(Circulation. 1996;93:349-355.)
© 1996 American Heart Association, Inc.
Articles |
Time-Related Normalization of Maximal Coronary Flow in Isolated Perfused Hearts of Rats With Myocardial Infarction
From the Departments of Pharmacology (H.J.M.G.N.-V., J.J.M.D., J.F.M.S.), Physiology (L.H.E.H.S.), and Pathology (M.J.A.P.D.), Cardiovascular Research Institute Maastricht, University of Limburg, the Netherlands.
Correspondence to H.J.M.G. Nelissen-Vrancken, Department of Pharmacology, University of Limburg, PO Box 616, 6200 MD Maastricht, Netherlands.
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Abstract |
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Background In the present study, we investigated the time dependency and regional differences of the vascular adaptation of the myocardium after myocardial infarction (MI) in rats.
Methods and Results MI was induced by total occlusion of the left anterior descending coronary artery. Time-dependent adaptation of the coronary vasculature was determined by histological staining of endothelial cells and measurement of basal and maximal coronary flow at days 0, 4, 7, 21, 35, and 90 after surgery in isolated retrogradely perfused hearts of sham-operated and infarcted rats. Cardiac function was determined during anterograde perfusion. In a separate group of experiments, regional myocardial flow was measured with radiolabeled microspheres in sham-operated and infarcted hearts to determine local differences in adaptation. Basal coronary flow was completely normalized within 7 days, whereas maximal coronary flow was not normalized until 35 days after MI. Normal growth, as observed in sham-operated hearts, resulted in a parallel increase in coronary flow and tissue mass from day 7 to 35 after surgery. In contrast, the increase in coronary flow was lower than the hypertrophic response in the right ventricles and septa of infarcted hearts, whereas a parallel increase in tissue mass and coronary flow was observed in the left ventricles of these hearts. These functional data were supported by structural data that showed the presence of numerous and dilated vessels, especially in the border zone of the infarcted and noninfarcted tissue.
Conclusions These observations demonstrate that vessel growth, predominantly in the region adjacent to the infarcted zone, results in complete normalization of coronary vasodilatory capacity within 35 days after MI.
Key Words: myocardial infarction • blood flow • vasculature
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Because the myocardium under physiological conditions is totally dependent on aerobic metabolism, an increase in myocardial oxygen consumption requires an increase in coronary blood flow. This so-called coronary flow reserve of the myocardium is age-related1 and, moreover, is altered in pathophysiological conditions. Preservation of depressed coronary flow reserve was observed, for instance, in myocardial hypertrophy caused by hypertension (pressure overload),1 2 3 4 whereas complete normalization of the coronary flow reserve was demonstrated in the rat within a few weeks after volume overload.2 Four weeks after MI, decreased maximal coronary flow and coronary flow reserve were observed in the surviving myocardium.5 The depressed coronary reserve was suggested to be related to both developed hypertrophy and elevated preload because minimal coronary resistance correlated with myocyte cross-sectional area and LV end-diastolic pressure.
Induction of MI by total occlusion of part of the coronary vasculature diminishes coronary flow substantially.6 Consequently, the blood supply to the ischemic area can be improved by dilatation of the remaining vessels and development of collateral vessels.7 8 9 In the acute phase, collateral flow can be achieved by recruitment of preexisting vessels; in the chronic phase, new vessels can be formed.7 8 9 On this basis, the acute response after MI diminishes the coronary flow reserve, whereas the chronic response results in a normalization of coronary flow reserve.10
The growth of coronary vessels usually is very slow in adult rats.11 Induction of vessel growth has been described in cardiac hypertrophy resulting from pressure overload, thyroxine, or anemia.10 11 12 The increased DNA synthesis in the surviving part of the ventricles after MI, as demonstrated by van Krimpen et al,13 is partly localized in endothelial cells.14 This suggests vascular growth after MI. Anversa et al6 demonstrated an inadequate adaptation of the capillary vasculature to hypertrophy in the surviving part of the myocardium at 40 days after MI as measured by diffusion distance and capillary surface area. Furthermore, Karam et al5 showed a sustained reduction of maximal coronary flow 4 weeks after the induction of MI, which suggests a remaining perfusion deficit in the myocardium.
Because the time-dependent adaptation of the coronary vasculature after MI is not completely understood, we investigated the effect of MI on coronary flow in time. Therefore, both basal and maximal flows were determined in isolated Langendorff-perfused rat hearts several times between 0 and 90 days after sham surgery or MI. Furthermore, the development of blood vessels in time was visualized by histological staining of endothelial cells. Having established a diminished and normalized maximal coronary flow after 7 and 35 days, respectively, we determined regional differences in coronary flow after MI with radiolabeled microspheres at these times after sham surgery or MI.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animals
Male Wistar rats (Harlan-Winkelmann, Borchen, Germany) weighing 260 to 325 g were used. Rats had free access to standard food (Hope Farms) and tap water and were housed in groups of up to four rats. The experimental procedures were performed according to institutional guidelines and approved by the Ethical Committee for the Use of Experimental Animals of the University of Limburg (the Netherlands).
Surgery and Preparations
Myocardial Infarction
MI was induced by coronary artery ligation under
pentobarbital anesthesia (60 mg/kg IP).15 16
Intraoperatively, the rat was respired with room air (60 strokes per
minute; tidal volume, 3 mL) after the trachea was intubated. After
thoracotomy in the fourth left intercostal space, the heart was
exteriorized, and a 6-0 silk suture was passed under the LAD near the
origin of the pulmonary artery. In sham-operated rats, the
suture was looped through the myocardium next to the LAD.
After the heart was returned to its normal position, the suture was
tied. The ribs were pulled together with 3-0 silk, and the skin was
sutured. Rats were allowed to recover for 4, 7, 14, 21, 35, or 90 days.
For measurements during acute MI (t=0 days), the LAD was occluded
during isolated heart perfusion.
Isolated Heart Perfusion
Isolated hearts were perfused as described by Snoeckx et
al.17 Under pentobarbital anesthesia (60 mg/kg
IP), hearts of MI and sham-operated rats were excised rapidly and
immersed immediately in ice-chilled perfusion medium (see below).
After removal of lung and fat tissue, hearts were connected to the
aortic cannula of the perfusion system, and retrograde perfusion
(Langendorff perfusion model) was started at a diastolic
aortic pressure of 60 mm Hg. The left atrium also was connected to a
cannula for anterograde perfusion (ejecting heart model) for
cardiac function measurements.17 18
The hearts were perfused with a modified Krebs-Henseleit solution ([mmol/L] NaCl 130, KCl 5.6, CaCl2 2.2, MgCl2 1.2, NaH2PO4 1.2, NaHCO3 25.0, glucose 10.0, and pyruvate 5.0). The solution was maintained at 37°C, gassed with 95% O2 and 5% CO2 (PO2 >600 mm Hg) to obtain a pH of 7.4, and continuously filtered (1.2-µm Millipore filter) throughout the perfusion period. The hearts were paced at 5 Hz.
A catheter (PE-50) was inserted into the LV through the apex and connected to a pressure transducer (Gould Spectramed DTX+, Spectramed) to measure LV pressure. Aortic pressure was measured by a pressure transducer connected to the inflow of the aortic cannula. During retrograde perfusion, coronary flow was measured by an electromagnetic flow probe (Skalar) mounted in the aortic inflow tract. During anterograde perfusion, aortic flow was measured by the electromagnetic flow probe, whereas coronary flow was measured by collection of the coronary outflow in a graduated cylinder. CO was calculated as the sum of coronary flow and aortic flow. Except for CO, all hemodynamic variables were monitored continuously or calculated on-line by a computer.
Staining of Endothelial Cells of the
Myocardium
In separate groups of rats, endothelial cells
were stained in paraffin-embedded sections of the
myocardium of rats with MI (days 7, 14, 35, and 90). Under
ether anesthesia, the hearts of rats with MI were arrested
in diastole by injection of 2 mL of 0.1 mol/L
CdCl2 into the inferior caval vein and perfused
with a catheter in the abdominal aorta with PBS (pH 7.4) containing 0.5
mg/mL nitroprusside for 5 to 10 minutes at a pressure of 
100 mm Hg.
Thereafter, the hearts were perfusion-fixed for 10 minutes with
10% phosphate-buffered formalin (1:1 diluted in PBS) containing
0.5 mg/mL nitroprusside. The hearts were removed and stored in 10%
phosphate-buffered formalin for 24 hours at room temperature.
Subsequently, the hearts were cut into 4-mm transverse slices and
embedded in paraffin.
To determine endothelial cells in the myocardium, 4-µm transverse sections were stained with the lectin GSI (Sigma Chemical Co), as described previously by Kuizinga et al.14 Therefore, the sections were dewaxed and rehydrated, and endogenous peroxidase was inhibited by methanol/H2O2 (0.3%) for 15 minutes. The sections were incubated overnight with the biotinylated lectin GSI (1:100) at room temperature; then the sections were incubated with the alkaline phosphatase–conjugated biotine-avidine complex (1:200, Dakopatts) for 30 minutes at room temperature and developed with fast blue BB (Sigma Chemical Co).
Measurements
Retrograde Perfusion Studies
The
hearts were prepared for retrograde perfusion at day 4, 7,
21, 35, or 90 after sham surgery or induction of MI. After
equilibration of the isolated hearts, basal values of coronary
flow were determined. Thereafter, maximal coronary
vasodilatation was obtained by subsequent injections of 0.5 mL
adenosine (1 mmol/L), nitroprusside (1 mmol/L), and
adenosine plus nitroprusside (1 mmol/L each). At day 0, MI was
induced acutely after equilibration of the perfused hearts. Basal and
maximal values of coronary flow in acute MI were measured under
steady state conditions (within 10 to 20 minutes of ligation of the
LAD). Except at day 0, all hearts were subjected to anterograde
perfusion after retrograde perfusion.
Anterograde Perfusion
Studies
After retrograde perfusion the hearts were prepared for
anterograde perfusion to measure cardiac function. Therefore,
the hearts were exposed to different combinations of preload (5, 10,
15, and 20 mm Hg) and afterload (diastolic aortic pressure,
60, 100, and 140 mm Hg). Aortic flow, coronary flow, aortic
pressure, and LV pressure were determined after stabilization. At the
end of the experiments, the ventricles were weighed, and infarct size
was determined (see below).
Microspheres Studies
In
separate groups, differences in regional distribution of
coronary flow between days 7 and 35 after MI were determined
with radiolabeled microspheres. Hearts were prepared for
Langendorff perfusion 7 and 35 days after sham surgery or induction of
MI. After equilibration of the isolated hearts, basal values of
coronary flow were measured, and 5000 radiolabeled
microspheres (141Ce or 103Ru 15 µm in
diameter) per 1 g tissue were injected.19 After a single
injection of 0.5 mL of adenosine plus nitroprusside (1 mmol/L
each), maximal coronary flow was measured, followed by
injection of 5000 radiolabeled microspheres
(103Ru or 141Ce) per 1 g tissue.
141Ce and 103Ru were used in a randomized
order.
At the end of the microspheres experiments, atria and adherent tissues were removed before the ventricles were quickly frozen (-20°C) and cut into transverse slices of 1 to 2 mm. Then all slices of sham-operated hearts were divided into RV, septum, and LV, whereas the slices of MI hearts were stained with nitro blue tetrazolium20 to distinguish between infarcted and noninfarcted tissue. Infarct size was determined in the midventricular slice (see below). Thereafter, all slices were divided in RV, septum, center of MI, border zone (border of LV and MI), and the rest of the (surviving) LV. The atria (including adhesive tissues) and the different parts of the ventricles were weighed and counted for radioactivity (1282 Compu Gamma, LKB Wallac).21 Absolute flows in the different parts of the heart could be calculated from total basal and maximal coronary flow measured by the electromagnetic flow probe during perfusion. To compare coronary flow in hearts at 7 and 35 days after surgery, the flows in the different parts of the heart were normalized for the weight of the corresponding tissue parts.
Cautious isolation of the heart resulted in adherent tissue (eg, residuals of lung tissue and bronchi) that was difficult to remove from the atria after perfusion. The amount of adherent tissue varied in the different experimental groups (predominantly sham-operated versus MI; not quantified). Because the adherent tissue does not contribute to coronary flow, it will differentially underestimate the flow normalized for the corresponding weight in the atria and total heart. To avoid these problems, total ventricular flow was calculated out of total heart flow and atrial flow.
Measurement of Infarct Size
To measure infarct
size, the hearts were cut into transverse
slices of 1 to 2 mm, resulting in five to six slices. In the retrograde
and anterograde perfusion studies, the
midventricular slice was fixed with formalin and
embedded in paraffin; then transverse sections (4 µm) were stained
according to the modified AZAN technique.13 In the
microspheres studies, the slices were stained with nitro blue
tetrazolium20 ; then the midventricular
slice was used for measurement of infarct size. Infarct size was
determined by planimetry and expressed in percentage of LV
circumference, calculated as the average of infarct sizes of
endocardial and epicardial surfaces.22 23
The infarct size of hearts at day 0 (retrograde and anterograde studies) was not determined because both staining methods were not suitable for detection of infarcted area after acute MI.
Data Analysis
Only hearts with infarct sizes >21% were
used in the MI groups
because smaller infarcts do not have detectable
hemodynamic consequences in vivo.24
Data of time-related experiments were compared with values obtained at day 0 by one-way ANOVA and Dunnett's test (retrograde perfusion studies) or compared between the time groups by one-way ANOVA and Bonferroni's test (anterograde studies). Data of sham-operated and MI rats were compared by Student's t test for unpaired observations (retrograde perfusion and microspheres studies) or by two-way ANOVA (anterograde studies). Data were expressed as mean±SEM. Differences were regarded to be statistically significant at P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Retrograde and Anterograde Perfusion Experiments
Hemodynamic values of sham-operated hearts during anterograde perfusion were comparable among the different times (Table 1
). CO was significantly reduced
in hearts with MI in relation to sham-operated hearts at day 35
after surgery, independent of preload and afterload (Fig 1).
Comparable differences between sham-operated and
MI hearts were found at days 4, 7, 21, and 90 after surgery (data not
shown). These observations demonstrate that the hearts with MI can
attain normal CO levels only at relatively high preload and low
afterload levels, suggesting mechanical failure of the hearts.
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) or infarction (
) as measured at
different combinations of preload and afterload (*P<.05).
Data are expressed as mean±SEM.
Because
of normal growth, both body weight and total
ventricular weight increased over time in sham-operated
rats (Table 2). At all times, body weight was lower in
MI compared with sham-operated rats. Differences were significant
only at days 0, 7, and 90 and were not due to differences in weight
before surgery except for day 0 (data not shown). Total
ventricular weight was greater in MI than in
sham-operated rats (significant at day 90). If we take into account
that >40% of the LV was infarcted and thus atrophic, the greater
increase in total ventricular weight over time suggests the
development of hypertrophy in the noninfarcted part of the
MI hearts. We did not apply the ratio of ventricular weight
to body weight as an indicator for development of
hypertrophy over time because formation of
peripheral and cardiac edema can influence
ventricular weight and body weight differently over time.
Furthermore, the development of both atrophy and
hypertrophy in hearts with MI implies that normalization of
coronary flow for total ventricular weight of both
sham-operated and MI hearts was not appropriate in these
experiments.
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As Fig 2A shows, basal coronary flow of
sham-operated rats increased over time. This increase parallels the
increase in total ventricular weight (Table 2
). Ligation of
the LAD during perfusion (day 0) resulted in a reduction of basal
coronary flow by 25% (before, 14.0±0.8 mL/min; after,
10.8±0.8 mL/min). Within 7 days, basal coronary flow in MI
hearts was normalized compared with sham-operated hearts (sham,
13.6±0.6 mL/min; MI, 14.2±0.9 mL/min). At that time, maximal
coronary flow was still significantly lower in MI than in
sham-operated hearts (Fig 2B). Complete normalization of the
maximal coronary flow was achieved after 35 days (sham,
21.9±1.2 mL/min; MI, 21.2±0.6 mL/min), whereas at day 90,
maximal
coronary flow was significantly higher than in
sham-operated hearts (sham, 24.1±0.5 mL/min; MI, 25.9±0.7
mL/min).
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Microspheres Experiments
The increases in total ventricular
weight and maximal
regional myocardial flow of sham-operated hearts from day 7 to 35
were similar to those found in the retrograde perfusion experiments
(Tables 2 and 3). In contrast to the findings in
the
retrograde perfusion experiments, total ventricular weight
of MI hearts at day 35 was significantly higher compared with
sham-operated hearts. Furthermore, maximal regional myocardial flow
in MI hearts at day 35 was still slightly but significantly lower than
in sham-operated hearts. The latter, however, was not due to a
lower flow in the MI hearts in the present experiment but to a
relatively high flow in the sham-operated hearts.
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To relate maximal
regional myocardial flow values between groups of
sham-operated hearts and between groups of MI hearts, the flows in
RVs, septa, and different LV sections were corrected for the
corresponding tissue weights (Fig 3A and 3B). In
sham-operated hearts, the maximal flows of all sections were
comparable between days 7 and 35 (Fig 3A). In contrast, the
maximal
flows in RVs and septa of MI hearts were significantly lower at day 35
compared with day 7 (RV, 21.2±1.2 and 27.5±2.2
mL·min-1·g-1;
septum, 19.8±0.8 and 25.5±2.4
mL·min-1·g-1,
respectively), whereas maximal flows in the different LV sections were
comparable between days 7 and 35 (Fig 3B). Regional
distribution of
coronary flow under basal conditions was similar to that after
maximal dilatation (data not shown).
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Fig 4 shows the
relation between the increase in
absolute flow and weight at day 35 compared with day 7 in the RV,
septum, and LV (in MI hearts, the rest of the surviving LV). Therefore,
the mean values of the absolute flow or weight of the RV, septum, and
LV at day 35 were subtracted from the mean values of the absolute flow
or weight of the corresponding parts at day 7. The increase in flow and
weight in the (surviving) LV in MI hearts was comparable to that during
normal growth. In contrast to what is observed in sham-operated
hearts, the increase in weight in the RV and septum in MI hearts was
not paralleled by a comparable increase in flow.
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flow) and the difference
in weight at days 7 and 35 (
Histology
Fig 5 illustrates the presence of
endothelial cells in the proximity of the infarcted
area at different times after MI. A regular distribution of capillaries
around cardiomyocytes can be observed in the noninfarcted
area (Fig 5A). The abundance and dilatation of blood vessels in
the
infarcted area of the myocardium increase in time, as
demonstrated clearly in Fig 5B through 5E. Within 7 days,
GSI-stained
vessels are present without preferential orientation in the
granulation tissue in the border zone of the infarcted and noninfarcted
area. From day 14 to 90 after MI surgery, the blood vessels are
oriented parallel to the scar tissue at both the epicardial and
endocardial sites of the scar tissue.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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To investigate the time dependency of the development of collateral flow by recruitment of preexisting vessels or development of new vessels after MI, we examined acute and chronic effects of MI on basal and maximal coronary flow in isolated perfused rat hearts. Induction of MI resulted acutely in a reduction in basal and maximal coronary flow. The basal coronary flow in MI hearts was completely normalized within 1 week, whereas the maximal coronary flow was normalized after 5 weeks after MI. This normalization of maximal coronary flow in MI hearts was regionally dependent. The increase in myocardial flow lagged behind the tissue growth in the RV and septa of MI hearts, whereas a parallel increase in flow and weight was observed in the surviving LV. These observations suggest that the normalization of the maximal coronary flow is due predominantly to an increase in flow in the proximity of the infarcted area. This is supported histologically by the presence of numerous and dilated vessels in the infarcted region of MI hearts in time.
Normalization of coronary flow for total heart weight in both
sham-operated and MI hearts is not appropriate in the present
experiments because of a thinning of the infarcted area (atrophic
response) and hypertrophy of the surviving
myocytes.25 26 27 The latter process
explains the observed
significant difference between ventricular weight of
sham-operated and MI hearts at day 90 (Table 2). When we take
into
account that >40% of the LV is infarcted and becomes
atrophic,26 the surviving part of the hearts must also be
hypertrophic at days 21 and 35. In contrast to MI hearts, the increase
in coronary flow in sham-operated hearts observed in time
results only from normal growth of the ventricles because the ratio of
coronary flow to heart weight of sham-operated hearts is
similar in time (data not shown).
Basal Coronary Flow
Induction of MI by total occlusion of the
LAD results in an acute
decrease in both basal and maximal coronary flow. The basal
coronary flow in MI hearts increases to a preocclusive level
within 4 days, is comparable between MI and sham-operated hearts
from day 7 to 35, and is significantly elevated in MI hearts 90 days
after MI. An elevated basal coronary flow also was observed in
in vivo experiments,5 although the elevation was already
observed 4 weeks after MI surgery. A possible explanation for such an
increase in basal coronary flow is dilatation of the remaining
coronary vessels that supply the ischemic (border)
zone. Furthermore, a rise in basal coronary flow may be due to
a higher oxygen demand of the surviving myocardium of
infarcted hearts because the efficiency of the oxygen consumption is
lower after MI. The latter has been demonstrated in in vivo experiments
in which a normal oxygen consumption in MI hearts (approximated by the
product of arterial pressure and heart rate) resulted
in decreased stroke work.24 The time discrepancy between
the in vivo5 and the present experiments may be due to
differences in oxygen demand or the presence of neurohumoral regulation
mechanisms in vivo.
Maximal Coronary Flow
The maximal coronary flow obtained with
a combination of
adenosine and nitroprusside was used in this study as a measure
for the total amount of perfusable coronary
vessels.28 The observed normalization of maximal
coronary flow within 35 days in MI hearts suggests vessel
growth associated not only with normal tissue growth but also with the
developed hypertrophy (see above) or with the processes in
the infarcted part of the myocardium. In vivo, maximal
coronary blood flow also was depressed in infarcted hearts 4
weeks after surgery.5 However, a decreased afterload in MI
rats in vivo can be responsible for the depressed maximal
coronary flow. Although we observed a normalized maximal
coronary flow, the adaptation of the capillary vasculature
seems to be inadequate, as suggested by a lower capillary surface area
and an elevated diffusion distance in the surviving LV of hearts with
both small and large infarctions 40 days after surgery.6
The discrepancy between functional and structural
parameters for adaptation in MI hearts can be explained by
regional differences in vascular adaptation because the structural
parameters were measured only in the surviving
LV.6 An enhanced response of (new) coronary blood
vessels to vasodilating substances also can be an explanation because
we observed the presence of dilated blood vessels in the proximity of
the infarcted area (Fig 5).
Regional Myocardial Flow and Structural Evidence
Adaptation
of myocardial tissue mass after MI can differ
regionally because a combination of normal growth and
hypertrophy occurs in the surviving parts of the
myocardium.6 29 Furthermore, development of
scar tissue and scar contraction results in shrinkage of the infarcted
part of the myocardium. Ultimately, these processes may
result in regional differences in adaptation of vessel growth. In the
present experiments, the normal relation between tissue growth and
the increase in coronary flow is demonstrated in
sham-operated hearts in which the tissue growth in all parts of the
heart is paralleled by an increase in coronary flow. In
MI hearts, however, tissue growth is not paralleled by a
comparable increase in coronary flow in the RV and septum. This
result is in agreement with observations in cardiac
hypertrophy in hypertension in which the increase in flow
or vascular density is not proportional to the hypertrophic growth
response,1 10 11 30 although
the degree of the increase in
coronary flow seems to depend on the duration of
hypertension.31 32 In contrast to the RV and septum,
the
increase in coronary flow in the surviving part of the LV of MI
hearts compensates completely for the increase in tissue growth.
Assuming that the hypertrophic response to stretch is comparable in
septum and surviving LV, the contradiction between the increases in
flow and weight in surviving LV and septum cannot be explained by a
smaller increase in weight in the surviving LV. This suggests that a
greater stimulus for vessel growth is responsible for the parallel
increase in flow and weight in the surviving LV. That the development
of new vessels in the LV is indeed responsible for the parallel
increase in tissue growth and coronary flow is supported by the
presence of numerous and dilated vessels in the proximity of the
infarcted area (Fig 5). The regionally dependent adaptation of
vessel
growth after MI may be related to regional differences in stimuli for
vessel growth, possibly because of differences in metabolic
demand or neurohumoral regulation mechanisms.
Conclusions
The present experiments demonstrate a region- and
time-dependent adaptation of the coronary vascular bed to
chronic MI. The increase in coronary flow in the proximity of
the infarcted area, which is associated with an increase in vessel
number, seems to be predominantly responsible for the normalization of
the maximal coronary flow in infarcted hearts 5 weeks after
surgery.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grant 902-18-291 from the Dutch Heart Foundation and NWO (the Netherlands). We thank Richard N. Cornelussen, Peter J.A. Leenders, and Elsbeth A. Raes for expert technical assistance.
Received November 22, 1994; revision received March 29, 1995; accepted August 29, 1995.
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