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Am J Physiol Heart Circ Physiol
281: H1913–H1918, 2001.
Microvascular pressure measurement reveals a coronary
vascular waterfall in arterioles larger than 110 ␮m
J. PIETER VERSLUIS, JOHANNES W. HESLINGA,
PIETER SIPKEMA, AND NICO WESTERHOF
Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Universiteit,
1081 BT Amsterdam, The Netherlands
Received 5 December 2000; accepted in final form 5 July 2001
rat; servo-null; FITC-dextran; coronary flow; microvasculature
THE CORONARY PRESSURE-FLOW RELATIONSHIP
in diastole
exhibits an intercept with the pressure axis, the socalled zero-flow pressure intercept (Pint) (6). This Pint is
present in blood-perfused and crystalloid-perfused
hearts (22). The level of the intercept depends on the
vasoactive state of the vascular bed (4) and is present
even with maximal vasodilatation (13). A Pint higher
than venous pressure implies that the effective perfusion pressure is decreased, i.e., with a higher Pint, a
higher perfusion pressure is needed to generate the
same flow. Pint might be caused by a waterfall mechanism (6) or an intramyocardial compliance (19). Most
studies report pressure-flow relationships at the entrance of the coronary vasculature. These data give a
pressure intercept for the entire vasculature (12) so
Address for reprint requests and other correspondence: J. P. Versluis, Laboratory for Physiology, Van der Boechorststraat 7, 1081 BT
Amsterdam, The Netherlands (E-mail: [email protected]).
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that it is not possible to decide where the waterfall is
located. Recently, Kanatsuka et al. (11) measured local
flow in the subepicardium and related this to aortic
pressure. However, relations between local flow and
local pressure in the microvasculature, which could
give the localization of Pint conclusively, have not been
reported to date.
A vascular waterfall is independent of venous pressure until it exceeds the intercept pressure. By increasing venous pressure, two subsequent intercepts can be
found in isolated skeletal muscle (5). However, in isolated hearts and perfused papillary muscles, it is impossible to control venous pressure due to Thebesian
outflow. Therefore, only measurements of pressure in
smaller vessels along the vasculature can elucidate the
location of vascular waterfalls in the myocardium.
In the present study, we measured pressure-flow
relationships in perfused diastolic papillary muscle.
We measured pressure at the entrance (septal artery)
and at the microvascular level using the servo-null
technique (23), applying a range of perfusion pressures. In this way, we could obtain Pint in several sizes
of vessels of the vasculature and find the location of the
waterfall.
METHODS
Experimental setup. All animals were treated in accordance with the National Institutes of Health Guide for the
Care and Use of Laboratory Animals (National Research
Council, Washington, DC, 1996) as approved by the Council
of the American Physiological Society and under the regulations of the Institutional Animal Care and Use Committee.
Male Wistar rats (Harlan; Zeist, the Netherlands) weighing
275–300 g were used in all experiments (n ⫽ 12). Papillary
muscles were obtained as previously described (16). The
muscle was placed in an organ bath with a standard Tyrode
solution containing (in mM) 128.3 NaCl, 4.7 KCl, 1.05 MgCl2,
0.42 NaH2PO4, 1.0 CaCl2, 11.1 glucose, and 20.2 NaHCO3.
This solution was equilibrated by gassing continuously with
95% O2-5% CO2 (pH 7.4) and kept at a temperature of 27°C.
When adenosine (0.1 mM) was added to the superfusion and
perfusion fluid, no further increase in flow could be found,
indicating maximal vasodilatation.
The costs of publication of this article were defrayed in part by the
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0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society
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Versluis, J. Pieter, Johannes W. Heslinga, Pieter Sipkema, and Nico Westerhof. Microvascular pressure measurement reveals a coronary vascular waterfall in arterioles
larger than 110 ␮m. Am J Physiol Heart Circ Physiol 281:
H1913–H1918, 2001.—Pressure-flow relationships at the entrance of the coronary circulation in the diastolic myocardium exhibit a zero-flow pressure intercept (Pint). We tested
whether this intercept is the same throughout the vascular
bed. Microvascular pressure-flow relationships were therefore measured in vessels of various sizes of the maximally
dilated vasculature of perfused unstimulated papillary muscle using the servo-null technique. From these relationships,
Pint were calculated with nonlinear regression. The Pint at
the level of the septal artery (diameter, 150–250 ␮m) was
23.2 ⫾ 4.4 cmH2O (n ⫽ 12). In arterioles with a diameter
range between 24 and 110 ␮m, Pint was 1.7 ⫾ 0.5 cmH2O (n ⫽
6, P ⬍ 0.01), significantly lower than in the septal artery but
significantly higher than zero, and not dependent on vessel
size. In venules with the same diameters, Pint was 1.1 ⫾ 1.1
cmH2O (n ⫽ 4), which was not different from zero. We
conclude that, in the dilated vascular bed of the papillary
muscle, two vascular waterfalls are found. The first waterfall
is located in arterioles between 150 and 110 ␮m. The second
waterfall is probably located in the small postcapillary
venules.
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VASCULAR WATERFALL IN CORONARY CIRCULATION
using a modified dissection microscope (SV 11, Zeiss) with
520-nm high-pass filters (Zeiss) in front of the oculars. In this
way, vessels with a diameter ⬎20 ␮m were visible.
Microvascular pressure (Pmv) was measured using a servonull pressure system (model 5A, Instrumentation for Physiology and Medicine; San Diego, CA) based on the original
technique used by Wiederhielm et al. (23). We used relative
large pipettes (diameter ⬎1 ␮m) (7) that are very sensitive to
changes in pressure but not sensitive to plugging. Details of
the technique used were described before by Heslinga et al.
(9, 10). Micropipettes were pulled in a two-step protocol using
a micropipette puller (BB-CH, Mecanex SA; Geneva, Switzerland). The tip diameter (outer diameter) of the pipettes
was typically 2–5 ␮m, whereas the length of the tip was
⬃200 ␮m. The pipettes were filled with a 2 M NaCl solution.
The pipette was mounted on an oil-driven micromanipulator
(MM0-203, Narishige; Tokyo, Japan), allowing precise movements in three dimensions.
The validity of the recorded pressure was tested in three
ways. 1) Once in the lumen of a vessel, the servo-null system
should not change the mean pressure recorded when its gain
is increased. An increase in gain of the servo-null system only
induced high-frequency oscillations around the mean pressure. If the pipette was clogged or pressed against the wall of
the vessel, an increase in gain would lead to an increase in
recorded pressure. 2) Pipettes were filled with 1% carbon
black solution. While applying counter pressure on the pipette, a small volume of carbon black solution was released in
the vessel if the pipette was inserted in the vasculature. The
black solution would then move with the flow along the vessel
lumen. In the interstitial space, injection with carbon black
would lead to a diffuse spot of ink in the muscle. In this way,
we could also distinguish between arterioles and venules by
evaluating the direction of the flow. Flow toward the tendon
of the muscle was considered to be arteriolar and that toward
the base was considered to be venular. This was confirmed by
the pressure drop between Pinput and Pmv, which was higher
in venules compared with arterioles. 3) A step in perfusion
pressure should lead to an almost simultaneous step (re-
Fig. 1. Schematic drawing of the experimental setup for intravascular
pressure measurements. Note that the
muscle is suspended in a muscle bath.
For further details, see text. Pperf, perfusion pressure; Pinput, input pressure
of the muscle; ⌬P, pressure difference.
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The organ bath was part of the experimental setup, as
shown in Fig. 1. A silk thread was tied to the tendon and
attached to a force transducer (AE801, Mikro-Elektronikk;
Horten, Norway). The septal artery was then cannulated.
The cannula was attached to a reservoir with Tyrode solution
via a glass capillary (resistance). Changing the O2-CO2 pressure above the Tyrode solution alters the perfusion pressure.
Perfusion pressure could be a constant value or a continuous
increase in pressure (“ramp pressure,” see Pressure-flow relationships). The pressure drop across the resistance capillary was measured with two combined pressure difference
meters (type LX160ID, National Semiconductor; Santa
Clara, CA). The flow through the resistance was found to be
proportional to the pressure drop over the glass capillary
(16).
In each experiment, the flow through the system, before
attachment to the muscle, was measured using a pressure
step protocol. In this way, the perfusion pressure could be
corrected for the pressure drop over the capillary and the
pressure at the tip of the cannula was determined. This
pressure at the level of the septal artery was considered to be
the input pressure of the muscle (Pinput). Pinput was also
measured in one experiment to show that the calculations
were accurate. In this experiment, the slope between the
calculated Pinput and measured septal artery pressure was
1.01 (r2 ⫽ 0.99), which was not different from 1. Thus in all
experiments Pinput-flow relationships were determined in
diastolic (not electrically stimulated) muscles at 80% of the
maximum length (Lmax).
Microvascular pressure. Because the muscles were perfused with Tyrode solution, microvessels were not visible.
With fluorescent-labeled large molecules, microvessels can be
visualized without the risk of diffusion of the fluorescence
through the interstitial space. Therefore, FITC-dextran (4
mg/ml, mol wt 150,000, Sigma; Bornem, Belgium) was added
to the perfusate to visualize the vasculature. We used a
modified halogen light source (KL 1500, Schott) with a 450to 490-nm band-pass filter (Zeiss; Weesp, The Netherlands)
to excite the FITC-dextran. The emitted light was visualized
VASCULAR WATERFALL IN CORONARY CIRCULATION
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P x ⫽ A ⫻ 关1 ⫺ exp共⫺F/F0兲兴 ⫹ R ⫻ F ⫹ Pint
(1)
where Px is either Pinput or Pmv, F is total flow, and R, A, and
F0 are parameters of the model: parameter A is the amplitude of the exponential function, R is the resistance in the
linear part of the relation, and F0 is the curvature of the
relation. With the use of this model, Pint can be determined in
an objective way from the relation between F and Px (22).
Pressure measurements using the servo-null technique were
performed in microvessels of the papillary muscles. The measured local Pmv was plotted against total flow, resulting in a
local pressure-flow relationship. The data were then fitted to
Eq. 1.
Flow was expressed per gram of muscle weight. The muscle weight was calculated from the muscle dimensions and
the density of cardiac tissue (1.06 g/cm3). It was assumed
that local flow is a constant fraction of the total flow. From
Eq. 1, it can be calculated that using a constant fraction of
flow has no effect on the value of Pint and, therefore, total flow
can be used to calculate Pint in the peripheral vasculature.
This was also illustrated by Kanatsuka et al. (11), who
reported the different flows at three levels of the vascular bed
but still found the same Pint because they used aortic pressure in their relationships. The other values of Eq. 1 do not
give meaningful information when total flow is used instead
of local flow, and will therefore not be reported.
Statistics. All values are expressed as means ⫾ SE. Comparisons between parameters from the total vasculature and
from arterioles and venules were made with ANOVA, followed by Tukey’s post hoc test for comparison between all
groups. P values ⬍ 0.05 were considered significant.
RESULTS
Figure 2 shows a recording of a local pressure measurement (Pmv) in an arteriole with a diameter of 37
␮m together with overall flow and Pinput as a function
of time. Pinput was used to construct the pressure-flow
relationship at the entrance, and Pmv was used to
calculate the local pressure-flow relationships. Both
entrance and local pressure-flow relationships in the
same muscle are depicted in Fig. 3. These data were
fitted to Eq. 1 (dotted line in Fig. 3). Figure 3 shows
that the intercept pressure at the entrance (septal
artery) of the muscle is ⬃20 cmH2O, whereas in the
arteriole (37 ␮m) it is ⬃2 cmH2O. The average relative
pressure (Pmv/Pinput) over the vasculature was calculated using Eq. 1 at a flow of 90 ml 䡠 min⫺1 䡠 g⫺1. Pmv/
AJP-Heart Circ Physiol • VOL
Fig. 2. Example of a recording from a microvascular pressure (Pmv)
measurement. Pmv (top) was recorded in an artery with an inner
diameter of 37 ␮m.
Pinput was 0.61 ⫾ 0.16 for the arterioles and 0.17 ⫾ 0.03
for venules.
Pmv was measured in vessels with a diameter ranging from 24 to 110 ␮m. The relationship between vessel
diameter and Pint was tested with linear regression
analysis. Because there was no significant relationship
between those two parameters (P ⬎ 0.05) in arterioles
and venules, respectively, we pooled the data for arterioles in one group and those for venules in another
group.
The averages of the calculated Pint are given in Fig.
4. The intercept pressures of pressure-flow relationships at the entrance were significantly different from
zero. The intercept in the septal artery (23.2 ⫾ 4.4
cmH2O, n ⫽ 12) with a diameter ranging from 150 to
250 ␮m was significantly higher than that in arterioles
ranging between 110 and 24 ␮m (1.7 ⫾ 0.5 cmH2O, n ⫽
6). The latter intercept pressure was also significantly
different from zero. The intercept pressure (1.1 ⫾ 1.1
cmH2O, n ⫽ 4) in venules with a diameter of 24–110
␮m was not different from zero.
DISCUSSION
We found that Pint is not the same throughout the
vascular bed and is significantly lower in arterioles
than in the septal artery. In venules, the intercept
pressure was not different from zero. We could not
show a relation between the vessel diameter (range
24–110 ␮m) and local intercept pressure. Thus two
waterfalls appear to exist; the first vascular waterfall
is located in arterioles larger than 110 ␮m, and the
second is located in vessels smaller than ⬃25 ␮m.
Microvascular pressure. We were able to measure
pressure at different sites in the vasculature of the rat
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sponse time ⬍100 ms) in Pmv (10). In the case that the pipette
was positioned in the interstitial space, a long response time
(2 s) is found.
Pressure-flow relationships. Perfusion pressure in the supplying septal artery (Pinput) was changed from 15–100
cmH2O using a ramp pressure protocol. The perfusion pressure was changed by using a 20-ml syringe coupled to an
injector (model 11, Harvard Apparatus; South Natick, MA).
The syringe was coupled to the reservoir (Fig. 1). The injector
was set to a constant speed, increasing the pressure in the
syringe and thus in the reservoir. The resulting increase in
flow was measured. The slope of the pressure ramp was
0.60 ⫾ 0.06 cmH2O/s, allowing capacitance-free flow increase
(12). Our setup did not allow us to reduce perfusion pressure
to zero pressure, and therefore we had to extrapolate to Pint
in most cases. The measured coronary pressure-flow relationships were fitted to a model described by Van Dijk et al. (22)
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VASCULAR WATERFALL IN CORONARY CIRCULATION
Fig. 4. Average data for the zero-flow pressure intercept (Pint) of the
total (n ⫽ 12) and peripheral vasculature in perfused papillary
muscles. Local measurements are divided into arterial (n ⫽ 6) and
venous (n ⫽ 4) groups. **P ⬍ 0.01 vs. Pint at the entrance, as
measured with an ANOVA with Tukey’s post hoc test; †P ⬍ 0.05,
significantly different from zero.
Fig. 5. Example of a local pressure-flow relationship within a single
muscle. The relationship measured during a pressure ramp (closed
circles) was not different from that with a stepwise increase in
perfusion pressure (open circles).
Fig. 3. Typical examples of pressure-flow relationships. The dotted
line represents the result of a fit to Eq. 1. A: pressure-flow relationship in a perfused papillary muscle at the entrance. B: relationship
between Pmv and total flow in the same muscle. Pmv was recorded in
an artery with an inner diameter of 37 ␮m (see Fig. 2). Note that the
fit to the model (Eq. 1) was performed on the inverse of these
relationships.
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right ventricular papillary muscle. The main advantage of using isolated perfused papillary muscle is that
it does not depend on the perfusion for O2 supply (16).
This means that perfusion pressure can be altered at
will without affecting the oxygen supply. Our experiments were performed under maximal vasodilatation
and in diastole. In crystalloid-perfused rat hearts at
100 mmHg (136 cmH2O), the flow is ⬃15 ml 䡠 min⫺1 䡠 g⫺1
(16). In papillary muscle weighing ⬃1 mg, we found
that the flow was 46.3 ⫾ 8.0 ml 䡠 min⫺1 䡠 g⫺1 (n ⫽ 12).
This flow is probably too high because part of the
septum is also perfused (16) but is not included in the
weight. Therefore, it is difficult to make the distinction
between muscle and septum.
Although significant heterogeneity of flow exists in
the heart (3), it is unlikely that this is also true within
the papillary muscle preparation. In this part of the
heart, all muscle cells run in parallel with the capillaries. To determine an intercept in the smaller arterioles,
total flow and local pressure were used. Therefore, we
had to assume that local flow was a constant fraction of
total flow. Even if heterogeneity exists in our preparation, it would not lead to different values for Pint as
long as the fraction of total flow is constant. This is
shown clearly in the dog subepicardium, where Kanatsuka et al. (11) measured red blood cell velocities at
three levels of the vasculature and constructed pressure-flow curves with aortic pressure. The data of these
authors show that the amount of flow (red blood cell
velocity) does not affect the value of the pressure intercept when the same pressure is used in the pressure-flow relationships. This implies that the pressureflow intercept we found is also independent of flow (see
also METHODS). Although flow itself had no impact on
the value found for Pint, we discarded all experiments
with high flows (⬎90 ml 䡠 min⫺1 䡠 g⫺1) because we suspected that in those preparations at least part of the
flow was leaking through a cut side branch in the
septum.
We evaluated if the pressure ramp was slow enough
to exclude capacitative flow. Our change of pressure
over time of ⬃0.6 cmH2O/s (0.04 mmHg/s) was considerably slower than what was shown to be necessary for
a capacitance free relation by Aversano et al. (3 mmHg/s)
(2). Thus we can assume that flow in our preparation
was free of capacitance effects. This was confirmed by
the fact that within a single experiment the same
relationship was observed using both a pressure step
and a ramp protocol (Fig. 5). We found the local pressure-flow relationships to be curved, whereas in dog
VASCULAR WATERFALL IN CORONARY CIRCULATION
AJP-Heart Circ Physiol • VOL
bly caused by the mechanical properties of the arterioles larger than 110 ␮m (5). The second waterfall can
be explained on the basis of IMP (10), although effects
of surface tension cannot be ruled out (17).
There is evidence that IMP is closely related to
ventricular pressure (8, 14). Extrapolation to zero left
ventricular pressure gives a value of ⬃2 mmHg on the
basis of the data of Heineman and Grayson (8). Our
data and those of Heslinga et al. (10) suggest that, in
our preparation without external (ventricular pressure), IMP is also slightly but significantly above zero.
This might be due to the formation of edema. However,
Heslinga et al. (9) have shown that even in unperfused
papillary muscles (i.e., without edema), a significant
IMP exists.
To find this second waterfall, closure of vessels is not
necessary. This was shown by Sipkema and Westerhof
(18), who used latex microtubes to study the effect of
surrounding pressure on the pressure-flow relation of a
small vessel. In this model, the external pressure is
transmitted to the pressure inside the tube. At the
distal end of the tube, both pressures will be equal due
to the pressure drop over the tube. The collapsible end
of the tube acts as a resistance to flow (“Starling resistor”). In this part of the tube, the transmural (internal ⫺ external) pressure is zero. The pressure in the
horizontal part of the pressure-volume (pressure-diameter) relation, where large volume changes take place
for small pressure changes, equals the value of the
waterfall (Pint). This intercept is equal to the external
(i.e., intramyocardial) pressure. Thus closure of vessels
is not required to find a pressure intercept that is
related to IMP.
Several authors (17, 21) have suggested that a venous waterfall exists in whole heart preparations. Recently, Aldea et al. (1) showed that changes in pressure
in or around a diastolic heart increase Pint. This is
accompanied by an increase in coronary venous pressure. These authors also found evidence for regional
differences in Pint between the subendocardium and
subepicardium. In our preparation, venous pressure is
zero, but if venous pressure is high, it might overrule
the second waterfall we observed.
In intact heart, it might well be that the ventricular
pressure is the main determinant of the height of the
second waterfall (8, 14). This could, in the heart, lead to
regional differences in Pint, because it has been shown
that there are regional differences in IMP values (15).
This suggests that a second waterfall can exist, which
is closely related to IMP. We therefore hypothesize
that, during systole, the increase in IMP (10, 20)
causes Pint in vessels smaller than 25 ␮m to increase,
making the second waterfall pressure the dominating
one.
In conclusion, we determined that Pint is ⬃15 times
lower in arterioles with diameters smaller than 110
␮m than in the feeding septal artery. Pint in arterioles
between 24 and 110 ␮m is not size dependent, whereas
in venules Pint is absent. We therefore propose a double
waterfall model to explain the coronary Pint. One
waterfall is located in arterioles larger than 110 ␮m
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hearts, Bellamy (4) found straight pressure-flow relationships. However, Aversano et al. (2) have shown
that using an increasing pressure gives a more curved
pressure-flow relation than using a decreasing pressure. Curved relationships in the arrested (diastolic)
whole heart have been reported by several authors (1,
11, 13, 22). However, for the whole heart, other mechanisms may contribute to the curvature. A possible
mechanism could be that decreased perfusion pressure
causes a sequential “drop out” of perfusion of layers of
the heart. This would lead to a decrease in the vascular
volume perfused and increase the curvature of the
pressure-flow relation, as was shown by Downey and
Kirk (6). Another mechanism that may play a role is
that a decrease of the intravascular pressure may
result in decreased vessel diameter, and hence an increase of transmural pressure, thereby increasing the
resistance leading to a curved pressure-flow relationship (18).
Diastolic zero-flow pressure intercept. We evaluated
the pressure-flow relationships at three levels in the
vasculature of the papillary muscle at 80% Lmax. The
results at the entrance are in agreement with our
earlier data, where an overall diastolic Pint of 19.6 ⫾
6.6 cmH2O was found (10). In whole maximally dilated
dog hearts, values of 12–15 mmHg (16–20 cmH2O)
were reported (11, 13). Van Dijk et al. (22) showed a
Pint of 20.4 ⫾ 3.9 cmH2O in blood-perfused and 27.5 ⫾
5.6 cmH2O in Tyrode solution-perfused cat hearts. We
found that Pint for arterioles between 24 and 110 ␮m
was much smaller (⬃15 times) than in the septal artery. No correlation was found between Pint and diameter in the septal artery. Because the septal artery is
150 to 250 ␮m in diameter, this means that the large
decrease in Pint is taking place in vessels between 150
and 110 ␮m, suggestive of a waterfall at this level.
We (10) found earlier that the intramyocardial pressure (IMP) in diastolic papillary muscle is ⬃1.8 ⫾ 0.5
cmH2O (means ⫾ SE). This is similar to the Pint we
found in the arterioles. Measurements showed that in
venules the Pint is not significantly different from zero.
IMP have also been measured in whole heart preparations (8, 14). These data show that IMP in the ventricular wall is correlated with left ventricular pressure.
This would suggest an IMP of zero in case of absence of
ventricular pressure. Our results could be explained by
formation of edema. However, a small IMP could be
measured in the papillary muscle preparation without
perfusion and apparent edema formation (9). In our
experiments, care was taken to perfuse the preparation
only in the case of a pressure measurement, thus
minimizing edema formation.
To explain our results, we propose a model with two
distinct waterfalls, somewhat in analogy to what
Braakman et al. (5) suggested. The first waterfall has
an intercept pressure of ⬃20 cmH2O and is located in
arterioles between 110 and 150 ␮m in diameter. The
second waterfall is located in vessels smaller than 24
␮m, perhaps at the capillary level or at the postcapillary venules, and has a waterfall pressure of ⬃2
cmH2O equal to IMP (10). The first waterfall is proba-
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VASCULAR WATERFALL IN CORONARY CIRCULATION
and one waterfall is located between small arterioles
and venules, possibly in the capillaries or postcapillary venules.
This work was supported by The Netherlands Heart Foundation
Grant 94-069 and by National Heart, Lung, and Blood Institute
Grant HL-44399-01.
12.
13.
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