© 1996 American Heart Association, Inc.
Articles |
Generation of New Intercellular Junctions Between Cardiocytes
A Possible Mechanism Compensating for Mechanical Overload in the Hypertrophied Human Adult Myocardium
From the World Health Organization Cardiovascular Center and the Department of Medicine and Department of Pathology at the University of Texas Medical Branch (S.Y., T.N.J.), Galveston, and the Osaka (Japan) Medical College (K.S., M.O., K.K.).
Correspondence to Thomas N. James, MD, Office of the President, University of Texas Medical Branch, Galveston, TX 77555-0129.
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Abstract |
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Abstract Intercellular dehiscence is a common cardiocytic response to pathological conditions. However, little consideration has been given to the possibility of new intercellular junctions developing between cardiocytes within developed myocardium. To examine this possibility as it may relate to useful compensation for hemodynamic overloads, changes in cardiocytic connection were evaluated by scanning electron microscopy in hypertrophied myocardium of adult human hearts. Transmural myocardium of left ventricle was obtained at autopsy from five hearts with concentric hypertrophy, five hearts with eccentric hypertrophy, and five control hearts (noncardiac death). After formalin fixation, the number of cardiocytes connected to an individual cardiocyte was counted in tissues from the middle portion of the transmural samples by scanning electron microscopy. Cardiocytic diameter and connective tissue volume fraction were measured on the transmural sections by light microscopy. In concentrically hypertrophied hearts presenting both increased cardiocytic diameter and connective tissue volume fraction, the number of other cardiocytes connected to an individual cardiocyte (4.60±0.10 [mean±SE]) was significantly increased (P<.05) compared with control hearts (4.19±0.12) or eccentrically hypertrophied hearts (4.11±0.10). The increase in junctions per cardiocyte in concentrically hypertrophied hearts suggests that new connections had been generated. More junctions developing during hypertrophy could add another structural advantage to those of cardiocytic hypertrophy and connective tissue proliferation as compensatory adjustments to hemodynamic overload in concentrically hypertrophied hearts.
Key Words: intercalated disk • cell adhesion • scanning electron microscopy • concentric hypertrophy • eccentric hypertrophy
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Intercellular connections (intercalated disks) are crucial for both electrical and mechanical functions of every cardiocyte. It is only through many such junctions that contractile performance of individual cells can be integrated for optimal systolic function of the heart. Dissociation of intercellular junctions is a frequent response to pathological circumstances.1 Various special morphological features of intercellular disruption have been observed in association with different pathological conditions in diseased human myocardium as well as under experimental manipulation.2 Little consideration, however, has been directed toward the opposite phenomenon, ie, the generation of new intercellular junctions between cardiocytes.
Intercalated disks are present early in the development of the human fetal heart.3 It has been suggested that once the basic form of intercalated disks is completed in developing mammalian myocardium, there is a subsequent expansion of existing components of specialized ultrastructure of the junction to form the mature intercalated disks.4 For example, a recent study of human ventricular myocardium demonstrated that the distribution patterns of gap junctions and fascia adherens change during postnatal development.5 Expression of N-cadherin has been found in the developing myocardium, and this molecule is thought to play an essential role in the adhesion of growing cardiocytes.6 N-Cadherin is also abundantly present in the intercalated disks of adult myocardium.7 Separated cardiocytes of adult rat myocardium dispersed in culture medium will reassociate and generate new intercellular attachments similar to the original intercalated disks.8 However, we know of no study directed at the possible development of new intercellular junctions between adult human cardiocytes.
The present study was done to examine whether adult human myocardial cells would generate new intercellular junctions, possibly as an adjustment to altered hemodynamic loads. In the human heart, cardiocytic hypertrophy is found either alone or associated with connective tissue proliferation. Fibrosis may be primary or secondary to cardiocytic loss.9 10 11 12 13 14 15 16 In these circumstances, a skeletal remodeling of the fascicular network might also occur in the hypertrophied myocardium by generating new intercellular junctions between cardiocytes at cell sites not previously connected. The putative remodeled skeletal framework of myocardium, in conjunction with cardiocytic hypertrophy and fibrosis, could provide an especially beneficial adaptation to increased mechanical loads placed on the heart.
In adult hearts, death of a cardiocyte is inevitably associated with complete loss of cell contact with neighboring surviving cardiocytes. Cardiocytic hyperplasia alone does not appear to be an effective compensation for cell loss in developed human myocardium.13 On the other hand, functional restoration of the disrupted network could be accomplished by generation of new intercellular junctions between cardiocytes that were not previously connected.
To determine whether new intercellular junctions are actually generated between cardiocytes in developed hypertrophied myocardium, the number of cardiocytic connections were semiquantitatively evaluated by means of scanning electron microscopy in the adult ventricular myocardium of hearts with hemodynamic overloads.
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Materials
Fifteen hearts obtained at autopsy included five with concentric left ventricular hypertrophy, five with eccentric left ventricular hypertrophy, and five control hearts. The hearts with concentric hypertrophy were obtained from adult patients with sustained systemic hypertension who died of renal or cerebrovascular complications or of coincidental malignancy. The hearts with eccentric hypertrophy were obtained from adult patients with predominant or pure aortic regurgitation and fatal congestive heart failure. The normal hearts were obtained from adult patients who experienced noncardiac death. The case identity, heart weight, and clinicopathological diagnosis are displayed in Table 1
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Methods
The hearts were weighed before fixation with 10%
neutral
formalin. After fixation was completed, transmural samples of
myocardium were obtained from the posterolateral free wall
of the left ventricle about one third of the distance from the
atrioventricular sulcus to the apex of the heart. Each
sample was divided in half, one half for scanning electron microscopy
and the other for light microscopy. Several small blocks 
5 mm across
were cut from the middle layer of the transmural myocardium
for scanning electron microscopy. Transmural sections for light
microscopy were prepared from two different cuts of the myocardial
tissues, one transverse and the other longitudinal in terms of
ventricular cavity geometry, so that myocardial fascicles
of different orientations could be evaluated.17
Light Microscopy
The transmural histological sections were
prepared with hematoxylin-eosin and Mallory-azan stains. On
both transverse and longitudinal histological sections,
the compact zone of the ventricular myocardium
was divided into 10 serial wall layers at equal intervals, extending
from the endocardium to the epicardium. In each wall layer, five
myocardial sites were selected by random sampling from the transverse
sections with hematoxylin-eosin stain, and five sites were
similarly taken from the longitudinal sections. Photographs were
made from all 10 myocardial sites at x100 magnification and
enlarged five times to x500 magnification. Cardiocytic diameters were
measured from transverse sections of all nucleated cells on the 10
prints, and an average was obtained. The shortest diameters at the
nucleus levels were obtained only from distinctively transverse cross
sections of cardiocytes.12
Ten photographs from each wall layer were similarly obtained from both the transverse and longitudinal sections with Mallory-azan stain. From these, the percentage area of interstitial space was calculated by the point-counting method18 19 in each wall layer on the 10 prints. Point counting was done with transparent sheets imprinted with a grid of squares (10 mm per side). Points lying on amorphous matrices as well as connective tissue fibers were counted as the interstitial space area. Points occupied by blood vessels were excluded. Approximately 2000 points were counted from each wall layer. Analysis of the photographs was performed in a blind manner without knowledge of the origin of the histological sections. Samples for scanning electron microscopy came from the middle portion of the transmural myocardium and corresponded to approximately the fourth to seventh layers of the 10 serial wall layers extending from the endocardium to the epicardium.
Scanning Electron Microscopy
The cuboidal blocks for scanning
electron microscopy were washed
several times in 0.1 mol/L phosphate buffer solution at pH 7.2 and then
processed by the methods similar to those previously
described.20 The tissue blocks were immersed in 8N
hydrochloric acid in a test tube, shaken in a water bath at 60°C for
40 to 60 minutes, and then placed in buffer overnight. To remove the
remnants of digested connective tissue, the tissue specimens were
further immersed in a detergent (1% Triton X-100) and vibrated in an
ultrasonic unit (Branson B 12) at room temperature for 1 to 3 hours.
For visualization of detailed cell surfaces and junctions by scanning
electron microscopy, the residual debris of connective tissue was
further digested by collagenase type II (Cooper Biomedical
Co) at a concentration of 10 mg/10 mL in the buffer for 6 to 8 hours at
37°C. After dehydration through a graded series of alcohols to 100%
ethanol, the specimens were processed for critical-point drying in
liquid carbon dioxide in a Hitachi HCP-1 critical-point dryer.
After the complete digestion of connective tissue and critical-point drying, the interspaces between myocardial fascicles were visible under a stereomicroscope. Some interspaces were completely opened manually using tweezers with sharp tips. The fascicular frontal surfaces facing the opened interspace were studied by scanning electron microscopy. For this purpose, specimens were placed on aluminum mounts with silver conducting paste, coated with gold in an Eiko 1B-3 ion coater, and examined with a Hitachi S-800 scanning electron microscope at an accelerating voltage of 20 kV, with direct magnifications of x40 to x2000. Photographic final magnifications were from x55 to x2760. On the scanning microscopic photographs, cardiocytic arrangement was examined on the fascicular surface, and the number of cardiocytes connected to any individual cardiocyte was counted.
Statistics
Heart weight was compared among three study groups
using
one-way ANOVA. Tukey's criterion was applied for pairwise
comparisons. Cardiocytic diameters of 10 serial wall layers were
compared among the three study groups by using ANOVA for split
plot–type design with factors of groups and layers. For each
group, one-way ANOVA was performed to determine the differences
among layers. To evaluate the profile of layers, the "sum of
squares" of layers was decomposed to linear, quadratic, and the
higher-order components using orthogonal polynomials. In each
layer, cardiocytic diameters were compared among the three groups by
using the Kruskal-Wallis test, and Tukey's criterion was applied for
pairwise comparisons. The numbers of cardiocytes connected to
an individual cardiocyte were compared among three groups by
using one-way ANOVA. Tukey's criterion was applied for pairwise
comparisons.
Connective tissue percentage areas of 10 serial wall layers were compared using ANOVA in a manner similar to that used for cardiocytic diameters. To evaluate the profile of layers, the sum of squares of layers was decomposed to the orthogonal polynomials. A mean value of the connective tissue area in every heart was obtained from the values of the 10 layers, and Tukey's criterion was applied for pairwise comparisons.
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Results |
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Hearts with concentric hypertrophy (mean weight, 564 g) and with eccentric hypertrophy (mean weight, 651 g) were significantly heavier (P<.05) than control hearts (mean weight, 266 g). There was no significant difference in heart weight between concentric and eccentric hypertrophy.
Histological Findings With Light
Microscopy
Cardiocytic Diameter
In each of 10 serial
wall layers of every heart, the cardiocytic
diameters were measured in 50 cardiocytes, and an average
was calculated. Mean±SE values of the cardiocytic diameters are
displayed in Fig 1. Mean values calculated from the
diameters of all 10 layers were 14.9±0.6 µm (mean±SD) in the
control group, 18.3±1.4 µm in the concentric group, and
22.9±2.3
µm in the eccentric group. The results of the split plot–type
ANOVA indicate that group-by-layer interaction was highly
significant (P<.001). That is, the profiles of cardiocytic
diameter found at increasing transmural distance from the endocardium
to the epicardium were different among the three groups. Neither group
effect (P=.0571) nor layer effect (P=.7885)
was
statistically significant. In the control group, there was no
significant difference in diameter among the 10 layers (one-way
ANOVA, P=.1178). There were, however, statistically
significant differences in cardiocytic diameter among the 10 layers in
both the concentric hypertrophy group (P=.0052)
and the eccentric hypertrophy group (P=.0366).
Decomposition of the sum of squares of layers to linear, quadratic, and
the higher-order components indicates that a quadratic component
was highly significant in each group (control, P<.005;
concentric, P<.001; and eccentric, P<.001) (Fig
1). The results of the Kruskal-Wallis tests indicated
significant
(P<.05) differences among the three groups in the second
and tenth layers of 10 serial wall layers extending from the
endocardium to the epicardium (control<eccentric, P<.05;
control versus concentric or concentric versus eccentric,
P=NS). The difference in the first layer of the 10 serial
layers was not quite statistically significant
(P=.0539).
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Interstitial Space Percentage
Area
The mean±SE values of interstitial space percentage
areas of 10 serial wall layers are displayed in Fig 2.
Mean values of the percentage area calculated from the 10 layers of
each heart were 20.8±1.8% (mean±SD) in the control group,
26.1±5.4% in the concentric group, and 31.2±3.1% in the
eccentric
group. In the split plot–type ANOVA, group-by-layer
interaction was not significant (P=.3866). That is, the
profiles of the interstitial space percentage area found at
the increasing transmural distance were not statistically different
among the three groups. However, whereas the differences in the
connective tissue area among 10 serial wall layers (layer effect) were
significant (P<.01), the differences among the three groups
(group effect) were not quite statistically significant
(P=.0535). Decomposition of the sum of squares of layers
using orthogonal polynomials indicates that the linear component had
the most variation (94%). This result means that the connective tissue
percentage area had a linear association with layers (Fig 2). A
mean
value in hearts with eccentric hypertrophy was
significantly larger than that of control hearts (P<.05),
even though there were no significant differences between concentric
and eccentric hypertrophy nor between the control condition
and concentric hypertrophy.
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Scanning Electron Microscopic Findings
After the elimination
of connective tissue by the digestion
procedure, a myocardial fiber network was well presented on the
fascicular frontal surface facing the opened interspaces. The detailed
scanning electron micrographs of the fiber network displayed the
structural components of cardiocytes as well as their
intercellular junctions (Figs 3 through
7).
The structure of these intercellular junctions (intercalated disks) was
recognized as the slight depression of a narrow line that transversely
crossed the fiber surface. A cardiocyte possessed an axis along
the direction of the myocardial fascicles, and most intercalated disks
were located at either axial end of a cardiocyte and formed
end-to-end connections. Some intercalated disks made lateral
intercellular connections that formed an invagination from or to the
adjacent cardiocyte (Fig 6). Scanning electron micrographs in
the present study did not reveal any intercellular connections of
the end-to-side form.
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Numbers of Cardiocytes Connected to an
Individual
Cardiocyte
There are two types of connections for any individual
cardiocyte in the present study: end-to-end
connections at either axial end of an individual cardiocyte and
lateral connections by invagination. The total number of all
cardiocytes and separate numbers of each type of
cardiocyte connected to an individual cardiocyte were
counted (Figs 3 through
7
).
The sum of cardiocytes connected at
either axial end (ie, the number of cardiocytes with
end-to-end connections) were also counted.
The number of cardiocytes
connected to an individual
cardiocyte was counted in 50 cardiocytes in each heart
and then averaged. The mean±SE values of the counted numbers in the
three study groups are displayed in Table 2. Among the
three study groups, there were statistically significant differences in
the number of all cardiocytes connected to an individual
cardiocyte, the number of cardiocytes with
end-to-end connections, and the number of cardiocytes
with lateral connections (one-way ANOVA). The number of
cardiocytes with end-to-end connections and the number
of cardiocytes with lateral connections in each of 15 hearts
are depicted in Fig 8.
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The number of all cardiocytes
connected to an individual
cardiocyte was significantly increased in hearts with
concentric hypertrophy (4.60±0.10 [mean±SE]) compared
with control hearts (4.19±0.12) and also hearts with eccentric
hypertrophy (4.11±0.10). The number of cardiocytes
with end-to-end connections was also significantly increased in
hearts with concentric hypertrophy (4.44±0.12) compared
with control hearts (4.01±0.11). The number of cardiocytes
with lateral connections was significantly decreased in hearts with
eccentric hypertrophy (0.06±0.02) compared with control
hearts (0.17±0.02). The results of pairwise comparison using
Tukey's
criterion are displayed in Table 2.
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Discussion |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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A three-dimensional concept of myocardial structure is necessary in evaluating the intercellular connections of cardiocytes. In light microscopy and transmission electron microscopy, the findings are limited to two-dimensional display of thin tissues, unless reconstruction is performed from serial sections. Scanning electron microscopy has three-dimensional advantages for geometric studies of cardiocytes21 but requires an understanding of its own methodological limitations, such as the absence of back views. In the present study, we counted the numbers of cardiocytes connected to individual cardiocytes on the scanning views of frontal surfaces of the myocardial fibers.
Heart weight was significantly increased in both concentric and eccentric hypertrophic hearts compared with control hearts and was comparable to the heart weight in conditions of pathological hypertrophy generally.9 10 In myocardium with concentric hypertrophy, the number of all cardiocytes connected to any individual cardiocyte was significantly increased compared with control myocardium. This suggests that new intercellular junctions were generated between cardiocytes at some stage or multiple stages during the development of concentric hypertrophy.
A cardiocyte may connect with another cardiocyte
through more than one intercellular junction, as seen in Fig 4.
In this
case, the incidence of cell junctions of an individual
cardiocyte will not always be the same as the number of other
cardiocytes connected to the individual cell. Then, the
increase in the number of connected cardiocytes in concentric
hypertrophy might imply the generation of new intercellular
junctions specifically between cardiocytes not previously
connected with each other. Such new junctions may provide not only new
mechanical or electrical coupling but also a new biological
communication between the two cardiocytes by sharing
intracellular signals such as calcium ions and cAMP through nexuses or
other well-differentiated components of cell junctions.
At the middle layer of the ventricular walls (sites similar to those where the scanning electron microscopic studies were done), both cardiocytic diameter and interstitial space percentage area were increased. Generation of new intercellular junctions may logically be expected to occur in close association with processes of cardiocytic hypertrophy and connective tissue proliferation in myocardium with concentric hypertrophy. Force transmission through these new junctions could effectively adjust for a variety of increased stresses placed on hypertrophied myocardium.
Connective tissue is increased in hypertrophied myocardium not only as a primary proliferative phenomenon but also as a process of replacement fibrosis in association with cardiocytic injury and loss.9 10 11 12 13 14 15 16 22 23 Additionally, cardiocytic injury or loss is associated with various extents of dissociation of the intercellular junction up to a complete loss of cell contact. This, at least initially, results in a decrease in the number of cardiocytes connected to the surrounding surviving cells. However, our finding of an increased number of connected cardiocytes in concentric hypertrophy suggests that new intercellular junctions developed. It will be difficult if not impossible to quantify how many original junctions may be lost during development of hypertrophy, but the true gain in junctions is probably more than what we have been able to quantify.
A significant increase was found in the number of connected
cardiocytes in concentric hypertrophy, which were
primarily found in the form of end-to-end connections. Some
examples were seen to connect with six or more other
cardiocytes (Figs 4 through 6).
For mechanical advantages, the
increased number of junctions seen in concentrically hypertrophied
myocardium could favorably modulate the power of
contraction for any individual cardiocyte. The same advantage
may exist for improved geometry of propagation of electrical excitation
of hypertrophied cardiocytes, although one also could
conversely anticipate a harmful redistribution of electrical
propagation in some geometric examples.
The number of cardiocytes with lateral connections was much less than the number of cardiocytes with end-to-end connections in the group with concentric hypertrophy as well as in the other two study groups. When compared with cardiocytes with end-to-end connections, any two cardiocytes connected through the lateral connection by invagination appear to be more rigid in terms of their relative positions. Shift to a lateral direction or a sliding direction could hardly occur between the cardiocytes with lateral connections. In this sense, the lateral connections might resist more effectively an intercellular force in a direction transverse to the cardiocytic axis or a shearing stress capable of causing slippage between the cardiocytes situated in parallel. The formation of multiple intercalated disks has been postulated as an adaptive response to the increased stresses accompanying ventricular hypertrophy.24 25 26 In the present study, however, there was no significant increase in the number of cardiocytes with lateral connections in concentric hypertrophy, only in the number of cardiomyocytes with end-to-end connections.
In contrast to its possible advantages, the skeletal remodeling with new cardiocytic connections may also have untoward effects. Electrophysiological properties such as the excitation propagation pathway must be affected, and this could paradoxically facilitate abnormal conduction in some areas, predisposing the myocardium to reentrant arrhythmias. One study of canine myocardial infarction27 has shown a reduction in the number of neighbor cells connected by intercalated disks to any single myocyte in the healed infarct border zone tissue, and any such change may distort the normal pattern of electrical activation and thus predispose the tissue to electrical instability. The cardiocytic geometric remodeling thus may have either a helpful or harmful effect on the electrical excitation of myocardium.
Cardiocytes with the new intercellular junctions may also have disadvantages in relation to mechanical performance (including not only contraction but also relaxation and diastolic filling) that are of the type shown for hypertrophied myocardium.28 29 30 31 32 Here, as with electrical activation, it all depends on how the functional geometry is changed.
Recently, a wide spectrum of proteins has been identified as adhesion molecules between cells of various types.33 34 35 Of these various cell adhesion molecules, N-cadherin has been demonstrated in association with intercellular connection in developing myocardium and in adult myocardium.5 6 7 Considering the diversity of distribution and functions of cell adhesion molecules in the regulation of dynamic cell-to-cell contact in various tissues, it seems likely that even the normal intercellular junctions of cardiocytes may not be static but constantly changing,36 37 regulated by numerous biological mechanisms in addition to cell adhesion molecules. An immunohistochemical study of the spatial distribution of electrical and mechanical intercellular connections in the neonatal human ventricle has suggested that the age-dependent changes in the distribution patterns may parallel the functional requirements of the ventricles, including myocardial remodeling in adaptation to the hemodynamic changes.5 A simple apposition of the sarcolemmas could be strengthened by any adhesive materials between the cardiocytes, and the more intricate components of intercellular connections (notably the fasciae adherens) may become enlarged. Fibrosis has been suggested as a morphological feature consistent with dissociation of cardiocytic electrical coupling.27 37 38 39 However, extracellular matrices such as collagen, fibronectin, and laminin may also be incorporated in the early stages of the generation of new cardiac connections, since many components of cell adhesion molecules are known to bind to these matrices.35 40
Cardiocytic division and proliferation (unlikely in mature hearts) could theoretically form an alternate explanation for the increase in number of connected cardiocytes. However, two such new cardiocytes would still have to share the cardiocytes that formerly connected with the original single cardiocyte, and each of the divided cardiocytes should have smaller numbers of connected cardiocytes. Thus, cardiocytic division and proliferation would not adequately explain the increase in number of cardiocytes connected to individual cardiocytes.
In the myocardium of hearts with eccentric
hypertrophy, there was no increase in the number of
cardiocytes connected to an individual cardiocyte. Both
cardiocytic diameter and interstitial space percentage
area, however, were increased when compared with control hearts.
Furthermore, increasing cardiocytic diameter with increasing transmural
distance from the endocardium to the epicardium was a characteristic
finding quite different from that in the myocardium with
concentric hypertrophy (Fig 1). Others have also found that
the pattern of ventricular hypertrophy is
distinctively different between concentric and eccentric forms in terms
of chamber
geometry.9 10 11 13
Ventricular
responses to the hemodynamic load at the different
transmural distance may differ as well. The mechanical load
characteristic of hearts with eccentric hypertrophy may
simply not provoke the compensatory mechanism of the cytological
remodeling with generation of new intercellular junctions. Cardiocytic
hypertrophy in the middle layers of the
ventricular wall with eccentric hypertrophy was
found to be less prominent (the ventricular wall was the
same area where the cardiocytic connections were examined in the
present study). This could explain the lack of increase in the
number of the connected cardiocytes in the
myocardium of eccentric hypertrophy, in the
sense that cellular hypertrophy and increase in
intercellular junctions may be parallel or closely sequential adaptive
processes. Whether they may be causally or functionally related remains
unknown. We have no information regarding possible new intercellular
junctions in the myocardium at other transmural
distances.
The interstitial space percentage area was linearly
decreased from the endocardium to the epicardium in both concentric and
eccentric hypertrophy (Fig 2). However, in the middle layer
studied by scanning electron microscopy, the extent of fibrosis was
more prominent in eccentric hypertrophy. This more
prominent fibrosis could be a negative influence in the development of
new junctions, by spatially separating the neighboring
cardiocytes. The number of cardiocytes with lateral
connections was significantly decreased in hearts with eccentric
hypertrophy compared with control hearts. This might also
be attributed to fibrous tissue actively separating cardiocytes
situated in parallel and thus diminish any opportunity for lateral
connections to form. The difference in the number of
cardiocytes with end-to-end connections and the
difference in the number of lateral connections were both distinctive
features of the intercellular junctions and the geometric remodeling
when myocardium with concentric hypertrophy was
compared with myocardium with eccentric
hypertrophy (Fig 8).
Even though there was no significant difference in weight between concentric and eccentric hearts, the hemodynamic compensation or deteriorated performance of the myocardium was probably different in the two groups. All five hearts with eccentric hypertrophy presented clinical features of fatal congestive heart failure, but none of the five hearts with concentric hypertrophy did. Therefore, the differences in the intercellular junction, cardiocytic hypertrophy, or interstitial fibrosis between the two study groups could be attributed not only to the different kinds of hemodynamic overload but also to the extent of heart failure irrespective of the types of hypertrophy.
Study Limitations
Scanning electron microscopic study does
not reveal intercellular
junctions that might be located at the back surfaces of the myocardial
fibers. Light microscopic study with serial sections of canine
myocardium has demonstrated that individual
cardiocytes were connected by intercalated disks to an average
of 9.1 other cardiocytes.41 This discrepancy from
the average number of 4.2 cardiocytic connections in the control hearts
in the present study may be attributable to species difference but
is more likely indicative of the absence of back surface views in
scanning electron microscopy. Our observation is limited to the
fascicular frontal surfaces facing the opened interspace. The absence
of any intercellular connections directed to the open interspace could
also explain the discrepancy in the number of cardiocytic
connections.
Tissue sampling for scanning electron microscopy was arbitrarily limited to the middle layer of the left ventricular wall. In this layer, the myocardial fibers were arranged to form a relatively uniform lamellar configuration, and this facilitated the tissue preparations for scanning electron microscopy. Considering the different cardiocytic diameters or interstitial space percentage areas at different transmural levels, a better understanding of geometric remodeling could be achieved by complete scanning electron microscopic study of numerous different myocardial layers across the wall of the heart.
Conclusion
Results of the present study suggest that the
generation of
new junctions between cardiocytes does occur in adult human
myocardium with concentric but not eccentric
hypertrophy. The remodeling of the myocardial framework
associated with these new intercellular junctions probably combines
with cardiocytic hypertrophy and interstitial
fibrosis to compensate for altered hemodynamic
overloads. Any intervention promoting or initiating the generation of
new intercellular junctions could be beneficial in myocardial
adjustment to increased mechanical overloads and serve as a
compensation for cardiocytic loss. However, there are also some
potential electrical and mechanical disadvantages that could confound
these putative benefits.
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Acknowledgments |
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This study was supported by the Pegasus Fund of the University of Texas Medical Branch, Galveston. We would like to thank the Departments of Pathology of Osaka Medical College, Tenri Hospital, Kitano Hospital, Osaka Police Hospital, and Hirakata Municipal Hospital for supplying heart specimens.
Received July 25, 1995; accepted November 20, 1995.
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