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(Circulation. 1995;92:2306-2317.)
© 1995 American Heart Association, Inc.
Articles |
The Cellular Basis of Pacing-Induced Dilated Cardiomyopathy
Myocyte Cell Loss and Myocyte Cellular Reactive Hypertrophy
From the Departments of Medicine and Physiology, New York Medical College, Valhalla, NY.
Correspondence to Piero Anversa, MD, Department of Medicine, Vosburgh Pavilion, Room 302, New York Medical College, Valhalla, NY 10595.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Rapid ventricular pacing leads to a cardiac myopathy consisting of an increase in chamber dimension, mural thinning, elevation in ventricular wall stress, and congestive heart failure, mimicking dilated cardiomyopathy in humans. However, contrasting results have been obtained concerning the mechanisms of ventricular dilation and the existence of myocardial hypertrophy. Moreover, questions have been raised regarding the occurrence of myocardial damage and cell loss in the development of the experimental myopathy.
Methods and Results The functional and structural characteristics of the heart were studied in conscious dogs subjected to left ventricular pacing at 210 beats per minute for 3 weeks and 240 beats per minute for an additional week. At the time the animals were killed, measurements of myocardial structural integrity and myocyte shape, size, and number were determined by morphometric analysis of the myocardium in situ and enzymatically dissociated cells. The experimental protocol used was associated with overt cardiac failure documented by an increase in left ventricular end-diastolic pressure and a decrease in left ventricular systolic pressure and +dP/dt in combination with tachycardia, ascites, and pulmonary congestion. Although cardiac weights were not altered, cavitary diameter was increased and wall thickness was decreased from the base to the apex of the heart. Multiple foci of replacement fibrosis, comprising 6% of the myocardium, were detected across the left ventricular wall. Measurements of myocyte size and number documented a 39% loss of cells in the entire ventricle and a 61% increase in volume of the remaining viable myocytes. Myocyte hypertrophy was characterized by a 33% increase in cell length and a 23% increase in transverse area, resulting in a 23% increase in the cell length–to–cell diameter ratio. Pacing did not alter the relative proportion of mononucleated, binucleated, and multinucleated myocytes in the myocardium.
Conclusions Myocyte cell loss and myocyte reactive hypertrophy are the major components of ventricular remodeling in pacing-induced dilated cardiomyopathy.
Key Words: ventricles • myocytes • myocardium • pacing
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Dilated cardiomyopathy defines a myocardial disease characterized by left ventricular or biventricular dilation, cardiac hypertrophy, and severely depressed myocardial performance.1 In its late stage, tissue damage with collagen accumulation in the ventricular wall is present, but the magnitude of myocardial scarring contributes only in part to the expansion in cavitary volume.2 3 4 5 6 Myocyte elongation, through the in-series addition of newly formed sarcomeres, constitutes the major factor responsible for the increase in chamber size.7 Myocyte diameter also increases, although the lateral expansion of myocytes is modest and inadequate to preserve the wall thickness–to–chamber diameter ratio within normal values.7 As a consequence, decompensated eccentric hypertrophy characterizes the unfavorable evolution of idiopathic dilated cardiomyopathy in humans.7 8 Similarly, rapid ventricular pacing in animals leads to a cardiac myopathy consisting of an increase in chamber dimension, mural thinning, elevation in ventricular wall stress, alterations in coronary blood flow, and congestive heart failure,9 10 11 12 13 14 mimicking the human disease.1 7 However, contrasting results have been obtained concerning the mechanisms of ventricular dilation11 14 and the existence of myocardial hypertrophy.11 14 15 16 Measurements of myocyte length in paced pigs have indicated a consistent increase in this parameter, whereas myocyte width has been found to be decreased.11 17 Moreover, questions have been raised regarding the occurrence of myocardial damage and cell loss in the development of experimental myopathy.11 14 16 18 Importantly, measurements of myocyte size and number have not been obtained in this model, and scattered myocyte loss and collagen accumulation have been shown to play an essential role in the onset and progression of ventricular dysfunction in ischemic heart disease,19 20 pressure-overload hypertrophy,21 aging,22 and a combination of these multiple variables in humans23 and animals.24 Myocyte loss may occur in a diffuse, scattered manner, becoming apparent only by quantitative analysis of the myocardium.19 22 This is not an unlikely possibility because a significant component of pacing-induced heart failure involves defects in endothelium-mediated responses of the coronary circulation.25 Such an impairment in the vasodilatory capacity of intermediate-sized arteries and arterioles may generate focal areas of ischemia across the ventricular wall, resulting in necrotic myocyte cell death. A continued loss of myocytes can be expected to produce a greater workload on the remaining myocytes,19 22 which, coupled with a increase in systolic and diastolic wall stress,10 14 may serve as a chronic mechanical stimulus for cellular growth. Therefore, the effects of rapid ventricular pacing on tissue injury, myocyte size, shape, and number were analyzed in dogs with overt signs of congestive heart failure to determine whether myocyte cell loss and cellular enlargement were relevant variables of wall restructuring in this type of cardiac myopathy.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animals
Mongrel dogs weighing 18 to 20 kg were instrumented with catheters, probes, and a corkscrew electrode in the left ventricle attached to a portable external pacemaker (Pace Medical EV3434), as described previously.25 26 Briefly, each dog was sedated with acepromazine (1 mg/kg SC) and then anesthetized with sodium pentobarbital (25 mg/kg IV). A Tygon catheter (Cardiovascular Instruments) was placed in the descending thoracic aorta, and a solid-state manometer (Konigsberg P6.5) was placed in the left ventricle through the apex, with the use of sterile surgical techniques. The dogs were allowed to recover from surgery for 10 to 14 days. Initial experiments were conducted when they were afebrile and had been trained to lie quietly without restraint on the laboratory table. The heart then was paced at 210 beats per minute for 3 weeks and at 240 beats per minute for an additional week. The heart was initially paced at 210 beats per minute to achieve a mild form of ventricular dysfunction and subsequently at 240 beats per minute to obtain physiological parameters and clinical symptoms of congestive heart failure (for review, see Reference 27). The control group was similarly instrumented, but the heart was not paced. Sixteen sham-operated control dogs and 14 paced dogs were included in this study. The protocols were approved by the Institutional Animal Care and Use Committee of New York Medical College and conform to the Guiding Principles for the Use and Care of Laboratory Animals of the American Physiological Society and the National Institutes of Health.
For the objective of this study, it is important to indicate that the electrode was inserted in the midportion of the left ventricular free wall near the apex and its location confirmed at surgery. At the dissection of the heart, the wire connecting the pacing lead was cut, but the electrode was not removed. This reference point allowed sampling of tissue for histological analysis at a distance of at least 3 cm from the electrode. Moreover, myocardial sections obtained from the base of the heart were significantly more distant, and the interventricular septum was completely separated from the electrode.
Ventricular Function
Hemodynamic studies were performed with
the dogs
in a conscious state with the pacemaker turned off. Once the steady
state was reached, the hemodynamic measurements were
made. Systemic arterial pressure, left
ventricular systolic pressure, left
ventricular end-diastolic pressure, and
left ventricular dP/dt were obtained.26
Specifically, before these determinations, the pacemaker was turned off
for nearly 2 hours. This is the time required for coronary
blood flow and especially heart rate to reach a constant level.
Perfusion Fixation
At the completion of the hemodynamic
determinations, hearts were perfusion-fixed in situ. Dogs were
anesthetized with sodium pentobarbital (25 mg/kg IV) and
mechanically ventilated. The thorax was opened in the left fourth
intercostal space. A catheter was placed in the left fourth intercostal
space. A catheter was placed in the left ventricle through a stab
wound. Heparin (3000 units, Lyphomed) was injected
intravenously, and the heart was arrested with a bolus
injection of saturated potassium chloride. The aorta was cannulated for
retrograde perfusion, and the right atrial appendage was cut to allow
outflow of perfusate. Perfusion pressure was adjusted to the
mean arterial pressure measured in vivo. The left
ventricular chamber was filled with fixative and kept at a
pressure equal to the in vivo measured end-diastolic
pressure throughout the fixation procedure.28 After
perfusion with pH 7.2 phosphate buffer for 3 minutes, the
coronary vasculature was perfused for 10 minutes with a
solution containing 2% paraformaldehyde and 2.5%
glutaraldehyde. Subsequently, the heart was excised and
the weights of the left ventricle, interventricular
septum, and the right ventricle were recorded. The separate
measurement of left ventricular free wall and septum
weights were obtained following the estimations of
ventricular dimensions listed below. This part of the study
included 7 controls and 7 paced hearts.
Ventricular Dimensions
The major intracavitary axis of the
left ventricle was measured
by inserting a probe from the base to the apex parallel to the
longitudinal diameter. Care was taken to avoid inclusion of muscle at
the apical region in the estimation of this parameter.
Subsequently, each left ventricle was serial-sectioned into thick
rings perpendicular to the longitudinal axis to obtain six equally
spaced parallel planes from the base to the apex in which the average
wall thickness of the free wall and septum and chamber luminal diameter
were measured. These determinations could not be obtained at the two
extremes of the left ventricle, the apex, and base. The
trabeculae carnae and papillary muscles attached to the
wall were not included in the assessment of wall thickness. Fifteen
measurements each in the anterior and posterior aspects of the left
ventricular free wall and interventricular
septum were collected in each section and their values averaged for
each of the three regions. The minimal and maximal diameters of the
ventricular chamber at each of the six sampled levels were
determined, and their geometric mean was computed.29
Moreover, the measurements of wall thickness, chamber radius, and left
ventricular end-diastolic pressure were
used to compute midwall circumferential diastolic wall
stress at each of the six sites examined from base to apex.
Light Microscopic Morphometry
Tissue samples were obtained
from the anterior aspect of the
left ventricular free wall and
interventricular septum. Four tissue fragments were
collected from section 1 near the base, section 4 in the middle, and
section 6 adjacent to the apex, for both the free wall and septum.
Thus, 12 tissue blocks for the ventricle and 12 for the septum were
sampled. These specimens were embedded in paraffin;
histological sections were prepared, and these sections
were stained with hematoxylin and eosin and trichrome for morphometric
analysis. In these sections, which contained the entire
thickness of wall and septum, 20 consecutive fields, each from the
endomyocardium, midmyocardium, and
epimyocardium of the wall and the left, intermediate,
and right side of the septum, were examined at a calibrated
magnification of x400 with a reticle containing 42 sampling points
(105844, Wild Heerbrugg Instruments Inc). This reticle defined an
uncompressed tissue area of 62 500 µm2, which was
used to determine the number of lesions represented by foci
of damage per unit area of myocardium. Moreover, the
fraction of points lying over these foci was measured to compute the
volume fraction of lesions in the myocardium. These
sections also were used to measure the volume fraction of myocytes and
interstitium in regions of the wall and septum in which tissue injury
was not present. This analysis was performed by examining
10 fields in each area of the myocardium.
Myocyte Isolation
In a separate group of control (n=9)
and paced hearts (n=7),
myocytes were enzymatically dissociated for the evaluation of cell size
and shape. This analysis was restricted to the left
ventricular free wall. At the end of the
hemodynamic measurements, hearts were removed, a
portion of the anterior aspect of the left ventricle was dissected
free, and a large branch of the left anterior descending artery was
identified and cannulated for perfusion with collagenase.
The solutions were supplements of modified commercial MEM Eagle Joklik.
HEPES-MEM contained (in mmol/L) NaCl 117, KCl 5.7, NaHCO3
4.4, KH2PO4 1.5, MgCl2 17, HEPES
21.1, and glucose 11.7, with amino acids and vitamins, 2 mmol/L
L-glutamine, and 21 mU/mL insulin; pH was adjusted to 7.2
with NaOH. Osmolality of this solution is 292 mOsm. Resuspension medium
was HEPES-MEM supplemented with 0.5% bovine serum albumin, 0.3
mmol/L calcium chloride, and 10 mmol/L taurine, adjusted to 292 mOsm.
The cell isolation procedure consisted of three main steps. (1) Low
calcium perfusion: Blood washout and collagenase (selected
type II, Worthington Biochemical Corp) perfusion of the
myocardium was carried out at 32°C with HEPES-MEM gassed
with 85% O2, 15% N2. (2) Mechanical
tissue dissociation: After removing the myocardium from the
cannula, the endomyocardium and
epimyocardium were separated and minced.
Collagenase-perfused tissue was subsequently shaken in
resuspension medium containing creatine, collagenase, and
0.3 mmol/L calcium chloride. Supernatant cell suspensions were washed
and resuspended in resuspension medium. (3) Separation of intact cells:
Intact cells were enriched by centrifugation and
discarding the supernatant. This procedure was repeated four to five
times in each preparation in order to remove nonmyocyte cells,
cell debris, and residual collagenase. Each
centrifugation was performed at 30g for 3
minutes. Rectangular trypan blue, excluding cells, constituted around
75% to 85% of all myocytes. The average number of myocytes collected
per 1 g of myocardium was 7 to 8x106
and 4 to 5x106 in control and paced hearts,
respectively (Fig 1
).
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Distribution of Nuclei and Myocytes
Intact cells were
recovered from the pellet, washed, and fixed
in 2.5% glutaraldehyde in phosphate buffer.
Approximately 50 to 100x103 myocytes were suspended in
bis-benzimide H33258, 500 µg/mL, for 15 minutes at room
temperature. Subsequently, myocytes were centrifuged at
100g for 5 minutes, the supernatant was discarded, and
smears were made from these preparations. This was performed with a
microscope working in epifluorescence mode, equipped with a
set of excitation-emission filters for bis-benzimide
H33258. A random sampling of 1000 myocytes from the left ventricle in
each heart was used to determine the relative frequency of
mononucleated, binucleated, and multinucleated cells.
Structural Properties of Myocytes
Measurements of myocyte
geometric dimensions were accomplished
through the aid of a computerized image analysis system
(Morrell Instruments): 200 myocytes from each left ventricle were
measured to obtain length, width, and area. Moreover, cell volume was
derived from these geometric parameters. The distribution
of myocytes isolated from the left ventricle for each of the two animal
groups was divided according the number of cells in an established
range of lengths. The range of lengths used in the present study
was 10 µm from 70 to 320 µm. Histogram buckets then were
established with a size of 10 µm, and frequency distribution
histograms were constructed by plotting number of cells on the ordinate
and cell length range on the abscissa. A similar approach was followed
for the analysis of the distribution of cell cross sections and
volumes. Moreover, average sarcomere length was calculated from the
linear distance encompassing between 25 and 50 contiguous sarcomeres in
100 cells per ventricle measured at a final magnification of x1000.
These determinations were obtained in binucleated myocytes. An
additional sampling consisting of 20 each mononucleated, trinucleated,
and tetranucleated myocytes was collected in each heart.
For the estimation of myocyte volume, the following procedure was used. Isolated cells when placed in physiological medium assume a cross-sectional area, which resembles a flattened ellipse. The ratio of the minor axis (b) to the major axis (a) of the ellipse was 0.384±0.065 in myocytes from control dogs and 0.413±0.088 in myocytes from paced animals. The ratio between the minor and major axis was determined by confocal microscopy (see below). Cell volume (VC) was calculated assuming an elliptical cross section with a major axis that was equivalent to cell width and a minor axis that was computed from the measured ratios. Cell length (L) was measured directly:
 | (1) |
Confocal Microscopic Measurements of Myocyte Cell
Volume
The quantitative analysis discussed above to obtain
measurements of the average volume of mononucleated,
V(c)n, binucleated, V(c)2n,
trinucleated, V(c)3n, and multinucleated,
V(c)mn, myocytes in the ventricular
myocardium was complemented with a new procedure. Isolated
myocytes were stained with fluorescein isothiocyanate 1
µg/mL for 30 minutes at room temperature to visualize the cell
cytoplasm and with propidium iodide to label the nuclei. Subsequently,
measurements of cell area for mononucleated,
(c)n, binucleated,
(c)2n, trinucleated,
(c)3n, and multinucleated,
(c)mn, myocytes were collected by confocal
microscopy. Importantly, with the same system, it was possible to
measure the thickness, 
(c)n,
(c)2n,
(c)3n, and
(c)mn, of these different cell
populations by
optical sectioning of each cell in the Z plane. Therefore,
the average volume of each cell type, V(c)n,
V(c)2n, V(c)3n, and
V(c)mn, was computed from
 | (2) |
The confocal measurements of cell volume were restricted to 5 mononucleated, 16 binucleated, 7 trinucleated, and 5 tetranucleated myocytes in control left ventricles. Corresponding values in paced hearts were 5 mononucleated, 19 binucleated, 4 trinucleated, and 4 tetranucleated. The cells examined were randomly sampled by measuring only myocytes vertically oriented in the microscopic field. The proportion between the width and thickness of myocytes was used to obtain the average cell volume in the larger population of cells measured in the preceding section (see above).
Number of Myocytes
The aggregate number of myocytes in the
left
ventricular free wall was obtained by combining
measurements obtained by the in situ analysis of the
myocardium with the estimations of myocyte cell volume,
collected from enzymatically dissociated cells. Specifically, the total
volume of the left ventricular myocardium,
VT, was first determined by dividing its weight by
the specific gravity of muscle tissue, 1.06 g/mL (Reference 30).
Subsequently, the absolute volume of viable tissue, V, was assessed
from the product of the ventricular volume and the
volume percent of myocardium not affected by replacement
fibrosis, Vv:
 | (3) |
The total volume of myocytes in the left ventricular free wall, V(c)T, then was calculated from V and the volume fraction of myocytes in the viable tissue, V(c)V:
 | (4) |
From the morphometric measurement of the volume fraction of myocytes in the myocardium, V(c)V, and the proportion of mononucleated, F(c)n, binucleated, F(c)2n, trinucleated, F(c)3n, and multinucleated, F(c)mn, cells determined in enzymatically dissociated myocytes, the volume percent of mononucleated, V(c)Vn, binucleated, V(c)V2n, trinucleated, V(c)V3n, and multinucleated, V(c)Vmn, cells in the tissue was obtained:
 | (5) |
 |
This
information combined with the quantitative evaluation of
the absolute volume of myocytes in the ventricle, V(c)T
(see Equation 4
), allowed the estimation of the aggregate
volume of
mononucleated, V(c)Tn, binucleated,
V(c)T2n, trinucleated, V(c)T3n,
and multinucleated, V(c)Tmm, cells:
 | (6) |
Finally, the number of mononucleated, N(c)n, binucleated, N(c)2n, trinucleated, N(c)3n, and multinucleated, N(c)mn, cells in the ventricle was computed.
 | (7) |
Data Collection and Analysis
All tissue samples were coded,
and the code was broken at the
end of the experiment. Results are presented as mean±SD
computed from the average measurements obtained from each dog.
Statistical significance for comparisons between two measurements was
determined with the unpaired two-tailed Student's t
test. Statistical significance for comparisons among measurements
within the wall of each ventricle was determined with one-way
ANOVA. Statistical significance in multiple comparisons among
independent groups of data in which ANOVA and the F test indicated the
presence of significant differences was determined by the Bonferroni
method.31 Values of P<.05 were considered
significant. Because measurements presented were not obtained
in all animals, n values for each parameter determined are
listed in the text or the legend of each figure.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Ventricular Function
Fig 2
illustrates that
ventricular
pacing at the regimen performed here resulted in a significant
impairment of cardiac performance. Heart rate was increased
41% (controls, 85±18 beats per minute; paced, 120±17 beats per
minute; P<.0001), and mean arterial pressure
was reduced 15% (P<.0001). Moreover, left
ventricular systolic pressure was decreased 24%
(P<.0001), whereas left ventricular
end-diastolic pressure was increased 295%
(P<.0001). Left ventricular positive dP/dt was
46% (P<.0001) lower in the paced group. These alterations
in physiological parameters of
ventricular dynamics were all obtained in dogs in a
conscious state and with the pacemaker turned off. Of relevance,
animals subjected to ventricular pacing gained weight
during the interval examined and displayed clinical symptoms and signs
of severe pump failure. Tachycardia, tachypnea, ascites,
pulmonary congestion, and pleural effusion was present in
these animals. In summary, ventricular pacing for 4 weeks
resulted in congestive heart failure.
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Cardiac Anatomy
The weights of the left ventricular free
wall,
interventricular septum, and right ventricle of control
hearts were 81±12 g, 41±6 g, and 48±7 g. Corresponding
values in
paced hearts were 83±21 g, 42±14 g, and 52±9 g. None of
the
differences found between the two groups of animals were statistically
significant. However, the lack of changes at the organ weight level
after pacing did not exclude modifications in wall thickness, chamber
diameter, and longitudinal axis, which characterize
ventricular size and shape. With the exception of the
estimation of the longitudinal axis, which constitutes a single
measurement, wall thickness and chamber diameter of the left ventricle
were obtained in six subsequent rings from base to apex. The thickness
of the interventricular septum was analyzed in
a similar manner. The apical and basal portions were not included in
this analysis because of the impossibility of obtaining these
parameters at the two ends of the heart. Fig 3 illustrates that
the thickness of the anterior aspect
of the left ventricular free wall decreased 21%
(P<.01), 18% (P<.006), 18%
(P<.006), 14% (NS), 16% (NS), and 20%
(P<.002) from base to apex. Corresponding changes in the
posterior portion of the ventricle were -16% (NS), -16%
(P<.02), -17% (P<.02), -13% (NS),
-20%
(P<.03), and -20% (P<.005). The thickness of
the interventricular septum also consistently
decreased at all levels. When the individual values were combined to
compute an average measurement of the anterior and posterior regions of
the ventricle and septum, wall thickness was decreased 18%
(P<.003), 17% (P<.005), and 16%
(P<.001), respectively.
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The modifications in chamber
diameter as a result of
ventricular pacing are shown last in Fig 3. This
parameter increased mostly in the ring adjacent to the
base, 35% (P<.0001), whereas the changes in the two rings
near the apex were not statistically significant. The expansions at
levels 2, 3, and 4 were 27% (P<.0002), 25%
(P<.0001), and 21% (P<.004). As an average,
chamber diameter increased 23% (P<.02) in paced hearts.
These alterations provoked an 85% (P<.0001), 63%
(P<.0001), 64% (P<.0001), 55%
(P<.0001), 50% (P<.02), and 46%
(P<.05) increase in chamber diameter–to–wall
thickness ratio from base to apex (data not shown). In addition, the
major longitudinal axis of the left ventricle increased 7%
(P<.04), from 59±3.1 mm to 63±2.7 mm. The changes in
transverse and longitudinal chamber diameters implied a 62% increase
in cavitary volume. The combination of these anatomic changes with the
increase in left ventricular end-diastolic
pressure generated a significant elevation in diastolic
wall stress at all levels, from base to apex (Fig 4). In
summary, ventricular pacing for 4 weeks resulted in chamber
dilation, wall thinning, and a marked increase in diastolic
wall stress.
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Myocardial Damage
The observations above indicating that
major changes occurred in
ventricular anatomy with pacing, in the absence of
alterations in gross cardiac weights, suggested that myocardial injury
and myocyte reactive hypertrophy were present.
Alternatively, modifications in myocyte shape without cellular
hypertrophy could have occurred. Fig 5A
illustrates that multiple foci of replacement fibrosis due to discrete
losses of myocytes were found across the ventricular wall
in all paced dogs. The interventricular septum also was
affected, but tissue damage was mostly restricted to the left portion
of the septum. The sites of injury were characterized by areas of
scarring, with little or no vessel profiles and inflammatory cells, or
by more recent lesions with fibroblast and capillary proliferation,
leukocytes, and mononuclear infiltrates (Fig 5B). Foci of acute
myocytolytic necrosis were also detected (Fig 5C).
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Fig
6 illustrates the volume percent (Fig 6A and
6B) and
numerical density (Fig 6C and 6D) of foci of
replacement fibrosis in
the left ventricular free wall. Although these
parameters were different from control values, regional
variations in the three principal layers of the wall were not
demonstrable on a statistical basis (Fig 6A and
6C). The
endomyocardium exhibited consistently higher
values than the midmyocardium and the
epimyocardium, but these differences did not reach
statistical significance. An identical evaluation performed in the
interventricular septum is shown in Fig 6B and
6D. The
left portion exhibited more extensive damage than the intermediate and
right side of the septum. Measurements of the volume composition of the
myocardium in regions not affected by replacement fibrosis
showed that the percentage of myocytes was 80±2% in controls and
79±2% in paced hearts. Corresponding values for the
nonmyocyte compartment were 20±2% and 21±2%. In summary,
ventricular pacing for 4 weeks resulted in chronic damage
of the myocardium of the left ventricular free
wall and interventricular septum.
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Proportions of Myocyte Populations in the
Myocardium
The analysis of the distribution of mononucleated,
binucleated, trinucleated, and multinucleated myocytes in the left
ventricular free wall of control and paced dogs is shown in
Fig 7. Binucleated myocytes comprised the majority of
cells in both groups of animals, and mononucleated cells were the
second most frequent cell type. Significantly smaller components were
represented by trinucleated and multinucleated myocytes.
Ventricular pacing was associated with no statistically
significant changes in any group of cells. Sarcomere length remained
constant in all cells, averaging 1.88±0.10 µm (n=7) and
1.89±0.09
µm (n=7) in myocytes from control and paced hearts, respectively.
In
summary, ventricular pacing for 4 weeks did not alter the
proportion of the different myocyte populations in the
ventricular myocardium.
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Myocyte Size and Shape
A range of muscle cell lengths was
observed in enzymatically
dissociated left ventricular myocytes obtained from the
anterior aspect of the left ventricular free wall in
control and paced hearts. The interventricular septum
was not included in this part of the study. Moreover, the description
of myocyte parameters given below was restricted to
binucleated myocytes of control and paced animals. An analysis
of the distribution of myocyte lengths of control animals demonstrated
that this parameter was evenly balanced around the mean
value (Fig 8A). Moreover, the majority of the cells
measured were close to the mean. After ventricular pacing,
there was a shift to the right of this curve, which indicated that an
increase in average cell length occurred in failing dogs (Fig
8B). Only
a small fraction of cells was shorter than 120 µm in this group. On
the other hand, this cell length comprised a significant fraction of
myocytes from control hearts. Fig 8C and 8D
shows the changes in the
distribution of the cross-sectional area of myocytes after
ventricular pacing. In comparison with control myocytes,
myocyte transverse area in paced dogs was shifted to the right,
revealing the presence of a population of cells wider than those seen
in nonpaced animals. Cells from failing hearts documented a
distribution of cell area that encompassed a greater range than that
seen in controls. A similar shift to the right was detected in the
distribution of myocyte cell volume with pacing, demonstrating that
myocyte cellular hypertrophy occurred in this model (Fig 8E and
8F).
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Average length and cross-sectional area of
binucleated myocytes in
each heart were computed from these individual measurements to yield a
mean value in each of the two groups of animals (Table).
Pacing resulted in a 33% increase in length of binucleated myocytes.
When this length change was examined in terms of number of sarcomeres,
paced myocytes possessed 24 more sarcomeres than control cells
(control, 72±5; paced, 96±4; 32%; P<.001). As a
consequence of pacing, myocyte cross-sectional area increased 23%,
and the phenomenon resulted in a 23% (P<.05) increase in
the length-to-diameter ratio of myocytes. The changes in length
and cross-sectional area of mononucleated, trinucleated, and
tetranucleated myocytes in control and paced hearts are also listed in
the Table. Cell length was increased in these myocytes, whereas
the
transverse area expanded in mononucleated cells and decreased in
tetranucleated myocytes. These changes implied a variation in cell
configuration with pacing.
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Fig 9 illustrates that
ventricular pacing
produced a 61% (P<.004) increase in volume of binucleated
myocytes that represented the larger fraction of the
myocyte population. Moreover, mononucleated myocytes that constituted
the second most frequent cell type enlarged by 158%
(P<.0001). Conversely, trinucleated and tetranucleated
myocytes did not exhibit significant changes in cell volume. In
summary, ventricular pacing for 4 weeks resulted in myocyte
cellular hypertrophy.
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Myocyte Dimensions by Confocal Microscopy
Fig
10 illustrates 16 optical sections, 1 µm
apart, of a myocyte obtained from a paced dog. By this
three-dimensional section reconstruction, myocyte cell volume was
measured and, in this specific case, was found to be 40 418
µm3. It also should be apparent that with this approach,
information was obtained concerning the relationship between cell width
and cell thickness (Fig 11), which was used to
compute cell cross sections and volumes illustrated in Fig 8E
and 8F.
Based on the analysis of randomly sampled myocytes, the average
volumes of mononucleated (control, 16 200±3300
µm3, n=5; paced, 27 400±8000
µm3, n=5; 69%, P<.02), binucleated
(control, 25 800±2200 µm3, n=16; paced,
38 000±3400 µm3; 47%, P<.0001),
trinucleated (control, 47 500±7000 µm3, n=7;
paced, 52 400±4800 µm3, n=4; 10%, NS), and
tetranucleated (control, 55 000±7400 µm3, n=5;
paced, 54 800±8700 µm3, n=4; 0%, NS) cells also
were measured by confocal microscopy in control and paced dogs. These
cellular parameters were comparable to the mean values of
each cell population described in the preceding section. In summary,
the hypertrophic growth of myocytes after 4 weeks of
ventricular pacing was confirmed through
three-dimensional optical section reconstruction by confocal
microscopy.
|
|
Myocyte Number
Although the results described above
documented that the
experimental protocol was associated with tissue injury and myocyte
hypertrophy, the question remained concerning the extent of
myocyte loss that occurred in pacing-induced heart failure. The
evaluation of the volume percent and numerical density of lesion
profiles in the myocardium discussed in the preceding
section did not allow a computation of the number of myocytes lost in
the ventricle. This is because, as a consequence of myocytolytic
necrosis, there are variable and unknown amounts of swelling in
cells and interstitial space and a progressive lateral and
radial shrinkage of the damaged area.8 Scar formation, the
contraction of necrotic tissue with time, and reactive growth responses
in the unaffected myocardium all represent dynamic
processes that continuously change the proportion of viable and
nonviable myocardium in the ventricle. However, the
availability of left ventricular free wall weight,
magnitude of myocardial damage, volume percent of myocytes in the
myocardium, and average cell volume of the different
myocyte populations allowed the estimation of the total number of each
cell type in the ventricle.
This was accomplished by calculating first
the fraction of tissue
occupied by the various myocyte populations in the ventricle. The
percentage of myocardium constituted by mononucleated
myocytes was 1.94±0.82% and 2.29±0.17% in control and paced
hearts,
respectively. Corresponding values for binucleated myocytes were
74.50±1.61% and 71.12±2.47%. Trinucleated and tetranucleated
cells
comprised significantly smaller portions of the tissue. These two cell
types involved 0.80±0.52% and 2.79±1.38% in controls and
1.95±0.86% and 3.88±2.23% in experimental animals. Only the
differences between binucleated (P<.01) and trinucleated
(P<.01) myocytes were statistically significant.
Subsequently, the aggregate volume of myocytes represented
by mononucleated (controls, 1.47±0.62 cm3; paced,
1.67±0.12 cm3, NS), binucleated (controls,
56.52±1.22 cm3; paced, 52.01±1.80 cm3;
P<.0001), trinucleated (controls, 0.61±0.40
cm3, paced, 1.43±0.63 cm3;
P<.05), and tetranucleated (controls, 2.12±1.01
cm3; paced, 2.84±1.63 cm3, NS) cells in
the ventricle was obtained. This parameter, in combination
with the mean cell volume of each myocyte population, allowed the
calculation of the total number of each cell group in the heart. Fig
12 illustrates that the left ventricular
free wall of control dogs contains 2.34x109 myocytes,
whereas this parameter was reduced to 1.42x109
in paced animals, mostly because of a 47% and 40% reduction in
mononucleated (P<.05) and binucleated cells
(P<.0001). These changes resulted in a 39%
(P<.0001) loss in the aggregate number of
ventricular myocytes. In summary, ventricular
pacing for 4 weeks resulted in a significant amount of myocyte cell
loss in the myocardium.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The results of the current study demonstrate that chronic severe tachycardia was associated with congestive heart failure and a marked elevation in diastolic wall stress from the base to the apex of the left ventricle. This abnormal hemodynamic state was accompanied by extensive ventricular remodeling consisting of chamber dilation and mural thinning, which affected the ventricle at all levels along the major longitudinal axis. Moreover, discrete areas of myocardial injury characterized by sites of acute myocytolytic necrosis and multiple foci of replacement fibrosis in various phases of healing were detected across the ventricular wall. The magnitude of myocyte loss was considerable and involved both mononucleated and binucleated cells. The myocyte cellular hypertrophic response was commensurate with the extent of myocyte loss, resulting in a preservation of cardiac weights. Importantly, myocyte enlargement included increases in myocyte length and diameter, but myocyte elongation was the prevailing form of reactive cell growth. Thus, the anatomic modifications coupled with ventricular pacing are the consequence of three structural events: myocyte cell loss, myocyte cellular hypertrophy, and an increase in cell length–to–diameter ratio.
Myocyte Cell Loss and Ventricular
Function
Data in this investigation indicate that sustained
tachycardia resulted in a 39% loss of myocytes in a period
of 4 weeks, and this phenomenon was associated with left
ventricular failure. The mural distribution of myocardial
damage in the left ventricle provided direct evidence that clusters of
myocytes were lost in the inner, middle, and outer layers of the wall.
The volume percent and numerical density of lesion profiles were
consistently higher in the endomyocardium than
in the midmyocardium and epimyocardium,
suggesting that myocyte cell death occurred prevalently in the
subendocardial region of the ventricle. Important differences appear to
exist between the effects of left ventricular pacing used
here and those of right ventricular
pacing.14 15 In the latter case, tissue injury and
myocyte
loss have not been observed, and the severe depression in cardiac pump
function has been attributed to a number of factors, including
impairment of subendocardial flow and vasodilator reserve mediated by
the marked elevation in left ventricular
end-diastolic pressure.13 In addition,
structural arrangements of myofibrils in myocytes have been claimed as
critical components of the reduction in force generating ability of the
myocardium.14 Defects in the regulation and
signaling pathway of ß-adrenergic receptors have been
documented12 32 in combination with alterations in
calcium
handling33 of the myopathic cardiac muscle. These cellular
abnormalities have been linked to the altered diastolic
function in this model16 and are considered to play a
major role in the development of the decompensated dilated
heart.13 32 33 However, tissue injury
with collagen
accumulation in the ventricular wall has been observed
previously and proposed as a relevant mechanism of
ventricular dysfunction and failure.18 Indices
of myocyte cell loss have also been obtained in pigs after rapid
ventricular pacing.11 Although differences in
the duration of pacing, location of the electrode, and program of
stimulation exist in these studies, it is difficult to reconcile these
various observations.
In recent years, several studies in humans7 20 22 23 and animals19 21 24 34 35 36 37 have demonstrated that myocyte cell loss is a consistent finding of cardiac failure of various etiology. Myocyte loss accompanies the evolution of different myopathies and appears to precede the impairment in ventricular pump function.34 38 39 Moderate losses of myocytes, scattered throughout the wall, have a profound impact on ventricular performance.19 Myocyte death, diffuse in nature, seems to have a greater influence on cardiac hemodynamics than an equivalent loss of myocytes in a segmental fashion.19 Experimental results40 41 and observations in humans42 43 44 have indicated that occlusion of a major coronary artery resulting in acute myocardial infarction leads to overt failure when the destruction in muscle mass involves 40% to 50% of the myocyte population of the left ventricle. Moreover, it has been shown that nonocclusive coronary artery constriction, coupled with a 20% diffuse myocyte death, is associated with alterations in cardiac hemodynamics that are not commonly seen with infarcts of comparable size.19 Similar results have been obtained after systemic hypertension.21 39 At present, there is no information concerning the minimal magnitude of cell loss required to depress cardiac performance in dogs when cell death occurs segmentally or in a scattered manner across the wall. However, the current findings strongly suggest that a 39% reduction in the aggregate number of myocytes is associated with the terminal phases of the cardiac myopathy. This may constitute a difference between the experimental myopathy examined here and that in humans.7 Ventricular weight is relatively unchanged in the dog model, whereas it is markedly increased in humans. Such a phenomenon may be dependent on the variability in the duration of the disease process, the magnitude of myocyte loss, the extent of reactive myocyte growth, or a combination of these factors.
Results in this investigation cannot establish whether the 6.37% of replacement fibrosis measured across the left ventricular wall accounted for the entire 39% loss of myocytes with rapid ventricular pacing. On the basis of observations made in other animal models8 19 21 38 and humans,7 22 39 this extent of myocardial damage has to be considered responsible for a large fraction of myocyte cell death but cannot be interpreted as the exclusive mechanism of the reduction of cells in the ventricle. In this regard, myocyte necrosis may have occurred in a scattered fashion, involving single or small groups of cells. Such a phenomenon would lead to local expansions of the interstitial space, which would be difficult to detect through relative volume measurements. This type of adaptation has been observed previously with aging in rats38 and humans.22 Importantly, rapid ventricular tachycardia may have resulted in the activation of programmed cell death in the myocardium, and this mechanism may have contributed to the overall loss of myocytes in the ventricle. Programmed myocyte cell death has been documented recently during postnatal development of the heart in vivo45 and after ischemic reperfusion injury in vitro.46 Apoptotic cell death typically involves individual cells, and, in contrast to necrotic myocyte cell death, inflammatory reaction, fibroblast stimulation, vascular proliferation, and scar formation are absent.47 48 49 This possibility may shed light on some of the apparent contrasting results obtained with pacing-induced dilated cardiomyopathy.11 14 16 18 Ventricular dilation cannot occur in the absence of both cell death and cellular hypertrophy.50
Myocyte Cellular Hypertrophy and
Ventricular Wall Stress
Findings in this investigation indicate that
myocyte cellular
hypertrophy occurred as a result of chronic severe
tachycardia, and cellular enlargement was capable of
compensating for myocyte cell loss. However, this cellular reactive
response did not normalize diastolic wall stress, which
remained markedly elevated. Since the aggregate amount of myocytes in
the ventricle decreased 5% and intracavitary volume increased 62%,
the ventricular muscle mass–to–chamber volume
ratio decreased 41% with rapid pacing. These anatomic modifications
are consistent with ventricular shape changes
characteristic of decompensated eccentric
hypertrophy,8 the form of
hypertrophy that distinguishes the transition from
compensated pressure, and/or volume-overload
hypertrophy to myocardial dysfunction and end-stage
cardiac failure.51 52 An increasing pressure load
induces
concentric ventricular hypertrophy in which
wall thickness increases without chamber enlargement, leading to an
augmentation in myocardial mass-to-volume ratio. On the other
hand, an increased volume load typically induces enlargement of the
ventricular chamber volume and a corresponding expansion in
myocardial tissue volume to retain a constant muscle
mass–to–chamber volume
ratio.8 51 52 These
factors characterize eccentric hypertrophy in the
well-balanced stage in which chamber dilatation is accompanied by a
proportional increase in wall thickness, so the ratio of wall thickness
to chamber radius is not altered.8 When these relations
are not preserved, decompensated eccentric hypertrophy
develops, as observed here in the cardiomyopathic
heart. In accordance with previous
results,8 19 21 24 38
diastolic Laplace overloading may represent the
prevailing mechanical stimulus implicated in the growth response of the
myocardium in this setting.
The dimensional changes of ventricular myocytes in pacing-induced dilated cardiomyopathy involved a prevailing increase in cell length rather than in diameter, resulting in a significant reduction in the cell diameter–to–cell length ratio. Such a modification in myocyte shape is the direct consequence of the magnitude of increase in diastolic load at the cellular level. Moreover, this configurational alteration constituted one of the major mechanisms of ventricular dilation after pacing. These observations are consistent with previous findings in the pig model.11 17 The possibility also may be raised that architectural rearrangement of myocytes with side-to-side slippage of muscle cells may have contributed to the expansion in cavitary volume.53 Side-to-side slippage of myocytes would generate a reduction in the mural number of cells, wall thinning, and chamber enlargement. This pattern of ventricular dilation was not investigated here, but it has been inferred previously in wall thickness changes accompanying variations of ventricular volume in the intact heart in vitro54 after ventricular dysfunction,55 myocardial ischemia,56 infarction,53 and during early postnatal development.57
Myocyte Cell Volume and Number
In the last three decades,
several methodologies have been
described for the evaluation of myocyte size and number in the
mammalian heart. These techniques involved the quantitative
analysis of tissue
sections,7 19 20 21 22 23 53 57
the
evaluation of enzymatically dissociated
myocytes,11 15 or
a combination of both.38 58 The morphometric
procedure offers an in situ approach that yields reliable information
on the volume composition of the myocardium and number of
myocyte nuclei in the
tissue.19 20 21 22 23
In contrast, myocyte
isolation provides accurate data on the frequency distribution of
nuclei per cell.11 38 58 By use of both
techniques, the
numbers of mononucleated, binucleated, trinucleated, and tetranucleated
myocytes in the ventricle have been calculated.38 58
However, the estimation of the volume fraction of
myocardium occupied by each myocyte population has been
problematic. Similarly, the determination of the average
cell volume of mononucleated and multinucleated myocytes has never been
obtained. The lack of these parameters has made difficult
the characterization of the hypertrophic reaction of the different
myocyte populations of the heart under any condition of overload. These
limitations have been overcome by the technique described in this study
which combined an in situ morphometric analysis with the
determination of cell configuration and dimensions of isolated
myocytes. By the use of confocal microscopy, three-dimensional
optical reconstruction of single myocytes could be obtained. On this
basis, the contribution of each myocyte population to the overall
muscle mass of the ventricular myocardium was
determined. Moreover, the volumes of mononucleated and multinucleated
cells and their changes with rapid ventricular pacing were
established.
Limitations of the Study and Conclusions
There are several
limitations in the current investigation that
must be acknowledged. (1) The number of dogs was relatively small, and
age differences among the animals could not be carefully evaluated. (2)
The measurements of myocyte size, shape, and number could not be
obtained in the same hearts. (3) The necessity of isolating
ventricular myocytes by enzymatic digestion may have
affected the accuracy of sampling. Smaller mononucleated myocytes or
larger multinucleated cells may have been preferentially preserved
during isolation, so that samples collected may not be
representative of the actual proportion of cell
populations in the tissue. (4) The distribution of
diastolic wall stress from the apex to the base of the
heart was not directly measured but was computed by combining
hemodynamic estimations obtained in vivo with anatomic
parameters determined in the diastolic arrested
perfusion fixed heart. This is particularly important because the
effects of these manipulations necessary for the fixation and
histological analysis of the
myocardium may have altered significantly the in vivo
properties of the heart. Although these limitations have to be
considered, the results of the present study suggest that the
cardiomyopathic heart associated with rapid
ventricular pacing is characterized by myocyte cell loss,
reactive myocyte cellular hypertrophy, and reduction in
ventricular mass–to–chamber volume ratio. Whether
myocyte loss is the prevailing etiological factor responsible for the
development of decompensated eccentric hypertrophy in this
model requires further investigation.
|
Acknowledgments |
|---|
This work was supported by grants HL-38132, HL-39902, HL-4056, HL-50142, and PO-1-HL-43023 from the National Heart, Lung, and Blood Institute. The expert technical assistance of Maria Feliciano is greatly appreciated. Dr Ervin Szoke was a visiting fellow from the Semmelweis University, Budapest, Hungary.
Received March 3, 1995; revision received April 26, 1995; accepted May 18, 1995.
|
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