Impaired Skin Capillary Recruitment in Essential
Hypertension Is Caused by Both Functional and Structural
Capillary Rarefaction
Erik H. Serné, Reinold O.B. Gans, Jan C. ter Maaten, Geert-Jan Tangelder,
Ab J.M. Donker, Coen D.A. Stehouwer
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Abstract—Capillary rarefaction occurs in many tissues in patients with essential hypertension and may contribute to an
increased vascular resistance and impaired muscle metabolism. Rarefaction may be caused by a structural (anatomic)
absence of capillaries, functional nonperfusion, or both. The aim of this study was to assess the extent of structural
versus functional capillary rarefaction in the skin of subjects with essential hypertension. We examined skin capillary
density with video microscopy before and during maximization of the number of perfused capillaries by venous
congestion (structural capillary number) and before and during postocclusive reactive hyperemia (capillary recruitment,
which may have a structural and/or functional basis). The study group was composed of 26 patients with never-treated
essential hypertension and 26 normotensive control subjects. In both groups, intermittently perfused capillaries in the
resting state were an important functional reserve for recruitment during postocclusive hyperemia. Recruitment of
perfused capillaries during postocclusive reactive hyperemia was decreased in the hypertensive subjects compared with
normotensive control subjects (47.9⫾6.8 versus 55.3⫾8.2 capillaries/mm2, respectively; P⬍0.01). During venous
occlusion, maximal capillary density was significantly lower in the hypertensive subjects than in the control subjects
(52.5⫾6.6 versus 57.2⫾8.6 capillaries/mm2, respectively; P⬍0.05), suggesting structural rarefaction. However, in the
hypertensive subjects compared with the normotensive subjects, a smaller proportion of the maximal number of
capillaries was perfused during postocclusive hyperemia (91.6⫾7.5% versus 97.2⫾2.7%, respectively; P⬍0.05),
suggesting an additional functional impairment of capillary recruitment. If the difference in capillary numbers during
venous congestion (⬇4.6 capillaries/mm2) truly reflects the structural difference between the normotensive and
hypertensive subjects, then, at most, 62% (4.6/7.4⫻100%) of the difference in capillary numbers during postocclusive
hyperemia (⬇7.4 capillaries/mm2) can be explained by structural defects, and at least 38% can be explained by
functional defects. In conclusion, in patients with essential hypertension, recruitment of perfused capillaries is impaired,
which can be explained by both functional and structural rarefaction. (Hypertension. 2001;38:238-242.)
Key Words: hypertension, essential 䡲 microcirculation 䡲 capillaries 䡲 vascular resistance
A
pressure and flow patterns, may have consequences not only
for peripheral vascular resistance but also for muscle perfusion and metabolism.11,12
Direct intravital video microscopy, a dynamic method for
studying skin capillaries,13–15 has recently been used to
investigate whether capillary rarefaction in essential hypertension is caused by a structural (anatomic) absence of
capillaries or by functional nonperfusion.1 Because this technique depends on the presence of erythrocytes inside capillaries for their identification, this method has the potential for
missing nonperfused capillaries. To expose more nonperfused
capillaries, both venous congestion and reactive hyperemia
after arterial occlusion have been used.1,8,11,12,15–17 Whereas
decreased number of capillaries and arterioles, or socalled microvascular rarefaction, is a well-established
abnormality that occurs in many tissues in patients with
essential hypertension.1– 4 Experimental5–7 and human1,8 studies suggest that this microvascular rarefaction contributes to
an increase in vascular resistance and antedates the onset of
sustained hypertension.8,9 In addition, decreased capillary
density affects the spatial pattern of flow in the microvascular
bed, causing a nonuniform distribution of blood flow among
exchange vessels.5 Changes in capillary perfusion have been
shown to influence skeletal muscle metabolism (ie, oxygen
uptake and insulin-mediated glucose uptake) in the rat hindlimb.10 Hence, microvascular rarefaction, by affecting both
Received July 10, 2000; first decision September 5, 2000; revision accepted February 14, 2001.
From the Department of Medicine, Academic Hospital (E.H.S., A.J.M.D., C.D.A.S.), the Department of Physiology (G.-J.T.), and the Institute for
Cardiovascular Research (E.H.S., G.-J.T., A.J.M.D, C.D.A.S.), Vrije Universiteit, Amsterdam, The Netherlands; and the Department of Medicine,
University Hospital Groningen (R.O.B.G., J.C.t.M.), Groningen, The Netherlands.
Reprint requests to Dr Coen D.A. Stehouwer, Department of Medicine, Academic Hospital Vrije Universiteit, De Boelelaan 1117, 1007 MB,
Amsterdam, The Netherlands. E-mail [email protected]
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
238
Serné et al
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peak capillary density during venous congestion is thought to
depend mainly on the anatomic number of capillaries,1,15
postocclusive reactive hyperemia may be used to detect
functional recruitment of initially nonperfused capillaries,11,12,15 which reflects both functional and structural
factors.
By use of these techniques, a recent study demonstrated
that both capillary density in the resting state and peak
capillary density during venous congestion were significantly
decreased in hypertensive subjects. In addition, postocclusive
reactive hyperemia caused a decrease in the number of
perfused capillaries rather than recruitment of nonperfused
capillaries in both normotensive and hypertensive subjects.1
These findings led to the conclusion that the reduction in
capillary density in hypertensive subjects was caused by a
structural absence of capillaries. In contrast, we11,12,16 and
others17 have observed recruitment of initially nonperfused
capillaries during postocclusive reactive hyperemia in both
normotensive and hypertensive subjects. In addition, capillary recruitment has been shown to be decreased in hypertensive subjects, whereas capillary density in the resting state
was similar between normotensive and hypertensive subjects.12,15 Moreover, in normotensive and hypertensive subjects, capillary recruitment during postocclusive reactive
hyperemia was inversely associated with blood pressure.11,12
An explanation for these apparent discrepancies may be a
methodological difference in defining capillary recruitment.
Capillaries work on a “rota system”; ie, some are temporarily
perfused, whereas others are temporarily shut down,15 causing temporal heterogeneity in capillary perfusion. During
direct intravital microscopy without dyes, the open time, ie,
the time that capillaries are filled with erythrocytes, varies
greatly among different capillaries in the same visual field.
Some capillaries seem to be continuously filled with erythrocytes, whereas others are intermittently perfused. In 1
study,1 capillary density in the resting state was determined
by counting for 5 minutes to presumably detect all intermittently and continuously perfused capillaries; however, we
only counted capillaries that were continuously perfused
during a short (15-second) period,11,12,16 because intermittently perfused capillaries may be an important functional
reserve that can be recruited during postocclusive reactive
hyperemia.
The aim of the present study was to investigate whether
methodological differences in determining capillary density
in the resting state could explain these apparent discrepancies
in the literature. In addition, we investigated the hypothesis
that postocclusive reactive hyperemia may lead to an increase
in the number of perfused capillaries (capillary recruitment)
by prolonging the integrated open time of capillaries that are
intermittently perfused in the resting state. Finally, we assessed the extent of structural versus functional capillary
rarefaction in explaining the defects of capillary recruitment
in the skin of subjects with essential hypertension.
Methods
Subjects
Twenty-six nondiabetic subjects with never-treated essential hypertension and 26 normotensive healthy control subjects matched for
Capillary Rarefaction in Essential Hypertension
TABLE 1.
239
Characteristics of the Study Population
Hypertensive
Subjects
Normotensive
Subjects
Total, n
26
26
Male, n
15
15
Age, y
49.1⫾10.8
49.1⫾10.4
Body mass index, kg/m2
27.9⫾4.9
25.1⫾2.9*
SBP, mm Hg
155⫾9.6
128⫾6.8†
DBP, mm Hg
101⫾8.3
80⫾6.9†
Characteristics
Subjects
Heart rate during daytime, bpm
76⫾11
76⫾7.9
Fasting plasma glucose, mmol/L
5.0⫾0.5
4.8⫾0.4
Fasting serum total cholesterol, mmol/L
5.2⫾0.8
5.3⫾0.9
Fasting HDL cholesterol, mmol/L
1.4⫾0.4
1.5⫾0.4
Fasting serum triglycerides, mmol/L
1.4⫾0.7
1.2⫾0.9
Values are mean⫾SD. SBP indicates systolic blood pressure; DBP, diastolic
blood pressure.
*P⬍0.05 and †P⬍0.001 for hypertensive vs normotensive subjects.
age and gender participated in the present study (Table 1). All were
white and nonsmokers. The inclusion criteria for the hypertensive
subjects were as follows: blood pressure as determined by triplicate
office measurement ⬎140/90 mm Hg and (for ethical reasons)
⬍180/110 mm Hg, age 30 to 70 years, normal fasting glucose
according to the criteria of the American Diabetes Association,18 and
no signs or symptoms of cardiovascular or other concomitant
disease. Secondary forms of hypertension were excluded by medical
history and standard laboratory tests. The study protocol was
approved by the local ethics committee, and informed consent was
obtained from each subject.
Intravital Capillaroscopy
The capillaroscopy studies were conducted in a standardized manner
by using capillary microscopy equipment as previously described in
more detail.11,12,16
Reactive hyperemia after 4 minutes of arterial occlusion was used
to assess functional recruitment of capillaries.11,12,16,17 A visual field
of 1 mm2 was recorded before and after arterial occlusion with a
digital cuff (Digit cuff, Hokanson), and the images were stored on
videotape. The number of capillaries was counted offline by a single
experienced investigator (E.H.S.) from a freeze-framed reproduction
of the videotape and from the running videotape if it was uncertain
whether a capillary was present or not. The investigator counting the
capillaries was blinded to the hypertensive status and blood pressure
data of the study subjects. Capillary density in the resting state was
counted during a 15-second period and a 3-minute period. During the
15-second period, only continuously perfused capillaries were
counted, although intermittently perfused capillaries were also visible. During the 3-minute period, all (continuously and intermittently)
perfused capillaries were counted. Directly after release of the cuff,
the number of continuously perfused capillaries was counted. (The
increase in capillary number occurs within a few seconds.) Capillary
density was defined as the number of erythrocyte-perfused capillaries per square millimeter of nailfold skin. This procedure was then
repeated by using a visual field adjacent to the first visual field. Data
concerning capillary densities are the mean of these 2 measurements.
Percentage capillary recruitment was assessed by dividing the
increase in capillary density during postocclusive reactive hyperemia
by the capillary density in the resting state. (Note that this procedure
yields 2 different estimates of percentage capillary recruitment,
depending on whether capillary density in the resting state is defined
by counting for 15 seconds or for 3 minutes.) The day-to-day
coefficient of variation of percentage capillary recruitment during
240
Hypertension
August 2001
TABLE 2. Capillaroscopy Data in Hypertensive and
Normotensive Subjects
Hypertensive
Subjects
Capillaroscopy Data
Normotensive
Subjects
During reactive hyperemia after arterial
occlusion
Skin temperature, °C
31.3⫾0.9
31.5⫾0.9
39.3⫾5.0
38.8⫾4.7
45.8⫾4.9‡§
52.6⫾5.7§
47.9⫾6.8‡
55.3⫾8.2
8.5⫾2.4㛳
16.7⫾4.9
2.0⫾2.5
2.7⫾3.4
21.7⫾5.8㛳
43.1⫾10.9
4.2⫾5.2
4.8⫾5.9
Capillary density in the resting state
15-s count,* capillaries/mm2
2
3-min count,† capillaries/mm
Peak capillary density, capillaries/mm2
Absolute increase from the resting state
15-s count,* capillaries/mm2
2
3-min count,† capillaries/mm
Capillary recruitment
15-s count,* %
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3-min count,† %
During venous congestion
Skin temperature, °C
31.2⫾0.9
31.2⫾0.9
Peak capillary density, capillaries/mm2
52.5⫾6.6¶#
57.2⫾8.6**
Capillary density in 26 normotensive subjects (filled bars) and 26
hypertensive subjects (open bars) in the resting state, counted
for 15 seconds and 3 minutes, and during postocclusive reactive hyperemia and venous congestion. Probability values concern differences between normotensive and hypertensive subjects. *Differences between different procedures in normotensive
and hypertensive subjects.
Results
for both groups). Both postocclusive reactive hyperemia and
venous congestion increased the number of perfused capillaries. The increase in capillary density from the resting state
with reactive hyperemia was significant in both the normotensive (16.7⫾4.9 capillaries/mm2, P⬍0.0001) and the hypertensive (8.5⫾2.4 capillaries/mm2, P⬍0.0001) subjects
when the 15-second baseline count was used. When the
3-minute baseline count was used, the increase in capillary
density was also significant in both the normotensive
(2.7⫾3.4 capillaries/mm2, P⬍0.001) and the hypertensive
(2.0⫾2.5 capillaries/mm2, P⬍0.001) subjects. From the video
image, it was obvious that part of the perfused capillaries
visible during postocclusive reactive hyperemia, directly after
release of the arterial occlusion, consisted of capillaries that
were intermittently perfused in the resting state.
Venous congestion was associated with a significantly
greater capillary number than was postocclusive reactive
hyperemia in both the hypertensive subjects (P⬍0.01) and the
normotensive subjects (P⬍0.05). The number of capillaries
perfused during postocclusive reactive hyperemia (expressed
as a percentage of the maximal capillary number after venous
congestion) was significantly lower in the hypertensive than
in the normotensive subjects (91.6⫾7.5% versus 97.2⫾2.7%,
respectively; P⬍0.05). The number of capillaries perfused in
the resting state (counted for 3 minutes and expressed as a
percentage of the maximal capillary number after venous
congestion) was also significantly lower in the hypertensive
than in the normotensive subjects (87.9⫾6.5% versus
93.1⫾2.6%, respectively; P⬍0.05). If the difference in capillary numbers during venous congestion (⬇4.6⫾8.6 capillaries/mm2, Table 2) truly reflects the structural difference
between the normotensive and hypertensive subjects, then at
most ⬇62% (4.6/7.4⫻100%) of the difference in capillary
numbers during postocclusive hyperemia (⬇7.4⫾8.1 capillaries/mm2, Table 2) can be explained by structural defects,
and at least 38% can be explained by functional defects.
Table 2 and the Figure show the capillaroscopy data. A
significantly larger number of perfused capillaries could be
detected when capillary density in the resting state was
counted for 3 minutes instead of only 15 seconds (P⬍0.001
A reduction in the density of capillaries (rarefaction) has been
demonstrated in many tissues in patients with essential
Values are mean⫾SD.
*Continuously perfused capillaries.
†Continuously plus intermittently perfused capillaries.
‡P⬍0.01, 㛳P⬍0.001, and ¶P⬍0.05 for hypertensive vs normotensive
subjects after adjustment for body mass index; §P⬍0.001 for 15-s count vs
3-min count; and #P⬍0.01 and **P⬍0.05 for venous occlusion vs postocclusive reactive hyperemia.
postocclusive reactive hyperemia was 8.3⫾4.9%, as determined in 9
subjects on 2 occasions.
Fifteen minutes after performing the postocclusive reactive hyperemia procedure, we applied venous congestion, with the digital cuff
inflated to 60 mm Hg for 60 seconds, to expose a maximal number
of nonperfused capillaries. Using the same visual fields that were
used during postocclusive reactive hyperemia, the capillaries were
counted in the 60-second recordings. The day-to-day coefficient of
variation of peak capillary density during venous congestion was
9.5⫾7.1%, as determined in 9 subjects on 2 occasions. Venous
congestion at 60 mm Hg for 120 instead of 60 seconds did not
increase the number of visible capillaries further (determined in 9
healthy subjects, data not shown).
Statistical Analysis
Data are expressed as mean⫾SD, unless stated otherwise. Comparison of normotensive and hypertensive subjects was performed with
the Student’s t test or a nonparametric variant in case of a nonnormal
distribution of the variables. MANOVA was used to compare
microvascular measurements between the groups after adjustment
for differences in body mass index. A paired Student’s t test was
used to compare capillary densities before and during postocclusive
reactive hyperemia and venous congestion. A 2-tailed value of
P⬍0.05 was considered significant. All analyses were performed on
a personal computer using the statistical software package SPSS,
version 9.0.
An expanded Methods section can be found in an online data
supplement available at http://www.hypertensionaha.org.
Discussion
Serné et al
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
hypertension.1– 4 This rarefaction, by affecting both pressure
and flow patterns, may have consequences for peripheral
vascular resistance1,11,12,16 and for muscle perfusion and
metabolism.10 –12
The present study demonstrates that the number of capillaries perfused in the resting state was reduced in the
hypertensive subjects compared with the normotensive subjects when both continuously and intermittently perfused
capillaries were counted for 3 minutes. No difference in
capillary density could be detected when only the number of
capillaries continuously perfused in the resting state was
counted for 15 seconds. In the hypertensive subjects, peak
capillary density during postocclusive reactive hyperemia
was decreased. During postocclusive reactive hyperemia, a
substantial part of the capillaries perfused directly after
release of the arterial occlusion consisted of capillaries that
were intermittently perfused in the resting state. Therefore,
capillaries intermittently perfused in the resting state seem to
be an important functional reserve that can be recruited
during postocclusive reactive hyperemia. The present study
confirms previous findings that the maximal number of
capillaries seen with venous congestion exceeds that seen
with postocclusive reactive hyperemia and is lower in hypertensive subjects, suggesting a structural reduction in capillary
density.1,15 In the hypertensive subjects compared with the
normotensive subjects, however, a smaller proportion of the
maximal number of capillaries was perfused in the resting
state and during postocclusive reactive hyperemia, thus suggesting an additional functional impairment of capillary
perfusion and capillary recruitment in these patients.
Our results strongly suggest that the discrepant findings
from earlier studies1,11,12,15–17 can be explained by the different definitions of capillary density in the resting state and
during postocclusive reactive hyperemia used in these studies. From the video image, it was obvious that part of the
perfused capillaries visible during postocclusive reactive
hyperemia, directly after release of the arterial occlusion,
consisted of capillaries that were intermittently perfused in
the resting state. This suggests that capillaries that are
intermittently perfused in the resting state may be an important reserve that can be recruited during postocclusive reactive hyperemia. Therefore, the reduced number of capillaries
in the resting state during the 3-minute count and during
postocclusive reactive hyperemia in the hypertensive subjects
may be due to a decreased number of intermittently perfused
capillaries. These abnormalities do not simply reflect the
functional consequences of a structural absence of capillaries,
because even though the maximal number of capillaries in the
hypertensive subjects, compared with the normotensive subjects, should have been sufficient to allow the same absolute
or relative numbers of capillaries to be perfused in the resting
state, the hypertensive subjects demonstrated a reduced absolute and relative (absolute number expressed as a percentage of maximal skin capillary density) number of perfused
capillaries in the resting state. Likewise, peak capillary
density during postocclusive reactive hyperemia (expressed
as a percentage of maximal skin capillary density) was lower
in the hypertensive subjects, although again the maximal
number of capillaries should have allowed the absolute and
Capillary Rarefaction in Essential Hypertension
241
relative increase in capillary number during postocclusive
reactive hyperemia to be similar in both groups. These data
are consistent with a true functional impairment of capillary
perfusion and capillary recruitment in the hypertensive subjects. If the difference in capillary numbers during venous
congestion truly reflects the structural difference between the
normotensive and hypertensive subjects, then at least 38% of
the difference in capillary numbers observed during postocclusive hyperemia can be explained by functional defects.
The mechanisms that are responsible for the functional
impairment of capillary recruitment during postocclusive
reactive hyperemia in essential hypertension remain elusive.
Postocclusive reactive hyperemia that is used to induce
capillary recruitment is thought to be determined at the level
of the small arterioles19 and to be independent of the
autonomic nervous system.20,21 The myogenic response to a
change in intravascular pressure is postulated to be the prime
stimulus determining peak hyperemia, whereas local metabolic factors act in a synergistic role to prolong the response.21–23 An occlusion of 4 minutes, as applied in the
present study, is thus expected to cause vasodilatation not
only through the mechanism of myogenic vasodilatation but
also through an additional metabolic vasodilatatory stimulus.17,24 The role of the endothelium in modulating the
myogenic response is controversial,25 but in hypertension,
arteriolar vasomotor responses to changes in intraluminal
pressure are due to at least 2 mechanisms: one that is intrinsic
to vascular smooth muscle (ie, myogenic) and a second that
involves the endothelium.26 Therefore, an increased sensitivity to vasoconstrictor stimuli27 or a reduced endotheliumdependent vasodilatation28 of small precapillary arterioles
may be a mechanism explaining the impaired recruitment of
capillaries in essential hypertension. In agreement, a progressive decrease in vasodilating capacity from low to high blood
pressure in both muscle and skin vessels has been demonstrated during postocclusive reactive hyperemia.29 It should
be realized, however, that the intermittent character of capillary flow and capillary flow distribution is determined not
only by the precapillary arteriolar network but also by
characteristics of the capillary network itself.30
At present, it is unclear whether venous occlusion at
60 mm Hg for 1 minute allows visualization of a truly
maximal number of skin capillaries during intravital video
microscopy. One study suggested that this procedure, maintained for 2 minutes, is the most effective method for
maximizing the number of capillaries.15 Venous congestion
increases the venous back pressure, which allows the passive
trapping of red cells in nonperfused and intermittently perfused capillaries, enhancing the visualization of red blood
cell–filled capillaries. Prolonged venous occlusion, on the
other hand, could increase precapillary resistance through the
venoarteriolar response, and this effect may be even more
pronounced in subjects with essential hypertension.31 This
may explain why, in our hands, 2 minutes instead of 1 minute
of venous congestion did not lead to a further increase in
capillary density. Nevertheless, it should be realized that,
with direct intravital video microscopy, only perfused capillaries are visible and that the actual structural capillary
number may be underestimated.
242
Hypertension
August 2001
In conclusion, the present study demonstrates that capillaries that are intermittently perfused in the resting state are an
important reserve that can be recruited during postocclusive
reactive hyperemia. In essential hypertension, recruitment of
perfused capillaries is impaired, which can be explained by
functional and structural rarefaction for ⬇38% and ⬇62%,
respectively.
Acknowledgments
This study was supported by grants from the Diabetes Fonds
Nederland (Drs Stehouwer and Serné) and the Dutch Kidney
Foundation (Dr ter Maaten).
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Hypertension. 2001;38:238-242
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