Rarefaction of Skin Capillaries in Borderline Essential
Hypertension Suggests an Early Structural Abnormality
Tarek F.T. Antonios, Donald R.J. Singer, Nirmala D. Markandu,
Peter S. Mortimer, Graham A. MacGregor
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Abstract—We recently showed that rarefaction of skin capillaries in the dorsum of the fingers of patients with essential
hypertension is due to the structural (anatomic) absence of capillaries rather than functional nonperfusion. It is not
known whether this rarefaction is primary (ie, antedates the onset of hypertension) or secondary (ie, as a consequence
of sustained and prolonged elevation of blood pressure [BP]). The aim of the present investigation was to study skin
capillary density in a group of patients with mild borderline hypertension to assess whether rarefaction antedates the
onset of sustained elevation of BP. The study group included 18 patients with mild borderline hypertension (mean supine
BP, 136/83 mm Hg), 32 normotensive controls (mean BP, 126/77 mm Hg), and 45 patients with established essential
hypertension (mean BP, 156/98 mm Hg). The skin of the dorsum of the fingers was examined by intravital capillary
videomicroscopy before and after venous congestion at 60 mm Hg for 2 minutes. Patients with borderline essential
hypertension had the lowest resting capillary density when compared with normotensive controls and patients with
established hypertension. Maximal capillary density with venous congestion in the borderline group remained the
lowest. The study confirmed that patients with borderline essential hypertension have skin capillary densities that are
equally low as or even lower than patients with established hypertension. Both groups had significantly lower capillary
densities than normal controls. One explanation for the results is that capillary rarefaction may be due to an early
structural abnormality in essential hypertension. (Hypertension. 1999;34:655-658.)
Key Words: hypertension, essential n microcirculation n capillaries n blood vessels, rarefaction
R
arefaction of capillaries and arterioles is now a wellestablished abnormality that occurs in many tissues in
patients with human essential hypertension.1–5 We recently
showed that the rarefaction of capillaries in the skin of the
dorsum of the fingers in patients with essential hypertension
is due to the structural (anatomic) absence of capillaries
rather than nonperfusion or functional rarefaction.1 It is not
yet known whether this rarefaction is primary (ie, antedates
the onset of hypertension) or secondary (ie, occurring as a
consequence of prolonged elevation of blood pressure).
Previous studies indicated that rarefaction may occur in
patients with borderline essential hypertension and only
intermittent elevations of blood pressure.6 The use of the term
“borderline hypertension” has been most confusing. According to the 1999 World Health Organization–International
Society of Hypertension (WHO-ISH) guidelines for the
management of hypertension,7 which are based on the sixth
report of the United States’ Joint National Committee (JNCVI),8 the definition of borderline mild hypertension is a
systolic blood pressure (SBP) between 140 and 149 mm Hg
and a diastolic blood pressure (DBP) between 90 and
94 mm Hg. A more physiologically oriented definition of
borderline hypertension is a state in which blood pressures
have been documented within the normal range (ie, ,140/
90 mm Hg), but on at least 2 occasions, they have been
documented as above that level.9 The aim of this study was to
assess whether rarefaction of skin capillaries in patients with
essential hypertension is an early abnormality that antedates
the onset of the sustained elevation of blood pressure or if it
is a secondary phenomenon that occurs as a consequence of
the raised blood pressure.
Methods
Subjects
Subjects consisted of 18 patients with mild borderline essential
hypertension (whose blood pressures have been documented within
the normal range [,140/90 mm Hg] but on at least 2 occasions were
above that level but ,150/95 mm Hg), 45 patients with previously
untreated, established essential hypertension (SBP.160 mm Hg
and/or DBP.95 mm Hg), and 32 normotensive controls
(SBP,140 mm Hg and DBP,85 mm Hg on repeated measure-
Received March 18, 1999; first decision March 25, 1999; revision accepted May 24, 1999.
From the Blood Pressure Unit (T.F.T.A., N.D.M., G.A.M.), Dermatology Unit, Department of Medicine (P.S.M.), and the Clinical Pharmacology Unit,
Department of Pharmacology and Clinical Pharmacology (T.F.T.A., D.R.J.S.), St. George’s Hospital Medical School, London, U.K.
Correspondence to Dr Tarek F.T. Antonios, Clinical Pharmacology Unit, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE,
U.K. E-mail [email protected]
T.F.T.A. designed the study, recruited subjects, collected and analyzed the data, and wrote the article. D.R.J.S. helped write the article. N.D.M. helped
recruit subjects and take measurements. P.S.M. and G.A.M. were responsible for overall supervision and also helped write the article.
© 1999 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
655
656
Hypertension
October 1999
Baseline Characteristics of Study Subjects
Variable
Borderline
Hypertensive
Patients
(n518)
Age, y
45.463.4
Gender, men/women
Established
Hypertensive
Patients
(n545)
Normotensive
Controls
(n532)
476061.8
51.562.1
P value by
ANOVA
0.179
11/7
29/16
Weight, kg
76.963.7
84.563.1
74.262.2
Height, cm
170.062.6
171.961.5
171.461.5
0.787
Body mass index, kg/m2
Hip/waist ratio
18/14
0.314
26.161.0
28.660.9†
25.260.6
0.009
119.563.0
113.661.8*
120.262.7
0.065
Blood pressure, mm Hg
Supine
136/8363/1†
156/9862/1‡
126/7762/1
,0.0001
Standing
136/8863/2†
15210263/2‡
122/8062/1
,0.0001
10161§
11861§
9461
,0.0001
Supine
7463†
7562‡
6862
0.017
Standing
7663†
8162‡
7362
0.006
Mean
Pulse, bpm
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Room temperature, °C
30.6
30.4
31.2
0.89
Skin temperature, °C
24.2
24.2
24.4
0.39
Mean capillary density, No. per field (0.68 mm2)
Before venous congestion
5764‡
5863§
7663
,0.0001
With venous congestion
6364§
7063§
9363
,0.0001
Values are expressed as mean6SEM.
*P,0.05, †P,0.01, ‡P,0.005, §P,0.0001, by Bonferroni’s post hoc test vs normotensive controls.
ments). All patients were assessed in the Blood Pressure Unit of St
George’s Hospital Medical School, and they were included in the
study if no underlying cause for their high blood pressure was found.
Patients with a history of connective tissue disease, diabetes mellitus,
or skin diseases or who were on vasoactive drugs were excluded
from the study. The protocol was approved by the local Ethics
Committee of St. George’s Hospital. Written informed consent was
obtained from each patient.
Intravital Capillaroscopy
All capillaroscopy studies were done in parallel. Subjects were
studied in the morning between 9 and 11 AM after an overnight fast.
The capillaroscopy studies were performed in a temperaturecontrolled laboratory (21°C to 24°C) after the study subjects had
rested for at least 20 minutes in the semisupine position. Room
temperature was monitored before and during the studies and, if
necessary, the temperature was adjusted by the use of fan heaters or
air conditioning. Patients were seated with the left forearm and hand
supported at the heart level. Both the hand and the forearm rested on
a splint surrounded by a vacuum pillow (a specially constructed
pillow filled with polyurethane foam that can be molded to any
desired shape by creating a vacuum) to restrict movement. Videomicroscopy with an epi-illuminated microscope containing a 100-W
mercury vapor lamp light source, a PL 6.3/0.2 objective (Wild-Leitz
type 307 to 143.004, Leica UK Ltd), and a final magnification of
3196 was used. Microscopic images were recorded with a chargecoupled device camera (Hitachi; model, CCD HV-725K) and transferred with a videoscaler (VS-1000) and videotimer (For-A VTG 33)
for storage onto a video recorder (Panasonic; model, AUC 7350).
The skin of the dorsum of the middle phalanx of the nondominant
(usually, left) hand was examined. Four microscopic fields
(0.68 mm2 each) centered around an ink spot were recorded continuously for 5 minutes to detect intermittently perfused capillaries.
Still-frame video prints (Sony Multiscan Video-Printer UP-930)
obtained from each recorded field were analyzed offline. The
number of capillaries per field was counted by hand from these prints
and from live playback of the recorded tapes. Skin temperature was
monitored throughout the study with a temperature probe on the
dorsum of the left index finger (YSI Telethermometers). Patients
with cold hands or with Raynaud’s phenomenon were excluded from
the study.
Maximization of Visualized Skin Capillaries
The enhancing effect of venous congestion on the visualization of
skin capillaries by videomicroscopy was previously reported.10 We
recently showed that venous congestion maximizes the number of
visible capillaries1 more than reactive hyperemia; it does this by
increasing their red cell content. In this study, a miniature blood
pressure cuff was applied to the base of the left middle finger and the
cuff was then inflated and maintained at 60 mm Hg for 2 minutes;
further images were recorded with the use of 1 of the 4 microscopic
fields chosen at random.
Blood Pressure and Heart Rate
Blood pressure was measured with a semiautomatic ultrasound
sphygmomanometer (ArterioSonde, Roche) with an appropriate cuff
size. Supine and standing BP were taken as the mean of 3 readings
obtained at 1- to 2-minute intervals with the patient in the corresponding position.
Blood Analysis
Venous blood was taken without stasis after the patient had been
sitting upright for 10 minutes. Variables measured included serum
electrolytes, urea, creatinine, uric acid, glucose, total cholesterol,
triglycerides, and full blood count.
Statistical Analysis
All results are given as means6SEM. The data were processed by
StatView 5.0 (SAS Institute Inc). ANOVA and Bonferroni’s post hoc
tests were used to compare groups. P,0.05 was considered statistically significant.
Antonios et al
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Skin capillary density before and after venous congestion in 18
patients with borderline hypertension, 45 patients with untreated
essential hypertension, and 32 normotensive controls.
Results
The Table shows baseline characteristics and capillaroscopic
data in the study subjects before and after 2 minutes of venous
congestion at 60 mm Hg. A significant reduction (30%)
occurred in mean capillary density at baseline (before venous
congestion) in the borderline and established hypertensive
subjects compared with the normotensive controls (5764 and
5863 compared with 7663 per 0.68 mm2, respectively;
P,0.0001) (Figure). With venous occlusion, capillary density increased significantly in both hypertensive groups (36%
in the borderline group and 30% in the established hypertensive subjects); however, maximal capillary density was
significantly lower in both groups as compared to normotensive controls (6365, 7063, and 9363/field, respectively;
P,0.0001) (Figure).
Early Capillary Rarefaction in Hypertension
657
Our study also agreed with the results of Noon et al,12 who
found that people with high blood pressure whose parents
also had high blood pressure had fewer capillaries on the
dorsum of their fingers, suggesting that defective angiogenesis may be an etiological component in the inheritance of
high blood pressure.12 Also, Draaijer et al13 found that
sodium-resistant borderline hypertensives had a possible
structural reduction in nailfold skin capillary density when
compared with both sodium-sensitive and control subjects.
In the Tecumseh blood pressure study, Julius et al14 found
that subjects with borderline hypertension had elevated minimal forearm vascular resistance (measured during maximal
dilatation), indicating a structural decrease in the crosssectional area of the vascular bed (rarefaction), and a decreased peak Doppler E/A ratio on echocardiography (evidence of diastolic dysfunction).
A number of studies demonstrated that an elevated cardiac
output frequently occurs in patients with borderline hypertension15–17 and, as the cardiac output returns to normal levels, a
state of sustained DBP elevation is demonstrable.18,19 In
actuality, patients with borderline hypertension may have
elevated, normal, or reduced cardiac output, and with advancing age, the cardiac output declines in these patients.20
Recently, a number of studies showed that individuals with
borderline hypertension, even in the adolescent age range,
may have a relative enlargement of the left ventricle as
compared with normotensive patients.21 Primary structural
rarefaction of capillaries may support the theory of reduced
angiogenesis and diminished microvascular growth in primary hypertension.
In conclusion, the study demonstrates significantly low skin
capillary densities in patients with mild intermittent borderline
essential hypertension, equivalent to the densities in patients
with established hypertension. This suggests that rarefaction
may be an early event in the development of hypertension and
not secondary to the sustained elevation of blood pressure. The
study also strongly suggests that much of the reduction in
capillary density in hypertension is due to the anatomic absence
of capillaries, rather than a functional reduction.
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human essential hypertension, with only mild intermittent
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Rarefaction of Skin Capillaries in Borderline Essential Hypertension Suggests an Early
Structural Abnormality
Tarek F. T. Antonios, Donald R. J. Singer, Nirmala D. Markandu, Peter S. Mortimer and
Graham A. MacGregor
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Hypertension. 1999;34:655-658
doi: 10.1161/01.HYP.34.4.655
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1999 American Heart Association, Inc. All rights reserved.
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