© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Regional differences in electrical and mechanical properties of myocytes from guinea-pig hearts with mild left ventricular hypertrophy
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
* Corresponding author. Tel.: +44 (1865) 220133; fax: +44 (1865) 221977.
Received 4 December 1996; accepted 8 April 1997
 |
Abstract |
|---|
 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Objective: To investigate electrical and mechanical properties of single myocytes isolated from different regions of the left ventricle in control and hypertrophied hearts. Methods: Mild cardiac hypertrophy was induced in guinea-pigs by aortic constriction. Myocytes were isolated from basal sub-endocardial, basal mid-myocardial and apical sub-epicardial layers of the left ventricle. Action potentials were stimulated at 1 Hz. Membrane currents were measured using the switch-clamp technique. Cell shortening was measured using a photodiode array. Results: In control hearts mean action potential duration (APD) was longer in sub-endocardial myocytes than in sub-epicardial myocytes. In hypertrophy APD was prolonged in sub-epicardial and mid-myocardial myocytes and unchanged in sub-endocardial myocytes (APD90 ms, control: sub-endocardial 273±12, mid-myocardial 254±14, sub-epicardial 229±9; hypertrophy: sub-endocardial 259±13, mid-myocardial 291±9, sub-epicardial 268±11, P<0.05, ANOVA). There was no significant regional difference in APD in hypertrophied hearts. In control hearts L-type calcium current (ICa) was similar in all regions. In hypertrophy ICa was increased in sub-epicardial and mid-myocardial myocytes and reduced in sub-endocardial myocytes. Calcium-activated tail currents were not regionally different in control or hypertrophied hearts, but were increased in hypertrophy. Conclusions: Changes in electrical and mechanical properties associated with hypertrophy are not homogeneous throughout the left ventricle. The difference in APD between sub-endocardial and sub-epicardial myocytes seen in control hearts is lost in hypertrophy. These results may favour the propagation of re-entry arrhythmias in hypertrophied hearts.
KEYWORDS Action potential duration; Hypertrophy; Ventricular myocytes; Calcium current; Guinea pig
|
1 Introduction |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Action potential duration (APD) is prolonged in sub-endocardial myocytes compared with sub-epicardial myocytes isolated from the hearts of dog [1, 2], cat [3], rabbit [4], human [5, 6], and rat [7, 8]. Each of these species displays an early repolarization phase in the ventricular action potential which is attributable to transient outward current (Ito). The difference in APD between sub-endocardial and sub-epicardial myocytes may in part be accounted for by a greater density of Ito in sub-epicardial compared to sub-endocardial myocytes [1, 3–5, 8]. Guinea-pig myocytes, which do not express Ito [9, 10], nevertheless demonstrate regional differences in APD in multicellular [11]and in single cell preparations [12]. We have recently shown that regional differences in APD in normal guinea-pig myocytes may be attributed in part to differences in sodium–calcium exchange current and in delayed rectifier current (IK) [12]. Differences in IK and the background rectifier current (IK1) between sub-endocardial and sub-epicardial myocytes have been demonstrated in cat [13]but not dog [14]or rat [8].
Although prolongation of APD is the most consistent electrophysiological change observed in cardiac hypertrophy (for a review, see Hart [19]), few studies have addressed the question of whether APD prolongation in hypertrophy is uniform throughout the left ventricle. Using the Goldblatt model of hypertension in the rat, Keung and Aronson (1981) showed that APD was prolonged in myocardium from the endocardial surface, but only the second half of the action potential was prolonged in epicardial muscle [15]. Bénitah et al. [16]have reported significant differences in Ito density in myocytes isolated from septum, left ventricular free wall, and apex in rat hearts [16], and they demonstrated that regional differences in Ito were reduced in hypertrophy [16]. To our knowledge, no reports exist on the regional distribution of the properties of other membrane currents in hypertrophied myocytes from any species.
We have chosen to use a model of mild, pressure-overload hypertrophy in the guinea-pig which has previously been characterized, and which displays major prolongation of APD [10]. The aim of this study was to find out whether or not such changes are uniform within the left ventricle.
|
2 Methods |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
2.1 Model of hypertrophy
Cardiac hypertrophy was produced by constriction of the abdominal aorta and the treatment of all animals was in accordance with the Home Office Guidance on the Operation of the Animals (Scientific Procedures) Act 1986 (HMSO). Female Dunkin-Hartley guinea-pigs (300–350 g) were anaesthetised using fentanyl and fluanisone (Hypnorm®), 1 ml·kg–1, and ketamine 5 mg·kg–1, both administered as intramuscular injections. A midline abdominal incision was made. The abdominal aorta immediately distal to both renal arteries was isolated and constricted by placement of a silver clip (0.5 mm diameter). Papaverine (0.15 mg) was infused locally to reduce vasospasm and heparin 500 U was given to prevent thrombus formation. The incision was closed in two layers with silk sutures. Sham-operated animals were treated in the same way but no clip was placed. At the time of isolation there were no overt signs of heart failure: i.e., there were no pleural or pericardial effusions, no ascites and the animals were not cyanosed.
2.2 Cell isolation
Single myocytes were isolated from three discrete regions of the left ventricular free wall using a standard enzymatic dispersion technique as described previously [10]. The animals were humanely killed by cervical dislocation. Animals weighing more than 1 kg were killed using pentobarbitone sodium, 200 mg·kg–1. The heart was quickly removed and placed in warm Tyrode solution (for composition, see below) before the aorta was cannulated on a Langendorff apparatus and the heart perfused for 4 min with a nominally Ca2+-free solution. The solution was changed to an enzyme-containing solution for a further 5 min before the heart was removed. The left ventricular free wall was dissected free. Tissue samples were isolated using careful dissection with fine scissors from a sub-epicardial layer at the apex, from a sub-endocardial layer at the base, and from a deeper mid-myocardial layer at the base. The three tissue samples were then placed in separate flasks containing fresh enzyme solution (with no protease added). Cells were harvested after further 5 and 10 min digestion periods, and were washed twice in Tyrode solution containing 5 mg·ml–1 bovine serum albumin (Sigma). Myocytes were finally re-suspended in Dulbecco's modified Eagle medium supplemented with 2 mg·ml–1 Ultraser GTM (Gibco BRL, Paisley, Scotland). The myocyte suspension was stored at 20±1°C and cells were used within 12 h of isolation.
2.3 Electrophysiological techniques
For electrophysiological recordings myocytes were layered onto the floor of a perfusion chamber situated on the stage of an inverted microscope (Diaphot, Nikon, UK). Cells were superfused with a Tyrode solution (for composition, see below) at a flow rate of 1–2 ml·min–1 at 35±1°C. Micropipettes were fabricated from borosilicate capillary tubing (GC200TF-15, Clarke Electromedical Instruments, Pangbourne, UK) and pulled on a vertical puller (Narishige, Japan). Membrane voltage and current were measured using the voltage-clamp technique (Axoclamp-2A, Axon Instruments, USA) in conjunction with high-resistance microelectrodes (15–20 M
when filled with 2 M KCl). Cell length was monitored using a photodiode array system (S-series, Reticon, USA) as described previously [17], with a temporal resolution of approximately 4 ms. Analog signals (current, voltage, and cell length) were digitized by a 12-bit analog-to-digital converter (CED 1401, Cambridge Electronic Design, UK) and stored on-line to computer for subsequent off-line analysis.
2.4 Experimental protocols
Action potentials were elicited in current-clamp mode by a 1 ms injection of current at a frequency of 1 Hz. The current level was adjusted to approximately 50% above threshold. Action potential duration was measured at 10, 50 and 90% repolarisation levels (APD10, APD50, and APD90, respectively). Calcium-activated tail currents were obtained by interrupting the action potential 100 ms after depolarisation, by voltage-clamping back to the resting membrane potential [18]. L-type calcium current was elicited by 300 ms step depolarisations from a holding potential of –45 mV to test potentials ranging from –60 to +100 mV. Steady-state activation curves were obtained by calculating the relative chord conductance for each cell from the current–voltage relationship, and steady-state inactivation curves were constructed by plotting relative current amplitude obtained using a standard double-pulse protocol. Cell membrane capacitance was measured using a voltage ramp protocol [10].
2.5 Solutions
The composition of the isolation Tyrode solution was as follows (mmol·l–1): NaCl 130; KCl 5.4; MgCl2 3.5; NaH2PO4 0.4; glucose 10; HEPES 5; CaCl2 0.75; pH 7.2 at 35°C with NaOH. The nominally Ca2+-free solution contained no added calcium, and EGTA (0.1 mmol·l–1). The enzyme solution contained collagenase (1 mg·ml–1, Worthington Biochemical Corporation, New Jersey), protease (0.05 mg·ml–1, Sigma) and Ca2+ (0.05 mmol·l–1). The composition of the superfusion solution was (mmol·l–1): NaCl 134; KCl 5.4; MgCl2 1.2; CaCl2 1.8; glucose 11.1; HEPES 5; pH 7.4 with NaOH.
2.6 Statistics
Data are expressed as mean±s.e.m. and n indicates the number of cells used in each group. Five pairs of animals were used and data were collected from approximately equal numbers of cells per region from each animal. The Kolmogorov-Smirnov Goodness of Fit test was used to verify a normal distribution for all parameters. In order to assess the influence of both hypertrophy and region on action potential characteristics, data from all 6 groups were initially analysed with two-way analysis of variance (2-way ANOVA) using hypertrophy and region as factors. A significant interaction between the two factors shows that the effects of hypertrophy are different in the different regions and therefore regional differences should be assessed separately in control and hypertrophied hearts. One-way analysis of variance (1-way ANOVA) was then used to assess regional differences in the properties of myocytes isolated from either control or hypertrophied hearts. Multiple comparisons between the individual groups were then made using either Student-Newman-Keuls post-hoc analysis or Student's unpaired t-test. Statistical significance was assessed at the 0.05 level.
|
3 Results |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Animals were sacrificed 157±2 days post-operation at which time the heart weight to body weight ratio was 11% greater in the clipped group compared to the sham group of animals (mean for the sham group was 3.09±0.11 mg·kg–1, clipped group 3.44±0.08 mg·kg–1, n = 5, P<0.05, t-test). There was no difference in the lung weight to body weight ratio (sham group 5.6±0.4 mg·kg–1, clipped group 5.5±0.3 mg·kg–1, n = 5, n.s.) or liver weight to body weight ratio (sham group 34.8±2.3 mg·kg–1, clipped group 35.3±3.2 mg·kg–1, n = 5, n.s.).
3.1 Action potential configuration
Fig. 1 shows representative action potentials, at 1 Hz, from sub-endocardial and sub-epicardial myocytes isolated from control and hypertrophied hearts. The control records show that APD of the sub-endocardial myocyte is considerably longer than that of the sub-epicardial myocyte, as expected from previous work [11, 12]. However, the action potentials recorded from the hypertrophied myocytes are closely similar in duration. Mean data for action potential characteristics are summarised in Table 1.
|
|
Table 1 shows mean data for action potential characteristics of myocytes isolated from both control and hypertrophied hearts. In control hearts there are significant differences in mean APD between sub-endocardial, mid-myocardial and sub-epicardial myocytes (P<0.05, 1-way ANOVA). Mean APD90 of sub-endocardial myocytes is longer than the APD90 of mid-myocardial and sub-epicardial myocytes by 7.5 and 19%, respectively. However, in hypertrophied hearts the regional differences in APD are smaller, and mean APD90 is not significantly different between each of the three regions studied.
Fig. 2 illustrates the effects of hypertrophy on representative action potentials recorded from each of the three regions studied. Hypertrophy prolongs APD in sub-epicardial and mid-myocardial myocytes, but no prolongation can be seen in the sub-endocardial action potential. Mean data (Table 1) confirm that APD at 10, 50 and 90% repolarisation levels are prolonged in sub-epicardial and mid-myocardial myocytes (P<0.05, t-test) in hypertrophy and that APD90 of endocardial myocytes is reduced by 6% (not significant). Changes in APD associated with hypertrophy are significantly different in the three regions studied (P<0.05, interaction between region and hypertrophy, 2-way ANOVA).
|
We shall now compare more fully the differences in APD between the regions in control hearts with the differences in hypertrophy (see Fig. 1). In normal hearts there is a difference in mean APD90 of 44 ms between sub-endocardial and sub-epicardial myocytes (P<0.05, 1-way ANOVA); in hypertrophy the difference is reduced to only –9 ms (n.s.). In control hearts the difference in mean APD90 between sub-endocardial and mid-myocardial is 19 ms, in hypertrophy this difference in mean APD90 is increased, and opposite in direction being –32 ms. The difference in mean APD90 between sub-epicardial and mid-myocardial myocytes is similar in both control (–25 ms) and hypertrophied (–23 ms) hearts.
Hypertrophy is associated with different changes in action potential amplitude in the three regions studied (P<0.01, interaction between region and hypertrophy, 2-way ANOVA). In hypertrophy action potential amplitude is increased by 6 mV in both sub-epicardial (P<0.05, t-test) and mid-myocardial (P<0.05, t-test) myocytes, and is not significantly different in sub-endocardial myocytes. The change in action potential amplitude may be attributed to changes in the peak of the action potential as the resting potential was similar in all three regions and was unchanged in hypertrophy.
3.2 Voltage-clamp experiments
3.2.1 Cell membrane capacitance
Cell membrane capacitance was estimated under voltage-clamp conditions using a ramp protocol and mean data are shown in Table 2. The mid-myocardial myocytes have significantly greater mean capacitance than the other two groups. Hypertrophy is associated with an increase in cell capacitance in all three groups (P<0.001, 2-way ANOVA). Cell membrane capacitance was increased by 14% in sub-endocardial, by 18% in sub-epicardial, and by 23% in mid-myocardial myocytes. In control hearts the difference in cell membrane capacitance between the three regions is not statistically different (P = 0.2, 1-way ANOVA). However, in hypertrophied hearts regional differences in cell membrane capacitance reach significance (P<0.01, 1-way ANOVA); the capacitance of mid-myocardial myocytes is larger than that of the other two regions.
|
3.2.2 L-type calcium current
An increase in L-type calcium current may be partly responsible for the prolongation of action potential duration in this model of hypertrophy [10]. Fig. 3 shows representative current records taken from individual sub-endocardial, sub-epicardial and mid-myocardial myocytes isolated from control and hypertrophied hearts. L-type calcium current was elicited by a 300 ms step depolarisation to 0 mV from a holding potential of –45 mV. The holding current density (measured at –45 mV) was similar in control cells from each region (sub-endocardial 2.3±0.2 pA·pF–1, n = 23; mid-myocardial 2.1±0.2 pA·pF–1, n = 26; sub-epicardial 2.1±0.5 pA·pF–1, n = 26) and unchanged in hypertrophy (sub-endocardial 2.2±0.1 pA·pF–1, n = 24; mid-myocardial 2.6±0.2 pA·pF–1, n = 24; sub-epicardial 2.4±0.2 pA·pF–1, n = 24). Table 2 shows that peak current amplitude is the same in the control cells from each region (P = 0.5, 1-way ANOVA). Hypertrophy is associated with significantly different changes in peak current amplitude in the three regions (P<0.05, interaction between region and hypertrophy, 2-way ANOVA). Mean data show that peak current is increased by 26% in sub-epicardial (P<0.01, t-test) and by 32% mid-myocardial myocytes (P<0.001, t-test), but peak current amplitude is unchanged in sub-endocardial myocytes. As a consequence of these differential changes in peak inward current there is a significant difference in peak inward current between the three regions in hypertrophied hearts (P<0.01, 1-way ANOVA).
|
Hypertrophy is associated with different changes in current density in sub-endocardial and sub-epicardial myocytes (P<0.05, interaction between region and hypertrophy, 2-way ANOVA). Mean ICa density is increased in sub-epicardial myocytes by 9%, but is reduced in sub-endocardial myocytes by 24%.
Isochronal current density, measured at 290 ms after depolarisation, is similar in control myocytes from the three regions. In hypertrophy isochronal current density is increased in sub-epicardial (by 111%, P<0.05, t-test) and in mid-myocardial myocytes (by 50%, P<0.05, t-test), but is unchanged in sub-endocardial myocytes.
Fig. 4 shows mean steady-state activation (d
) and inactivation (f) curves for ICa. In control animals there is a regional difference in the half-activation potential, which is unchanged in hypertrophy. The inactivation curves are not significantly different between regions in either control or hypertrophy groups, but the hypertrophy group shows a small shift in the half-inactivation potential to less negative potentials.
|
) and inactivation (f3.2.3 Calcium-activated tail currents
An inward calcium-activated tail current attributable to Na+–Ca2+ exchange can be elicited by repolarisation back to the resting potential part way through an action potential [18]. We found no regional difference the exchange tail current density in control hearts (sub-endocardial –2.2±0.2 pA·pF–1, n = 15; mid-myocardial –1.9±0.2 pA·pF–1, n = 16; sub-epicardial –1.9±0.2 pA·pF–1, n = 10). In hypertrophy tail current density was increased by a similar amount in all regions (P<0.002, 2-way ANOVA, mean control current density for all regions –2.0±0.2 pA·pF–1, n = 41; hypertrophy –2.5±0.1 pA·pF–1, n = 66).
3.3 Unloaded cell shortening
Fig. 5 displays mean data for various characteristics of unloaded cell shortening in the regional groups of myocytes. Resting cell length is significantly lower in sub-endocardial myocytes in both control and hypertrophy groups, compared with the other regions (P<0.01, 2-way ANOVA). However, there is no significant regional difference in either relative shortening amplitude, time to peak contraction, or time to 10% relaxation (TR10) of cell shortening elicited in response to action potentials at 1 Hz. Hypertrophy is associated with a significant slowing of time to peak contraction and of relaxation time (P<0.02 for hypertrophy, P = n.s. for region, 2-way ANOVA), but there is no change in the peak amplitude of unloaded cell shortening. Averaging the data across the regional groups gives the following results: peak cell shortening was 10.2±0.5% (n = 73) in control, 10.5±0.5% (n = 75, n.s.) in hypertrophy; time to peak contraction was 151±4 ms (n = 73) in control, 167±5 ms (n = 75) in hypertrophy (P<0.01, t-test); TR10 was 36±1 ms (n = 73) in control, 43±2 ms (n = 75) in hypertrophy (P<0.01, t-test).
|
Peak cell shortening measured simultaneously with the calcium-activated tail current showed no regional variation, and was increased by 33% in hypertrophy (control 4.65±0.5%, n = 41; hypertrophy 6.19±0.5%, n = 66; P<0.03 for hypertrophy, P = n.s. for region, 2-way ANOVA).
|
4 Discussion |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Prolongation of action potential duration is the most consistently recognised electrophysiological change in cardiac hypertrophy [19]. This study shows that APD prolongation is not uniform in all regions of the left ventricular free wall, and that endocardial myocytes show no prolongation of the action potential in hypertrophy. The regional differences in action potential characteristics observed in control hearts are altered in hypertrophy.
4.1 Regional differences in action potential characteristics in hypertrophy
These data confirm the presence of significant regional differences in APD in normal guinea-pig hearts [11, 12]and in common with other species [1, 3–8, 20], APD of sub-endocardial myocytes is longer than that of sub-epicardial myocytes. The effects of hypertrophy were surprisingly different in the regional samples. The expected prolongation of APD was found in sub-epicardial and mid-myocardial myocytes, but the mean APD of sub-endocardial myocytes was reduced, although this change does not reach statistical significance. This is the first time that differential regional changes in APD in response to hypertrophy have been reported in the guinea-pig. Although the changes in APD are different in sub-endocardial and sub-epicardial myocytes, the increase in cell capacity is similar in both regions. Mid-myocardial myocytes show a greater increase in cell capacity with hypertrophy but a similar prolongation of APD to the sub-epicardial group. Therefore the differential changes in APD cannot be accounted for by the relative degree of hypertrophy in each region, as measured by a change in cell capacity.
The effects of hypertrophy on action potential amplitude varied between the regions, an increase in AP amplitude being detected in sub-epicardial and mid-myocardial myocytes and a small decrease in sub-endocardial myocytes. There were parallel changes in early repolarisation, in that APD10 was significantly prolonged in sub-epicardial and mid-myocardial myocytes and slightly reduced in the sub-endocardial group. These results may possibly be attributed in part to the small increase in ICa density in the sub-epicardial and mid-myocardial myocytes, and the small decrease in ICa density in the sub-endocardial myocytes. In view of the minor changes in ICa it is possible that differential changes in Na+ current properties may be more important in the regional changes in the early part of the action potentials.
4.2 Regional differences in membrane currents
Calcium current has been reported to be similar in sub-endocardial and sub-epicardial myocytes isolated from the normal rat heart [8]and we show here that ICa density is similar in the three regions in both control and hypertrophied guinea-pig hearts. Previous work has shown an increase in ICa density and a +11.5 mV shift in its half-inactivation potential in a similar model of hypertrophy [10]. The smaller changes in ICa density and gating variables observed in the present experiments may be due to the region of origin of myocytes or to the imposition of greater aortic constriction producing a greater stimulus to hypertrophy [19]. Since these changes in ICa properties are small, they are unlikely to account for the changes in APD in hypertrophy.
The increase in late, isochronal current observed in sub-epicardial and mid-myocardial myocytes may contribute to prolongation of the plateau phase of the action potential and further experiments are required to establish the ionic nature of this current change, which is not observed in sub-endocardial myocytes. Under these experimental conditions, a component of the isochronal current may be due to IK. Previous work has shown significant regional differences in IK in normal guinea-pig [21]and cat [13]hearts. These regional differences in IK may be altered in hypertrophy and thereby contribute to the differential changes in APD.
Several studies have shown increased current density (e.g., [10]) and protein expression (e.g., [22]) of the Na+–Ca2+ exchanger in hypertrophy. In normal hearts there is no regional difference in amplitude of calcium-activated tail currents attributable to Na+–Ca2+ exchange [18]. In hypertrophy exchange current density is increased by a similar amount (24%) in all three regions. An increase in Na+–Ca2+exchange current may in part underlie the prolongation of APD [10]observed in sub-epicardial and mid-myocardial myocytes. However, this current change would be expected to prolong APD in sub-endocardial myocytes and other mechanisms: for example, an increase in IK, must operate to obviate APD prolongation in this group.
4.3 Regional differences in cell shortening
Regional differences in myocyte contraction have not been extensively studied in normal hearts. Peak amplitude of cell shortening has been found to be greater in sub-endocardial than in sub-epicardial myocytes in the rat [8]and guinea-pig [12], but cell shortening is similar in these regions in the rabbit [23]. In this study we have found no regional difference in peak unloaded cell shortening (elicited by an action potential at 1 Hz) in myocytes from control or hypertrophied hearts. The lack of any alteration in peak shortening amplitude in hypertrophy correlates with the absence of major changes in calcium current density in these experiments. Prolongation of time to peak contraction and of relaxation have been described previously in hypertrophy [24–27].
4.4 Altered repolarisation sequence and arrhythmogenesis in hypertrophied hearts
Cardiac hypertrophy is associated with a higher incidence of arrhythmias and an increase in sudden death. In normal hearts the longer action potential of basal sub-endocardial myocytes ensures that the topographical sequence of repolarisation is the reverse of depolarisation [28–30]. In hypertrophy, however, heterogenous changes in APD may result in major alterations in the sequence of repolarisation. It has been suggested that the longer APD of sub-endocardial myocytes may help prevent re-entry. In hypertrophy, APD is longer in mid-myocardial cells than in sub-endocardial, and the possibility of re-entry arrhythmias may therefore be increased. Furthermore, equalisation of steep gradients in APD across the left ventricular wall in hypertrophy may provide an electrically more favourable environment for the maintenance of spiral waves of depolarisation, which have been suggested to underlie polymorphic tachycardias and ventricular fibrillation [31].
Time for primary review 51 days
|
Acknowledgements |
|---|
This work was sponsored by the British Heart Foundation. Jane Shipsey is a British Heart Foundation Junior Research Fellow. We would like to thank Mr. J.C. Coutinho for his technical assistance.
|
References |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
- Litovsky S.H, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res (1988) 62:116–126.
[Abstract/Free Full Text] - Liu D.-W, Gintant G.A, Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ Res (1993) 72:671–687.
[Abstract/Free Full Text] - Furukawa T, Myerburg R.J, Furukawa N, Bassett A.L, Kimura S. Differences in transient outward currents of feline endocardial and epicardial myocytes. Circ Res (1990) 67:1287–1291.
[Abstract/Free Full Text] - Fedida D, Giles W.R. Regional variations in action potentials and transient outward current in myocytes isolated from rabbit left ventricle. J Physiol Lond (1991) 442:191–209.
[Abstract/Free Full Text] - Wettwer E, Amos G.J, Posival H, Ravens U. Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin. Circ Res (1994) 75:473–482.
[Abstract/Free Full Text] - Näbauer M, Beuckelmann D.J, Überfuhr P, Steinbeck G. Regional defferences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation (1996) 93:168–177.
[Abstract/Free Full Text] - Shipsey SJ, Ryder, KO, Bryant SM, Hart G. Regional action potential changes in isolated ventricular myocytes from rats with catecholamine-induced cardiac hypertrophy. J Physiol Lond 1995;489:142P.
- Clark R.B, Bouchard R.A, Salinas-Stefanon E, Sanchez-Chapula J, Giles W.R. Heterogeneity of action potential waveforms and potassium currents in rat ventricle. Cardiovasc Res (1993) 27:1795–1799.
[Abstract/Free Full Text] - Hirano Y, Hiraoka M. Barium-induced automatic activity in isolated ventricular myocytes from guinea-pig hearts. J Physiol Lond (1988) 395:455–472.
[Abstract/Free Full Text] - Ryder K.O, Bryant S.M, Hart G. Membrane current changes in left ventricular myocytes isolated from guinea pigs after abdominal aortic coarctation. Cardiovasc Res (1993) 27:1278–1287.
[Abstract/Free Full Text] - Watanabe T, Rautaharju P.M, McDonald T.F. Ventricular action potentials, ventricular extracellular potentials, and the ECG of guinea pig. Circ Res (1985) 57:362–373.
[Abstract/Free Full Text] - Main MC, Bryant SM, Hart G. Electrical and mechanical characteristics of guinea-pig ventricular myocytes from apical epicardium and basal endocardium. J Physiol Lond 1995;483:8P.
- Furukawa T, Kimura S, Furukawa N, Bassett A.L, Myerburg R.J. Potassium rectifier currents differ in myocytes of endocardial and epicardial origin. Circ Res (1992) 70:91–103.
[Abstract/Free Full Text] - Antzelevitch C, Sicouri S, Litovsky S.H, et al. Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ Res (1991) 69:1427–1449.
[Free Full Text] - Keung E.C.H, Aronson R.S. Non-uniform electrophysiological properties and electrotonic interaction in hypertrophied rat myocardium. Circ Res (1981) 49:150–158.
[Abstract/Free Full Text] - Bénitah J.-P, Gomez A.M, Bailly P, et al. Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat hearts. J Physiol Lond (1993) 469:111–138.
[Abstract/Free Full Text] - Boyett M.R, Moore M, Jewell B.R, Montgomery R.A.P, Kirby M.S, Orchard C.H. An improved apparatus for the optical recording of contraction in single heart cells. Pflüger's Arch (1988) 413:197–205.[CrossRef][Web of Science][Medline]
- Egan T.M, Noble D, Noble S.J, Powell T, Spindler A.J, Twist V.W. Sodium–calcium exchange during the action potential in guinea-pig ventricular cells. J Physiol Lond (1989) 411:639–662.
[Abstract/Free Full Text] - Hart G. Cellular electrophysiology in cardiac hypertrophy and failure. Cardiovasc Res (1994) 28:933–946.
[Free Full Text] - Coraboeuf E, Nargeot J. Electrophysiology of human cardiac cells. Cardiovasc Res (1993) 27:1713–1725.
[Free Full Text] - Main MC, Bryant SM, Hart G. Delayed rectifier current density is greater in guinea-pig left ventricular epicardial myocytes than endocardial myocytes. J Mol Cell Cardiol 1996;28:P18.
- Studer R, Reinecke H, Bilger J, et al. Gene expression of the cardiac Na+–Ca2+ exchanger in end-stage human heart failure. Circ Res (1994) 75:443–453.
[Abstract/Free Full Text] - Chamunorwa J.P, O'Neill S.C. Regional differences in rest decay and recoveries of contraction and calcium transient in rabbit ventricular muscle. Pflüger's Arch (1995) 430:195–204.[CrossRef][Web of Science][Medline]
- Lecarpentier Y, Waldenström A, Clergue M, et al. Major alterations in relaxation during cardiac hypertrophy induced by aortic stenosis in guinea pig. Circ Res (1987) 61:107–116.
[Abstract/Free Full Text] - Naqvi R.U, MacLeod K.T. Effect of hypertrophy on mechanisms of relaxation in isolated cardiac myocytes from guinea pig. Am J Physiol (1994) 267:H1851–H1861.[Web of Science][Medline]
- Schouten V.J.A, Vliegen H.W, van der Laarse A, Huysmans H.A. Altered calcium handling at normal contractility in hypertrophied rat heart. J Mol Cell Cardiol (1990) 22:987–998.[CrossRef][Web of Science][Medline]
- Siri F.M, Krueger J, Nordin C, Ming Z, Aronson R.S. Depressed intracellular calcium transients and contraction in myocytes from hypertrophied and failing guinea pig hearts. Am J Physiol (1991) 261:H514–H530.[Web of Science][Medline]
- Noble D, Cohen I. The interpretation of the T wave of the electrocardiogram. Cardiovasc Res (1978) 12:13–27.
[Free Full Text] - Kanai A, Salama G. Optical mapping reveals that repolarisation spreads anisotopically and is guided by fiber orientation in guinea pig hearts. Circ Res (1995) 77:784–802.
[Abstract/Free Full Text] - Efimov I.R, Huang D.T, Rendt J.M, Salama G. Optical mapping of repolarisation and refractoriness from intact hearts. Circulation (1994) 90:1469–1480.
[Abstract/Free Full Text] - Jalife J, Gray R. Drifting vortices of electrical waves underlie ventricular fibrillation in the rabbit heart. Acta Physiol Scand (1996) 157:123–131.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Hasegawa, S. Nakatani, H. Kanzaki, H. Abe, and M. Kitakaze Heterogeneous Onset of Myocardial Relaxation in Subendocardial and Subepicardial Layers Assessed With Tissue Strain Imaging: Comparison of Normal and Hypertrophied Myocardium J. Am. Coll. Cardiol. Img., June 1, 2009; 2(6): 701 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, S. Tandan, J. Cheng, C. Yang, L. Nguyen, J. Sugianto, J. L. Johnstone, Y. Sun, and J. A. Hill Ca2+/Calmodulin-dependent Protein Kinase II-dependent Remodeling of Ca2+ Current in Pressure Overload Heart Failure J. Biol. Chem., September 12, 2008; 283(37): 25524 - 25532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Garcia-Webb, A. J. Taberner, N. C. Hogan, and I. W. Hunter A modular instrument for exploring the mechanics of cardiac myocytes Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H866 - H874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kohl, C. Bollensdorff, and A. Garny Effects of mechanosensitive ion channels on ventricular electrophysiology: experimental and theoretical models Exp Physiol, March 1, 2006; 91(2): 307 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Shah, F. G. Akar, and G. F. Tomaselli Molecular Basis of Arrhythmias Circulation, October 18, 2005; 112(16): 2517 - 2529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Szentadrassy, T. Banyasz, T. Biro, G. Szabo, B. I. Toth, J. Magyar, J. Lazar, A. Varro, L. Kovacs, and P. P. Nanasi Apico-basal inhomogeneity in distribution of ion channels in canine and human ventricular myocardium Cardiovasc Res, March 1, 2005; 65(4): 851 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kohl Cardiac cellular heterogeneity and remodelling Cardiovasc Res, November 1, 2004; 64(2): 195 - 197. [Full Text] [PDF]
|
|
|
|
|
|
M.E Diaz, H.K Graham, and A.W Trafford Enhanced sarcolemmal Ca2+ efflux reduces sarcoplasmic reticulum Ca2+ content and systolic Ca2+ in cardiac hypertrophy Cardiovasc Res, June 1, 2004; 62(3): 538 - 547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Oikarinen, M. S. Nieminen, M. Viitasalo, L. Toivonen, S. Jern, B. Dahlof, R. B. Devereux, P. M. Okin, and for the LIFE Study Investigators QRS Duration and QT Interval Predict Mortality in Hypertensive Patients With Left Ventricular Hypertrophy: The Losartan Intervention for Endpoint Reduction in Hypertension Study Hypertension, May 1, 2004; 43(5): 1029 - 1034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Katra, E. Pruvot, and K. R. Laurita Intracellular calcium handling heterogeneities in intact guinea pig hearts Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H648 - H656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J Janse Electrophysiological changes in heart failure and their relationship to arrhythmogenesis Cardiovasc Res, February 1, 2004; 61(2): 208 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F R Quinn, S Currie, A M Duncan, S Miller, R Sayeed, S M Cobbe, and G L Smith Myocardial infarction causes increased expression but decreased activity of the myocardial Na+--Ca2+ exchanger in the rabbit J. Physiol., November 15, 2003; 553(1): 229 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R de Groot, C. A Schumacher, A. O Verkerk, A. Baartscheer, J. W.T Fiolet, and R. Coronel Intrinsic heterogeneity in repolarization is increased in isolated failing rabbit cardiomyocytes during simulated ischemia Cardiovasc Res, September 1, 2003; 59(3): 705 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Diffee and D. F. Nagle Regional differences in effects of exercise training on contractile and biochemical properties of rat cardiac myocytes J Appl Physiol, July 1, 2003; 95(1): 35 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Sears, S. M. Bryant, E. A. Ashley, C. A. Lygate, S. Rakovic, H. L. Wallis, S. Neubauer, D. A. Terrar, and B. Casadei Cardiac Neuronal Nitric Oxide Synthase Isoform Regulates Myocardial Contraction and Calcium Handling Circ. Res., March 21, 2003; 92 (5): e52 - e59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
D. Lacroix, P. Gluais, C. Marquie, C. D'Hoinne, M. Adamantidis, and M. Bastide Repolarization abnormalities and their arrhythmogenic consequences in porcine tachycardia-induced cardiomyopathy Cardiovasc Res, April 1, 2002; 54(1): 42 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Wolk, K. P. Sneddon, J. Dempster, K. A. Kane, S. M. Cobbe, and M. N. Hicks Regional electrophysiological effects of left ventricular hypertrophy in isolated rabbit hearts under normal and ischaemic conditions Cardiovasc Res, October 1, 2000; 48(1): 120 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Riemer and L. Tung Focal extracellular potential: a means to monitor electrical activity in single cardiac myocytes Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1383 - H1394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.A. McIntosh, S.M. Cobbe, and G.L. Smith Heterogeneous changes in action potential and intracellular Ca2+ in left ventricular myocyte sub-types from rabbits with heart failure Cardiovasc Res, January 14, 2000; 45(2): 397 - 409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wolk Arrhythmogenic mechanisms in left ventricular hypertrophy Europace, January 1, 2000; 2(3): 216 - 223. [Abstract] [PDF]
|
|
|
|
|
|
G. F. Tomaselli and E. Marban Electrophysiological remodeling in hypertrophy and heart failure Cardiovasc Res, May 1, 1999; 42(2): 270 - 283. [Full Text] [PDF]
|
|
|
|
|
|
S. M Bryant, S.J. Shipsey, and G. Hart Normal regional distribution of membrane current density in rat left ventricle is altered in catecholamine-induced hypertrophy Cardiovasc Res, May 1, 1999; 42(2): 391 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Bryant, X. Wan, S.J. Shipsey, and G. Hart Regional differences in the delayed rectifier current (IKr and IKs) contribute to the differences in action potential duration in basal left ventricular myocytes in guinea-pig Cardiovasc Res, November 1, 1998; 40(2): 322 - 331. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||