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1 Institute of Cardiovascular Science and Medicine, University of Hong Kong, Hong Kong Special Administrative Region, China; and 2 Montreal Heart Institute, Montreal, Quebec, Canada HIT IC8
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Heart failure (HF) produces important
alterations in currents underlying cardiac repolarization, but the
transmural distribution of such changes is unknown. We therefore
recorded action potentials and ionic currents in cells isolated from
the endocardium, midmyocardium, and epicardium of the left ventricle
from dogs with and without tachypacing-induced HF. HF greatly increased
action potential duration (APD) but attenuated APD heterogeneity in the
three regions. Early afterdepolarizations (EADs) were observed in all
cell types of failing hearts but not in controls. Inward rectifier
K+ current (IK1) was homogeneously
reduced by ~41% (at 
60 mV) in the three cell types. Transient
outward K+ current (Ito1) was
decreased by 43-45% at +30 mV, and the slow component of the
delayed rectifier K+ current (IKs)
was significantly downregulated by 57%, 49%, and 58%, respectively,
in epicardial, midmyocardial, and endocardial cells, whereas the rapid
component of the delayed rectifier K+ current was not
altered. The results indicate that HF remodels electrophysiology in all
layers of the left ventricle, and the downregulation of
IK1, Ito1, and
IKs increases APD and favors occurrence of EADs.
heterogeneity; early afterdepolarizations; congestive heart failure; arrhythmias
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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HEART FAILURE (HF) is associated with a high mortality (14), with up to 50% of deaths being sudden and unexpected due to ventricular tachycardia or fibrillation (43). The mechanisms underlying ventricular arrhythmogenesis in electrically remodeled failing hearts are not fully understood (32, 44). Studies have consistently found prolongation of cardiac action potential (AP) duration (APD) in myocardial tissues and/or cells from different models of experimental HF (26, 44) and from explanted tissues of humans with terminal HF (3). Abnormalities in repolarization can predispose to dispersion of repolarization, leading to nonexcitable gap reentry (6), and AP prolongation also favors the development of early afterdepolarizations (EADs), which can induce triggered arrhythmias (9).
The ionic current mechanisms underlying AP prolongation in the failing heart have been described in several species, including humans (44). It is generally believed that K+ current (IK) downregulation is involved in the abnormal ventricular repolarization of failing hearts (see reviews) (30, 44). These IK include 4-aminopyridine (4-AP)-sensitive transient outward K+ current (Ito1), inward rectifier K+ current (IK1), and the rapid and slow components of the delayed rectifier K+ current (IKr and IKs, respectively), although discrepant observations have been reported (44).
It has been recognized that electrical heterogeneity is an important determinant of normal cardiac electrical function. In the ventricular wall, distinct AP morphologies and APDs have been demonstrated in endocardium, midmyocardial layer, and epicardium of canine (1) and human (8, 16) hearts. The longest APDs have been found in ventricular midmyocardial cells of various species, including the guinea pig (41), pig (42), dog (40), and human (8, 16). Distinctive pharmacological responsiveness has been studied in detail in canine hearts (1). In addition, differential responses of epicardium and endocardium to ischemia were described in canine ventricular tissues and cells (24). However, little is known about how HF-related electrical remodeling is expressed transmurally in ventricles. Rapid ventricular tachypacing induces a cardiomyopathy in canine hearts with hemodynamic changes similar to those seen in human HF (28). The present study used the canine model to determine how transmural heterogeneity of cellular electrophysiology is remodeled and to evaluate how major membrane ionic currents responsible for AP repolarization (e.g., Ito1, IK1, IKr, and IKs) are affected by transmural electrical remodeling based on observations in cells isolated from the subendocardium, midmyocardial layer, and subepicardium of failing hearts.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Pacing-induced HF model. All animal care and handling procedures followed the Guidelines of the Canadian Council for Animal Care. Ventricular pacing-induced canine HF was produced with well-established procedures (13, 21). Briefly, adult mongrel dogs of either sex (20~25 kg) were anesthetized, and artificial respiration was maintained via an endotracheal tube connected to a Harvard-type mechanical ventilator. Under sterile conditions, a unipolar endocardial pacing lead (Medtronic; Minneapolis, MN) was inserted through the right jugular vein, and the distal end of the lead was screwed into the right ventricular apex under fluoroscopic guidance and connected to a custom-modified pacemaker (model 8084, Medtronic), which was placed subcutaneously at the base of the neck. After the dogs had recovered from the operation for 2 days, the pacemaker was programmed to stimulate the ventricles at 240 beats/min with the use of 0.42-ms square-wave pulses of 1.5-fold threshold current.
After 4-5 wk of chronic tachycardia, clinical symptoms of terminal HF were evident, including loss of appetite, lethargy, dyspnea, and ascites. Severe HF was confirmed in eight randomly selected dogs by transthoracic two-dimensional echocardiography. The echocardiography was performed before pacemaker stimulation and after 5 wk of ventricular pacing with a standard echocardiography system (Hewlett-Packard; Andover, MA). Rapid ventricular pacing induced significant dilation of the right and left ventricles and led to a decrease in the left ventricular ejection fraction from 54.6 ± 2.6% before pacing to 24.7 ± 1.1% after 5 wk of pacing (P < 0.01). Similar changes in AP and ionic currents were found in HF animals with or without echocardiography. Therefore, the data were combined for the HF group. Three of twenty-eight programmed animals died suddenly on the fifth week before the experiments, and, therefore, twenty-five animals served as the HF group. In seven other animals, the pacemaker was not activated (sham group). No difference in cardiac electrophysiological properties and ionic currents was found between cells from sham animals [e.g., mean APD at 90% repolarization (APD90) at 1 Hz: 275 ± 28, 332 ± 37, and 237 ± 38 ms in epicardial, midmyocardial, and endocardial cells, respectively] and those from normal nonoperated animals (n = 10, mean APD90: 289 ± 31, 325 ± 42, and 247 ± 29 ms in corresponding cell types), so the sham and normal control group data were combined.Cardiac cell preparation.
Left ventricular tissues from isolated control and failing hearts were
obtained via a left thoracotomy after dogs were anesthetized with
morphine (2 mg/kg sc) and 
-chloralose (120 mg/kg iv) under ventilation with room air. Hearts were initially placed in oxygenated Tyrode solution, and the left anterior descending coronary artery was
cannulated. Ventricular cells were enzymatically isolated with a
procedure described previously (16, 19). Briefly, the free
transmural wall of the anterior left ventricle (~30 × 50 mm)
was removed along with the coronary artery branch irrigating it. The
free wall was perfused with oxygenated, nominally Ca2+-free
Tyrode solution for 20-30 min, and the solution was then changed
to one containing 200-300 U/ml collagenase (CLS II, Worthington Biochemical; Freehold, NJ) for 60-100 min. Regional cells were separated from the digested tissue. Subendocardial and subepicardial cells were taken from the endocardial and epicardial surfaces (<1 mm
thick), whereas midmyocardial cells were dissociated from the
midmyocardial layer. The cells were placed in a high-K+
storage solution (see Solutions) and gently triturated with
a Pasteur pipette. The isolated cells were kept in the medium at least
1 h (at room temperature) before use. Only quiescent rod-shaped cells showing clear cross-striations were used.
Solutions.
The Tyrode solution contained (in mmol/l) 136 NaCl, 5.4 KCl, 1.0 MgCl2, 1.8 CaCl2, 0.33 NaH2PO4, 10 glucose, and 10 HEPES; pH was
adjusted to 7.4 with NaOH. The high-K+ storage medium
contained (in mmol/l) 20 KCl, 10 KH2PO4, 10 glucose, 70 K-glutamate, 10 
-hydroxybutyric acid, 10 taurine, 0.5 EGTA, and 20 mannitol and 0.1% albumin; pH was adjusted to 7.2 with KOH. The pipette solution contained (in mmol/l) 20 KCl, 110 K-aspartate, 1.0 MgCl2, 10 HEPES, 5.0 EGTA (0.05 for the
recording of APs), 0.1 GTP, 5.0 Na2-phosphocreatine, and
5.0 Mg2-ATP; pH was adjusted to 7.2 with KOH. For
Ito1 determination, external Na+ was
replaced by equimolar choline. BaCl2 (0.5 mmol/l) was used to inhibit IK1, and CdCl2 (200 µmol/l) was used to block Ca2+ current
(ICa). Ca2+-dependent transient
outward chloride current (ICl,Ca or
Ito2) was inhibited by 5 mmol/l EGTA in the
pipette solution and by the addition of Cd2+ to the
external solution. The experiments were conducted at 36°C (for AP,
IKs, and IKr recordings)
or room temperature (22°C, for IK1,
Ito1, and ICa recordings).
Data acquisition and analysis.
The whole cell patch-clamp technique was used. Borosilicate glass
electrodes (1.0 mm outer diameter) were pulled with a
Brown-Flaming puller (model P-87) and had tip resistances of 2-3
M
when filled with pipette solution. The tip potentials were
compensated before the pipette touched the cell. A gigaseal (>10 G)
was obtained, and the cell membrane was ruptured by gentle suction to
establish the whole cell configuration. Liquid junction potentials
after membrane rupture between the external and pipette solutions
(10.5 ± 0.3 mV) were not corrected except for recordings of APs
and IK1. Data were acquired by the use of an
Axopatch 200A and/or 200B amplifier (Axon Instruments; Foster City,
CA). Command pulses were generated by a 12-bit digital-to-analog
converter controlled by pCLAMP software (Axon Instruments). Recordings
of the AP and membrane currents were low-pass filtered at 2 kHz and
stored on the hard disk of an IBM-compatible computer.
60
mV divided by the voltage drop. Membrane capacitance was 145.5 ± 6.1, 150.3 ± 7.2, and 148.7 ± 6.9 pF, respectively, in
endocardial (n = 76), midmyocardial (n = 73), and epicardial (n = 68) cells from control
hearts [P = not significant (NS)] and 151.5 ± 7.6, 157.3 ± 8.1, and 154. 4 ± 7.4 pF in endocardial (n = 102), midmyocardial (n = 114), and
epicardial (n = 112) cells from failing hearts
(P = NS vs. controls). Series resistance was electronically compensated.
Only cells with stable IK for 5 min after
membrane rupture were used for study. To further exclude possible
effects of IK rundown on the current
measurement, the time course of changes of IK
was monitored after rupture of the patch membrane in a set of
experiments in cells from control and failing hearts. No apparent rundown was observed for at least 15 min after membrane rupture in the
three cell types from the two groups. Therefore,
IK was determined between 5 and 12 min after
rupture of the cell membrane.
Nonlinear curve-fitting programs (Clampfit in pCLAMP 6 or SigmaPlot,
Jandel Scientific; Rafael, CA) were used to perform curve-fitting procedures. Results are presented as means ± SE. Paired and
unpaired Student's t-tests were used as appropriate to
evaluate the statistical significance of differences between two group
means, and ANOVA was used for multiple groups. Values of
P < 0.05 were considered to indicate statistical significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Remodeling of heterogeneous AP in ventricular cells of HF.
Transmembrane potential was recorded in current clamp mode with normal
Tyrode bath solution at 36°C. Cardiac AP characteristics (at
0.5-2 Hz) are illustrated in Fig. 1
in cells isolated from the ventricular epicardium, midmyocardial layer,
and endocardium of control and failing canine hearts. In control
cardiac cells (Fig. 1A), APs showed only a small phase 1 (top) in endocardial cells, whereas they displayed a
prominent phase 1 and a significant "spike-and-dome" configuration
in midmyocardial (middle) and epicardial (bottom)
cells. APD was substantially shorter in endocardial and epicardial
cells than in the midmyocardial cells, especially at the low
stimulation rates of 0.5 and 1 Hz. Figure 1B shows that AP
characteristics were substantially altered in the three cell types from
failing hearts. The phase 1 and spike-and-dome configuration of the AP
was clearly diminished in epicardial and midmyocardial cells, and the
APD was prolonged in all regions. Average data for APD and resting
membrane potential at 0.5 Hz are summarized in Table
1. APD was significantly longer in
midmyocardial cells than in endocardial or epicardial cells from
control hearts at lower rates, consistent with previous reports
(1, 40). The heterogeneous electrophysiology seen in
controls was diminished by an inhomogeneous prolongation of APD in
failing hearts. Mean values of APD90 at 0.5 Hz were
increased by 218 ms (59%), 150 ms (32%), and 295 ms (91%),
respectively, in epicardial, midmyocardial, and endocardial cells.
Figure 2 illustrates rate-dependent
properties of APD at 50% repolarization and APD90 in cells
from control and failing hearts.
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EADs in cells from failing hearts.
Figure 3 displays EADs recorded in
endocardial, midmyocardial, and epicardial cells from failing hearts
observed during APs recorded with the use of a train of 10 pulses (2-ms
duration) at 0.5 Hz. EADs were never observed in cells from control
hearts. The incidence of EADs was 17% in endocardial (10 of 59 cells), 34% in midmyocardial (22 of 65 cells), and 20% in epicardial (12 of
60 cells) cells, respectively. In all cell types, EADs appeared as
single and/or multiple oscillations of the AP, and oscillations of the
AP decreased or disappeared when the frequency increased to 1 or 2 Hz.
The mean proportion of APs showing EADs was 0.46, 0.10, and 0.02 at
0.5, 1, and 2 Hz, respectively.
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Changes in IK1.
IK1 was determined in normal Tyrode solution
containing 10 µmol/l nifedipine. Figure
4A illustrates whole cell
IK1 elicited by 300-ms voltage steps between
110 and 30 mV from 40 mV, as shown in the inset, in
endocardial cells from control (left top) and failing
(right top) hearts. IK1 amplitude was
substantially reduced in the cells from the failing heart. The current
was fully inhibited by 0.5 mmol/l Ba2+ in control
(left bottom) and failing (right bottom) cells.
Figure 4B shows current-voltage (I-V)
relationships of IK1 in cells from control and
failing hearts. No difference in inward or outward IK1 was found among the three cell types from
control and failing hearts. However, IK1 density
was significantly suppressed for both inward (110 and 100 mV) and
outward (70 to 30 mV) components in cells from failing hearts
(P < 0.05 or P < 0.01 vs. control). The expanded outward component (Fig. 4C) of the
IK1-V relations shows that
IK1 density was significantly decreased in the
three cell types of failing hearts at 70 to 30 mV.
IK1 density at 60 mV was reduced by 40.9%,
40.7%, and 41.1%, respectively, in epicardial (6.1 ± 0.6-3.6 ± 0.3 pA/pF), midmyocardial (5.4 ± 0.5-3.2 ± 0.2 pA/pF), and endocardial (5.6 ± 0.5-3.3 ± 0.3 pA/pF) cells (P < 0.01 vs.
control). The results indicate that IK1 is
homogeneously reduced in the three cell types from failing hearts and
may account at least in part for prolonged APD in cells from failing
hearts.
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Changes in Ito1.
It is well known that canine ventricular cells exhibit two components
of transient outward currents: Ito1 and
Ito2 (or ICl,Ca) (45). We focused on Ito1, which is
decreased in failing human (3, 29) and canine
(13) ventricular cells, to study whether alteration of
Ito1 is transmurally homogeneous across the
ventricular wall. Ito1 was recorded using 300-ms
voltage steps to between 30 and +60 mV from 80 mV (see Fig.
5A, inset). Figure
5A illustrates Ito1 traces in
epicardial cells from control (left) and failing (right) hearts. Ito1 was
substantially decreased in the cell from the failing heart. Figure
5B displays mean I-V relationships of peak Ito1 in control (left) and
failing (right) cells. Density of
Ito1 is clearly smaller in endocardial cells
(n = 25) than in epicardial (n = 23)
and midmyocardial (n = 21) cells from control hearts,
consistent with previous reports (23). Although the Ito1 gradient remained,
Ito1 density was reduced in endocardial (n = 38), midmyocardial (n = 45), and
epicardial (n = 41) cells from failing hearts
(P < 0.05 or P < 0.01 vs. control at
+10 to +60 mV). At +40 mV, Ito1 was decreased by
43%, 45%, and 43%, respectively, in epicardial (6.6 ± 0.3-3.8 ± 0.4 pA/pF), midmyocardial (6.3 ± 1.0-3.5 ± 0.6 pA/pF), and endocardial (3.2 ± 0.3-1.8 ± 0.3 pA/pF) cells (P < 0.01 vs.
control). The results indicate that Ito1 is homogeneously downregulated across the ventricular wall of failing hearts, contributing to the diminished phase 1 of the AP.
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1 and 2) of
Ito1 were 21.3 ± 9.5 and 289.5 ± 54.2, 25.7 ± 13.4 and 332.1 ± 64.8, and 27.6 ± 14.7 and 258.4 ± 69.2 ms, respectively, in epicardial, midmyocardial,
and endocardial myocytes in the control group, whereas in HF
1 and 2 were 24.1 ± 9.4 and
312.5 ± 59.6, 27.7 ± 14.2 and 341.6 ± 85.7, and
29.3 ± 12.6 and 271.5 ± 68.3 ms in the corresponding cell
types (n = 10 for each cell type, P = NS vs. control).
Changes in IKs.
IKs is believed to be an important repolarizing
current in mammalian hearts, and its lesser expression in the
midmyocardium contributes in part to APD heterogeneity in canine
ventricles (22). We measured IKs
under conditions of Na+- and extracellular
K+-free solution in the presence of 10 µmol/l nifedipine,
5 mmol/l 4-AP, 1 µmol/l atropine, and 5 µmol/l E-4031. Under
extracellular K+-free conditions,
IKr is greatly diminished, whereas the density of IKs is augmented (22, 38).
IK1 is also practically eliminated (19,
20, 22). Figure 6A
illustrates representative IKs tracings in cells
from the epicardium, midmyocardial layer, and endocardium of control
hearts recorded with 3-s voltage steps to between 30 and +50 mV from
a holding potential of 60 mV, followed by 2-s repolarizations to 30
mV (see Fig 6A, inset). The developing currents
observed during depolarization steps and the tail currents (IKs,step and IKs,tail,
respectively) were smaller in midmyocardial cells than in epicardial or
endocardial cells of control hearts. Figure 6B plots
complete data for IKs,tail. Shown are current densities measured at 30 mV after a 3-s pulse to +30 mV. Each point
represents results from an individual cell. The thick lines indicate
the mean values for each group. The density of
IKs,tail was substantially less in midmyocardial
cells (1.9 ± 0.2 pA/pF, n = 31, P < 0.05) than in epicardial (2.8 ± 0.3 pA/pF, n = 27) and endocardial (2.6 ± 0.3 pA/pF, n = 29)
cells, consistent with previous reports (22).
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IKr.
To study whether alteration of IKr contributes
to the prolonged APD, we used the IKr blocker
E-4031 as a tool to define IKr as the
E-4031-sensitive component (37) in control and failing cells. The experiments were performed under conditions similar to those
for IKs except for the inclusion of 5.4 mmol/l
K+ in the bath. As Fig.
8A shows, the membrane
currents were initially measured at ~5 min after rupture using the
voltage steps shown in the inset, and recordings were
repeated after application of 5 µmol/l E-4031 for 5-7
min. E-4031-sensitive current (IKr) was obtained by digital subtraction of currents before and after the blocker. Figure 8B shows that no regional differences in the
I-V relation of E-4031-sensitive
IKr were observed in the three cell types of
control hearts. No significant change in IKr was
found in cells from failing hearts (P = NS vs.
control).
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L-type Ca2+ current.
L-type Ca2+ current (ICa,L) was
evoked by voltage steps to between 40 and +50 mV from 50 mV in
control and failing cells under Na+- and
K+-free conditions. Figure
9A displays representative
ICa,L recorded with the protocol shown in the
inset in control (left) and failing (right) cells. I-V relationships of
inward peak ICa,L are shown in Fig.
9B (control) and Fig. 9C (HF) with the peak
current being observed at +10 mV in the three cell types from control
and failing hearts. No significant differences were found in
ICa,L density or kinetics as a function of cell
type or disease at any voltage. The density of
ICa,L at the voltage (+10 mV) corresponding to peak current was 9.2 ± 0.8, 8.9 ± 0.8, and 8.7 ± 0.7 pA/pF, respectively, in epicardial, midmyocardial, and
epicardial cells of control hearts (P = NS) and
9.5 ± 0.7, 9.9 ± 1.2, and 9.4 ± 0.8 pA/pF in
the corresponding regions of failing hearts (P = NS vs.
control).
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1 and
2 of ICa in control hearts were
11.6 ± 1.4 and 73.6 ± 4.4, 11.7 ± 1.7 and 69.3 ± 5.6, and 12.9 ± 1.5 and 75.7 ± 9.7 ms, respectively, in
epicardial, midmyocardial, and endocardial cells (P = NS), and, in failing hearts, 1 and 2 were
12.3 ± 1.5 and 68.4 ± 6.8, 13.7 ± 1.8 and 73.6 ± 8.7, and 11.3 ± 1.5 and 72.1 ± 8.9 ms in corresponding regional cells, respectively (n = 11 in each cell type,
P = NS vs. control). Recovery 1 and
2 of ICa from inactivation were 27.3 ± 5.9 and 334.1 ± 61.7, 22.5 ± 7.1 and
312.8 ± 47.2, and 24.7 ± 8.7 and 298.9 ± 54.6 ms in
control epicardial, midmyocardial, and endocardial cells, respectively.
In the HF group, the recovery 1 and 2
were 23.5 ± 6.7 and 317.2 ± 49.6, 27.1 ± 7.5 and
294.8 ± 53.6, and 25.3 ± 10.3 and 309.4 ± 48.5 ms in
the corresponding cell types (n = 12 for each cell
type, P = NS vs. control).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we found the first evidence, to our knowledge, that tachycardia-induced canine HF causes transmural electrical remodeling and attenuates the transmural heterogeneity in APD. EADs were observed in cells from the endocardium, midmyocardial layer, and epicardium of failing hearts, and several ionic currents were remodeled. IK1, Ito1, and IKs were reduced in the three cell types of failing hearts; however, IKr and ICa,L were not significantly affected. Reductions in IK1 and Ito1 were transmurally homogeneous, whereas IKs was affected to a relatively greater extent in the epicardium and endocardium than in the midmyocardium, eliminating the transmural IKs gradient observed in the normal heart.
Comparison with previous findings of AP remodeling in HF. APD is significantly prolonged in cells and tissues dissociated from ventricles of different species with HF induced by various mechanisms, including pressure and/or volume overload in rats, cats, and guinea pigs as well as chronic ventricular tachycardia-induced HF in dogs and rabbits (26, 44). In ventricular cells from failing human hearts, the cardiac APD also shows significant prolongation (3). Delayed repolarization is believed to be the cellular mechanism for the prolonged QTc on clinical electrocardiograms observed in HF patients with ventricular hypertrophy and/or dilated cardiomyopathy (5, 15), and the mechanisms of sudden death in patients with HF may be related to those of the acquired long QT syndrome (26). Our results provide the additional information that the transmurally heterogeneous AP morphology and APD seen in the control heart are attenuated in failing hearts (see Figs. 1 and 2 and Table 1). EADs are observed in the three cell types from failing hearts and may induce triggered activity that causes ventricular arrhythmias (1, 44).
The attenuated APD heterogeneity we saw is not consistent with observations in mild cardiac hypertrophy in the guinea pig (4), which increased APD in epicardial and midmyocardial cells but decreased APD in endocardial cells. Studies in vivo exhibit spatial and temporal dispersion of QT intervals on electrocardiogramss in humans (2) and of monophasic APs in animals (33). However, these differences may reflect alterations in APD in different zones of the heart (e.g., apex vs. base) while transmural heterogeneity decreases.Comparison with previous findings of ionic current remodeling in HF. It is well known that AP morphology and APD depend on the balance between depolarizing and repolarizing currents. Therefore, both depolarizing and repolarizing currents were studied to clarify the ionic mechanisms of the prolonged AP in failing hearts, and several membrane currents were found to be involved (30, 44). Ito1 has consistently been observed to be downregulated in tachypacing-induced HF in dogs (13) and rabbits (36) and in terminally failing human hearts (3, 29), although discrepant results have been reported in other models and species (44). The present study demonstrated that density of Ito1 was decreased, and kinetics of Ito1 were not changed in failing hearts, consistent with a report from Kaab et al. (13) in the same model and species. We provide further information that the transmural gradient of Ito1 distribution is not changed, but the current density is similarly reduced in all regions (see Fig. 5). Downregulation of Ito1 is related to the decreased phase 1 of the AP clearly present in HF cells (Fig. 1). It has been demonstrated that the mRNA transcripts coding the Ito1 channel in the rat (Kv4.2) (7) are decreased in parallel with reduced Ito1 density in hypertrophied cells (34). The mRNA for Kv4.3 coding for Ito1 in humans (7) was found to be reduced by a similar extent to Ito1 in the failing human left ventricle (12).
Observations regarding changes in IK1 in cells from hypertrophied and/or failing hearts are discrepant. Some of these differences may be due to the intensity, nature (e.g., hypertrophy vs. failure), initiating stimuli, and duration of cardiac disease (44). However, downregulated IK1 expression was consistently observed in tachypacing-induced canine HF (13) and in failing human hearts (3). In the present study, we found that IK1 density was homogeneously reduced (both inward and outward components) in endocardial, midmyopcardial, and epicardial cells of failing hearts, which contributes in part to the prolonged APD. IKr and IKs are believed to play an important role in repolarization of cardiac APs in mammalian hearts, including dogs (22) and humans (17). The downregulation of IKr and/or IKs may contribute to delayed repolarization in HF. Decreased IKr and IKs were recently observed in ventricular cells from rabbits with pacing-induced HF (46). A preliminary study (18) has reported that IKs was reduced in cells from terminally failing human hearts compared with mildly diseased cells. In the present study, we found that IKs, and not IKr, was significantly reduced in all three regions, consistent with a recent report (48) in hypertrophic rabbit hearts in which only IKs, not IKr, was reduced in ventricular endocardial and epicardial cells. Our results showed that the percentage of IKs reduction was greater in epicardial and endocardial cells than in midmyocardial cells, which may contribute in part to the inhomogeneous prolongation of APD in the three regions. The elimination of the transmural APD gradient in HF may be due to the associated elimination of the transmural IKs gradient. It is believed that alteration of intracellular Ca2+ handling may account for the abnormalities in excitation-contraction coupling in the failing heart and is involved in the occurrence of EADs (11). However, studies of ICa,L have been discrepant. The density of ICa,L has been found to be unchanged, increased, or decreased in different models and species (44). In general, ICa,L is increased in mild-to-moderate hypertrophy and decreased in severe hypertrophy and HF (44). In hypertrophied guinea pig hearts, inhomogeneous changes in ICa,L were considered to contribute to a transmurally heterogeneous prolongation of ventricular APD (4). Schroder et al. (39) found that single Ca2+ channels exhibited increased availability and opening probability in cells isolated from failing human hearts, but whole cell ICa,L did not show significant differences, when compared with nonfailing cells, in agreement with a previous report in humans (27). Recently, it has been found that the L-type Ca2+ channel number is reduced and channel open times are increased in ventricular cells from pacing-induced canine failing hearts, so that overall ICa,L density is unchanged (10). The results of the present study showed no significant change in ICa,L density and kinetics in cells from the endocardium, midmyocardial layer, and epicardium, consistent with other reports in the same model and species (13).Limitations of the present study. The present study was performed in cells isolated from the endocardium, midmyocardial layer, and epicardium of the left anterior ventricular wall of control and failing canine hearts. We cannot exclude the possibility that heterogeneous electrophysiology still exists in other regions of the ventricle in failing hearts, such as between the base and apex of the left ventricle and between the right and left ventricles and/or septum. Another limitation is that the present study focused only on Ito1, IK1, IKr, IKs, and ICa,L. We did not assess other currents, such as the Na+/Ca2+ exchange current (INaCa) and late Na+ current (INa,L), which have also been reported to contribute to regional heterogeneity in canine ventricles (50, 51). Whether alteration of INaCa and/or INa,L contributes to the higher incidence of EADs in failing midmyocardial cells remains further experimental study. Another limitation is that membrane currents, including ICa, were studied with 5 mM pipette EGTA, resulting in strong intracellular Ca2+ buffering and very low free Ca2+ concentrations. This approach was necessary to prevent contamination of ICa by Ito2 and to optimize cell stability. However, it would have prevented us from detecting any changes due to altered intracellular Ca2+ handling. In addition, membrane currents were measured at a slow rate (0.2 Hz) to prevent possible rate-dependent inactivation of the currents. This rate is much slower than that of spontaneous APs and the APs that we recorded; however, we did not observe any change in current kinetics, suggesting that our results are pertinent to AP changes.
Potential significance of our findings. It is well known that heterogeneity of cellular electrophysiology is present across the ventricular wall in mammalian hearts of several species, including dogs and humans. The present study is the first of which we are aware to study the remodeling of APs and ionic currents in cells across the left ventricular wall in a well-defined canine model of HF. Spontaneous EADs were observed in the three regions of failing hearts, and the incidence of EADs was higher in midmyocardial cells than in endocardial and epicardial cells. It seems that midmyocardial cells are more susceptible to EADs in failing hearts, as in response to cardioactive agents under nondiseased conditions (1). In multicellular preparations and intact hearts, EADs constitute an important cellular mechanism for triggered activity (1, 47). It appears that downregulation of multiple K+ channel currents, i.e., Ito1, IK1, and IKs, is responsible for the delayed repolarization and favors the genesis of EADs in the three regions, which is consistent with earlier simulation studies (25, 35). Therefore, pharmacological therapy to activate or potentiate IK (48) may be efficacious in controlling life-threatening ventricular arrhythmias in patients with HF. In addition, gene therapy to increase IK1 and/or IKs may be effective against arrhythmias induced by electrical remodeling. It has been reported that overexpression of human K+ channels may terminate EADs in cultured rabbit ventricular cells (31).
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ACKNOWLEDGEMENTS |
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The authors thank Haiying Sun for excellent technical support and data analysis.
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FOOTNOTES |
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This study was supported in part by grants from the Research Grant Council of Hong Kong (7338/01M), Quebec Heart Foundation, and Fonds de Recherche de l'Institute de Cardiologie de Montreal.
Address for reprint requests and other correspondence: G.-R. Li, L4-55, New Medical Faculty Complex, Univ. of Hong Kong, 21 Sassoon Rd., Pokfulam, Hong Kong SAR, China (E-mail: grli{at}hkucc.hku.hk).
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. Section 1734 solely to indicate this fact.
May 30, 2002;10.1152/ajpheart.00105.2002
Received 8 February 2002; accepted in final form 1 May 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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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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S. Zicha, L. Xiao, S. Stafford, T. J. Cha, W. Han, A. Varro, and S. Nattel Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts J. Physiol., December 15, 2004; 561(3): 735 - 748. [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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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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N. Ueda, D. P Zipes, and J. Wu Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of long QT 3 Cardiovasc Res, July 1, 2004; 63(1): 69 - 76. [Abstract] [Full Text] [PDF]
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J. M. Cordeiro, L. Greene, C. Heilmann, D. Antzelevitch, and C. Antzelevitch Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1471 - H1479. [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. Fernandez-Velasco, N. Goren, G. Benito, J. Blanco-Rivero, L. Bosca, and C. Delgado Regional distribution of hyperpolarization-activated current (If) and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts J. Physiol., December 1, 2003; 553(2): 395 - 405. [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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H.-S. Wang and I. S Cohen Calcium channel heterogeneity in canine left ventricular myocytes J. Physiol., March 15, 2003; 547(3): 825 - 833. [Abstract] [Full Text] [PDF]
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; n = 48), M (
; n = 46), and Epi
(
; n = 44) cells of control hearts.
However, inward and outward components of IK1
density were reduced in Endo (
; n = 64), M (
; n = 84), and Epi
(
; n = 62) cells from failing hearts.
C: expanded outward component of
IK1-V relation curves.
* P < 0.05 and ** P < 0.01, HF
vs. control. TP, test potential. Data shown are means ± SE.
