(Circulation. 1998;98:1921-1927.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Characteristics and Distribution of M Cells in Arterially Perfused Canine Left Ventricular Wedge Preparations
From Masonic Medical Research Laboratory, Utica, NY.
Correspondence to Dr Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501. E-mail ca{at}mmrl.edu
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Abstract |
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Background—Much of the characterization of the M cell to date has been accomplished using isolated tissues and cells. This study uses an arterially perfused wedge preparation to examine the characteristics and distribution of M cells within the anterior wall of the canine left ventricle under more physiological conditions.
Methods and Results—Floating microelectrodes were used to record transmembrane action potentials simultaneously from epicardial, M region, and endocardial or subendocardial Purkinje sites in isolated arterially perfused canine left ventricular wedge preparations. A transmural ECG was recorded concurrently. M cells with the longest action potentials were found in the deep subendocardium in wedge preparations isolated from the anterior wall of the left ventricle. Fairly smooth transitions in action potential duration (APD) were observed except in the region between epicardium and deep subepicardium. Tissue resistivity increased 2.8-fold in this region and much more modestly in the deep subendocardium. Dispersion of APD90 across the left ventricular wall averaged 51±19 and 64±25 ms at basic cycle lengths of 1000 and 2000 ms, respectively, whereas transmural dispersion of repolarization time was smaller (34±18 and 45±25 ms), owing to the endocardial to epicardial activation sequence.
Conclusions—We conclude that the qualitative differences between the 3 ventricular cell types previously described in isolated tissues and cells are maintained in intact canine left ventricular wall preparations in which the myocardial cells are electrically well coupled. As anticipated, differences in APD are quantitatively smaller because of electrotonic interactions among the 3 cell types. Our data indicate that transmural dispersion of repolarization is the result of intrinsic differences in APD of cells spanning the ventricular wall as well as a heterogeneous distribution of tissue resistivity across the wall.
Key Words: M cells • electrophysiology • heterogeneity • hypokalemia • action potentials
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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M cells are distinguished by the ability of their action potentials to prolong disproportionately compared with those of other ventricular myocardial cells in response to a slowing of rate and/or to agents that prolong action potential duration (APD).1 2 M cells have been described in the ventricles of human,3 4 dog,1 5 guinea pig,6 and rabbit7 hearts. The only mammalian species in which they were thought to be lacking is the pig,8 but their absence in this study may be related to maturity rather than species differences.9 Histologically, M cells appear similar to epicardial and endocardial cells. Electrophysiologically and pharmacologically, they are more similar to Purkinje cells, although important differences have been described.
Much of the characterization of the M cell to date has been accomplished using isolated tissues and cells studied under less than physiological conditions (for review see references 10 through 12). Although these methodologies have permitted a critical assessment of the intrinsic properties of this unique cell type, they have provided little information about the interaction of M cells with their neighbors or their characteristics within the functional syncytium that comprises the ventricular myocardium.
To observe M cells in an environment in which they are electrically well-coupled to neighboring cells, we developed an arterially perfused preparation consisting of a wedge of canine left ventricle in which we are able to simultaneously record transmembrane activity from epicardial, M, and endocardial or subendocardial Purkinje sites along the transmural surface of the ventricular wall using floating glass microelectrodes.13 In this study, we use the wedge preparation to define the distribution of M cells across the anterior ventricular wall of the canine left ventricle and to study their action potential characteristics under more physiological conditions.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Arterially Perfused Wedge of Canine Ventricle
Mongrel male dogs weighing 20 to 25 kg were anticoagulated with heparin and anesthetized with pentobarbital (30 to 35 mg/kg IV). The chest was opened via a left thoracotomy, and the heart was excised and placed in a cardioplegic solution consisting of cold (4°C) or room-temperature Tyrode's solution containing 8.5 mmol/L [K+]o. Transmural wedges with dimensions of
2x1.5x1 cm to 3x2x1.5 cm
were dissected from the anterior wall of the left ventricle. The tissue
was cannulated via a small (diameter 
100 µm) native branch of
left descending coronary artery and perfused with cardioplegic
solution. The total time from excision of the heart to cannulation and
perfusion of the artery was <4 minutes in all experiments. Unperfused
tissue, readily identified by its maintained red appearance
(erythrocytes not washed away), was carefully removed using a razor
blade. The preparation was then placed in a small tissue bath and
arterially perfused with Tyrode's solution of the
following composition (mmol/L): 129 NaCl, 4 KCl, 0.9
NaH2PO4, 20
NaHCO3, 1.8 CaCl2, 0.5
MgSO4, and 5.5 glucose, buffered with 95%
O2 and 5% CO2 (37±1°C).
The perfusate was delivered to the artery by a roller pump
(Cole Parmer Instrument Co). Perfusion pressure was monitored
with a pressure transducer (World Precision Instruments, Inc) and
maintained between 40 and 50 mm Hg by adjustment of the perfusion
flow rate. The preparations remained immersed in the
arterial perfusate, which was allowed to rise to a
level 2 to 3 mm above the tissue surface when possible. It was
often difficult to maintain the floating microelectrode impalements
with the bath solution above the height of the tissue. In many
experiments, the level of the solution had to be lowered to just below
the top of the wedge. Temperature gradients could be observed in the
wedge along the superior-inferior axis under these
conditions. Large temperature gradients (cooler temperatures on top)
typically resulted in an M-cell action potential (AP) that outlasted
the end of the T wave. This problem was greatly minimized and, in most
cases, eliminated by placing a series of coverslips at the top of the
tissue chamber so as to insulate it from the much cooler room air.
Temperature gradients were quantified using a fine tip temperature
sensor. Experiments in which the temperature gradients were not
adequately controlled (
T >1.5°C) were excluded from the study. In
a few cases, we normalized the transmembrane signals to the peak
amplitude of the AP when the amplitude of these signals was reduced due
to less than optimal impalement; the temporal parameters of
the scaled AP (eg, APD90) were identical to those
of the well-impaled response. The ST-segment depression initially observed normalized within 10 to 15 minutes of start of perfusion. In preparations in which an ST-segment deviation of >10% of the amplitude of the transmural QRS voltage persisted beyond the initial 15-minute period, the preparation was discarded. With this criteria, we were able to select wedge preparations that remained electrically stable for a period of at least 4 hours.14
Recordings of Transmembrane Action Potentials
The wedge preparations were allowed to equilibrate in the tissue
bath until electrically stable, usually 1 hour. The preparations were
stimulated using bipolar silver electrodes insulated except at the tips
and applied to the endocardial surface.
Transmembrane action potentials were simultaneously
recorded from the epicardial, M, and endocardial or subendocardial
Purkinje sites using 3 to 4 separate intracellular floating
microelectrodes (DC resistance, 10 to 20 M
) filled with 2.7 mol/L
KCl and connected to a high-input impedance amplifier (Figure 1
). Transmural distances were measured
using an eyepiece micrometer mounted in a binocular
microscope. Recordings were designated to 1 of 10 or 11
transmural bins.
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All amplified signals were digitized, stored on magnetic media and WORM-CD, and analyzed using Spike 2 (Cambridge Electronic Design). All APD measurements are reported at 90% repolarization (APD90).
Measurement of Tissue Resistivity Within the Left Ventricular
Wall
Mathematical simulations have suggested that the morphology of
the T-U complex in the ECG may be greatly influenced by the
distribution of tissue resistance within the ventricular
wall.15 In the present study, we provide a
direct test of this hypothesis. We assess the distribution of
resistance across the ventricular wall by measuring total
tissue resistivity (Rt), which reflects
extracellular and intracellular resistivity in
parallel.16
The perfused wedge was suspended in a water-saturated atmosphere to
obtain a constant ratio of extracellular to intracellular
resistance.16 A subthreshold current (I) was
delivered across the wall via 2 silver plates placed at the endocardial
and epicardial sides of the wedge. The silver plates were 1x1
cm2, similar in size to the surfaces of the wedge
to ensure that the current flow was uniform across the wedge. The
results of tissue-resistivity measurements were similar, independent of
the polarity of the applied current. The specific tissue resistance
(rt) across the transmural wall was mapped using
2 extracellular electrodes spaced 1 mm (x) apart and
advanced across the wall in increments of 1 mm:
 | (1) |
 | (2) |
) from the current injection site, extracellular
and intracellular currents become constant and flow parallel through
the remainder of the preparation.16 At sites
<3 from the current source, the measured rt
will be overestimated. Corrected values of rt can
be calculated using the following approach: Extracellular voltage
difference Vo(x) produced by injected current I
can be estimated from the cable equation as follows (see equation 5 in
reference 16):
 | (3) |
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 | (4) |
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is 0.5 mm, Rt in the first
millimeter of epicardium and endocardium was calculated by substituting
these values in equation 4
:
 | (5) |
Histology of Transmural Slice
Left ventricular tissues were isolated from adult
mongrel dog hearts, fixed in 10% buffered formalin for 24 hours, and
embedded in paraffin. Several transverse sections of 5-µm thickness
were cut and stained with hematoxylin and eosin according to standard
procedures.18 Briefly, sections were
deparaffinized in Hemo-De (Fisher Scientific) for 10 minutes and then
rehydrated in graded ethanols ranging from 100% to 50%. The sections
were then rinsed with water and stained with Mayer's hematoxylin
(Sigma Chemical Co) for 5 minutes. The sections were rinsed in water,
differentiated in acid alcohol for 1 minute, and then counterstained
with eosin Y for 5 minutes. The sections were then rinsed in
water for 2 minutes, dehydrated in graded ethanols ranging from 50% to
100%, and mounted using Permount (Fisher Scientific). Tissue sections
were analyzed and photographs were obtained using Polaroid
Microcam camera attached to a Leica microscope.
Statistics
Statistical analysis of the data was performed using
Student's t test for paired data or 1-way ANOVA coupled
with Scheffé's test. All results are expressed as mean±SD
unless otherwise indicated.
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Results |
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In addition to the specialized conducting cells of the His-Purkinje system, 3 myocardial cell types have been described in the ventricles of mammalian hearts. The presence of a more prominent transient outward current (Ito) contributes to the appearance of a prominent notch in the early phase of epicardial and midmyocardial action potentials, whereas a smaller delayed rectifier current (IKs) and larger late sodium current (INa) contribute to the appearance of longer action potentials in midmyocardial M cells.11 12 These distinctive characteristics of the 3 myocardial cell types are illustrated in Figure 2
. The 3 top action potentials were
simultaneously recorded from the epicardial,
endocardial, and M regions of a wedge preparation stimulated from the
endocardial surface at a basic cycle length (BCL) of 1000 (Figure 2A)
and 4000 (Figure 2B) ms. The lower traces depict action potentials
recorded from a subendocardial Purkinje in the same preparation.
The Purkinje response is longer than that of the M cell and can also be
distinguished from that of the M cell by the absence of a distinct
notch. Among the myocardial cells, the action potential of the
epicardial cell is the briefest, whereas that of the M cell is the
longest; thus the difference in APD between the epicardium and M region
defines the maximal transmural dispersion of APD
(Table).
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Transmural dispersion of APD in the wedge ranged between 32 and 85 ms
and averaged 64±25 ms at a BCL of 2000 ms (Table). This contrasts with
an average dispersion of APD of 105±45 ms in isolated tissue slices
and 170±51 ms in myocytes. These differences are anticipated, because
3-dimensional electrical coupling of cells in the wedge permits
electrotonic influences that abbreviate the APD of the M cell below its
intrinsic value and prolong the APD of epicardial and endocardial
cells above their intrinsic durations.14
To assess the distribution of cell types across the anterior free wall, we used a roving floating microelectrode in conjunction with 2 stationary microelectrodes at epicardial and endocardial sites to map the distribution of action potential characteristics across the wall in arterially perfused wedge preparations isolated from canine ventricles.
Figure 3 illustrates the results obtained
from one such preparation. APD at 90% repolarization
(APD90), briefest at the epicardial border,
increases sharply in the deep subepicardium and then more gradually,
peaking within the subendocardium. Average transmural conduction time
was 29.3±1 ms (at BCL=1000 ms), and the average thickness of the wedge
preparations was 12.9±1.5 mm; the average conduction velocity of
44 cm/s is comparable to that recorded in
vivo.19 The dispersion of repolarization time
(RT= APD90+conduction time) across the wall is
less than the transmural dispersion of APD90
because of the endocardial-to-epicardial activation sequence.
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Figure 4 summarizes the results of 15
experiments. APD90 is significantly shorter in
epicardial cells than in either M cells (deep subendocardium) or
endocardial cells. A sharp transition of APD is observed between
epicardium and deep subepicardium, with more gradual transitions
appearing throughout the remainder of the wall. The data clearly
indicate that M cells with the longest action potentials are located in
the deep subendocardium in the anterior wall of the canine left
ventricle.
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) and 4000 ms (
). Transmural distances at 0% and
100% represent epicardium and endocardium, respectively. Error
bars represent SEM (n=15).
The sharp transitions of APD90, observed in
Figures 3 and 4, suggest the presence of a resistive barrier between
epicardium and deep subepicardium. To test this hypothesis, we measured
tissue resistivity across the left ventricular wedge. The
distribution of Rt, a reflection of intracellular
and extracellular resistivity in parallel, measured across the left
ventricular wall is illustrated in Figure 5 (n=5). Rt values
in the region between epicardium and deep subepicardium (0% to 20% of
transmural thickness) average 410±55 cm, 2.8-fold greater
than that in midmyocardium (average resistivity of the 20%
to 80% segment of the wall was 148±11 cm; P<0.01).
The Rt between endocardium and deep
subendocardium was observed to vary greatly, yielding a mean value of
203.4±47.9 cm, 1.4-fold greater than that in
midmyocardium (P=0.3, Figure 5).
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The dramatic increase in Rt near the epicardial
border may be because of differences in either ro
or ri secondary to changes in the extracellular
matrix or gap junctional resistance, respectively. Figure 6 shows a representative
example of the histology encountered in this part of the
ventricular wall. The segment, consisting of the epicardial
third of a transmural slice, shows a sharp transition of cell
orientation in the region of high tissue resistivity. Similar sharp
transitions in cell orientation in the deep subepicardium were observed
in 8 of 8 preparations.
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Previous studies have demonstrated major differences in the APD-rate
relations of the 3 ventricular myocardial cell types. When
studied in isolated tissues and myocytes, M cells display a steep rate
dependence, whereas epicardial and endocardial cells show relatively
little change in APD as a function of rate. The electrotonic currents
that flow during normal electrical coupling of cells in a functional
syncytium would be expected to blur these sharp distinctions in the
intrinsic behavior of the 3 cell types. As a test of this hypothesis,
we examined the rate dependence of action potential characteristics
using 3 simultaneous floating microelectrode
recordings obtained from the epicardial, endocardial, and M
regions (Figure 7).
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In support of the hypothesis, the APD90 rate
relation of the M cell was much less accentuated than previously
reported in isolated tissues and cells, whereas the APD90rate relations of epicardium and endocardium were
considerably more accentuated (Figure 7).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The discovery of cells in the midmyocardial layers of ventricular myocardium with unique repolarization properties has prompted investigations into the distinctive electrophysiological, pharmacological, and pathophysiological characteristics of these cells. The chief attribute of the M cell is the ability of its action potential to prolong disproportionately compared with that of other myocardial cells in the ventricle in response to a slowing of rate and/or to agents that prolong APD.1 2 5 The ionic basis for these features of the M cell includes the presence of a smaller slowly activating IKs20 as well as a larger late INa.21 The present study examines the characteristics and distribution of M cells within the intact wall of the canine left ventricle using floating glass microelectrodes to simultaneously record transmembrane action potentials from the transmural sites along the ventricular wall of an arterially perfused wedge preparation.
Previous studies have validated the model showing that action potentials along the transmural surface recorded using floating microelectrodes yield APD values very similar to the activation recovery interval (ARI) values recorded using intramural electrodes placed in the subtending tissue.22 23 The viability and electrical stability of the preparation over a 4-hour period was demonstrated as well.14
Transmural Distribution of APD
Although M cells have been described in a variety of species,
including humans, their precise location within the
ventricular wall has been investigated in greatest detail
in the LV of the canine heart. Whereas transitional cells are found
throughout most of the wall in the canine LV, M cells displaying the
longest action potentials (at slow rates) have been localized to the
deep subepicardium to midmyocardium in the lateral
wall,1 deep subendocardium of the
septum,24 and throughout the wall in the region
of the outflow tracts.5 10 The present study
demonstrates that in the anterior wall of the canine left ventricle, M
cells with the longest action potentials are located in the deep
subendocardium. The shift in the position of the M cells appears to
correspond to the myocardial layers described in early studies by
Streeter25 26 and more recently by Lukenheimer
and coworkers.27
Transmural Distribution of Resistivity
Theoretically, the manifestation of electrical
heterogeneity across the intact ventricular
wall depends on (1) the extent to which intrinsic action potential
characteristics of neighboring cells differ and (2) the extent to which
they are electrically coupled in the syncytium.28
Where coupling resistance is very low, intrinsic differences in the APD
of the different cell types will be obscured over relatively short
distances but may be perceptible over greater distances. As coupling
resistance increases, so does the ability to manifest differences of
APD at neighboring sites. The present study demonstrates a
heterogeneous distribution of resistance across the wall of
the canine left ventricle (Figure 5). The sharp increase in
Rt between the M region and epicardium can
account for the sharp increase in APD within this region of the wall.
This resistive barrier is probably still more important in the lateral
free wall of the left ventricle where the longest M cells are found in
the deep subepicardial to midmyocardial layers.1
Despite the relatively large increase in tissue resistivity in the deep
subepicardium, conduction in this region slowed only slightly,
consistent with cable theory predictions. The basis for the
sharp rise in tissue resistivity is not known, an abrupt shift in the
orientation of the myocardial cells in this part of the wall may
contribute (Figure 6). A similar shift in cell orientation has been
documented in the deep subepicardium of the human left ventricle, where
prolonged M-cell action potentials are first
encountered.3
Transmural Dispersion of Repolarization
The degree of transmural dispersion of repolarization observed
across the ventricular wall depends on the methods used to
record this parameter. In the absence of drugs, but at
slow rates, tissues or myocytes isolated from the M region display APDs
as much as a couple of hundred ms longer than those recorded from
endocardium or epicardium.1 20 29 30 When
recorded from the intact left ventricular wall of
arterially perfused wedge preparations, where the 3 cell
types are electrotonically well coupled, the dispersion of
repolarization is reduced to 51±19 ms (at BCL=1000 ms) because of
electrotonic forces that act to abbreviate the M-cell action potential
below its intrinsic APD and to prolong epicardial and endocardial cell
action potentials beyond their intrinsic APDs (Figures 2 through 6,
Table).14 A similar dispersion of repolarization
(30 to 40 ms at BCL=1400 to 1500 ms, anesthetized dogs) is
observed in the canine heart in vivo when monophasic action potentials
(MAP) or unipolar recordings are used to estimate the MAP
duration (MAPD) or ARI.31 32 ARI
measurements provide a reasonable approximation of local repolarization
time under all but extreme conditions (greatly exaggerated
repolarization gradients).22 In the accompanying
article,23 we will present evidence in
support of the hypothesis that the transmural dispersion of
repolarization contributes importantly to inscription of the
electrocardiographic T wave.
The transmural dispersion of repolarization observed under control conditions in the canine heart in vivo and in the wedge preparations increases dramatically in the presence of agents with Class III actions such as d-sotalol, erythromycin, and anthopleurin A because of the preferential action of these agents to prolong the APD of the M cell.14 22 23 Transmural repolarization gradients as large as 150 ms can be observed under these conditions. As will be illustrated in the accompanying paper, this amplification of transmural dispersion of repolarization is due to a preferential action of Class III agents to prolong the APD of the M cell.23
Another factor that can influence the degree to which transmural heterogeneity can be discerned is the method used to approximate repolarization time. Transmembrane action potential recordings provide the most direct and accurate measurement of local repolarization. ARI obtained using unipolar extracellular electrodes and measurement of local refractoriness provide a fairly good approximation.22 32 33 34 Whereas unipolar electrograms provide information that can be interpreted on the basis of biophysical theory,34 35 bipolar electrograms, although providing a sharper activation complex, generate a repolarization complex that is not as readily interpretable because it represents the difference in the activity of 2 sites. As a result, it is difficult to make a distinction between ARIs at the 2 sites; and when differences exist, they are likely to be obscured with bipolar recording techniques.
Recent preliminary reports point to the anesthesia employed as another confounding factor in the determination of transmural dispersion of repolarization in in vivo studies.36 The dispersion of repolarization measured across the anterior left ventricular wall (transmural MAP recordings) is considerably smaller when sodium pentobarbital is used for general anesthesia than when halothane is used. This difference, seen under baseline conditions, is still more exaggerated when an IKr blocker such as d-sotalol is infused.31 37 d-Sotalol produces a dramatic increase in transmural dispersion of repolarization when halothane is used for anesthesia but not when sodium pentobarbital is used.31 An abbreviation of the M-cell action potential but prolongation of the epicardial and endocardial APDs underlie these effect of pentobarbital to reduce transmural dispersion.
These and other differences in method may account for the failure of some studies to discern significant repolarization gradients across the canine left ventricular wall in vivo5 38 39 and the ability of others to demonstrate them reproducibly.31 32 40 A relatively small transmural dispersion of repolarization has been reported (at slow rates) in in vivo studies that have used pentobarbital for anesthesia5 31 38 versus studies that have used other agents including isoflurane32 and halothane.31 Although significant transmural repolarization gradients are observed with halothane and isoflurane, these gradients measured in vivo are slightly smaller than in the isolated wedge (following washout of anesthetic). Further studies are needed to determine whether this difference is because of an effect of the halothane (and also isoflurane) to reduce transmural dispersion of repolarization, although to a lesser extent than sodium pentobarbital, thus leading to underestimation of the transmural gradients present in the awake state. A wider field of view of the unipolar electrodes relative to transmembrane electrodes may also result in underestimation of transmural gradients. Finally, small differences in intercellular resistance between wedge and in vivo conditions could, in theory, contribute to differences in the degree to which transmural dispersion of repolarization is observed.
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Acknowledgments |
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We gratefully acknowledge the expert technical assistance of Judy Hefferon and Tengxian Liu. Our thanks also to Dr William Ofosu-Appiah for his contribution to the histological work and to Drs V.V. Nesterenko and S. Sicouri for reading the manuscript. This work was supported by grant HL-47678 from the National Institutes of Health, Bethesda, Md, and grants from the SADS Foundation, Salt Lake City, Utah; Medtronic Japan, Osaka; the Sixth and Seventh Manhattan Masonic Districts, New York, NY; and the Masons of New York and Florida.
Received January 30, 1998; revision received May 26, 1998; accepted June 10, 1998.
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