(Circulation. 2001;103:1585.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Left Ventricular Hypertrophy Decreases Slowly but Not Rapidly Activating Delayed Rectifier Potassium Currents of Epicardial and Endocardial Myocytes in Rabbits
From Main Line Health Heart Center, Wynnewood, Pa (X.X., Y.W., T.L., D.B.B., R.A.M., P.R.K.); HeartCare, Inc, Columbus, Ohio (S.J.R.); and the Department of Pharmacology, Merck Research Laboratories, West Point, Pa (J.J.S.).
Correspondence to Xiaoping Xu, PhD, Cardiology Foundation of Lankenau, Suite 558, MOB East, 100 Lancaster Ave, Wynnewood, PA 19096. E-mail xxujwang{at}aol.com
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Abstract |
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Background—Delayed rectifier K+ currents are critical to action potential (AP) repolarization. The present study examines the effects of left ventricular hypertrophy (LVH) on delayed rectifier K+ currents and their contribution to AP repolarization in both epicardial (Epi) and endocardial (Endo) myocytes.
Methods and Results—LVH
was induced in rabbits by a 1-kidney removal, 1-kidney vascular
clamping method. Slowly
(IKs)
and rapidly
(IKr)
activating delayed rectifier K+ currents
were recorded by the whole-cell patch-clamp technique, and APs were
recorded by the microelectrode technique. In normal rabbit left
ventricular myocytes,
IKs
densities were larger in Epi than in Endo (1.1±0.1 versus 0.43±0.07
pA/pF), whereas
IKr
density was similar between Epi and Endo (0.31±0.05 versus 0.36±0.07
pA/pF) at 20 mV. LVH reduced
IKs
density to a similar extent (
40%) in both Epi and Endo but had no
significant effect on
IKr in
either Epi or Endo. Consequently,
IKr was
expected to contribute more to AP repolarization in LVH than in
control. This was confirmed by specific
IKr
block with dofetilide, which prolonged AP significantly more in LVH
than in control (31±3% versus 18±2% in Epi; 53±6% versus 32±4%
in Endo at 2 Hz). In contrast, L-768,673 (a specific
IKs
blocker) prolonged AP less in LVH than in control. The very small
IKs
density in Endo with LVH is consistent with the greater
incidence of early afterdepolarizations induced in this region by
dofetilide.
Conclusions—LVH induces a decrease in IKs density and increases the propensity to develop early afterdepolarizations, especially in Endo.
Key Words: action potentials • hypertrophy • ion channels
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Left ventricular hypertrophy (LVH) is associated with abnormal ventricular electrophysiology and increased risk of sudden cardiac death that is thought to be due to malignant ventricular arrhythmia. The action potentials (APs) of hypertrophied ventricular myocytes have long and nonuniform repolarization times. This dispersion of action potential duration (APD) is a milieu in which early afterdepolarizations (EADs) can generate sustained and highly disorganized ventricular arrhythmia. The ionic mechanisms underlying the prolonged APD of hypertrophied myocytes are complicated.
Although the effects of LVH on L-type Ca2+ current (ICa,L), transient outward K+ current (Ito), and inward rectifier K+ current (IK1) have been extensively studied (for review, see Reference 11 ), LVH-induced modulation of the cardiac delayed rectifier K+ current (IK) has received less attention despite its importance in determining ventricular repolarization and APDs, which are prolonged in LVH.1 2 3 In feline right ventricular hypertrophy induced by pressure overload4 and LVH induced by aortic stenosis,5 total IK density was decreased in hypertrophied myocytes, but the individual components, slowly (IKs) and rapidly (IKr) activating delayed rectifier K+ currents, were not discriminated. Therefore, it is unknown whether decreases in IK density were due to changes in IKs, IKr, or both. In rabbit LVH induced by partial ligation of the abdominal aorta, IKr density was unchanged in hypertrophied myocytes compared with control myocytes, but IKs was not studied.6 Early studies of rabbit ventricular myocytes suggested that IK in rabbit myocytes consists of only a single rapidly activating component.7 8 9 More recent studies, however, have demonstrated that both IKr and IKs are present in rabbit ventricular myocytes.10 11 12
In the LVH model of rabbits with renovascular hypertension, we previously demonstrated that 3 months after renal artery banding, the ventricular myocytes isolated from the middle layer of LV free wall are hypertrophied and have prolonged APD, decreased IK1 density, increased Ito density, and unchanged ICa,L density compared with control myocytes.3 The purpose of this study was (1) to characterize the effects of LVH on IKs and IKr, the 2 K+ currents critical to AP repolarization, and (2) to compare the effects of specific IKs or IKr inhibition on AP repolarization and incidence of EADs in ventricular myocytes isolated from normal and LVH rabbits. Because the heterogeneity of K+ channel distribution in ventricular myocardium has been associated with the physiological heterogeneity of APD across the ventricular wall,13 14 15 16 myocytes isolated from the epicardial (Epi) and endocardial (Endo) layers of LVs were studied separately.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Experimental Animals
Male New Zealand White rabbits (1.4 to 2.0 kg) underwent unilateral nephrectomy and contralateral renovascular banding to produce LVH by techniques reported previously.17 Banded rabbits were studied 3 months after surgery when documented LVH had developed. Data were collected from 24 control and 26 LVH rabbits.
Myocyte Isolation
Single ventricular myocytes were isolated
by a method described
previously.17 After enzyme
perfusion, a thin layer (<1.5 mm) of tissue was dissected from
the Epi and Endo surfaces of the LV free wall, and myocytes were
dispersed.
Action Potential Recording
AP was recorded at 36±0.3°C by the standard
microelectrode technique. Microelectrodes had a resistance of 25 to 40
M
when filled with 3 mol/L KCl. Cells were superfused with a
solution containing (in mmol/L) NaCl 137, KCl 5,
MgCl2 1, CaCl2 2, glucose
10, and HEPES 10 (pH 7.4). AP was recorded at steady state with
various stimulus frequencies (0.2, 0.5, and 2 Hz). Because EADs
appeared in some of the APs recorded at 0.2 and 0.5 Hz under
certain conditions, quantitative analysis of APD was performed
only for the AP recorded at 2 Hz.
Membrane Current Recording
IKs
and IKr
were recorded at 36±0.5°C by the whole-cell patch-clamp
technique. Because of the small amplitude of
IKs and
IKr in
rabbit ventricular myocytes, the conditions used for
IKs and
IKr
recording were different, to better resolve each component.
Electrodes had a resistance of 3 to 4 M when filled with a pipette
solution containing (in mmol/L) potassium gluconate 119, KCl 15,
MgCl2 3.2, HEPES 5, EGTA 5, and
K2ATP 5 (pH 7.2). Series resistance was
compensated electronically 70% to 80%. Bath solution for
recording
IKs
contained (in mmol/L) NaCl 132, KCl 2,
CaCl2 1.8, MgCl2 1.2,
HEPES 10, and glucose 10, plus 1 µmol/L dofetilide and 0.6 µmol/L
nisodipine. Bath solution for recording
IKr
contained (in mmol/L) NaCl 132, KCl 5,
MgCl2 1.2, HEPES 10, and glucose 10, plus 0.4
µmol/L nisodipine. pH was 7.2 for both solutions. Liquid junction
potential was zeroed in the bath but not compensated under the
whole-cell condition.
IKr and IKs were isolated primarily by use of selective pharmacological blockade to measure each component of IK. IKr was defined as the dofetilide-sensitive current18 19 recorded during 1-second depolarizing voltage steps from a holding potential (Vh) of -50 mV to test potentials (Vt) between -40 and 30 mV in 10-mV increments. IKs was defined as the current sensitive to L-768,673, a selective IKs blocker,20 21 during 1-second depolarizing voltage steps from Vh of -40 mV to Vt between -20 and 60 mV in 20-mV increments. Interpulse interval was 12 seconds in both cases. Isochronal activation curves for IKs were determined from the peak amplitudes of the tail currents during return to the Vh of -40 mV after 5-second test pulses to various Vt. Tail currents (I) were normalized to the maximal tail current (Imax) obtained after a step to Vt of +70 mV.
Drugs
Dofetilide, L-768,673, and nisoldipine were gifts
from Pfizer, Merck & Co, and Bayer AG,
respectively.
Data Analysis
Data are expressed as mean±SEM. Cell numbers are
indicated in parentheses in the table and figures. Statistical
analyses were performed with GraphPad Prism 2.0 (GraphPad
Software, Inc). Two-way ANOVA was used to compare data of Epi and Endo
from control and LVH. Unpaired
t test was used to examine
statistically significant differences observed with the 2-way ANOVA.
Contingency tables were used to compare EAD incidence between control
and LVH. Fisher’s exact test was used for
P value
calculations.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Three months after renal artery banding, the ratio of heart weight to body weight increased from 2.15±0.03 g/kg (n=24) in control to 2.63±0.06 g/kg (n=26) in LVH (P<0.05). Cell membrane capacitance of ventricular myocytes isolated from Epi and Endo increased 23% and 29%, respectively, in LVH compared with control (Table
).
APD measured at 60% and 90% repolarization
(APD60 and APD90) at 2 Hz
was significantly prolonged in both Epi and Endo from LVH rabbits
compared with controls
(Table).
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The isolation of
IKs is
demonstrated in
Figure 1A.
IKs
current-voltage relations for control and LVH are compared in
Figure 1B for Epi and Endo. LVH significantly decreased
IKs
density in both Epi and Endo. The isochronal activation curves for
IKs were
essentially identical between Epi and Endo for a given condition;
therefore, regional data were averaged, and those results were plotted
for the control and LVH conditions in
Figure 1C.
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Example
IKr
traces at Vt from -30 to +20 mV are shown in
Figure 2A.
IKr
current-voltage relations for control and LVH are compared in
Figure 2B for Epi and Endo.
IKr
density was unchanged in LVH compared with control in either Epi or
Endo. The voltage-dependent activation of
IKr was
compared between control and LVH myocytes in
Figure 3 for Epi and Endo. The voltage-dependence of
activation of
IKr was
essentially identical for LVH and control myocytes.
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The effects of L-768,673 and dofetilide on AP were examined
to determine the relative contribution of
IKs or
IKr to
AP repolarization in control and LVH rabbits. AP example
recordings at 2 Hz are shown for myocytes from Epi and Endo of
normal and LVH in
Figures 4 and 5, and averaged percent increases in
APD90 induced by drugs are summarized in
Figure 6. APD is typically shorter in Epi than in Endo and
is universally prolonged by LVH
(Table
).
Inhibition of
IKs with
0.1 µmol/L L-768,673, a concentration expected to produce nearly
total
IKs
block, produced modest increases in APD
(Figure 4). APD prolongation was greater in Epi than in Endo
and notably, was significantly less for LVH than control
(Figure 6). In contrast, inhibition of
IKr with
0.1 µmol/L dofetilide, a concentration expected to produce nearly
total
IKr
block, caused a completely opposite pattern of APD changes, which were
also remarkably greater than those observed with
IKs
inhibition
(Figure 5). APD was increased more in Endo than in Epi and
more importantly, was prolonged more for LVH than control
(Figure 6).
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At a very low stimulus frequency of 0.2 Hz, spontaneous EAD
was observed in 2 of 12 myocytes from Epi and 5 of 21 from Endo of LVH.
Figure 7A shows an example trace of a spontaneously
occurring EAD recorded from an LVH Endo cell. In contrast,
spontaneous EAD was never observed in control (0.2 Hz) or in LVH at
stimulus frequencies 
0.5 Hz. Notably, L-768,673 (0.1 µmol/L) did
not induce EAD in Epi or Endo of either control or LVH (cell number
12 for each condition). In contrast, dofetilide (0.1 µmol/L)
induced EAD in almost all LVH Endo myocytes, and although it prolonged
APD in control Epi, it did not induce EAD
(Figure 7B). At 0.5 Hz, the incidence of EAD induced by 0.1
µmol/L dofetilide was 0 of 15 cells in Epi and 4 of 13 cells in Endo
for control, compared with 3 of 12 cells in Epi and 11 of 12 cells in
Endo for LVH. EAD incidence in Endo induced by 0.1 µmol/L dofetilide
was significant higher in LVH than control
(P<0.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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AP Prolongation in Hypertrophied Epi and Endo
LVH was induced consistently in rabbits 3 months after renal artery banding, as confirmed by significant increases in the ratio of heart weight to body weight. Hypertrophy occurred in both Epi and Endo, as demonstrated by the significant increases in cell membrane capacitance of myocytes from both LV layers. In control rabbits, APD was significantly longer in Endo than in Epi, as has been found in other animal species.15 22 23 In the present study in rabbits, we have shown that this gradient or dispersion of APD is at least partially due to a smaller IKs density in Endo than in Epi. Moreover, in LVH rabbits with renal artery banding, we have also shown that prolongation of APD was similar in Epi and Endo compared with control rabbits. APD90 at 2 Hz was increased by 24% in Epi and 22% in Endo. This result differs from findings in another rabbit study of LVH produced with perinephritis-induced hypertension, in which APD prolongation was more pronounced in Epi than in Endo.2 The underlying ionic mechanism for more pronounced AP prolongation in Epi than Endo in this model was not given. We also found that the average APD of Endo was the same as that of midlayer myocytes in both control and LVH rabbits.3
LVH Decreases
IKs but
Not IKr
Density
Pathology-induced modulation of
IKs and
IKr
varies with animal model. In LVH rabbits with renovascular
hypertension, we found an 40% decrease of
IKs
density in both Epi and Endo but no significant change of
IKr
density
(Table).
In another rabbit study, in which LVH was induced by partial ligation
of the abdominal aorta,
IKr
density was also found to be unchanged in hypertrophied myocytes
compared with controls; however, the effect of LVH on
IKs was
not studied.6 In a guinea pig
model with aortic banding,
IKs and
IKr
densities remain unchanged during cardiac hypertrophy and
failure.24 In midmyocardial
cells of dogs with chronic complete atrioventricular
block,
IKs
density decreased in both left and right ventricles, whereas
IKr
density decreased in the right ventricle
only.25 The renovascular
hypertension model of rabbits we used is similar to essential
hypertension in humans in that this model produces gradual
hypertrophy in the appropriate
ventricle.
Voltage-Dependent Activation of
IKs and
IKr
IKr
recorded from rabbit LV cells in this study
(Figure 2B) displayed a typical bell-shaped current-voltage
relationship, similar to that of guinea pig ventricular
myocytes,26 rabbit
sinoatrial node cells,27 and
ferret atrial myocytes.28
This pronounced inward rectification of
IKr is
due to its unique rapid inactivation, which occurs more quickly than
activation at more depolarized
potentials.29 30
Voltage-dependence of activation for
IKs or
IKr was
not different between Epi and Endo of control or LVH rabbits. LVH had
no effect on the voltage-dependence of activation of either
IKs or
IKr.
Similar to our findings, chronic complete
atrioventricular block in dogs has no effect on the
voltage-dependence of activation of
IKs or
IKr.25
The steady-state activation of total
IK does
not differ between normal and hypertrophied myocytes in feline right
ventricular
hypertrophy.4
Differential Modulation of AP by
IKs or
IKr
Block
In control rabbits, Epi had significantly larger
IKs
density than Endo, whereas both layers had similar
IKr
density. Therefore,
IKs was
expected to contribute more to AP repolarization in Epi than Endo,
whereas
IKr
would contribute more to AP repolarization in Endo than Epi.
Consistent with this argument, we found that in control
rabbits, the selective
IKs
blocker L-768,673 induced larger increases of
APD90 in Epi than Endo (21±3% versus
8.8±1.3%, P<0.05), whereas
the selective
IKr
blocker dofetilide induced greater prolongation of AP in Endo than Epi
(32±4% versus 18±2%,
P<0.05).
In LVH rabbits, because of a decreased IKs density and an unchanged IKr density in both Epi and Endo, the effects of IKs block on AP repolarization were significantly reduced in LVH. L-768,673 induced significantly smaller percentage increases of APD90 in both Epi (10±1% versus 21±3%) and Endo (5.1±0.6% versus 8.8±1.3%) in LVH rabbits compared with controls. Conversely, the decreased IKs in both Epi and Endo of hypertrophied myocytes made IKr more critical to AP repolarization in LVH rabbits. Blocking IKr with dofetilide induced significantly larger prolongation of AP in both Epi (31±3% versus 18±2%) and Endo (53±6% versus 32±4%) of LVH rabbits compared with controls at 2 Hz.
Spontaneous and Drug-Induced EAD
Among the 4 groups of myocytes that we studied, Endo
myocytes from LVH rabbits had the smallest
IKs
density
(Table).
At 0.2 Hz, spontaneous EAD was observed in 5 of 21 Endo cells and 2 of
12 Epi cells of LVH rabbits. Spontaneous EAD was not observed in any of
the myocytes of control rabbits we examined. Whereas block of
IKs by
L-768,673 failed to induce EAD, block of
IKr by
dofetilide commonly led to EAD, especially in Endo of LVH rabbits.
These observations may have important clinical implications, although
the potential proarrhythmic effect of dofetilide would be reduced in
vivo because of high heart rate and electrical coupling of myocardial
tissue. It is now well recognized that agents that are selective
blockers of
IKr have
the potential to produce excessive APD prolongation, leading to a
prolonged QT interval. In extreme instances, they can cause EAD, which
may underlie torsade de pointes arrhythmias observed with these
agents clinically. Insofar as the changes observed in this study in
rabbits are transferable to human cardiac hypertrophy and
heart failure, our findings suggest that
IKr
block in this diseased state could even be more proarrhythmic in this
patient population. In light of these recent observations, controversy
has arisen as to whether any class III action, ie, increase in APD or
cardiac refractoriness, could provide antiarrhythmic efficacy safely.
Unlike the excessive increases in APD especially at slow heart rates,
however, the limited increases observed with
IKs
block in this and other studies merit further study and consideration
for its antiarrhythmic or proarrhythmic potential. Under the conditions
of this study, there was no EAD induction even in the LVH rabbits with
IKs
block, raising the question of whether a controlled or limited increase
in cardiac refractoriness could provide antiarrhythmic action by
prevention of classic reentry. On the contrary, the reduction of the
repolarizing current
IKs with
LVH, which itself could be considered proarrhythmic and contributing to
the increased incidence of arrhythmias in this patient
population, raises a converse hypothesis: namely, could an agent that
increases a repolarizing current be of use in reversing or preventing
increases in APD and arrhythmias and other sequelae of heart
failure? One such agent that enhances
IKs was
described recently.31 Other
studies have attempted to address this issue by using
adenovirus-induced transfection to increase
K+ channel expression and augment
repolarizing K+
currents.32 33
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Acknowledgments |
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The authors would like to thank Merck & Co, Inc, for providing L-768,673 and Pfizer for dofetilide.
Received August 4, 2000; revision received September 27, 2000; accepted October 3, 2000.
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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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X. Xu, J. J. Salata, J. Wang, Y. Wu, G.-X. Yan, T. Liu, R. A. Marinchak, and P. R. Kowey Increasing IKs corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H664 - H670. [Abstract] [Full Text] [PDF]
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 J. J. Lynch Jr., J. J. Salata, A. A. Wallace, G. L. Stump, D. B. Gilberto, H. Jahansouz, N. J. Liverton, H. G. Selnick, and D. A. Claremon Antiarrhythmic Efficacy of Combined IKs and beta -Adrenergic Receptor Blockade J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 283 - 289. [Abstract] [Full Text] [PDF]
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G.-X. Yan, S. J. Rials, Y. Wu, T. Liu, X. Xu, R. A. Marinchak, and P. R. Kowey Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1968 - H1975. [Abstract] [Full Text] [PDF]
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