223
Capillary Recruitment and Pain Relief
on
Leg Dependency in Patients With
Severe Lower Limb Ischemia
Dirk Th. Ubbink, MD; Michael J.H.M. Jacobs, MD, PhD; Dick W. Slaaf, PhD;
Geert Jan W.J.M. Tangelder, MD, PhD; and Robert S. Reneman, MD, PhD
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Background. Patients suffering from severe lower limb ischemia may experience pain relief on
leg dependency despite the fact that dependency normally results in arteriolar vasoconstriction.
To clarify this possible paradox, skin microcirculation of the limb was investigated in 75
patients with different stages of lower limb ischemia and in 12 asymptomatic subjects.
Methods and Results. Using nailfold capillary video microscopy, red blood cell-perfused
capillary density and diameter and red blood cell velocity were assessed in supine and sitting
positions. Capillary density increased by changing from the supine to the sitting position,
especially in patients with limb-threatening ischemia (showing a 4.5-fold increase versus a
1.5-fold increase in asymptomatic subjects). In subjects without or with mild ischemia,
capillary perfusion was two to four times lower in the sitting than in the supine position. In
patients with limb-threatening ischemia, perfusion was strongly reduced, being slightly higher
in the sitting position. Patients with relief of pain while sitting did not always have a higher
capillary perfusion but did have a higher capillary density in the sitting position.
Conclusions. The arteriolar postural vasoconstrictive mechanism at the nutritive level is still
intact in subjects without or with mild ischemia but not in patients with severe ischemia.
Capillary recruitment rather than disturbed arteriolar vasoconstriction could explain why
patients with severe leg ischemia prefer leg dependency. (Circulation 1992;85:223-229)
P atients with severe lower limb ischemia may
experience relief of nocturnal or rest pain on
leg dependency. As yet, this phenomenon has
not been explained satisfactorily. Under physiological conditions, arteriolar vasoconstrictive mechanisms lead to reduced lower limb perfusion when
changing from the supine to the sitting position.1-3
The mechanism involved can be of central sympathetic45 and/or local origin. In the latter case, myogenic response and venoarteriolar axon reflex have
been considered.6'7 There are indications that these
mechanisms are disturbed in patients experiencing
relief of pain on leg dependency, resulting in enhanced rather than decreased perfusion on dependency.8-15 In these studies, skin perfusion was measured with the use of the 133Xe washout method,
From the Department of Surgery (D.Th.U., M.J.H.M.J.), Academic Hospital Maastricht, Departments of Biophysics (D.W.S.)
and Physiology (G.W.J.M.T., R.S.R.), Cardiovascular Research
Institute, Maastricht, The Netherlands.
Address for correspondence: M.J.H.M. Jacobs, MD, Department of Surgery, Academic Hospital, PO Box 5800, 6202 AZ
Maastricht, The Netherlands.
Received December 16, 1990; revision accepted September 3,
1991.
transcutaneous oximetry, or laser Doppler fluxmetry.
Techniques measuring total skin microcirculatory
blood flow do not allow the distinction between
capillary and thermoregulatory flow. Moreover, the
measured increases in flow were often limited.
It was the aim of the present study to investigate
the microcirculatory changes induced by leg dependency in patients with different stages of lower limb
ischemia. To this end, in these patients skin nutritive
flow was determined in both the supine and the
sitting positions by using intravital video microscopy
of the toe nailfold. Besides dynamic parameters,
morphological parameters were also assessed because improvement on dependency might not only
result from enhanced flow but also by an increase in
erythrocyte-perfused capillary density leading to an
enlarged surface area for exchange.
Methods
Patients
Twelve asymptomatic subjects and 75 patients suffering from arterial obstructive disease in at least one
leg participated in the study. The age of the 62 men
and 25 women ranged from 43 to 95 years (mean, 71
224
Circulation Vol 85, No 1 January 1992
TABLE 1. Patient Groups
ABI
n
Group
12
0-19%
1
24
20-39%
2
23
40-59%
3
16
4
60-95%
12
5
96-123%
ABI, ankle-to-brachial systolic
Ankle blood
Fontaine
pressure
(mm Hg)
1
0'
Age (years, range)
81 (77-89)
16
0
0
72 (53-81)
52
0
0
70 (43-95)
75
0
0
65 (45-76)
97
0
2
12
67 (51-82)
150
0
blood pressure index; Fontaine 0', no arterial disease.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
years). Their symptoms were intermittent claudication, rest pain, and/or ulceration. The patients were
divided into five groups (Table 1) according to their
ankle-to-brachial pressure index (ABI). This ABI
varied from 0% to 123%, being lowest in group 1 and
highest in group 5. Fifteen of the 25 patients with rest
pain experienced relief of pain on leg dependency.
They all had an ABI of 50% or less and clinically
belonged to Fontaine stage 3 or 4. Smoking habits
and drug treatment, especially those interfering with
vasoconstriction, are shown in Table 2.
Of the 12 subjects in group 5, two received medication for cardiac angina, one for hypertension, one
for a recent myocardial infarction, and one for atherosclerotic symptoms of the leg not investigated
here. These 12 subjects had a normal arterial system
in the investigated leg not only because the ABI in
this leg was higher than 95% but also because
analysis of the Doppler signals of the major leg
arteries showed no pathology, as opposed to the
arterial Doppler signals of the patients in groups 1-4.
The criteria to consider Doppler tracings to be
pathological were 1) no backflow, 2) decrease of
systolic signal and increased diastolic level caused by
reduced peripheral vascular resistance (i.e., diminished pulsatility), and 3) prolonged rise time to peak
velocity. Reduced backflow or a slightly reduced
signal amplitude was not considered pathological.
Subjects with insulin-dependent diabetes mellitus
were excluded from the study because this disease per
se influences microcirculatory autoregulation mechanisms.1617 However, 18 non-insulin-dependent diaTABLE 2. Patient Characteristics
Vasoactive
drugs
Relief Diabetes
Smokers
A B C
7
5
2
11 3 3
5
2
8
4
2
4
3
8
9
6
5
5
0
1
7
6
2
5
2
3
0
3
1
1
Table shows number of patients who experienced relief of pain
on dependency, noninsulin-dependent diabetics, smokers, and
number of patients using vasoactive drugs. Column A includes
arterial and venous dilators (one patient in group 2 and one in
group 4 used an angiotensin converting enzyme inhibitor); B,
/3-blocking agents; C, calcium antagonists.
Group
1
2
3
4
5
n
12
24
23
16
12
clinical stage
2
0
15
19
14
0
3
5
5
1
4
7
4
3
0
0
0
0
betics did participate in this study. Their findings were
interpreted separately to assess possible differences in
microvascular reactivity between diabetic and nondiabetic patients. All were well-regulated diabetics. Peripheral neuropathy was ruled out when patients
stated no experience of paresis or loss of sensibility
and skin tactile sensibility showed no abnormalities
during clinical examination. Patients refrained from
smoking and did not take caffeine or alcohol for at
least 1 hour before examination.
Experimental Protocol
Measurements were performed after 20 minutes of
acclimatization in sitting position in a room between
230 and 24°C. Patients were subjected to capillary
microscopy of the nailfold of the great toe (see
"Equipment") first in the sitting position and then in
the supine position. Measurements in the sitting
position were followed by a 10-minute interval in
which the setup was readjusted and the patient could
adapt to the supine position before repeating the
measurements. In this position, capillary microscopy
was performed after tilting the microscope and stage
about 45°. The patient was positioned on a bench
with the knee slightly (approximately 300) flexed so
that the foot could be placed on the stage of the
microscope.
In both positions, capillary density was investigated
first. Capillary diameter and red blood cell velocity
(RBCV) were then measured in usually four but at
least three capillaries. In patients in group 1, sometimes only three capillaries could sufficiently be investigated. The same capillaries could be identified
and measured easily in either position because every
capillary has a unique morphology. RBCV was assessed both at rest and during reactive hyperemia
after a 1-minute arterial occlusion induced by inflating
a cuff around the ankle. This hyperemia procedure
was performed in each of the at least three capillaries
investigated in both positions. To ensure that the
previous hyperemic response had subsided, the measurements in the different capillaries were performed
with an interval of at least 3 minutes, which is longer
than the duration of reactive hyperemia.18 In the
supine position, the leg was not completely straight
but had 300 flexion in the knee. In this position,
inflation of the ankle cuff cannot cause movement
artifacts of the foot under the microscope. The aver-
Ubbink et al Postural Microvascular Reactivity in Leg Ischemia
Filters
E3-----
Polariser
50% mir
..Hg
lamp ,
lens
raffin oil
Big toe
FIGURE 1. Schematic representation of capillary video microscopy
setup.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
age values of the capillary diameters and velocities, as
measured at rest and during reactive hyperemia, were
taken as the readings in both positions.
Systolic ankle and brachial blood pressure were
measured in the supine position by means of a cuff
and an 8-MHz Doppler probe to assess ABI. Brachial blood pressure was also measured with the Riva
Rocci method to calculate mean arterial pressure
(2/3 x diastolic pressure+ 1/3 x systolic pressure). Finally, systolic ankle blood pressure was measured in
the sitting position to calculate the orthostatic pressure increase after the change in posture.
Equipment
Capillary microscopy of the nailfold of the great
toe is an established technique to assess nutritional
skin circulation in patients with arterial occlusive
disease.19 The methods and equipment used have
been described in detail elsewhere.20 In short, the
nailfold to be investigated was covered with a drop of
paraffin oil to improve skin transparency. Capillaries
were visualized using a modified Leitz Orthoplan
microscope and a Leitz 4 x objective (numerical
aperture, 0.14) to measure capillary density. A Leitz
10x objective (numerical aperture, 0.30) was used
for velocity measurements. Magnification at the front
plane of the television camera (Philips Newvicon XQ
1275, 2/3-in. tube), positioned at the intermediate
image plane, was 5x and 12.5x, respectively. The
camera was rotated to orientate the capillaries parallel to the video lines. An image was produced on a
monitor screen (Philips LDH 2122, 12 in.) with a final
magnification of 165 x and 410 x. The images were
stored on tape for off-line analysis using a videocassette recorder (Sony Betamax SL-C9 ES). A schematic drawing of the system used is presented in
Figure 1.
Incident illumination was achieved using a Leitz
Ploemopak 2.1 system equipped with a Leitz polarizer (POL) cube. The light from a 100 -W mercury arc
was projected directly through the POL cube and the
225
objective lens onto the nailfold. The POL cube
consists of a 50% transmission/50% reflection mirror
in a 450 position with respect to the optical axis of the
microscope. The POL cube contains a polarizer in
the illumination pathway and a crossed analyzer in
the image-forming pathway to cancel the light reflected from lenses and skin surface.21,22 Neutral
density filters were used to adjust the light intensity
at the camera, and a heat absorption/reflection filter
was used to protect the skin against local temperature increases caused by the incident light.
Off-line Analysis
From the stored video images, the following parameters were assessed: 1) the number of erythrocyte-perfused capillaries per square millimeter of
nailfold skin (density) as counted (at rest) in a video
screen (effective surface area 1.86 mm2), that is,
about 1.6 mm proximal of the terminal row of
capillaries; 2) RBC (red blood cell) column width
(representing the diameter) in the arteriolar limbs of
the capillary loops in micrometers, measured halfway
between the visible base and the crest of the loop:
The distance between the measuring site and the
capillary crest varied from about 50 to 250 ,um.
Within this distance, the diameter did not vary
substantially; 3) RBCV (in micrometers/sec) assessed
at rest (Restv) and at peak reactive hyperemia
(Peakv): The velocity was measured with a flying spot
device. This instrument generates dots that move
over the monitor screen at a known, adjustable
speed. RBCV is assessed by synchronizing the moving dots with the blood cells and plasma gaps in the
arteriolar branch of the capillary.23 This technique
was used because very low velocities, as can be
expected in the patients studied, can be assessed in a
reproducible and more accurate manner than with
other techniques currently in use.24 Peak RBCV was
measured as follows: from the release of the cuff on,
the reactive hyperemia response is observed and the
velocity of the moving dots is synchronized continuously with the moving blood cells until the speed no
longer increases. At this moment, RBCV is read from
the display and is recorded as the peak velocity; 4)
Capillary volume flow (Volflow) at rest per square
micrometer of nailfold skin, that is, average
Restvxxrx (average capillary radius)2x capillary density per square micrometer; and 5) supine to sitting
velocity ratios, obtained by dividing the RBCV in
both positions in each patient: This ratio was used to
obtain better insight into the individual changes in
perfusion caused by changes in posture because it is
an index for the effectiveness of the postural vasoconstrictive mechanisms (vasoconstriction index).
This approach was taken because median ratios for a
group may be different from the ratios calculated
from the group median values. When RBCV was
zero in both the supine and the sitting positions, the
ratio was also regarded as zero.
Circulation Vol 85, No 1 January 1992
226
apillary diameter (um)
Capillary density (/mm2)
IlI
I
80-
I II
IV
*
i
X V
iii
ii
I
14
Iv
v
0
12
7
*
S
0
W
a.~~~a
10
8
40-
.a
6
~~~~~
20-
*
*
a*
*-
_*
-
a
*
*-
1
4
2
9
0
o
0
20%
oo%i
80%
60%
40%
100%
120%
0%
20%
Ankle to brachial pressure index
M
sitting
0
supine
°
med sit
0
40%
100%
80%
60%
120%
Ankle to brachial pressure index
*
med sup
sitting
m
supine
0
med sit
med sup
°
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
FIGURE 2. Scatterplot of capillary densities in sitting and
supine positions plotted against median ankle-to-brachial
index value of each group (med sit, median sitting; med sup,
median supine).
FIGURE 3. Scatterplot of capillary diameters in sitting and
supine positions plotted against median ankle-to-brachial
index value of each group (med sit, median sitting; med sup,
median supine).
Statistics
on RBC-perfused capillary
presented in Figure 2. In the supine
position, densities were similar in groups 2-5. In
group 1, however, the median density was only
8/mm2, which was significantly lower than the median
density of 27/mm2 in group 2 (p<0.005). RBCperfused capillary density was lower in the supine
than in the sitting position in all groups (p<0.05, NS
in group 4). This was especially noticeable in group 1
(supine, 8/mm2; sitting, 34/mm2). In the sitting position, densities did not differ significantly between all
groups and ranged from 34/mm2 in group 1 to 62/mm2
in group 2.
In Figure 3, individual data on capillary diameter
are shown. In all groups, the diameter was significantly smaller in the supine than in the sitting
position (p <0.05). Capillary diameters did not
change significantly between the groups but tended
to increase with a decrease in ABI.
The individual data on capillary Restv are presented in Figure 4. Induction of reactive hyperemia
did not lead to an increase of the Restv in the
The individual data
Because in each ABI group the results of all
parameters obtained were not symmetrically distributed, medians are presented to characterize group
values. The nonparametric Kruskal-Wallis test was
used to evaluate differences between the five groups
for statistical significance. The paired Wilcoxon
signed ranks test was used for statistical analysis of
differences between the two positions.
Results
Mean arterial blood pressures did not differ significantly between patient groups. Systolic ankle pressure was on the average 48 mm Hg higher in the
sitting than in the supine position because of the
increase in orthostatic pressure. This was a consistent
finding independent of ankle blood pressure in the
supine position. In each group, capillary microscopic
parameters in diabetics did not differ significantly
from those in nondiabetics in both positions and,
therefore, the diabetic and nondiabetic data were
pooled.
(11.ml-ql
pcbr4 hinnt-4 (-&nil
Y
1 I
1
III
|Iii I
'I II
I
*,
density
1
1
iIV
1
v
V
12-
are
Supine to sittina ratio
Ii
1 IIII
IV
500-
10-
400300-
*
200-
a
100^
1
20%
0%h
*a
6-
m
1
4-
i
1
40%
60%
80%
v
iv
8-
i
2-
100%
...I....
120%
-
0
0%
Ankle to brachial pressure index
0
sitting
m
supine
0
med sit
]
med
sup
20%
40%
60%
Ankle to brachial
80%
pressure
100%
120%
index
FIGURE 4. Scatterplots of red blood cell velocities at rest in sitting and supine positions (left panel) and supine to sitting ratios
(right panel) plotted against median ankle-to-brachial index value of each group. Dotted line at a ratio of 1 in right panel indicates
equal velocity in both positions. Med sit, median sitting; med sup, median supine.
..
Ubbink et al Postural Microvascular Reactivity in Leg Ischemia
Peesk supine to sitting ratio
velocity (,um/s)
Peak red blood cell
_----
--
--
II
I
III
'V
IV
I
124
50010-
400-
.a
*
*
a
3
3
*3
:.a~~~~~
300-
0:
200-
a:
V.
a
6-
~
1:-4
*.
4-
20%
40%
80%
60%
r....t
120%
100%
-
0%
Ankle to brachial pressure index
sitting
m
supine
0
med sit
0
med
V
.................--.........----...........-..-;..--
............
a5
O
*
IV
I.
I
2-
.
a
0°A6
1 111
II
0:~~~~~~~~
*~~~~~~~~~~~~~~
S t
1oo-
8-
-
.l*
227
20%
a*
60%
40%
Ankle to brachial
sup
80%
pressure
120%
100%
index
FIGURE 5. Scatterplots ofpeak red blood cell velocities in sitting and supine positions (left panel) and peak supine to sitting ratios
(right panel) plotted against median ankle-to-brachial index value ofeach group. Dotted line at a ratio of 1 in rightpanel indicates
equal velocity in both positions. Med sit, median sitting; med sup, median supine.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
capillary examined subsequently, indicating sufficiently long time intervals. In the supine position,
Restv was fairly similar in groups 2-5. In group 1,
however, the median velocity (17 gum/sec) was significantly (p<O.OO1) lower than the median values in
group 2 (168 gm/sec) through group 5. Restv in the
sitting position was not significantly different between the five groups.
As can be seen in Figure 4, individual capillary
Restv was about four to six times higher in the supine
than in the sitting position in groups 2-5 (p<0.005),
illustrating effective arteriolar vasoconstriction in the
sitting position. In contrast, Restv in group 1 increased on dependency, leading to ratios below unity.
However, this increase did not reach the level of
significancy.
In both positions, the trends in Peakv were similar
to those in Restv (Figure 5). In the supine position,
median Peakv was very low in group 1 (55 ,um/sec
compared with 175 ,um/sec in group 2). In groups 1
and 2, Peakv appeared to be only slightly higher than
the Restv, indicating the absence of reactive hyperemia. In the sitting position, Peakv decreased slightly
from a median of 120 gm/sec in group 5 to a median
of 59 ,um/sec in group 1 and was two to four times
higher in the supine than in the sitting position in
groups 2-5.
In groups 3-5, volume flow (Figure 6) was persistently lower in the sitting than in the supine position. In
group 1, however, in the supine position, volume flow
was markedly reduced (p<0.005) compared with the
other groups and increased significantly in the sitting
position (p<0.05), most probably due to capillary recruitment.
All patients with relief on dependency had an ABI
.50%. In this ABI range, the median ABI between
patients with and without relief did not differ significantly (data are shown in Table 3). Patients with
relief had considerably worse nutritive perfusion and
showed a significantly (p<0.05) larger capillary diameter and a lower RBCV and Peak RBCV in the
supine position and a lower vasoconstriction index
(1.21 and 3.48, respectively) than patients without
relief. However, capillary density in patients with
pain relief increased (p<0.002) when changing from
the supine to the sitting position and tended to be
more than the increase (p<0.005) in patients without
pain relief (2.7 versus twofold increase). Similar
changes were found for volume flow. The patients
with pain relief showed a fourfold increase, whereas
those without pain relief showed a decrease.
Discussion
The findings in the present study show that in
limb-threatening ischemia associated with ankle-tobrachial pressure indexes below 20%, skin capillary
perfusion is significantly impaired and cannot cope
with increasing demands, and the number of RBCperfused capillaries is significantly reduced. A
change in posture from the supine to the sitting
position leads to reduced skin perfusion in asymptomatic subjects and patients with mild disease.
However, in severely diseased patients, skin perfusion tends to increase with this change in posture.
.---1- 1. (,u3/s/um2)
Volume
flow
------ - --- --,I
I
IT
iv
v
a
0.60 0.40-
*
a
*,
0.20-
I.
20%
0%
40%
60%
80%
100%
120%
Ankle to brachial pressure index
0
sitting
M
supine
0
med
sit
med sup
FIGURE 6. Scatterplot of volume flow per square micrometer
of nailfold skin in sitting and supine positions plotted against
median ankle-to-brachial index value of each group. Med sit,
median sitting; med sup, median supine.
228
Circulation Vol 85, No 1 January 1992
TABLE 3. Patients With and Without Pain Relief on Dependency
Relief
p
No relief
ABI (%)
32
NS
35
Supine position
16
Density (mm-2)
NS
27
Diameter (gm)
8.5
<0.05
5.0
RBCV (gm/sec)
94
<0.05
143
Peak RBCV (gm/sec)
95.5
<0.05
171
Volume flow
0.029
NS
0.099
(mm3/sec/mm2)
Sitting position
Density (mm-2)
Diameter (gtm)
RBCV (,um/sec)
Peak RBCV (,um/sec)
Volume flow
43
8.0
51
62
NS
NS
NS
NS
53.5
7.0
37
87
(mm3/sec/mm2)
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
0.113
NS
0.072
Capillary microscopic data obtained in the supine and sitting
positions of patients with (n = 15) and without (n =36) relief of pain
on dependency and with ABI <50%. All values are presented as
medians.
ABI, ankle-to-brachial systolic blood pressure index; RBCV, red
blood cell velocity.
These findings indicate that in subjects with normal
or limited compromised circulation, the dependencyinduced arteriolar vasoconstriction is still intact, but
that this mechanism is disturbed in patients with
severe ischemia. This disturbance is likely to be local
in origin, but it is unknown whether it is caused by
diminished contractile properties of the smooth muscle cells in the arteriolar wall or by disturbances in
local reflex mechanisms.
It is an interesting observation that in both the
asymptomatic subjects and the patients with mild or
severe peripheral vascular disease, RBC-perfused
capillary density increased significantly on dependency, thereby enlarging the surface area for exchange. This increase in density can possibly be
explained by a rise in transmural pressure because
the effective perfusion pressure does not change on
dependency. In asymptomatic subjects and in patients with mild disease, the increase in density is
associated with arteriolar constriction; therefore, the
rise in capillary transmural pressure, if any, probably
results from the increase in venous pressure. The
transmural pressure increase on dependency is also
indicated by the tendency of the capillary diameter to
increase under these circumstances.
The observation that in not all patients with rest
pain, dependency leads to pain relief (despite the
fact that capillary density and blood flow increase
when changing to the sitting position) may be explained by the progressed state of the disease in
several of these patients. In some of them, rest pain
was present in both the supine and sitting positions;
although they reported having experienced pain relief on dependency in the past. This is of important
clinical diagnostic value because it indicates a terminal stage of the disease in which the nutritional
circulation will be insufficient in either position,
inevitably resulting in tissue necrosis. The same can
be said concerning severely diseased patients showing absence of reactive hyperemic response (i.e., loss
of flow reserve). Further reduction of arterial perfusion pressure with progression of the disease will not
lead to compensatory microvascular dilatation and
will thus induce tissue loss.
In this study, postural microvascular reactivity in
patients with noninsulin-dependent diabetes mellitus
could not be discerned from nondiabetics. It is also
possible that in both types of patients, atherosclerosis
is the dominating disease.
It is concluded that in the clinic, posturally induced
arteriolar vasoconstriction leading to diminished leg
perfusion on dependency can be assessed with the
use of capillary video microscopy. The findings in this
study show that patients with limb-threatening ischemia (ABI <20%) show disturbed arteriolar vasoconstriction resulting in enhanced capillary recruitment and increased nutritive RBCV. The relief of
pain on dependency may be explained by an increase
in RBC-perfused capillary density, which enlarges
the surface area for exchange rather than an increase
in capillary perfusion.
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KEY WORDS * ischemia * capillary microscopy * posture
vasoconstriction
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Capillary recruitment and pain relief on leg dependency in patients with severe lower
limb ischemia.
D T Ubbink, M J Jacobs, D W Slaaf, G J Tangelder and R S Reneman
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Circulation. 1992;85:223-229
doi: 10.1161/01.CIR.85.1.223
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