-/- cells. The elimination of
both Ito, f and
Ito, s also results in more profound
prolongation of the QT intervals compared with Kv4.2W362F-expressing
transgenic animals. Interestingly, the transient repolarizing wave,
which is the dominant repolarizing vector in the ECGs of adult
wild-type mice, is significantly reduced and slowed in
Kv4.2W362FxKv1.4-/- animals. By assessing ECGs
and response to selective K+ channel blockers,
Wang et al25 recently demonstrated that the
4-AP–sensitive K+ currents
(Ito, f,
Ito, s, and
IK, slow), which underlie the spatial
heterogeneity of action potential configurations in
mouse ventricle,17 contribute to the transient
repolarizing wave in ECGs recorded from adult mice. The decrease in
the amplitude and the slowing of the transient repolarizing wave in the
ECGs of Kv4.2W362FxKv1.4-/- mice, therefore,
likely reflect the (almost) complete absence of transient outward
K+ currents (Ito, f
and Ito, s) and the loss of the normal
heterogeneities in repolarization in these animals.
In contrast to the effects of expression of
Kv4.2W362F14 17 or the deletion of Kv1.416
alone, elimination of both Ito, f and
Ito, s in
Kv4.2W362FxKv1.4-/- animals produces profound
electrocardiographic abnormalities. Mobitz type I second-degree
atrioventricular block, for example, was observed in 4
of the 5 Kv4.2W362FxKv1.4-/- mice. In
addition, in 2 of these animals, higher-degree
atrioventricular block was evident. Spontaneous
ventricular tachycardia was also observed in 2
(of the 5) Kv4.2W362FxKv1.4-/- mice studied.
These observations suggest that the upregulation of Kv1.4 subunit
(and Ito, s) protects the mouse heart from
the arrhythmogenic effects of loss of
Ito, f in Kv4.2W362F-expressing animals
and that elimination of (most of) this upregulated
Ito, s in
Kv4.2W362FxKv1.4-/- animals results in
dramatic electrophysiological
consequences.
Atrioventricular block has also recently been reported in KvLQT1-deficient transgenic mice, demonstrating the functional importance of KvLQT1 K+ channels in murine atrioventricular conduction.26 Nevertheless, the molecular mechanism responsible for the development of atrioventricular block in the Kv4.2W362FxKv1.4-/- animals remains unclear. The finding that atrioventricular block is only prominent in the Kv4.2W362FxKv1.4-/- animals suggests that electrical remodeling (ie, upregulation of Ito, s) may also occur in the (atrioventricular) conducting system in Kv4.2W362F-expressing mice. If this interpretation is correct, the upregulation of Ito, s in AV nodal cells is protective, and elimination of both Ito, f and Ito, s significantly interrupts atrioventricular conduction. Clearly, experiments aimed at detailing the electrophysiological properties of voltage-gated K+ channels, especially the Ito, f and Ito, s channels, in the murine atrioventricular conduction system will be of great interest.
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Acknowledgments |
|---|
The financial support provided by NIH and the American Heart Association (B.L., J.M.N.), the Monsanto/Searle/Washington University Biomedical Agreement (J.M.N.), and the Midwest Affiliate of AHA (postdoctoral fellowship to W.G.) is gratefully acknowledged. We thank Andrew Benedict and Rebecca Hood for technical assistance throughout the course of this work. We also thank Drs Carla Weinheimer, Kathryn Yamada, Attila Kovacs, and Mike Courtois (Washington University School of Medicine) for assistance with the telemetric ECG recordings and echocardiography.
Received May 11, 2000; accepted May 18, 2000.
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M. H. Holmqvist, J. Cao, M. H. Knoppers, M. E. Jurman, P. S. Distefano, K. J. Rhodes, Y. Xie, and W. F. An Kinetic Modulation of Kv4-Mediated A-Current by Arachidonic Acid Is Dependent on Potassium Channel Interacting Proteins J. Neurosci., June 15, 2001; 21(12): 4154 - 4161. [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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M. R. Rosen The Real Thing Circ. Res., July 7, 2000; 87(1): 6 - 7. [Full Text] [PDF]
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B. London, W. Guo, X.-h. Pan, J. S. Lee, V. Shusterman, C. J. Rocco, D. A. Logothetis, J. M. Nerbonne, and J. A. Hill Targeted Replacement of Kv1.5 in the Mouse Leads to Loss of the 4-Aminopyridine-Sensitive Component of IK,slow and Resistance to Drug-Induced QT Prolongation Circ. Res., May 11, 2001; 88(9): 940 - 946. [Abstract] [Full Text] [PDF]
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J. M.B. Anumonwo, Y. N. Tallini, F. J. Vetter, and J. Jalife Action Potential Characteristics and Arrhythmogenic Properties of the Cardiac Conduction System of the Murine Heart Circ. Res., August 17, 2001; 89(4): 329 - 335. [Abstract] [Full Text] [PDF]
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Z. Kassiri, C. Zobel, T.-T. T. Nguyen, J. D. Molkentin, and P. H. Backx Reduction of Ito Causes Hypertrophy in Neonatal Rat Ventricular Myocytes Circ. Res., March 22, 2002; 90(5): 578 - 585. [Abstract] [Full Text] [PDF]
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W. Guo, H. Li, F. Aimond, D. C. Johns, K. J. Rhodes, J. S. Trimmer, and J. M. Nerbonne Role of Heteromultimers in the Generation of Myocardial Transient Outward K+ Currents Circ. Res., March 22, 2002; 90(5): 586 - 593. [Abstract] [Full Text] [PDF]
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R. Sah, G. Y. Oudit, T.-T. T. Nguyen, H. W. Lim, A. D. Wickenden, G. J. Wilson, J. D. Molkentin, and P. H. Backx Inhibition of Calcineurin and Sarcolemmal Ca2+ Influx Protects Cardiac Morphology and Ventricular Function in Kv4.2N Transgenic Mice Circulation, April 16, 2002; 105(15): 1850 - 1856. [Abstract] [Full Text] [PDF]
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