(Hypertension. 1997;30:1041-1046.)
© 1997 American Heart Association, Inc.
Articles |
Cardiac Myocyte Membrane Wounding in the Abruptly Pressure-Overloaded Rat Heart Under High Wall Stress
From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (T.A.F., P.F., R.A.K., M.A.P., J.M.P.), and the Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta (P.L.M., R.K.).
Correspondence to Janice M. Pfeffer, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail PFEFFER{at}BICS.BWH.HARVARD.EDU
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Abstract |
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Abstract The potential role of transient sarcolemmal membrane wounding as a signal transduction event for cardiomyocyte hypertrophy was evaluated in rats with short-term pressure overload caused by banding of the proximal aorta. This procedure resulted in significant increases in left ventricular systolic (1.5-fold) and end-diastolic (2.6-fold) pressures and wall stresses that were associated with significant wall thinning and cavitary enlargement. Quantitative image analysis of frozen sections of the stressed ventricles obtained 60 minutes after banding demonstrated a 6- to 10-fold increase in cytosolic staining with a horseradish peroxidase–labeled anti-albumin antibody compared with sham-operated controls, indicating that an increase in transient sarcolemmal membrane permeability (wounding) is an early response to an abrupt increase in hemodynamic load in vivo. We conclude that an intense hemodynamic stress in vivo can result in histologically detectable cardiomyocyte wounding.
Key Words: pressure overload • cardiomyocyte wounding • stress, left ventricular wall
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Introduction |
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Cardiac hypertrophy is the result of a sustained imposition of load on the ventricular muscle. Although it has been proposed that several mechanisms are linked to the hypertrophic response of neonatal cultured cardiac myocytes in vitro,1 2 3 4 the way in which abrupt hemodynamic changes are transduced into alterations in structure and function of the adult myocardium in vivo remains to be characterized. Because the adult cardiac myocyte has lost its capacity to undergo cytokinesis and therefore does not proliferate,5 its defined cellular program is limited exclusively to its enlargement. Changes in the geometry of the ventricular muscle and rearrangements of its fibers have been shown to be important in rat models of chronic pressure overload and myocardial infarction.6 7 Initiation of these changes may require cell-to-cell communication. Thus, it has been hypothesized that paracrine growth factors act as signaling molecules to promote this hypertrophic response. However, an important unresolved issue is to define those cellular mechanisms that promote the release of growth factors after the initial signal of imposed mechanical load.
Recently, a mechanism for this communication between cells has been described with the discovery of contraction-induced resealable sarcolemmal membrane disruptions (wounds) that have been observed in skeletal muscle as well as in isolated perfused hearts.8 9 In addition, this phenomenon has been reproduced in vitro by uniform electric-field pacing of adult cardiac myocytes in culture.10 In the intact animal, the importance of these findings in response to a defined mechanical load has not yet been investigated. Therefore, we used an animal model of abrupt pressure overload to determine the immediate functional and morphological changes associated with a rapid and sustained increase in ventricular load. First, we determined whether an acute increase in systolic and end-diastolic wall stresses leads to structural changes in the left ventricular (LV) myocardium and, second, we tested whether this abrupt increase in cardiac load would result in nonlethal membrane wounding in cardiac myocytes in response to this load.
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Methods |
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Aortic Banding Procedure
Adult female Wistar rats (Charles River) with a body weight of 204±3 g (range, 181 to 218 g) and aged 10 to 11 weeks were subjected to either an abrupt pressure overload by banding the proximal aorta or a sham operation. Hemodynamic measurements were made as described previously.11 In brief, the right carotid artery and jugular vein were cannulated with saline-filled polyethylene catheters (PE-50) and connected in series to 5F Millar micromanometers. The tip of the carotid arterial catheter was advanced into the ascending aorta, and measurements were made of baseline phasic and mean (arterial and venous) pressures and heart rate. A mid-sternal thoracotomy was performed by heat cauterization to expose the ascending aorta for the banding procedure. The proximal aorta and the aortic arch, including their major branches, were freed by blunt dissection and isolated by silk sutures (Deknatel 2-0). The carotid arterial catheter was secured with its tip in the proximal aorta. A 0.7-mm-diameter wire was placed along the aortic arch between the origins of the left common carotid and right brachiocephalic arteries. Previously placed sutures were tightened against the wire, which was then promptly removed to produce a predefined constriction across the aortic arch. Sham-operated animals underwent the same surgical procedure, except that the ligature was not tightened against the wire.
Hemodynamic Studies
To assess more fully the hemodynamic changes
that occur with constriction of the aorta, a subset of 14 animals
(aortic-banded, n=7; sham, n=7) underwent the surgical and banding
procedures as described above, except that the arterial
catheter was advanced into the left ventricle. The LV systolic
and end-diastolic pressures and venous pressure were
continuously recorded from baseline to 60 minutes after
constriction. To assess the effects of this banding procedure on the
passive pressure-volume characteristics of the left ventricle, the
heart was arrested in diastole with potassium chloride, and
a double-lumen catheter was inserted into the aorta and then advanced
into the left ventricle for the simultaneous infusion of
saline and recording of pressure over a range of 0 to 30
mm Hg.11 12 The ventricles were infused with formalin to
a volume that corresponded to 5 mm Hg on individual
pressure-volume curves, and then the ventricles (with the
closed-stopcock system) were immersed in formalin for 24 hours, after
which the right and left (including septum) ventricles were separated
and weighed. The pressure-volume curves thus generated were
analyzed at every unit mm Hg for the determination of
volume at any given pressure.
Diastolic wall stress,13 14 
d,
was derived using the formula
d=P(a2/b2-a2),
where P is LV end-diastolic pressure (mm Hg), a is the
internal radius, which is calculated as (3/4xVentricular
Volume)1/3, and b is the outer radius, which is calculated
as [3/4(Ventricular Volume+1.05
mL/gxVentricular Mass)1/3]. An approximation
of peak systolic wall stress, which occurs early in ejection,
was obtained by using the above-mentioned formula for
diastolic wall stress, except that P is peak
systolic pressure.
The wall thickness of formalin-fixed sections (perfusion-fixed and immersion-fixed at a common distending pressure) was analyzed by planimetric measurement of the LV wall. A transverse section was taken from the mid-ventricle, and a grid of intersecting vectors was overlaid on the projected slide (10-fold magnification) and aligned with the center of the ventricular cavity. The wall thickness was analyzed at eight different sectors in each heart and then averaged in 19 animals (aortic-banded, n=9; sham-operated, n=10). Values were calculated as millimeters of thickness normalized to the LV weight.
Tissue Sampling for Immunostaining Analysis
Animals designated for immunostaining
(aortic-banded, n=5; sham, n=5) underwent the same surgical procedures
as outlined for the hemodynamic studies, except that
the catheter was not advanced into the left ventricle; in this way, we
avoided damaging the endocardium.9 After we recorded
phasic and mean (arterial and venous) pressures, we
introduced a polyethylene catheter (PE-90) into the abdominal aorta
with its tip placed above the diaphragm. The left common carotid and
subclavian arteries were ligated, the banding suture was removed, and
the atria were incised. The heart was perfused with 150 mL of PBS at
37°C, which contained 0.1% procaine, at a rate of 11.5 mL/min to
wash out traces of blood. A constant perfusion pressure was maintained
to avoid distension of the left ventricle. Freshly prepared 8%
formalin (150 mL) was infused for fixation at a pressure between 25 and
35 mm Hg.
Image Analysis and Quantification of Cardiac Myocyte
Wounding In Vivo
The hearts that were designated for quantification of myocyte
wounding were immersed in fresh fixative solution (8% [wt/vol]
paraformaldehyde dissolved in PBS, pH 7.4) for 24 hours
and gradually infiltrated with 15%, 30%, and 60% (wt/vol) sucrose,
followed by incubation in embedding compound (Tissue Tek OCT) for 16
hours, as described previously.15 The hearts were mounted
side by side in pairs on a sectioning stub so that the apexes were at
the same level. The tissue block was trimmed to a depth of 8 mm
from the apex, and 5-µm sections were collected randomly at -27°C
along the longitudinal axis using a Zeiss HM 500 OM cryostat microtome.
Sections were placed onto Fisherbrand Superfrost Plus microscope slides
(Fisher Scientific) and immersed immediately in 8% (wt/vol) formalin.
The sections were washed in PBS, incubated in 10 mmol/L
ammonium chloride for 10 minutes, and after additional washes in PBS,
permeabilized in 0.2% Triton X-100. After
preincubation in blocking buffer containing 4%
heat-inactivated sheep serum (Sigma Chemical Co) and 0.05%
Triton-X-100, sections were incubated in blocking buffer containing 20
µg protein per milliliter of anti-rat serum albumin
conjugated to horseradish peroxidase (Cappel Research Products) for
4 hours at 37°C. After additional washes in PBS, anti-rat serum
albumin binding was visualized using the horseradish
peroxidase–diaminobenzidine reaction, with the exception of the cobalt
chloride.16
Quantification of cardiac myocyte immunostaining was performed using a computerized image analysis system (Image 1, Universal Imaging Corp) without knowledge of the identity of the sample. Briefly, sections were viewed with a Zeiss Axiophot microscope, and random images were taken with a MTI CCD 72 camera (Dage MTI). Images to be compared quantitatively were captured with the intensity of the transmitted light and the camera black and gain levels held constant. A total of 5519 LV and 5640 right ventricular (RV) fibers in the aortic-banded animals (n=5) and 4594 LV and 5209 RV fibers in the sham-operated animals (n=5) were analyzed. The number of wounded myocytes present in aortic-banded and sham-operated animals is expressed as a percentage of the total number of fibers analyzed.
Statistical Analysis
Results are expressed as mean±SEM except where indicated. For
analysis, 24 animals were partitioned into age- and
weight-matched study groups as defined in "Methods." A two-way
repeated measures ANOVA was applied to the hemodynamic
data to detect changes over time and between procedures.
Analysis of the pressure-volume data was performed using a
multivariate ANOVA. Unpaired Student's t
tests and nonparametric tests for comparison of the group
means (Kruskal-Wallis) were performed when appropriate. A value of
P<.05 was considered statistically significant.
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Results |
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Hemodynamic Effects of Abrupt Pressure Overload and Pressure-Volume Relationship
Before the aortic banding procedure, the sham-operated and aortic-banded rats had comparable systemic arterial and LV systolic pressures, central venous pressures, and heart rates (Table 1
). There were minor baseline
differences in LV end-diastolic pressure and wall stress
(LVED stress) and systolic wall stress (LVSP stress) between
sham-operated and aortic-banded animals, respectively, that achieved
statistical significance (Table 1 and Fig 1) (LVED pressure: 2.9±0.2 [range, 1.9
to 3.4] mm Hg versus 4.0±0.3 [range, 3.2 to 5.2] mm Hg,
P<.01; LVED stress: 0.50±0.09 versus 1.05±0.17
dyne/cm2x103, P<.01; LVSP stress:
20.9±3.9 versus 34.6±2.6 dyne/cm2x103,
P<.001). These data, however, were in the normal range of
values of age-matched animals in our previous experience, and we do not
consider the difference to be of biological consequence. After the
aortic banding procedure, animals had an increase in LV
systolic (1.5-fold) and end-diastolic (2.6-fold)
pressures that was sustained over the 60-minute period (Table 2). There was an increase in LVED
(4-fold) and LVSP (2.5-fold) stresses that occurred promptly and
remained elevated (Fig 1). Heart rate and central venous pressures in
the banded animals did not change significantly over time (Table 2).
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Ventricular volumes measured in the potassium-arrested
heart were increased in the aortic-banded rats (Fig 2). This shift to the right in the
pressure-volume relation was substantial in that aortic-banded rats had
volumes at 5 mm Hg (P<.06) that were 39% greater
than those of sham-operated rats, a difference in volumes that was
maintained at higher filling pressures. This increase in
ventricular volume was already present at low
(<2.5 mm Hg) filling pressures, achieving statistical
significance with a small sample size. The ventricular
filling that occurs along the linear portion of the pressure-volume
relation, from 0 to 2.5 mm Hg, is associated with distension of
the chamber from the collapsed state, with minimal stretching of the
myocardium. This volume (2.5 mm Hg) therefore
represents the size of the minimally deformed LV
chamber.12 The ventricles that underwent this procedure
did not differ in absolute or relative weight (Table 3).
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LV wall thickness was measured in hearts that were perfusion-fixed for
determination of myocyte wounding and immersion-fixed at a common
distending pressure after determination of the pressure-volume
relation. In aortic-banded animals (n=9), wall thickness (mm/g LV) was
significantly decreased compared with that of sham-operated animals
(n=10, P<.01) (Fig 3).
Indeed, the thickness of the LV wall of animals with banded aortas was
only 80% of that of animals that underwent the surgical protocol but
did not undergo the banding procedure.
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Analysis of Myocyte Wounding In Situ
An increase in reversible plasma membrane disruptions, ie, the
wounding of cardiac myocytes, was observed in the animals that
underwent the acute aortic banding procedure (Fig 4). In the sham-operated controls, the
image analysis of the myofibers revealed minimal wounding:
2.9±1.3% (range, 1% to 8%) in the RV tissue and 7.9±2.5% (range,
1% to 16%) of the myocytes in the LV tissue demonstrated cytosolic
uptake of albumin, a marker of nonlethal membrane
wounding.17 The extent of wounding of
ventricular myocytes between RV and LV tissue in the
sham-operated animals was not statistically different. The level of
wounding was substantially increased (6- to 10-fold) in the RV
(54.2±19.2% [range, 26% to 80%], P<.001) and LV
(45.6±15.7% [range, 28% to 62%], P<.001) tissues in
the aortic-banded compared with the sham-operated animals (Fig 5a and 5b).
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Discussion |
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The cardiac myocyte and its surrounding extracellular matrix are exposed to local forces, which are generated by the LV filling pressure and contractile force and imposed on the ventricular wall. The mechanisms, however, that transduce hemodynamic forces into myocyte growth under normal and pathological conditions in vivo are not known. Several different mechanisms may play a role in the hypertrophic response of the myocardium, including the release of locally synthesized peptide growth factors, the activation of stress-induced ion channels, mechanotransduction via integrin receptor binding, and internal cytoskeletal tension.18 19 20 21 22 23 Although an array of polypeptides and second-messenger systems that are associated with an induction of this hypertrophic response in vitro have been described, the more immediate link of mechanical stress to the initiation of this signaling cascade in vivo remains to be established.
The transfer of stress forces to the cell occurs first at the cell surface; plasma membranes therefore are suitable candidates as mechanotransduction elements. Alteration of membrane integrity therefore might influence the generation of intracellular biochemical signals. Reversible transient membrane disruptions (ie, wounding) occur in response to such a mechanical stress in the skeletal muscle of rats exposed to downhill running, as well as in dystrophic muscle.8 16 In this study, we investigated the effect of an abnormally high mechanical load on cardiac myocyte membrane wounding as a potential initial signaling event for the induction of cardiac growth.
The forces acting on and within the myocardium can be
described in terms of load. We therefore developed a rat model of
abrupt pressure and concomitant secondary volume overload specifically
designed to achieve a rapid and severe increase in cardiac load.
Proximal banding of the intrathoracic aorta was followed by a 1.5- to
2.6-fold increase in LV systolic and end-diastolic
pressures, respectively, and was associated with a profound increase in
LV systolic and end-diastolic wall stresses.
Importantly, this high wall stress was associated with changes in the
structural properties (volumes at 
2.5 mm Hg derived from the
passive pressure-volume relation) of the left ventricle of the
aortic-banded hearts. After having been subjected to this increase in
load for 60 minutes, the left ventricle was dilated and there was
global thinning of the ventricular wall. This increase in
LV volume was possibly the result of myocyte slippage due to
systolic expansion, as has been shown for acute myocardial
infarction.24
Previous studies have shown that atrial cardiac myocytes have the potential to allow a stretch-dependent transendocardial transfer of macromolecules into and through the myocardium to the base of the epicardium in vitro.25 In addition, membrane wounding of adult cardiac myocytes has been reported recently to occur in response to an increase in mechanical activity in vitro, as well as to the force of contraction produced by infusion of isoproterenol in isolated Langendorf perfused hearts.9 10 The major finding of our study is that a rapid increase in LV wall stress in this intact animal model is followed by a substantial increase in uptake of albumin, an index of sarcolemmal wounding in cardiac myocytes. Our previous experience in skeletal8 and cardiac muscle9 10 indicates that reversible membrane disruptions (wounding) are a common event caused by mechanical stress in muscle tissue and may also allow the release of intracellular cytoplasmic molecules that subsequently could have autocrine or paracrine effects. Moreover, the present experiments indicate that this increase in cellular permeability to macromolecules within the myocardium is an early event in response to an abrupt increase in ventricular load. Albumin, as a prototype of such a macromolecule, was chosen to establish this link between hemodynamic load and myocyte wounding because it has been validated as a marker for transient, sublethal sarcolemmal membrane disruptions.17 The possibility that the albumin could have been taken up by the T-tubular system was discounted by electron microscopic examination of stained ultrathin sections, which confirmed the presence of albumin only in the cytosolic compartment within the cardiac myocytes.9
Our data indicate also that even under the normal loading conditions of the nonbanded heart, in situ wounding of cardiac myocytes could be detected, although its frequency was much lower than that observed in isolated heart preparations.9 This finding, however, supports a link between the phenomenon of wounding and its relation to changes in cardiac load as a mechanism that has the potential to contribute to the regulation of normal cardiac growth in vivo. One candidate that links membrane wounding and release of an autocrine- or paracrine-acting growth stimulus in muscle is the family of fibroblast growth factors (FGFs). Both acidic and basic FGF (FGF1 and FGF2) have been shown to be important in normal development in vertebrates and to play an important role in the cellular response of many tissues to physiological stress.26 27 28 An increase in mechanical load can upregulate bFGF mRNA in skeletal muscle29 and proportionally augment the release of bFGF from cultures of differentiated human skeletal muscle.30 Mechanically induced cell injury causes an increase in bovine endothelial bFGF gene transcription and peptide synthesis.31 The accumulation of bFGF mRNA in adult cardiac myocytes is regulated by other polypeptide growth factors, including bFGF itself, which indicates that FGFs can play a role in the signaling process in cardiac hypertrophy in vitro.32
Both aFGF and bFGF have been found in the extracellular space within myocardial tissue by immunocytochemical localization.33 Because both FGF isoforms lack a peptide sequence that could mediate their transport out of the cell, another signaling event is required for their release, one of which might be cardiac myocyte wounding. Although it has been suggested that FGFs can be secreted independently of the endoplasmic reticulum–Golgi complex in vitro, such a mechanism has not yet been verified in muscle tissue.34 35 It has been postulated, however, that FGFs can be released from the muscle cell when the integrity of the plasma membrane is compromised.36
In summary, we have shown that an abrupt increase in mechanical stress in aortic-banded rats subjected to a severe pressure overload produces structural dilatation of the left ventricle and cardiac myocyte transient membrane wounding.
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Acknowledgments |
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This work was supported in part by grants HL36141 (Dr Kelly) and GM48091 (Dr McNeil) from the National Institutes of Health. Dr Fischer is the recipient of a postdoctoral fellowship award from the Deutsche Forschungsgemeinschaft, and Dr McNeil is the recipient of an American Heart Association Established Investigator award. We especially thank Joseph Gannon for his commendable help in performing the hemodynamic studies and Pamela Hsieh for her fine secretarial assistance.
Received March 31, 1997; first decision April 22, 1997; accepted April 22, 1997.
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