© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Intercellular coupling through gap junctions masks M cells in the human heart
aDepartment of Medical Physiology, University Medical Center, P.O. Box 85060, Utrecht 3508 AB, The Netherlands
bDepartment of Cardiology, University Medical Center, Utrecht, The Netherlands
cDepartment of Physiology, Academic Medical Center, Amsterdam, The Netherlands
dExperimental and Molecular Cardiology Group, Academic Medical Center, Amsterdam, The Netherlands
eInteruniversity Cardiology Institute, The Netherlands
fDepartment of Cardiology, The Middlesex Hospital, London, and Hatter Institute for Cardiovascular Studies, University College Hospital, London, UK
* Corresponding author. Tel.: +31-30-253-8900; fax: +31-30-253-9036. Email address: c.e.conrath{at}med.uu.nl
Received 11 September 2003; revised 5 February 2004; accepted 20 February 2004
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Objectives: M cells have been described in many mammalian species. They are thought to be relevant for the genesis of long QT intervals, afterdepolarizations and for dispersion in action potential duration and in repolarization time. Their role in the human heart is subject to debate. Methods: We simulated action potential propagation in a strand of transversally oriented myocytes running from endocardium towards epicardium through the left ventricular free wall. The characteristics of the myocytes were either based on the Priebe–Beuckelmann ventricular cell model or on the Luo–Rudy ventricular cell model. The former model is based on the latter and includes adaptations in order to mimic the human ventricular myocyte. The amount and location of M cells as well as the intercellular coupling through gap junctions were varied. Also, we assessed action potential duration in a Langendorff-perfused explanted human heart and in a wedge preparation obtained from such a heart. Results: At low, but physiological intercellular coupling conductance, the inclusion of M cells leads to a much longer ‘QT interval’ in the simulations than in the in vivo or isolated human heart. Dispersion in repolarization time becomes unphysiologically large when M cells are included in the strand and is also substantially larger than in the in vivo or isolated human heart. At stronger intercellular coupling this effect disappears. Conclusions: The manifestation of M cells is absent in the human heart, probably by effective intercellular coupling, turning them functionally "invisible".
KEYWORDS Cell communication; Computer modeling; Gap junctions; Membrane currents; QT-dispersion; Repolarization
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Gap junctions are transmembrane channels between adjacent cells. They permit exchange of small molecules and ions [1]. The principal pore forming protein in mammalian ventricular myocardium is connexin43 (Cx43) [2]. Gap junctions are a prerequisite for cardiac conduction and electrotonic interaction. Although each single cell of the heart is capable to repolarize on its own, repolarization synchronizes by electrotonic interaction. Therefore, intrinsic differences during repolarization tend to be canceled. In the mammalian heart inhomogeneities in repolarization are nevertheless prominent between different parts of the ventricles. They can briefly be summarized as differences between the right and left ventricle, between apex and base and between endocardium and epicardium (see for brief overview Ref. [3]). M cells, which have longer action potentials than subepicardial and subendocardial cells, were first observed in canine ventricle [4]. They have no specific morphological features and are localized in the midmyocardium, but both the width of this layer and its exact transmural location varies between species and also within an individual heart.
There are only three studies on M cells in the human heart [5–7]. In one study, cells were isolated from the right ventricle of patients with heart failure. Cells from the midmyocardial layer displayed action potentials which were about 100 ms longer than the subendocardial or subepicardial myocytes (at stimulation rate of 1 Hz) [5]. Also, in a perfused piece of left ventricular wall (‘wedge preparation’), the action potentials were about 100 ms longer in the midmyocardial layer than in subendo- or subepicardium [6]. In the only study in patients (undergoing coronary artery bypass surgery) no relevant differences in action potential duration (assessed by activation recovery intervals from unipolar electrograms) were found along the transmural axis [7]. The degree to which these M cells contribute to dispersion in repolarization and prolonged QT intervals has been subject of vivid debate during the last years [8,9].
We have used the Priebe–Beuckelmann computer model [10], which is based on the Luo–Rudy model of the guinea pig-type ventricular action potential [11] with adaptations for specific membrane currents as reported in man [10]. We have exploited this model in a strand of ventricular myocytes in which we varied (i) the intercellular coupling conductance, (ii) the width of the M cell layer, and (iii) the location of the M cells within the transmural wall. Also, we have extended patient data on activation recovery intervals [7] with data on transmural activation times [12] to assess (dispersion in) repolarization moments across the wall of the human ventricle. Finally, we have measured transmural differences in action potential duration in an explanted human heart during Langendorff perfusion and in a wedge preparation obtained from such a heart.
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2. Methods |
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2.1. Computer simulations
We used the model of single human ventricular myocytes by Priebe and Beuckelmann to represent subepicardial cells [10]. We reduced the current densities of the transient outward current (Ito), the slow component of the delayed rectifier (IKs) and the inward rectifier (IK1) in M cells and in subendocardial cells according to the scheme in Table 1. The reductions in current were based on data from literature [13–15]. The more important changes compared to the basic settings in the model of Priebe and Beuckelmann [10] were a reduction of Ito in the subendocardial cells to 25% [15] and a reduction of IKs in the M cells to 46% [14]. The cytoplasmic resistivity was set to 150
cm. For comparison, we used the 1999 version of the Luo–Rudy model [16], which differs from the parent model [11] in several respects, including the separation of IK into IKr and IKs, and the formulation of three different cell types: epicardial (100% IKs), M (29%), and endocardial (67%).
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We studied transmural dispersion of action potential duration (at 90% repolarization (APD90)) and of repolarization time, which was obtained by summing local activation times and local APD90, in a heterogeneous linear strand of 600 transversally coupled ventricular cells representing a transmural width of 1.2 cm (normal range 0.9–1.4 cm [17]). The orientation of cells was transverse based on data in man [18] and dog [19]. The strands could comprise a variable amount of M cells (0–100%). Moreover, the location of the layer of M cells was varied between endocardium and epicardium. Thus, in the case of subepicardially located M cells the first 360 (60%) cells were of the subendocardial type, the next 180 (30%) cells were of the M type, and the final 10% of the transmural width was taken by 60 subepicardial cells. This 60%–30%–10% distribution corresponds with experimental data [6]. Simulations without M cells simply consisted of 90% subendocardial and 10% subepicardial cells. Simulations were performed at gap junctional conductance ranging from 0.25 to 20 µS with values from 3 till 12 µS considered as physiological [20]. The strand was stimulated at 1 Hz from cell #1 at the endocardial side by injecting a
20% suprathreshold stimulus of 2 ms duration. The final action potential of a train of five (or 20 in case of the Luo–Rudy model) was used for analysis. For numerical integration of the differential equations, an efficient Euler-type scheme was applied with a fixed time step of 5 µs (or 2 µs in case of the Luo–Rudy model). In all simulations, we used stable-start values of the model state variables derived from a strand of 600 endocardial cells that were coupled at 2.5 µS. We minimized stimulus and end effects, which were restricted to <10 cells (cf. [21]), by discarding data obtained from cells 1 to 10 and 591 to 600 whenever we assessed dispersion in either APD90 or repolarization time.
2.2. Patient data
We used the only available in vivo data in man on activation times in 23 patients [12] and on action potential duration assessed by activation recovery intervals (ARIs) in 21 patients [7] to compile repolarization time. This was simply done by summing those two parameters. In those two patient studies [7,12], the same type of plunge electrodes were used during cardiovascular surgery. The electrodes with five terminals separated by 1.5 mm were inserted in the left ventricular wall and the most peripheral terminal was located 1 mm under the epicardium. Therefore, the data from this study are pertinent to the outer 7 mm of the in vivo human ventricle.
We explored differences in transmural APD90 values in an explanted human heart from a patient with terminal heart failure undergoing cardiac transplantation. The aorta was cannulated and perfused according to Langendorff. Epicardial and midmyocardial monophasic action potentials were recorded with wolfram electrodes with three terminals each. Midmyocardial recordings were obtained at 4 and 8 mm below the epicardial recordings. Details on the Langendorff perfusion and the recording techniques have been described previously [22]. A wedge preparation was made from an explanted hypertrophied left ventricle (dimensions 10 x 7 x 2 cm) from a patient with heart failure. After excision of the preparation 1 h was allowed for healing over. The preparation was perfused with the same human blood-Tyrode mixture as in Langendorff perfused hearts [22].
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3. Results |
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3.1. Variation of amount of M cells
Fig. 1 shows the results of computer simulations by which we assessed the effect of variation of the number of M cells at—low normal—intercellular coupling of 2.5 µS (normal range for intercellular coupling is between 3 and 12 µS [20]). The square at the right bottom of Fig. 1 indicates 60 subepicardial cells (10%) and the rectangular boxes indicate the percentage and location of the M cells (80%, 60%, 30%) bordering the subepicardium. The thinnest line shows the APD90 values in the absence of M cells when 90% of subendocardial cells are directly bordering the subepicardial rim. Also, a strand with only M cells is shown (100% M cells). For reference, the line at the top shows the intrinsic APD90 of single M cells.
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Any amount of M cells prolongs the APD90 of subepicardial cells. The APD90 of subendocardial cells remains unaffected by M cells even when their percentage would be as high as 60%. The maximum APD90 is about 30 ms longer with 30% M cells than in the absence of M cells. In the case of 30% M cells, the zenith of APD90 occurs at cell 447 and is 388 ms. It would take the activation front about 54 ms to travel from left (endocardium) till cell 447 at this amount of intercellular coupling. This would lead to a repolarization moment (and ‘pseudo-QT interval’) of 442 ms.
Fig. 1 also shows that the longest action potentials are at the subendocardium in simulations without M cells. Furthermore, the effect of electrotonic interaction on M cells per se may be appreciated from the difference between the line at the top (isolated M cells; APD90 416 ms) and the strand composed of 100% M cells only. At 2.5 µS the difference is about 18 ms, but this increases substantially at stronger coupling (data not shown).
3.2. Variation of location of M cells
Fig. 2 shows the effect of variation of the transmural location of a fixed amount of 30% of M cells at a normal intercellular coupling of 2.5 µS. The organization of Fig. 2 is similar to that of Fig. 1 (see previous section). The maximum APD90 (but not repolarization time; see Fig. 5A) is longest when the location of the layer of M cells is adjacent to the endocardium.
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3.3. Variation of intercellular coupling
Fig. 3 shows APD90 in strands with 60% of subendocardial cells, 30% of M cells and 10% of subepicardial cells. Open circles indicate APD90 in the uncoupled state. There are three degrees of intercellular coupling within the normal physiological range (2.5, 5 and 10 µS) [20]. In addition, we have decreased coupling by an order of magnitude below the physiological range (0.25 µS) and we have doubled it as well (20 µS). Two things are obvious. First, dispersion in APD90 becomes minimal even within the upper normal physiological range. Second, APD90 decreases dramatically as a function of intercellular coupling. Fig. 4 shows that similar simulations with the Luo–Rudy model yield much shorter APD90 values, which is not surprising, because this mammalian model is primarily based on guinea pig data. More importantly, however, there was no relevant dispersion at any of the tested intercellular coupling conductances. It is of interest that the average APD90 value along the strand decreased less dramatically with increasing intercellular coupling (Fig. 4) than with the Priebe–Beuckelmann model (Fig. 3). This suggests that intercellular coupling plays a more important role in reducing APD90 in larger hearts with longer action potentials (and higher membrane resistance during the repolarization phase) than in smaller hearts with shorter action potentials.
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3.4. Repolarization time and dispersion
Repolarization time is obtained by adding local APD90 to local activation time. Fig. 5A shows the latest repolarization times occurring in a strand (at any position) as a function of the percentage of M cells and their location, which was either subendocardial (bordering a rim of 10% subendocardial cells), or midmyocardial or subepicardial (bordering a rim of 10% subepicardial cells) at intercellular coupling of 2.5 µS. The longest repolarization times, which can be regarded as a ‘pseudo QT interval’, occur with 40% of M cells at subepicardial location. There is no further increase above 40% of M cells.
In the absence of any M cells, one might question how it is possible that a longest APD90 of only 358 ms (Fig. 1; trace ‘no M cells’ at cell #11) may lead to a latest repolarization time of 412 ms (Fig. 5A; 0% M cells). This results from the time needed for conduction. In the absence of M cells, the longest APD90 occurs at cell #11, but the latest repolarization occurs in cell #527. It should be noted that the assumption of 30% of M cells in combination with a subepicardial location, which has been described in the human heart [6], leads to rather long QT intervals.
Fig. 5B shows the more intricate relation between the percentage of M cells and their location on the one hand and, on the other hand, dispersion in repolarization time, i.e. the difference between the latest and the earliest moment of repolarization, along the strand again at intercellular coupling of 2.5 µS. Surprisingly, dispersion is smaller with 30% M cells as long as they are located close to the endocardium compared to the situation without M cells (compare filled circles at 0% and 30% of M cells in Fig. 5B).
Finally, Fig. 6A shows the effect of varying coupling of the myocytes in the situation of 30% of M cells at subepicardial location, bordering the 10% subepicardial rim. The organization of Fig. 6 is similar to that of Fig. 3, but shows repolarization times instead of APD90. The pivotal effect of the amount of intercellular coupling is obvious. Fig. 6B shows data from similar simulations with the Luo–Rudy model. As with the APD90 values (Figs. 3 and 4)
, the influence of M cells on the dispersion of repolarization times is less with the Luo–Rudy model than with the Priebe–Beuckelmann model.
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3.5. In vivo human data
Fig. 7 shows transmural activation-recovery intervals (ARIs) in 21 patients undergoing routine coronary artery surgery (taken from Ref. [7]). With the same technique activation times had been recorded in a comparable patient group [12]. These were used to compile the repolarization moments. Fig. 7 shows that there is no midmyocardial prolonged ARI or a midmyocardial late moment of repolarization as would be expected when M cells are able to manifest their intrinsic long APD90. Neither in the whole group, nor in individual patients such a gradient could be detected. These data allow two possible explanations: (i) in these patients, no intrinsic differences are present or (ii) intrinsic differences are present, but are abolished by intercellular coupling. There are two other striking differences between the in vivo data and the simulations. First, the latest repolarization time in the patients is substantially shorter than in the simulations, unless intercellular coupling of 20 µS would be physiological in man (compare Figs. 5A, 6A and 7
). Second, the dispersion in the patients is smaller than in the simulations (compare Figs. 5B and 7). In addition, the inclusion of M cells in the simulations enlarges the differences between the model and the in vivo data.
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3.6. Langendorff-perfused human heart and human wedge preparation
Fig. 8A shows monophasic APD90 values recorded with wolfram plunge electrodes at cycle length of 800 ms in a Langendorff-perfused explanted human heart. Recordings were made at four positions separated by 2 mm. At each position, the midmyocardial terminals were 4 mm below the subepicardium and the subendocardial terminals were another 4 mm below the midmyocardial position. As in the in vivo hearts (Fig. 7) there is no indication for a midmyocardial maximum in APD90 in the isolated human heart. This observation is of interest, because there is no influence of either anesthesia or the autonomic nervous system in the Langendorff-perfused heart.
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Finally, Fig. 8B shows data from a human wedge preparation. Important studies relating electrophysiological features of the M cell with a pseudo ECG have been performed in such a preparation in the dog [23,24]. Again, as in the human in vivo data (Fig. 7) and in the Langendorff-perfused human heart (Fig. 8A), not a single indication was found for a midmyocardial maximum in ‘ARIs’. This was also the case when pacing rate was decreased from the normal physiological value of 1 to 0.1 Hz.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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The inclusion of M cells in the strand composed of Priebe–Beuckelmann model cells [10] leads to longer APD90 and later repolarization as well as larger dispersion of both parameters than observed in patients. Shortening of APD90 to values below 300 ms (as in the in vivo heart; see Fig. 7) occurs only at strong intercellular coupling. At intercellular coupling of 20 µS, APD90 varies from 275 to 285 ms in the presence of M cells (Fig. 3) as observed in patients (Fig. 7). In the absence of M cells, APD90 varies from 264 to 275 ms (data not shown). Thus, strong intercellular coupling seems more important for a good match between simulation and patient data than the mere presence or absence of M cells.
4.1. Repolarization in the normal ventricle and the role of M cells
The contribution of IKs to repolarization is complicated by the fact that the current displays three types of regional inhomogeneity, at least in animal studies. First, the density of IKs is lower in the midmyocardium than in subendocardium and subepicardium [14]. Second, its density is larger at the base than at the apex of the heart [25] and, finally, IKs is about twice as large in the right compared to the left ventricle [26]. These regional inhomogeneities, however, have only been demonstrated in canine [14,26] and rabbit hearts [25].
Dispersion in membrane currents is reflected in dispersion in APD90 and in repolarization time. It may occur transmurally, but also between different regions of the ventricles (apex-base, or left-right differences in repolarization time). Our strand model does not take into account the latter two sources of dispersion, but the same is pertinent to the data presented in Figs. 7 and 8. It can be expected, however, that QT intervals are longer, and dispersion is larger, in whole human hearts compared to data from plunge electrodes at a particular site and also compared to a strand which only reflects transmural dispersion in the left ventricle. Thus, the fact that M cells already cause large dispersion in a strand, unless intercellular coupling is very strong, casts doubt on their functional significance in human hearts under normal conditions.
In a study of Li et al. [5], cells isolated from the midmyocardial ventricular wall had an APD90 of about 100 ms longer compared to APD90 of cells isolated from the subendocardium [5]. Also, in the human transmural wedge preparations obtained from the left ventricle of patients undergoing heart–lung transplantation such a difference was observed [6]. There is a huge difference (at least 100 ms) with our observations on activation-recovery intervals (ARIs) in a human wedge preparation (Fig. 8B). It has been shown more than a decade ago that these ARIs are markers of APD90 in dogs [27]. Recently, this close association was corroborated by the demonstration of a similar close relationship between ARIs and effective refractory periods in intact human hearts [28]. Our wedge preparation was substantially larger than the four preparations of Drouin et al. [6], which may have led to a different state of electrical uncoupling. However, whether the transmural repolarization gradients suggested by in vitro studies [5,6] are manifest in vivo at physiological heart rates and therefore are relevant to intact hearts of several species including man has been the subject of ongoing controversy [8,9,29–31] and will remain so as long as there are insufficient data in the human heart.
Four important issues have dominated the debate: (i) species difference, (ii) the role of heart rate, (iii) the role of intercellular coupling and (iv) the effect of anesthesia [7,32]. With respect to the species and heart rate issue it is underscored that in in vivo studies long action potential durations have been reported to be absent in the midmyocardium even in the "model species" for M cells [29], the dog, also when the M region is further challenged by the application of IKs blockers [33]. As far as the human heart is concerned, our data are sufficiently strong to conclude that only the issue of what should be considered as normal intercellular coupling remains to be settled.
4.2. Model dependence
Our present computer simulations based on both the Priebe–Beuckelmann model [10] and the Luo–Rudy model [11,16] appear to yield different results from a previous study on the role of M cells in dispersion in APD90 [16]. However, these differences can be readily explained by two essential differences in the selection of model parameters. First, the cellular orientation was longitudinal in the previous study [16], whereas we used a transversal cell orientation, which is much closer to reality [18,19] than a longitudinal cell orientation. Second, Viswanathan et al. [16] explored the effect of intercellular gap junction conductances of 2.5 µS and lower, whereas we assessed the effects between 0.25 and 20 µS, because the physiological range has been estimated to be between 3 and 12 µS based on data from human ventricle [20]. When we used the Luo–Rudy model in transversal orientation and with higher intercellular coupling conductance, dispersion in APD90 and repolarization time were smaller (Figs. 4 and 6B) than with the Priebe–Beuckelmann model (Figs. 3 and 6A).
4.3. Limitations of the study
The Priebe–Beuckelmann model is for a large part based on data obtained from human ventricular myocytes, but it should be realized that very little human data result from healthy control material for obvious reasons. The assumptions on the contribution of the two delayed rectifiers (IKr and IKs), the transient outward current (Ito) and the inward rectifier (IK1) to the repolarization phase should be appreciated against this background. It cannot be excluded that the densities of the membrane currents has been subject to remodeling as a consequence of several underlying pathophysiological processes [34–36].
Data on inhomogeneity of current density in the human ventricle are even more sparse. Furthermore, the Priebe–Beuckelmann model [10] is based on human data as far as possible, but the adaptations for the subendocardial myocytes and M cells (Table 1) are derived from animal research with the exception of the transient outward current [15]. Of course, this constitutes a serious limitation of our study.
Our model study in combination with our experimental data suggest that strong intercellular coupling annihilates the contribution of M cells to dispersion in repolarization time in the human heart. At this moment, it is not possible to exclude that the functional irrelevance of M cells in the human heart results from their mere absence. This remains of interest under pathophysiological conditions in association with pharmacological treatment with a potential for cellular uncoupling.
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Notes |
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Time for primary review 27 days
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