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1 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; and 2 Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We created a mouse model with a prolonged Q-T interval
and spontaneous arrhythmias by overexpressing the NH2
terminus and first transmembrane segment (Kv1.1N206Tag) of a
delayed rectifier potassium channel
(LQT+/
mouse). Analyses were performed
using whole cell recordings of cardiac myocytes, surface
electrocardiography, and programmed electrical stimulation. Action
potential duration (APD) was prolonged to the same extent and was more
highly variable in myocytes derived from
LQT+/ and LQT+/+ mice than
in myocytes derived from wild-type (WT) FVB mice. Under ketamine
anesthesia, the Q-T interval of both LQT+/+ and
LQT+/ mice was comparably prolonged
versus that of WT mice. Stimulation of the right ventricle using an
intracardiac catheter induced polymorphic ventricular tachyarrhythmias
in 50% of the LQT+/ mice and 36% of
the LQT+/+ mice, whereas polymorphic ventricular
tachyarrhythmias were not inducible in WT mice. The analyses of
LQT+/ and LQT+/+ mice
indicate that prolongation of the Q-T interval in LQT mice is
associated with prolonged APD, increased dispersion of APD among
cardiocytes, and inducibility of polymorphic ventricular tachycardia,
providing the substrate for spontaneous arrhythmias in these animals.
transgenic mice; long Q-T syndrome; Q-T interval; programmed stimulation; ventricular arrhythmias
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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GENETICALLY ENGINEERED MOUSE MODELS may increase our
understanding of the pathophysiology of inherited human diseases caused by mutations in genes that control cardiac development and function. Prolongation of the Q-T interval, polymorphic ventricular tachycardia, and an increased incidence of sudden death characterize the congenital long-QT syndrome (LQTS) (15). The prolonged ventricular repolarization and dispersion of refractoriness in LQTS is related to loss-of-function mutations that occur in genes encoding 
- or 
-subunits of
voltage-gated potassium channels in the heart such as KvLQT1,
MinK or HERG (6, 16-19). However, the precise
mechanism by which the mutations lead to cardiac arrhythmias is
uncertain. Many pharmacological models of LQTS have been proposed;
however, no genetic animal models are currently available.
Koren and colleagues (2) showed previously that an
NH2-terminal fragment that contains the first transmembrane
segment of the rat delayed rectifier K+ channel Kv1.1
(Kv1.1N206Tag) coassembles with Shaker-like
K+ channels in vitro and inhibits the currents coded by
Kv1.5 cDNA in a dominant negative manner when coexpressed in
Xenopus oocytes. Recently, Koren and co-workers (8)
demonstrated that the mechanism of the dominant negative effect of
Kv1.1N206Tag involves the trapping of Kv1.5 and Kv1.4
polypeptides in the endoplasmic reticulum. Cardiac myocytes derived
from these mice have prolonged action potential duration (APD) because
of a significant reduction in the current density of a rapidly
activating, slowly inactivating 4-aminopyridine-sensitive outward
K+ current (Islow) (12, 21).
Overexpression of Kv1.1N206Tag in the heart of heterozygous
transgenic mice (LQT+/) resulted in
prolongation of the Q-T interval and spontaneous ventricular
arrhythmias (21). Recently, several other models, using a dominant
negative or gene knockout approach against Kv4, MinK, or
MERG, with or without comparable Q-T prolongation, resulted in
inhibition of the currents encoded by these genes (1, 4, 9). Moreover,
the attenuation of Kv4-encoded currents also resulted in a significant
prolongation of the Q-T interval (4).
In the present study, we characterized mice homozygous for the transgene and compared the effect of additional copies of the transgene on APD and Q-T intervals. Moreover, we used this model system to determine whether sustained ventricular arrhythmias can be reproducibly induced by programmed ventricular stimulation in the LQT mouse and to evaluate the surface electrocardiogram (ECG) morphology of any induced ventricular arrhythmias.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study animals.
Derivation of the heterozygous (LQT+/)
mice used in this study has been described previously (12). To
characterize the effects of additional copies of the transgene, mice
homozygous for the Kv1.1N206Tag transgene (LQT+/+)
were obtained by breeding heterozygous male and female mice. Homozygosity of the F1 offspring was then evaluated by back-breeding with wild-type (WT) FVB mice. Studies were attempted in 19 WT, 20 LQT+/, and 16 LQT+/+
animals. Baseline ECGs were obtained on all animals. However, only
animals that completed the full stimulation protocol were included in
the electrophysiological analyses (15 WT, 14 LQT+/, and 14 LQT+/+
animals). The animals ranged in age from 12 to 30 wk. There were no
significant differences in body weight [31.8 ± 2.4 vs. 32.9 ± 2.4 vs. 32.4 ± 3.7 g, P = not significant (NS)] or age
(18 ± 5 vs. 20 ± 6 vs. 18 ± 5 wk, P = NS) among WT,
LQT+/, and LQT+/+ animals,
respectively. The average duration of the protocol was 59 ± 16 min.
and
LQT+/+ mice (P = NS). Studies were performed in
accordance with the guidelines of the Harvard Medical Area Standing
Committee on Animals, following approval by the Institutional Animal
Care and Use Committee.
Surface ECG. After the induction of anesthesia, a 12-lead electrocardiogram was obtained by placing needle electrodes subcutaneously in each limb (27-gauge needles) and by moving a single chest electrode to sequentially record the 6 V leads. The signal was amplified and filtered (from 1 Hz to 100 Hz; PPG ARC 6 recorder), digitized at a 500-Hz sampling rate using a 16-bit analog-to-digital converter (AT-M10-16XE-10; National Instruments), and stored on the hard drive of a personal computer. All ECG intervals (P, P-R, QRS, Q-T, Q-Tc, J-T, J-Tc, and R-R) and axes (P, QRS, T) were measured for each mouse by a blinded observer using the 12-lead printout. To correct the Q-T and J-T intervals (Q-Tc and J-Tc), we used the recently established correction formula for mice (12, 14).
Electrophysiological study protocol. With the use of an operating microscope, the right internal jugular vein was dissected and encircled with two 5-0 silk sutures without disrupting the blood flow. An incision was made between the sutures with microscissors. A quadrupolar 2-F stimulation catheter (NuMed, Nicholville, NY) was advanced to the right ventricle. The heart rate and cardiac rhythm were monitored continuously throughout the procedure. A heating lamp was used to maintain body temperature.
The stimulation protocol we used was similar to electrophysiological protocols used in humans (13) and recently adapted for mice (5). Briefly, bipolar voltage pacing thresholds were measured at both locations using a 1-ms pulse width. Stimulation was subsequently performed using twice the diastolic voltage threshold. Ventricular refractory period was measured using pacing trains of 20 beats at a basic cycle length of 100 ms with a single extrastimulus. The S1 interval was decremented by 10 ms between trains. However, in a preliminary analysis, this 10-ms interval proved too coarse to detect a difference among the groups. Therefore, the protocol was modified to use a 10-ms decremental interval to establish a preliminary right ventricular effective refractory period (RVERP). The S1 interval was then increased by 8 ms from this preliminary value, followed by 2-ms decrements to determine the final RVERP. This modified protocol was performed in seven WT, seven LQT+/, and six LQT+/+ animals.
To induce ventricular arrhythmias, we introduced extrastimuli following
a 10- or 20-beat train with a basic cycle length of 100 ms. After the
train, one extrastimulus was added. If arrhythmia was not inducible in
the mouse, second and third stimuli were added in a stepwise fashion.
In those mice in which arrhythmia was not inducible following the
addition of the third extrastimulus, the protocol was repeated
following a train with a basic cycle length of 70 ms. To assess the
adrenergic effects on the susceptibility to ventricular arrhythmias
that were not inducible in mice at baseline, 30 µg of isoproterenol
(200 µg /ml) were given intraperitoneally to obtain a stable heart
rate increase of at least 30% over the basal heart rate under
anesthesia. After several minutes, the ventricular pacing protocol was
repeated. Evoked groups of one to four extrasystoles were defined as
ventricular premature depolarizations, and five or more consecutive
complexes were defined as ventricular tachycardia. Ventricular
tachycardia was defined as discrete complexes with a clearly definable
rate, whereas ventricular fibrillation was defined as a morphology that
changes from beat to beat with no clearly definable rate (20).
Southern and Northern blotting.
Tail DNA was digested with BamH I and transferred to a nylon
membrane. The probe used contained a 505-bp PCR fragment derived from
the MyHC promoter (position 585 to 1090 bp) labeled with the DIG
system (Boehringer). The film was exposed for 30 min. Total RNA was
isolated using standard techniques. The probe used was a 600-bp
EcoR I-Cla I fragment derived from Kv1.1. Film
was exposed overnight.
Myocytes preparation and cellular electrophysiological study. Single myocytes were obtained as described previously (21) with a few modifications. Briefly, Langendorff-perfused hearts were prepared from the control and age-matched LQT adult FVB mice and subjected to 3-5 min of perfusion with nominally Ca2+- free Tyrode solution [containing (in mM) 137 NaCl, 5.4 KCl, 1.2 MgCl2, 10 glucose, 10 HEPES, and 0.25 Na2-EDTA; pH 7.35], followed by a perfusion with enzyme-containing Tyrode solution [0.5 mg/ml collagenase (type I; Worthington, Lakewood, NJ), 0.25 mg/ml hyaluronidase (Sigma, St. Louis, MO), and 1 mg/ml fatty acid-free BSA (Sigma)] for 8-12 min. The ventricles were then chopped into small pieces, incubated at 37°C in the same enzyme solution for 5-10 min, and mechanically dispersed. After repeated washings by a series of centrifugations at 500 rpm for 2-3 min, followed by resuspensions in 0.25 and then 0.5 mM Ca2+-containing Tyrode solution supplemented with 1-2% FCS, cells were stored in normal Tyrode solution (1.0 mM Ca2+) containing 2% FCS. Calcium-tolerant, rod-shaped ventricular myocytes with clear striations were selected randomly for the electrophysiological studies. APD was evaluated at room temperature as described previously (21).
Statistical analysis. Continuous variables were compared using an ANOVA with Sheffé's post hoc analysis. A Levene test was performed to test for homogeneity of variance. Variables with unequal variances were first log transformed and then retested. If the Levene statistic remained significant, the untransformed variable was compared using the Kruskal-Wallis H test. A chi-square test was used for categorical variables. All data are presented as means ± SD. P values <0.05 were considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Electrophysiological data.
Southern blotting of tail DNA obtained from mice homozygous for the
transgene (LQT+/+) revealed an increased intensity of the
transgene relative to the native MyHC gene in homozygotes compared
with the heterozygotes (LQT+/) (Fig.
1A). Furthermore, breeding the
LQT+/+ mice with control FVB mice resulted in F1 litters
that were all heterozygous for the transgene (data not shown),
confirming the presence of duplicate copies of the transgene in
LQT+/+ mice. Northern blot analysis of total cardiac RNA
revealed that Kv1.1N206Tag transcript is not detectable in WT
mice. Moreover, in LQT+/+ mice, an increase in the
steady-state levels of Kv1.1N206Tag transcript was observed
(Fig. 1B). To determine whether increased expression of the
transgene transcript modulates the phenotype, we characterized the APD.
Table 1 shows the APD parameters obtained from cardiac myocytes derived from WT,
LQT+/, and LQT+/+ hearts. As
reported previously (21), APD varied considerably with a significant
difference in variance among the groups (Levene statistics:
APD30, P < 0.02; APD50, P < 0.001; APD70, P = 0.001; APD90,
P = 0.064; where APD30-APD90 are
APDs at 30-90% of full repolarization). With the use
of nonparametric testing, the APD30, APD50,
APD70 and APD90 of cardiocytes derived from
LQT+/ and LQT+/+ mice were
significantly prolonged compared with those derived from WT mice.
However, there were no differences between the APDs of
LQT+/ and LQT+/+ mice (Fig.
2A). The frequency distribution of
APD50 and APD70 (Fig. 2, B and
C) reveals that both LQT+/ and
LQT+/+ myocytes tended to show a positive skew with a
significantly larger variance, indicating that these mice have
cardiocytes with substantially longer APDs as well as cardiocytes with
APDs that overlap those of WT cardiocytes.
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Electrocardiographic data.
Representative lead I surface ECG recordings of five anesthetized WT
(Fig. 3A) and five
LQT+/ and LQT+/+ mice are
shown (Fig. 3, B and C). A prolonged Q-T interval was found in LQT mice compared with that in WT mice (Table
2). Comparable differences were detected in
the J-T and J-Tc intervals (Table 2 and Fig. 3). Thus both the
LQT+/ and LQT+/+ mice were
characterized by a marked and comparable prolongation of the Q-T
interval. The average heart rate under ketamine anesthesia did not
differ among the three groups (Table 2). The P-R and QRS intervals did
not differ among the three groups. There was a tendency for a more
leftward P-wave axis in the LQT mice compared with that in WT mice.
This difference was statistically significant only for the comparison
between LQT+/ and WT mice. There were no
significant differences in the axis of the QRS or T wave (Table 2).
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Electrophysiological testing.
Ventricular pacing thresholds were comparable in the WT,
LQT+/, and LQT+/+ animals
(0.6 ± 0.2 vs. 0.7 ± 0.3 vs. 0.6 ± 0.3 V, respectively, all
P = NS). When ventricular refractory period was assessed with a
2-ms resolution, significant prolongation was demonstrated only in the
LQT+/+ animals (WT: 53 ± 6;
LQT+/: 56 ± 6; LQT+/+: 65 ± 8 ms; P < 0.02 for the main effect and P < 0.05 for WT vs. LQT+/+). Baseline Q-Tc intervals for these
animals were 56 ± 4, 76 ± 4, and 77 ± 8 ms, respectively
(P < 0.001). Both LQT+/ and
LQT+/+ animals had a significantly prolonged Q-Tc interval
compared with WT animals (P < 0.05 for both post hoc comparisons).
, and 10 of 14 LQT+/+
animals (P < 0.001, Fig. 4).
Ventricular tachycardia was not inducible in any WT animals with up to
three extrastimuli and isoproterenol but was inducible in 7 of 14 LQT+/ and 5 of 14 LQT+/+
animals (P < 0.01, Figs. 4,
5A, and 5B, i,
ii, and iii). The likelihood of induction in
LQT+/ did not differ significantly from
that in LQT+/+ mice. Of the mice in which ventricular
tachycardia was inducible, isoproterenol was required for induction in
5 of 7 LQT+/ and 2 of 5 LQT+/+ mice. Ventricular arrhythmias had a polymorphic
configuration with a duration of 300-6,488 ms (Fig. 5). All
arrhythmias terminated spontaneously. Short-duration ventricular
tachycardia was generally followed by sinus rhythm, whereas
longer-duration ventricular tachycardia was followed by escape
complexes with sinus bradycardia and eventual recovery of sinus rhythm,
suggesting hemodynamic compromise during prolonged episodes of
ventricular tachycardia (Fig. 5A). However, all animals
recovered from all episodes of ventricular tachycardia. No episodes of
ventricular fibrillation were observed.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We used 12-lead surface ECG and programmed electrical stimulation of
mice to further assess the role of the dominant negative mutant
Kv1.1N206Tag transgene in cardiac excitation. We report that
under ketamine and xylazine anesthesia, homozygous and heterozygous LQT
mice had prolongation of the Q-T interval. Analysis of APD revealed
similar prolongation in both LQT+/ and
LQT+/+ mice. Analysis of the RVERP revealed that it is
significantly prolonged in LQT+/+ mice, with an
intermediate value in LQT+/ mice that
was not significantly different from that in either WT or
LQT+/+ mice. Programmed electrical stimulation of the right
ventricle using a transvenous catheter induced polymorphic ventricular
tachycardia in a significant proportion of
LQT+/ and LQT+/+ mice,
whereas ventricular tachycardia was not inducible in WT FVB mice. The
results of this study demonstrate that the suppression of a specific
potassium current in mouse ventricular myocytes by genetic manipulation
resulted in prolongation of APD and Q-T interval and in inducible
polymorphic ventricular arrhythmias that are similar to those observed
in patients with LQTS.
Transgenic mouse models offer the opportunity to evaluate the physiological correlates of altered expression of voltage-gated potassium channels (11). In this study, we described the presence of Q-T prolongation in LQT mice. We evaluated the relationship between the transgene copy number, APD, and Q-T interval in mice. Doubling of the number of copies of the transgene resulted in an increase in the steady-state levels of the transcript. However, there was not further prolongation of the Q-T interval or APD with increasing copy number. These results confirm previous observations (12, 21) that the level of expression of the transgene transcript and polypeptide in heterozygous mice was sufficient to suppress the steady-state level of Kv1.5 polypeptide and inhibit most or all Islow (12, 21). The multiple copies of Kv1.1N206 transgene that are integrated into the genome of heterozygous LQT mice result in the expression of a sufficient amount of the dominant negative polypeptide. Thus, even in the presence of two wild-type alleles, the overexpressed truncated Kv1.1N206 polypeptide could suppress most of the expression of Islow, and further duplication did not have an additive dominant negative effect.
Here we demonstrated that cells derived from LQT mice have longer APD
with substantially larger variance. We speculate that the cells with
shorter APD may originate from a different region of the heart. Indeed,
Baker et al. (3) showed that APDs of epicardial cardiocytes in the WT
mouse heart were heterogenous, with the mean APD75 at the
apex shorter by 10 ms than the APD at the base. The heterogeneity of
APDs was more pronounced in transgenic hearts, with the mean
APD75 at the apex shorter by 29 ms than the APD at the
base. Furthermore, the effective refractory period at the apex of the
left ventricle is substantially shorter than at the base in
Langendorff-perfused LQT+/ hearts (3).
We therefore studied the outward potassium currents expressed in
cardiac myocytes derived from either the apex or the base of the left
ventricle. Our studies show that LQT+/
cardiocytes derived from these regions express similar densities of
transient outward K+ currents (Ito) (J
Zhou, M Murata, P Buckett, P Hwang, and G Koren, unpublished
observations). Interestingly, in LQT myocytes, the elimination of Islow was associated with a 70%
induction of a TEA-sensitive current with slower inactivation kinetics
(IKslow2) (22). Ongoing studies in our laboratory
suggest that a higher induction of IKslow2 in
apical cardiocytes may account for restricted prolongation of the APDs
at the apex and an increase in the APD heterogeneity observed in LQT hearts.
Here we report that, as expected, RVERP is significantly prolonged in
LQT+/+ mice compared with that in controls, whereas in
LQT+/ mice the difference did not
achieve statistical significance. The lack of significance may arise
from variable positioning of the catheter within different locations in
the right ventricle, because there is a significant gradient of the
effective refractory period between the apex and base (shorter at the
apex) (3). The slightly shorter RVERP in
LQT+/ mice compared with
LQT+/+ may have resulted from fortuitous placement of the
catheter in a more apical location in
LQT+/ mice.
Cardiac action potential represents a balance between multiple depolarizing and repolarizing currents. Reduced outward currents through voltage-gated potassium channels or persistent depolarizing currents through voltage-gated sodium channels can prolong the APD and create the long Q-T phenotype (6, 10, 16-19). Slowing of the heart rate in the presence of action potential prolongation may lead to increased incidence of early afterdepolarization, which may trigger polymorphic ventricular tachyarrhythmias such as torsade de pointes. These arrhythmias can later deteriorate to ventricular fibrillation and sudden death. Several mechanisms have been proposed to explain the development of polymorphic ventricular tachycardia and ventricular fibrillation. Recent work suggests that fast polymorphic ventricular tachycardia (with or without torsade de pointes configuration) is caused by reentrant excitation, which may be initiated by subendocardial (triggered) activity (7).
Recently, Barry et al. (4) reported the generation and characterization
of transgenic mice with the long Q-T phenotype following overexpression
of a dominant negative Kv4 polypeptide in the heart. The expression of
Kv4.2 pore mutant (Kv4.2W362F) in ventricular myocytes resulted
in attenuation of Ito. The APD and Q-T
prolongations were both greater than those observed in our LQT mice.
However, in contrast to our LQT mice, induction of arrhythmias could
not be elicited (JM Nerbonne, personal communication). These observations clearly suggest that prolongation of the APD and Q-T
interval are not sufficient for induction of arrhythmias. As previously
described, our LQT+/ mice are
characterized by an increase in the frequency of ventricular premature
beats and spontaneous episodes of ventricular tachycardia during
conscious telemetric monitoring of mice heterozygous for the transgene
(12). Baker et al. (3) also showed that programmed stimulation at the
apex of hearts derived from our LQT+/
mice perfused on a Langendorff system can elicit long-lasting reentrant
ventricular tachycardia. Optical mapping experiments revealed that the
ventricular tachycardia is initiated when the premature beat encounters
a functional line of block that causes unidirectional propagation.
Subsequent beats of ventricular tachycardia could be maintained for
>30 min. That work established that spatial dispersion of
repolarization with substantially longer effective refractory period at
the base created functional block and reentry, which underlies the
mechanism for ventricular tachycardia induced by programmed electrical
stimulation. Here we demonstrated that programmed electrical
stimulation of the right ventricle, in vivo, induced torsade de
pointes-like polymorphic ventricular tachycardia. We speculate that
programmed electrical stimulation of the right ventricle may induce
more than one reentrant pathway, which may underlie the polymorphic and
transient nature of the arrhythmia we observed in LQT mice. Thus these
LQT mouse ventricles can sustain what is likely to be a reentrant
arrhythmia with morphological features that are similar to clinically
observed torsade de pointes.
Limitations of our study. Polymorphic ventricular tachycardia cannot be induced in control mice. In that respect mouse hearts differ from those of larger mammals, including humans, in which polymorphic ventricular tachycardia may be induced even in normal hearts with a maximal stimulation protocol (S3) that includes isoproterenol. Initiation of ventricular tachycardia using programmed electrical stimulation is somewhat artificial; however, in every other regard, including the changing morphology and relatively high rates, this induced arrhythmia in LQT mice resembles clinical torsade de pointes. We recognize the limitations of a small animal model for arrhythmias. However, we would like to stress that these small animal models provide a unique opportunity to evaluate the mechanism of arrhythmias both in vivo and in vitro in intact hearts, where all cells are affected by the repolarization abnormality. This model will also provide an invaluable opportunity to assess the feasibility of in vivo gene transfer techniques as an approach to treatment. Such techniques, which can be somewhat nonuniform and therefore potentially of no value in the intact heart, can be evaluated in our model, which has a stable, readily assessable phenotype in terms of both a long Q-T interval on ECG and, more importantly, inducibility of ventricular tachycardia.
We have previously shown that ketamine anesthesia prolongs the Q-T interval in WT mice (14) and that this effect is enhanced in LQT+/ mice (12). However, sustained
arrhythmia can be induced in the Langendorff-perfused
LQT+/ mouse heart in the absence of
ketamine. Furthermore, we have observed spontaneous ventricular
arrhythmias in conscious, monitored LQT+/ mice, suggesting that ketamine is
not necessary for arrhythmia induction in this model.
In summary, the LQT mouse is the only genetic model with ventricular
arrhythmias that resemble those observed in patients with LQTS. This
model will be used to test for novel genetic and pharmacological
therapeutic approaches to preventing channel-related arrhythmias in
this and other models of LQTS.
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ACKNOWLEDGEMENTS |
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During this study, A. Jeron was a recipient of a fellowship from the Deutsche Forschungsgemeinschaft (Je235/1-1). B. London was a recipient of National Heart, Lung, and Blood Institute (NHLBI) Grant HL-02843 and an American Heart Association (AHA) Grant in Aid. G. Koren was a recipient of NHLBI Grant HL-46005 and an AHA Established Investigator Award. M. Murata is an awardee of a Research Fellowship from the Japan Heart Institute.
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FOOTNOTES |
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Part of this study was presented as an abstract at the AHA Annual Meeting, Dallas, TX, November 1998.
Present address of A. Jeron: Medizinische Klinik II, Universität Regensburg, Franz-Josef Strauss-Allee 11, 93042 Regensburg, Germany.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. Koren, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115 (E-mail: koren{at}calvin.bwh.harvard.edu).
Received 11 March 1999; accepted in final form 2 December 1999.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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