(Circulation. 1997;96:2061-2068.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Hypertrophy on Regional Action Potential Characteristics in the Rat Left Ventricle
A Cellular Basis for T-Wave Inversion?
From the Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Correspondence to Dr S.J. Shipsey, Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK.
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Abstract |
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Background In cardiac hypertrophy, ECG T-wave changes imply an abnormal sequence of ventricular repolarization. We investigated the hypothesis that this is due to changes in the normal regional differences in action potential duration. We assessed the contribution of potassium- and calcium-dependent currents to these differences. Both the altered sequence of ventricular repolarization and the underlying cellular mechanisms may contribute to the increased incidence of ventricular arrhythmias in hypertrophy.
Methods and Results Rats received daily isoproterenol injections for 7 days. Myocytes were isolated from basal subendocardial (endo), basal midmyocardial (mid), and apical subepicardial (epi) regions of the left ventricular free wall. Action potentials were stimulated with patch pipettes at 37°C. The ratio of heart weight to body weight and mean cell capacitance are increased by 22% and 18%, respectively, in hypertrophy compared with controls (P<.001). Normal regional differences in action potential duration at 25% repolarization (APD25) are reduced in hypertrophy (control: endo, 11.4±0.9 ms; mid, 8.2±0.9 ms; epi, 5.1±0.4 ms; hypertrophy: endo, 11.6±0.9 ms; mid, 10.4±0.8 ms; epi, 7.8±0.6 ms). The regional differences in APD25 are still present in 3 mmol/L 4-aminopyridine. Hypertrophy affects APD75 differently, depending on the region of origin of myocytes (ANOVA P<.05). APD75 is shortened in subendocardial myocytes but is prolonged in subepicardial myocytes (control: endo, 126±7 ms; epi, 96±10 ms; hypertrophy: endo, 91±6 ms; epi, 108±7 ms). These changes in APD75 are altered by intracellular calcium buffering.
Conclusions Normal regional differences in APD and the changes observed in hypertrophy are only partially explained by differences in Ito1. In hypertrophy, the normal endocardial/epicardial gradient in APD75 appears to be reversed. This may explain the T-wave inversion observed and will have implications for arrhythmogenesis.
Key Words: hypertrophy • action potentials • myocytes • endocardium • catecholamines
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Introduction |
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Regional differences in APD were originally deduced from the observation that the T wave in the ECG of some mammalian species (including humans and rats) is upright.1 Because the T wave is a reflection of ventricular repolarization, the direction of repolarization must normally be opposite to that of depolarization. Therefore, because depolarization normally spreads from the endocardial surface of the ventricle through the myocardium to the epicardial surface,2 it may be predicted that subendocardial myocytes have a longer action potential than subepicardial myocytes. Cardiac hypertrophy is associated with changes in T-wave morphology, implying that the sequence of repolarization is altered. To date, there has been only one study of endocardial/epicardial differences in APD in hypertrophy.3 However, this study (using muscle strip preparations) failed to demonstrate any correlation between endocardial/epicardial differences in APD and T-wave morphology in hypertrophy.
The aims of the present study were therefore (1) to confirm the existence of endocardial/epicardial differences in APD in the normal rat heart and to identify regional differences in the response to hypertrophy and (2) to assess the contribution that calcium-dependent and potassium currents may make to such regional differences and to hypertrophy-associated changes. Previous studies of action potential characteristics of isolated myocytes in hypertrophy have used the whole of the LV, including septum, to obtain myocytes. Our study is therefore the first comparison in isolated myocytes of regional differences in action potential characteristics associated with hypertrophy.
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Methods |
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Model of Hypertrophy
A rat model of catecholamine-induced cardiac hypertrophy previously described by Mészáros and Lévai was used.4 Male Wistar rats (weighing 180 to 200 g initially) were injected with isoproterenol 1 mg IP daily for 7 days. Weight-matched controls received the same volume (1 mL) of normal saline. Animals were killed 24 hours after the last injection. Treatment of animals was in accordance with the Home Office Guidance on the Operation of the Animals (Scientific Procedures) Act 1986 (H.M.S.O.).
ECGs were recorded in vivo the day after the last injection from 9 pairs of rats anesthetized with a combination of ketamine 5 mg/kg and fentanyl and fluanisone (Hypnorm) 1 mL/kg. Standard limb electrodes were attached to the legs of the unconscious, prone rats, and a six-lead ECG was recorded at a paper speed of 50 mm/s and a voltage gain of 0.05 mV/mm. These ECGs were subsequently blindly analyzed. Eight pairs of animals were used for measurements of blotted wet weight of organs and 10 pairs for electrophysiological recordings.
Isolation of Myocytes
Rats were killed by cervical dislocation. The heart was quickly
excised, suspended from a Langendorff column, and perfused with a
nominally calcium-free Tyrode's solution for 2 minutes, followed by an
enzyme solution containing collagenase (0.75 mg/mL,
Worthington Biochemical Corp) and protease (0.025 mg/mL, Sigma
Chemical Co) for a further 7 minutes. The LV free wall was then
removed, and the apical and basal portions were pinned out separately
so that thin slices of tissue could be dissected from the basal
endocardial and apical epicardial surfaces. Another slice of tissue was
excised below the basal subendocardium and discarded before a deep,
thicker slice of midmyocardium was retrieved. These three
tissue samples (referred to as endo, epi, and mid, respectively) were
then separately digested in fresh collagenase solution.
Cells were filtered from the solutions, centrifuged,
resuspended in DMEM, and stored at 20°C.
Electrophysiological Techniques
Cells were layered onto the coverslip of a perfusion chamber
situated on the stage of an inverted microscope (Nikon Diaphot). The
chamber was perfused with a modified Tyrode's solution at 35±1°C.
Patch pipettes (resistance, 4 to 7 M
when filled with solution) were
pulled from filamented glass tubing (GC150TF-15 Clark Electromedical
Instruments) on a horizontal puller (BB-CH-PC Mecanex SA). Membrane
voltage and currents were measured by the whole-cell patch-clamp
technique (Axopatch 2A, Axon Instruments). All analog signals were
digitized with a 12-bit A/D converter (1401, C.E.D.) and digitally
stored for off-line analysis.
Action potentials were stimulated at 0.2, 1, and 2 Hz in current-clamp
mode with a current pulse amplitude 
50% greater than threshold.
Action potential parameters were taken from a mean of five
individual action potentials recorded at steady state. Cell
membrane capacitance was measured with a standard voltage-ramp
protocol.5 After a change to 4-AP perfusion solution,
cells were stimulated at 1 Hz until action potentials and contraction
had reached a new steady state (3 minutes) before the action
potential protocols were repeated.
Solutions
Isolation Tyrode's solution contained (mmol/L) NaCl 130,
KCl 5.4, MgCl2 3.5, NaH2PO4 0.4,
glucose 10, HEPES 5, and taurine 20; pH 7.2 adjusted with NaOH. The
superfusion solution contained (mmol/L) NaCl 137, KCl 5.4, MgCl
1.2, glucose 10, and HEPES 5; pH 7.4. A stock solution of 3
mol/L 4-AP was diluted in perfusion Tyrode's solution to give a
final concentration of 3 mmol/L. The pipette solution
contained (mmol/L) KCl 140, MgCl2 2, Mg-ATP 5,
sodium phosphocreatine 5, and HEPES 10; pH 7.4 with KOH. In some
experiments, BAPTA 5 mmol/L was included in the pipette to
buffer intracellular calcium.
Statistics
Comparisons of ECG parameters and organ weights
between the isoproterenol-treated and control animals were performed by
Student's t test. Electrophysiological
parameters were initially assessed with two-way ANOVA using
the factors hypertrophy and region of origin of myocytes to
define the groups. (A normal distribution for each
parameter was confirmed with a Kolmogorov-Smirnov test.)
Post hoc analysis was performed with the Student-Newman-Keuls
technique, so that multiple comparisons between the data of the six
groups were valid. For all tests, P<.05 was taken as
statistically significant.
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Results |
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Evidence of Cardiac Hypertrophy
Organ weights. Blotted wet weights of organs from eight pairs of animals are shown in Table 1
. LV
weight, heart weight, and ratio of heart weight to body weight were
increased in the isoproterenol-treated group by 21%, 17%, and 22%,
respectively. Liver and lung weights were not significantly different,
and there was no macroscopic evidence of edema (pleural or pericardial
effusions), indicating that cardiac heart failure was not present
in these animals.
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Electrocardiograms. The ECGs of control rats
had upright T waves, with close concordance between the QRS and T-wave
axes and little interanimal variation (see Fig 1).
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In the isoproterenol-injected group, the QRS and T-wave axes were divergent and showed wide interanimal variation. The mean QRS amplitude was increased and the mean T-wave amplitude decreased compared with control.
Cell membrane capacitance. Cell membrane capacitance was not significantly different in myocytes from the three regions in either control or hypertrophy groups (mean cell capacitance, control: endo, 117±8 pF, n=22; mid, 110±9 pF, n=17; epi, 110±8 pF, n=21; hypertrophy: endo, 135±10 pF, n=19; mid, 127±11 pF, n=14; epi, 136±8 pF, n=22). Overall mean membrane capacitance was 18% greater in myocytes isolated from isoproterenol-treated rats than from controls.
Action Potential Configuration in Tyrode's Solution
Representative individual action potentials
recorded at 1 Hz from subendocardial and subepicardial myocytes
isolated from control rats are shown in Fig 2. The resting potentials are similar,
but APA and APD are greater for the subendocardial than the
subepicardial myocyte.
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Mean data for APA and APD25 show that
endocardial/epicardial differences in amplitude and
APD25 are significant (see Table 2). The mean APA and APD of midmyocardial
myocytes are intermediate between the subendocardial and subepicardial
values. Although the regional differences in APD75 of
control myocytes do not reach statistical significance
(P=.09), they are consistent with the predicted
transmural gradient in APD.6
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Mean data for myocytes isolated from hypertrophied hearts are shown in
Table 2
. As in control myocytes, the resting potential does not show
significant regional variation in hypertrophy. Action
potentials of subendocardial myocytes have greater amplitude and
APD25 than subepicardial myocytes, and regional differences
are significant, although less so than those seen in controls. The
regional differences in APD75 in hypertrophy
show the opposite pattern to that seen in control, with
APD75 being longest in subepicardial and shortest in
subendocardial myocytes in hypertrophy.
Comparison of data for hypertrophied myocytes with those of controls shows that hypertrophy is associated with a depolarization of the resting potential in all three regions. The peak of the action potential is also decreased in hypertrophy, so the APA is reduced compared with control (ANOVA P<.01).
Representative action potentials in Fig 3 show the changes in APD associated with
hypertrophy in myocytes isolated from each region. In
subendocardial myocytes, APD25 is unchanged and
APD75 shortened in hypertrophy compared with
control. In subepicardial myocytes, both APD25 and
APD75 are prolonged in hypertrophy. In
midmyocardial myocytes, APD25 is also prolonged in
hypertrophy, but there is no prolongation of
APD75. Analysis of the mean data (Table 2) shows a
significant increase in APD25 in subepicardial and
midmyocardial myocytes (Student-Newman-Keuls P<.05) but not
in subendocardial myocytes in hypertrophy. The changes in
APD75 associated with hypertrophy are also
different depending on the region of origin of the myocytes (ANOVA
P<.02; hypertrophy and region interact to
influence APD75). The APD75 of subepicardial
myocytes is longer in hypertrophy than in control, whereas
the APD75 of subendocardial myocytes is shorter in
hypertrophy (P<.001). Because the
hypertrophy-induced changes in APD75 are
discordant with those in APD25, they are not simply a
reflection of changes in the early part of the action potential.
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) hearts.
APD is dependent on the stimulation frequency for myocytes isolated
from both control (Fig 4A) and
hypertrophied (Fig 4B) hearts. The pattern of regional differences and
hypertrophy-induced changes in APD are the same at all
frequencies studied.
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),
midmyocardial (
), and subepicardial (
) myocytes isolated from
control (open symbols, top) and hypertrophied (solid symbols, bottom)
hearts. Same pattern of regional differences in APD is apparent at all
frequencies.
Action Potential Configuration in 4-AP
To assess the contribution of Ito1 to the
regional differences in action potential characteristics and changes
observed in hypertrophy, the same protocols were repeated
in the presence of 3 mmol/L 4-AP, a specific
inhibitor of
Ito1.7 8 9 10 11
Mean data for action potentials recorded after a change to 4-AP are
shown in Table 3. The application of 4-AP
hyperpolarizes the resting potential (by 2 mV) and increases APA and
APD in all myocytes. However, the patterns of regional differences in
APA and APD25 seen in Tyrode's solution are preserved; APA
and APD25 are greater in subendocardial than subepicardial
myocytes in both control and hypertrophy, and regional
differences in APA and APD25 remain statistically
significant. This suggests that there are regional differences in
4-AP–insensitive currents that affect the early part of the action
potential.
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After the application of 4-AP, the APD25 of myocytes from the same region was similar in control and hypertrophy, ie, the association of hypertrophy with a prolongation of APD25 is lost. This suggests that the hypertrophy-associated changes in APD25 observed in Tyrode's solution are due to changes in Ito1.
The influence of Ito1 can also be indirectly
assessed by comparison of the relative change in APD25
elicited by 4-AP. The percentage prolongation of APD25 is
greatest in subepicardial myocytes and least in subendocardial myocytes
in both the control and hypertrophy groups (see Fig 5), although the regional differences in
the effects of 4-AP are less in hypertrophy than in
control. These data support the hypothesis that
Ito1 density is greater in subepicardial than
subendocardial myocytes in control myocytes but that this difference is
reduced in hypertrophy.
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Action Potential Configuration in the Presence of
Intracellular BAPTA
Representative action potentials recorded from
subepicardial myocytes with patch electrode solutions with and without
BAPTA are shown in Fig 6A. The resting
potential is depolarized in the presence of BAPTA, but the upstroke and
early repolarization phase of the action potential are similar to those
recorded when intracellular calcium is not buffered. However, the
prominent late plateau phase of the rat action potential, which is
dependent on intracellular calcium,12 13 is abolished by
intracellular BAPTA.
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, n=142) BAPTA. In the absence of
BAPTA, there is no correlation between APD25 and
APD75 (r=.10), but when BAPTA is included in
patch solution, there is a linear relationship as shown
(r=.78, P<.001).
In Fig 6B, APD75 is plotted against APD25 for
action potentials recorded with and without BAPTA from myocytes in
Tyrode's solution. The range of APD25 is similar whether
BAPTA is included or not, but in the presence of BAPTA,
APD75 is much shorter. Moreover, action potentials
recorded without BAPTA show a wide scatter for APD75
and poor correlation between APD25 and APD75,
but in the presence of BAPTA APD75 is closely correlated to
APD25. Therefore, when BAPTA is included in the patch
solution, the regional differences and
hypertrophy-associated changes in APD75 mirror
those observed in APD25. Because of the close correlation
between APD25 and APD75 in the presence of
BAPTA, data for the two time points can be summarized together (see
Table 4).
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In myocytes isolated from control rats, APA and APD in the presence of
BAPTA have significant regional variation, being greatest in
subendocardial myocytes and least in subepicardial myocytes. In
hypertrophy, no regional difference in APA or APD is
detected. The changes in APD associated with hypertrophy
are different in the three regions (ANOVA hypertrophy
and region interaction, P<.05), with APD being prolonged in
both midmyocardial and subepicardial myocytes compared with controls
(P<.01) but unchanged in the subendocardial myocytes. This
is similar to the data for APD25 recorded without
BAPTA, which also showed hypertrophy to be associated with
a prolongation of APD25 in the midmyocardial and
subepicardial myocytes but not in subendocardial myocytes and a
reduction in regional differences in APD25 in
hypertrophy (cf Table 2).
Under conditions in which intracellular calcium is not buffered, hypertrophy is associated with a significant reduction in APD75 of subendocardial myocytes. However, when BAPTA is included in the patch solution, the APD75 of subendocardial myocytes is unaltered in hypertrophy.
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Discussion |
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These results demonstrate that there are regional differences in action potential characteristics in the normal rat heart. We have identified, for the first time, regional differences in the electrophysiological changes associated with cardiac hypertrophy. There is prolongation of the early repolarization phase of the action potential (APD25) of subepicardial and midmyocardial myocytes, which may be attributed to a reduction in Ito1 density. In subendocardial myocytes, however, APD25 is unchanged in hypertrophy, and the plateau phase of the action potential is significantly shortened because of changes in calcium-dependent currents (probably Na+-Ca2+ exchange). Midmyocardial myocytes show a combination of the characteristics of both subendocardial and subepicardial myocytes, with prolongation of APD25 but not of APD75 in hypertrophy (see Fig 3
). We have confirmed earlier work showing that catecholamine-induced hypertrophy in rats is associated with T-wave inversion.4 This and the counterclockwise ("left") shift of the mean QRS axis are similar to ECG changes observed in human cardiac hypertrophy, which suggests that comparable ventricular repolarization abnormalities may be present in cardiac hypertrophy both in the rat model and in humans.
Regional Differences in Action Potential Characteristics of
Normal Hearts
Apex/base differences in rat APD have previously been demonstrated
by Watanabe et al.14 They found that endocardial action
potentials recorded from ventricular wall preparations
could be classified by duration into short (found in basal, mid, and
apical regions of the right ventricle), intermediate (in mid and apical
regions of the LV), and long (basal LV). They also found that myocytes
isolated from the whole of both ventricles showed a range of APD that
could be divided into three groups and appeared to correspond to the
three types recorded from tissue preparations. However, they did
not explore possible endocardial/epicardial differences in APD
or attempt to isolate myocytes from specific regions.
Differences between action potentials of subendocardial and subepicardial myocytes have previously been demonstrated in rat,15 dog,16 rabbit,17 guinea pig,18 and humans.19 Our results confirm earlier work15 in showing APA and APD of subendocardial myocytes to be greater than those of subepicardial myocytes in normal rat hearts. We have found that regional differences in APA and APD25 are still detectable in the presence of 4-AP, which suggests that although Ito1 density may be greater in subepicardial than in subendocardial myocytes (as in humans,19 cats,20 rabbits,17 and dogs16 ), the magnitude of other rapidly activating currents must also differ between regions.
This article is the first report comparing the electrophysiology of
midmyocardial cells to subepicardial and subendocardial myocytes in the
rat. The action potential parameters of midmyocardial cells
are intermediate between the values for subendocardial and
subepicardial cells at all stimulation frequencies studied (0.2, 1.0,
and 2.0 Hz; see Fig 4). Sicouri and Antzelevitch21
identified a group of midmyocardial "M cells" with extreme
prolongation of the action potential at slow stimulation rates in dogs.
We found no evidence of M cells in the rat, because the midmyocardial
myocyte action potential characteristics show rate dependence similar
to that of myocytes from the other regions.
Increasing stimulation frequency produced an increase in APD25 and a decrease in APD75 in all regions. The prolongation of APD25 and small increase in APA seen with increasing stimulation frequency suggests that the recovery of the Ito from inactivation may be incomplete at the higher frequencies. Human action potentials also show a reduced early repolarization phase as frequency increases, which is also thought to be due to partial inactivation of Ito. Wettwer et al9 directly compared Ito1 in rat and human isolated myocytes and found that the kinetics of inactivation are similar, especially when the faster physiological heart rate of rats is taken into account.
Regional Changes in Action Potential Characteristics Associated
With Hypertrophy
The resting potential showed no significant regional variation
under any of our experimental conditions. The depolarization of the
resting potential in hypertrophy in this model, previously
ascribed to a reduction in Na+,K+-ATPase
activity,22 is uniform in the different regions.
Previous work in mammalian species has consistently shown a prolongation of APD in hypertrophy, both in isolated myocytes and in tissue preparations (reviewed in Reference 2323 ). However, the whole of the LV, including the septum, has been used to obtain isolated myocytes,24 25 26 despite regional differences in the response to hypertrophy being predictable from the ECG T-wave changes.6
Keung and Aronson3 investigated endocardial/epicardial differences in APD in rats with hypertrophy in LV tissue slices. However, they found regional differences in APD to be insignificant in both sham and hypertrophied rats, and the difference appeared to increase in hypertrophy. This is the opposite of what is expected from the observed T-wave inversion. The only other reported work on regional differences in action potentials in hypertrophy compared endocardial action potentials measured with a floating electrode within the right ventricle of the cat 3 days after pulmonary artery banding.27 The action potential plateau phase was altered in basal (but not apical) areas, and it was suggested that this reflected the local increase in wall stress produced in that model of hypertrophy.
We found significantly different changes in action potential characteristics in response to hypertrophy in myocytes isolated from the three regions. These changes result in a reduction of the normal endocardial/epicardial gradient in APD25 and a reversal of the gradient for APD75, which could explain the observed T-wave inversion. These changes will be considered in two parts, those affecting the early phases of the action potential and those affecting the plateau phase.
Changes in the Early Phase of the Action Potential
APA is reduced in hypertrophy in the three regions
whether 4-AP is included in the perfusion solution or not. This
suggests that in hypertrophy, net 4-AP–insensitive early
inward current is reduced. In hypertrophy, the
APD25 of subendocardial myocytes is similar to control but
the APD25 of subepicardial and midmyocardial myocytes is
prolonged. There is therefore a reduction in regional differences in
APD25 in hypertrophy, which may be due to a
reduction in Ito1 in midmyocardial and
subepicardial myocytes, with Ito1 remaining
unchanged in subendocardial myocytes. The reduction in the effect of
4-AP on APD25, especially in the subepicardial and
midmyocardial myocytes, supports this hypothesis and suggests that
regional differences in Ito1 are reduced in
hypertrophy. This finding is in agreement with Cerbai et
al,26 who showed a reduction in
Ito1 in myocytes isolated from the whole LV.
Moreover, Bénitah et al28 showed that
hypertrophy was associated with a reduction in
Ito1 that was greatest in myocytes isolated from
the LV free wall and apex, and that regional variation in
Ito1 density was reduced in
hypertrophy.
Changes in the Plateau Phase of the Action Potential
These data are the first report of APD being reduced in cardiac
hypertrophy in the rat. However, previous studies on
isolated rat myocytes have used intracellular calcium buffers, so
changes in the plateau phase of the action potential that depend on
intracellular calcium will not have been detected.
In this study, we found that hypertrophy was associated
with different changes in APD75 in myocytes isolated from
the three regions. In subepicardial cells, the plateau phase appears to
parallel that seen in control (see Fig 4), so the increase in
APD75 may simply follow from the increase in
APD25. Surprisingly, however, in subendocardial myocytes,
hypertrophy is associated with a significant reduction in
APD75. This reduction in APD75 in
hypertrophy is not observed when BAPTA is included in the
patch solution, suggesting that the decrease in APD75 is
due to a reduction in Na+-Ca2+ exchange, which
could arise from a reduction in L-type calcium current or in the
calcium transient or from reduced expression of the
Na+-Ca2+ exchanger protein.
Comparison between our results and previous work on changes in action potentials in LV hypertrophy is complicated by possible effects of species and model differences. There are known species differences in the relative importance of individual currents in the action potential. (Ito is significant in rats and humans but not in guinea pigs.9 It is thought that the L-type calcium current is of less importance in rats than in humans, guinea pigs, and ferrets and conversely, that calcium-dependent currents seem more important in rats than in other species.29 ) Moreover, the effects on different membrane currents may vary depending on the stimulus for hypertrophy (reviewed in Reference 2323 ). Despite these limitations, regional differences in APD and membrane currents in response to pathological stimuli are of increasing interest, especially because endocardial-epicardial differences in Ito1 have been found to be reduced in myocytes isolated from patients with heart failure.19
This study shows that isoproterenol-induced cardiac hypertrophy in rats is associated with a reduction in the regional differences in action potential characteristics, which may explain the T-wave inversion observed in this model. The early repolarization phase (APD25) is prolonged in subepicardial and midmyocardial myocytes in hypertrophy, probably because of a reduction in Ito1. In subendocardial myocytes, early repolarization is unchanged and the plateau phase is shortened in hypertrophy, probably because of a reduction in Na+-Ca2+ exchange. How these changes can be related to the increased incidence of sudden death30 and ventricular arrhythmias31 in LV hypertrophy in humans is less clear. It has previously been argued that there is an increase in APD heterogeneity in hypertrophy (reflected in increased T-wave dispersion) facilitating the development of reentry circuits and increasing the electrical vulnerability of hypertrophied myocardium (reviewed in Reference 3232 ). However, we found a decrease in the differences in APD between regions, and there was no increase in local heterogeneity within each region (ie, the SD of mean APD for each region did not increase in hypertrophy). Nevertheless, functional heterogeneity may exist in the intact heart, because histological studies of this model of hypertrophy have shown localized myocardial fibrosis, myocyte loss, and ischemic foci, and the effects of these features will be lost in the process of myocyte isolation.4
There have been few previous studies examining regional differences in action potentials in pathological conditions. Data obtained from myocytes isolated from the whole of the LV (which will be predominantly midmyocardial) have been extrapolated as though ventricular electrophysiology were homogeneous, despite the known regional differences in cellular electrophysiology within the normal LV. Our findings of discordant changes in APD in subendocardial and subepicardial myocytes from rats with isoproterenol-induced hypertrophy provide the first direct evidence of a disturbance of the normal endocardial-epicardial gradient in APD. The mechanisms giving rise to the different effects of hypertrophy on regional myocyte electrophysiology await further investigation.
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Selected Abbreviations and Acronyms |
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Received December 2, 1996; revision received April 3, 1997; accepted April 4, 1997.
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References |
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