Download Retinal Capillary Blood Flow

Retinal Capillary Blood Flow
Impaired Increase of Retinal Capillary Blood Flow to
Flicker Light Exposure in Arterial Hypertension
Martin Ritt, Joanna M. Harazny, Christian Ott, Ulrike Raff, Philipp Bauernschubert, Marina Lehmann,
Georg Michelson, Roland E. Schmieder
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Abstract—We hypothesized that the increase of retinal capillary blood flow (RCF) to flicker light exposure is impaired in
subjects with arterial hypertension. In 146 nondiabetic untreated male subjects with (n⫽50) or without (n⫽96) arterial
hypertension, RCF was measured before and after flicker light exposure noninvasively and in vivo using scanning laser
Doppler flowmetry. In addition, in a subgroup of 28 subjects, the change of RCF to flicker light exposure was again assessed
during parallel infusion of nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA). The increase of RCF to
flicker light exposure was lower in patients with untreated hypertension compared with normotensive subjects when expressed
in absolute terms (7.69⫾54 versus 27.2⫾44 AU; P adjusted⫽0.013) or percent changes (2.95⫾14 versus 8.33⫾12%; P
adjusted⫽0.023). Systolic (␤⫽⫺0.216; P⫽0.023) but not diastolic blood pressure (␤⫽⫺0.117; P⫽0.243) or mean arterial
pressure (␤⫽⫺0.178; P⫽0.073) was negatively related to the percent change of RCF to flicker light exposure, independently
of other cardiovascular risk factors. In the subgroup of 28 subjects, the increase of RCF to flicker light exposure was similar
at baseline and during parallel infusion of L-NMMA when expressed in absolute terms (20.0⫾51 versus 22.6⫾56 AU;
P⫽0.731) or percent changes (7.12⫾16 versus 8.29⫾18%; P⫽0.607). The increase of RCF to flicker light exposure is
impaired in arterial hypertension. In the subgroup of the total study cohort, nitric oxide was not a major determinant of the
increase of RCF to flicker light exposure. (Hypertension. 2012;60:871-876.)
Key Words: retina 䡲 capillary blood flow 䡲 vasodilatory properties 䡲 nitric oxide 䡲 arterial hypertension
A
rterial hypertension is a major determinant of morbidity
and mortality due to cardiovascular complications.1 Reduction in systolic and diastolic blood pressure levels was found
to reduce and slow the occurrence of cardiovascular events in
subjects with arterial hypertension2; however, blood pressure
levels per se might be unreliable indicators of cardiovascular risk
in the individual subjects. In arterial hypertension, elevated
blood pressure levels lead to structural and functional changes of
blood vessels and organ damage, such as retinopathy, thickening
of carotid arteries, large artery stiffening, left ventricular hypertrophy, and increased urinary albumin excretion, among others.
These subclinical parameters represent intermediate end points
that frequently precede major cardiovascular events and
indicate the need for aggressive medical blood pressure control
in context of individual global cardiovascular risk profile.2
Since the famous work by Keith, Wagener, and Barker,3
several studies have demonstrated the prognostic significance
of retinal vascular alterations for predicting morbidity and
mortality in subjects with arterial hypertension4–6; however,
owing to improvement in patient management, nowadays,
grade 3 and grade 4 hypertensive retinopathy are seldom
observed, and grade 1 and 2 hypertensive retinopathy reveal
low power for predicting cardiovascular events, the classical
classification system of hypertensive retinopathy, dating back
to the aforementioned work,3 has repeatedly been criticized in
the last 2 decades.7,8 In parallel, much research effort has
focused on the evaluation of early retinal alterations in
arterial hypertension as potential new parameters of hypertensive target organ damage and retinopathy.9–11
Impairment of peripheral vasodilatory properties12,13 represent early vascular changes in arterial hypertension. Of
clinical interest, impaired peripheral vasodilatory properties
was found to reveal prognostic significance, with respect to
adverse cardiovascular outcome in subjects with arterial
hypertension.14 Whether vasodilatory properties are impaired
in the retinal vascular bed in subjects with arterial hypertension has not yet been examined. Improvement in imaging
technology nowadays allows assessment of retinal capillary
blood flow noninvasively and in vivo in humans. Moreover,
exposure to flicker light was found to increase capillary blood
flow in the retinal circulation.15 The mechanisms for the
increase of retinal capillary blood flow to flicker light are
incompletely understood, but data in healthy subjects indicate
that nitric oxide might (at least, in part) be involved.16
In the current study, we hypothesized that the increase of
retinal capillary blood flow to flicker light is impaired in
Received February 5, 2012; first decision February 27, 2012; revision accepted June 6, 2012.
From the Department of Nephrology and Hypertension (M.R., J.M.H., C.O., U.R., P.B., M.L., R.E.S.) and the Department of Ophthalmology (G.M.),
University of Erlangen-Nüremberg, Erlangen, Germany; Department of Human Physiology, University of Warmia and Masuria, Olsztyn, Poland (J.M.H.).
Correspondence to Dr Roland E. Schmieder, Clinical Research Center, Department of Nephrology and Hypertension, University of ErlangenNüremberg, Ulmenweg 18, 91054 Erlangen, Germany. E-mail [email protected]
© 2012 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.112.192666
871
872
Hypertension
September 2012
subjects with arterial hypertension. Moreover, we aimed to
assess the contribution of nitric oxide on the flicker lightinduced increase of retinal capillary blood flow in a subgroup
of the study cohort.
Methods
Study Design and Study Population
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This observational study was performed at the Clinical Research Unit of
the Department of Nephrology and Hypertension, University of
Erlangen-Nüremberg, Germany. Study participants were recruited
through advertisements in local newspapers. Patients with arterial
hypertension (defined as systolic blood pressure ⱖ140 mm Hg and/or
diastolic blood pressure ⱖ90 mm Hg) and normotensive individuals
(systolic blood pressure ⬍140 mm Hg and diastolic blood pressure ⬍90
mm Hg) of male gender, between 18 and 75 years of age, were included.
Exclusion criteria were history or any present clinical evidence for
cardiovascular disease; atrial fibrillation or atrioventricular blockade,
grade II or higher; history or current use of any antihypertensive drug or
other medication; renal impairment (defined as estimated creatinineclearance ⬍60 mL/min according to the formula by Cockroft and
Gault); hepatic disease, diabetes mellitus (defined by fasting glucose
ⱖ126 mg/dL or on glucose-lowering medication or history of diabetes
mellitus); any form of secondary arterial hypertension; any significant
eye disease (including hypertensive retinopathy, grade III and IV), and
smoking. Blood pressure was measured in a sitting position, according
to World Health Organization criteria, 3⫻, and the average was
calculated. Before enrolment in the study, written informed consent was
obtained from each participant. The study protocol was approved by the
Clinical Investigations Ethics Committee of the University ErlangenNüremberg. The study was conducted in accordance with Good Clinical
Practice guidelines and in compliance with the Declaration of Helsinki.
Assessment of Parameters of Retinal Vessels
Measurement of Retinal Capillary Blood Flow
Retinal capillary blood flow was assessed using scanning laser
Doppler flowmetry at 670 nm (Heidelberg Engineering). Briefly, a
retinal sample of length 2.56 mm (256 points)⫻height 0.64 mm (64
lines)⫻0.30 mm (128 lines: values were averaged for each line and
point automatically) was scanned within 2 seconds, at a pixel
resolution of 10⫻10 ␮m. The confocal technique of the device
ensured that only the capillary blood flow of the superficial retinal
layer of 300 ␮m was measured.17 Measurements were performed in
the juxtapapillary area of the right eye, 2 to 3 mm temporally to the
optic nerve; the average from 3 singular measurements was taken.
Analysis of perfusion images was performed off-line with the
built-in software automatic full-field perfusion imaging analysis
(AFFPIA).18 AFFPIA automatically excludes vessels with a diameter ⬎30 ␮m, underexposed or overexposed pixels, and saccades from
the perfusion image, as previously described in detail.18 Thereby,
vessel diameters are detected by AFFPIA in reflectivity images, as
described previously.19 The mean retinal capillary blood flow was
calculated in the area of interest and expressed as arbitrary units.
Measurement of Changes of Retinal Capillary
Blood Flow to Flicker Light Exposure
Retinal capillary blood flow was measured before and after flicker light
exposure (10 Hz over 3 minutes; Roland Consult Stasche & Finger
GmbH). Flicker light stimulation leads to an increase of retinal capillary
blood flow.15 Flicker light exposure has no effects on systemic blood
pressure and heart rate, thereby minimizing potential systemic hemodynamic influences on retinal capillary blood flow.
Testing Whether the Increase of Retinal Capillary
Blood Flow to Flicker Light Exposure is at Least
in Part Mediated by Nitric Oxide
In the last subjects that could be recruited, we additionally implemented to measured changes in retinal capillary blood flow during
parallel infusion of nitric oxide synthase inhibitor N-monomethyl-Larginine (L-NMMA), aiming to test whether the increase of retinal
capillary blood flow to flicker light is mediated (at least, in part) by
nitric oxide in our subjects. Thereby, at least, in 28 subjects, the
change of retinal capillary blood flow to flicker light and the change
of retinal capillary blood flow to flicker light during parallel infusion
of L-NMMA was measured. In brief, after a resting phase of 15
minutes to ensure that retinal capillary blood flow has returned to
baseline levels, L-NMMA (3 mg/kg of body weight; Clinalfa,
Bachem AG) was administered intravenously as a bolus infusion
over 5 minutes, followed by constant infusion of L-NMMA (0.05
mg/kg body weight per minute) over further 25 minutes. Thus, the
total dose of L-NMMA was 3.25 mg/kg body weight. Immediately
after bolus infusion of L-NMMA, flicker light stimulation (10 Hz
over 3 minutes; Roland Consult Stasche & Finger GmbH) was
applied, and retinal capillary blood flow was measured again. If
nitric oxide, at least, in part, mediates the increase of retinal capillary
blood in response to flicker light, concomitant infusion of nitric
oxide synthase inhibitor L-NMMA during flicker light stimulation
will lead to a blunted or at least lower increase of retinal capillary
blood flow, in response to flicker light. Finally, we infused
L-arginine at a dosage of 100 mg/kg body weight over a period of 30
minutes. This was done for safety reasons, as previous examinations
from our laboratory have revealed that L-arginine at a dosage of
100/mg/kg body weight reverses the effects of L-NMMA on retinal
capillary blood flow. Retinal capillary flow was measured again after
L-arginine infusion to ensure that retinal capillary blood flow has
returned to baseline levels (data not shown).
No dilation of the pupil is required to perform the measurements
by the applied techniques, thereby avoiding concomitant pharmacological interaction. All examinations of retinal vasculature were
performed in sitting position after 20 minutes of rest, at room
temperature, and in daylight conditions between 8 AM and 2 PM but
before lunch. The readers (U.H. and S.A.) of retinal vasculature were
blinded to the clinical data of the subjects.
Statistics
All statistical analyses were performed using SPSS software (IBM
SPSS Statistics 19). Testing for normal distribution was performed
using Kolmogorov-Smirnov tests. Using this test, all parameters
were found to reveal a normal distribution. Results are given as
mean⫾SD in text and tables. Comparison between groups was
performed using the Student t test or, in case of adjustment for
possible confounders (including variables that differed with a P
value ⬍0.05 or tended to differ with a P value ⬍0.10 between the
hypertensive and normotensive group), using univariate analysis of
variance. Univariate correlation analyses were performed using
Pearson‘s correlation coefficient. Multiple linear regression analyses
were performed to determine whether blood pressure and cardiovascular risk factors were independently of possible confounders related
to the change of retinal capillary blood flow in response to flicker
light. Only 1 parameter per variable group (eg, LDL-cholesterol in
the lipid variable group) was eligible to be entered as an independent
variable, aiming to avoid statistical error due to collinearity. The
independent variables were entered simultaneously (multiple linear
regression, enter procedure). A 2-tailed P value ⬍0.05 was considered statistically significant.
Results
Baseline Clinical Characteristics
The clinical characteristics of the study participants, stratified
into subjects with arterial hypertension and normotensive controls, are given in Table 1: Subjects with arterial hypertension
were older and revealed higher body weight, body mass
index, blood pressure levels, heart rate, fasting glucose, and
triglyceride levels compared with normotensive patients.
Height, high-density lipoprotein (HDL)-cholesterol, lowdensity lipoprotein (LDL)-cholesterol, serum creatinine, and
Ritt et al
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873
Table 1. Clinical and Retinal Characteristics of the Study Cohort, Stratified Into Subjects With Arterial Hypertension and
Normotensive Controls
Characteristics
Hypertensive
Subjects (n⫽50)
Normotensive
Subjects (n⫽96)
40.5⫾7.8
36.8⫾8.9
0.011
...
P Value
P Value
Adjusted*/†
Clinical characteristics
Age (y)
Height (cm)
182⫾6.5
182⫾6.0
0.867
...
Weight (kg)
99.5⫾16
92.2⫾18
0.014
...
BMI (kg/m2)
30.0⫾4.9
27.8⫾5.0
0.012
...
Systolic blood pressure (mm Hg)
146⫾8.6
129⫾6.4
⬍0.001
...
Diastolic blood pressure (mm Hg)
88.4⫾7.0
76.5⫾6.4
⬍0.001
...
Mean arterial pressure (mm Hg)
108⫾6.2
93.8⫾5.2
⬍0.001
...
Heart rate (beats/minute)
75.5⫾9.9
71.2⫾10
0.015
...
Fasting glucose (mg/dl)
101⫾16
95.5⫾13
0.028
...
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Triglycerides (g/dl)
199⫾121
159⫾90
0.027
...
HDL-cholesterol (mg/dl)
50.4⫾13
49.2⫾8.7
0.564
...
LDL-cholesterol (mg/dl)
152⫾34
143⫾39
0.163
...
Serum creatinine (mg/dl)
0.91⫾0.1
0.89⫾0.1
0.212
...
118⫾22
120⫾20
0.496
...
Retinal capillary blood flow at baseline
(ie, before flicker light exposure) (AU)
360⫾89
334⫾83
0.077
0.229
Change of retinal capillary blood flow to flicker light exposure (AU)
7.69⫾54
27.2⫾44
0.021
0.012/0.013
Change of retinal capillary blood flow to flicker light exposure (%)
2.95⫾14
8.33⫾12
0.019
0.016/0.023
2
Estimated creatinine clearance (ml/min/1.73 m )
Retinal characteristics
y indicates years; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
*P adjusted for variables that differed with a P value of ⬍0.05 between the hypertensive and normotensive group (ie, age, weight, body mass index, heart rate,
fasting glucose, and triglyceride levels.
†P adjusted for variables that differed with a P value of ⬍0.10 between the hypertensive and normotensive group (ie, age, weight, body mass index, heart rate,
fasting glucose, triglyceride levels, and retinal capillary blood flow at baseline (ie, before flicker light exposure).
estimated creatinine clearance did not differ between the 2
groups.
Baseline Retinal Characteristics and Changes
of Retinal Capillary Blood Flow to Flicker
Light Exposure
The baseline retinal characteristics and changes in retinal
parameter to flicker light exposure of the study participants,
stratified into patients with arterial hypertension and normotensive controls, are also given in Table 1: Retinal capillary
blood flow at baseline (ie, before flicker light exposure) did
not differ between the 2 patient groups. The increase of
retinal capillary blood flow to flicker light exposure was
lower in subjects with arterial hypertension than in normotensive controls, irrespective whether expressed in absolute
terms or in percent changes, even after adjustment of the
analysis for possible confounders.
Univariate Correlation Analysis Between
Various Clinical Parameters and the Percent
Change of Retinal Capillary Blood Flow to Flicker
Light Exposure
Systolic blood pressure (Figure A) and mean arterial pressure
(r⫽⫺0.171; P⫽0.039) were negatively related to the percent
increase of retinal capillary blood flow to flicker light exposure.
The negative relationship of diastolic blood pressure to the
percent increase of retinal capillary blood flow to flicker light
exposure did not reach statistical significance (Figure B). None
of the other clinical parameters, including age (r⫽0.002;
P⫽0.980), height (r⫽0.115; P⫽0.168), weight (r⫽0.080;
P⫽0.337), body mass index (r⫽0.047; P⫽0.572), heart rate
(r⫽⫺0.008; P⫽0.924), fasting glucose (r⫽⫺0.005; P⫽0.956),
triglyceride levels (r⫽⫺0.053; P⫽0.529), HDL-cholesterol
(r⫽⫺0.114; P⫽0.175), LDL-cholesterol (r⫽⫺0.131; P⫽0.117),
serum creatinine (r⫽0.076; P⫽0.366) estimated creatinine
clearance (r⫽⫺0.007; P⫽0.933) and retinal capillary blood
flow at baseline (ie, before flicker light exposure) (r⫽⫺0.150;
P⫽0.072) revealed a significant relationship to the percent
increase of retinal capillary blood flow to flicker light.
Multiple Linear Regression Analysis Assessing the
Quantitative Role of Major Cardiovascular Risk
Factors in Relation to Each Other on the Percent
Change of Retinal Capillary Blood Flow to Flicker
Light Exposure
Systolic (model 1) but not diastolic blood pressure (model 2)
or mean arterial pressure (model 3) was negatively related to
the percent increase of retinal capillary blood flow to flicker
light exposure, independently of other cardiovascular risk
factors (see Table 2). None of the other cardiovascular risk
factors revealed such an independent relationship to the
percent increase of retinal capillary blood flow to flicker light
exposure (see Table 2).
874
Hypertension
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B
60
40
r=-0.214, P=0.010
20
0
-20
-40
110 120 130 140 150 160 170 180
Systolic blood pressure (mmHg)
Change of retinal capillary blood flow to
flicker light exposure (%)
Change of retinal capillary blood flow to
flicker light exposure (%)
A
60
r=-0.119, P=0.153
40
Figure. A, Relationship between the percent change of retinal capillary blood
flow to flicker light exposure and systolic
blood pressure. B, Relationship between
the percent change of retinal capillary
blood flow to flicker light exposure and
diastolic blood pressure.
20
0
-20
-40
60
70
80
90
100
110
Diastolic blood pressure (mmHg)
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Assessment of the Contribution of Nitric Oxide on
the Increase of Retinal Capillary Blood Flow to
Flicker Light Exposure in a Subgroup (nⴝ28) of
the Total Study Cohort
The clinical and retinal characteristics of these 28 subjects
were as follows: age, 38.9⫾5.5 years; height, 181⫾6.3 cm;
weight, 110⫾12 kg; body mass index, 33⫾3.9 kg/m2; systolic blood pressure, 135⫾10 mm Hg; diastolic blood pressure, 81⫾7.9 mm Hg; mean arterial pressure, 98.8⫾7.8
mm Hg; heart rate, 74.8⫾9.1 beats per minute; fasting
glucose, 101⫾23 mg/dL; triglycerides, 171⫾77 g/dL; HDLcholesterol, 48.6⫾11 mg/dL; LDL-cholesterol, 150⫾36 mg/
dL; serum creatinine, 0.92⫾0.1 mg/dL; estimated creatinine
clearance, 126⫾21 mL/min/1.73 m2; and retinal capillary
blood flow, 337⫾56 AU.
The increase of retinal capillary blood flow to flicker light
exposure did not differ compared with the increase in retinal
capillary blood flow to flicker light exposure during infusion
of L-NMMA when expressed in absolute terms (⫹20.0⫾51
versus 22.6⫾56 AU; P⫽0.731) or percent changes
(⫹7.12⫾16 versus 8.29⫾18%; P⫽0.607) in this subgroup of
the total study cohort.
Discussion
The major finding of our study is that the increase of retinal
capillary blood flow to flicker light exposure is impaired in
subjects with arterial hypertension compared with normotensive controls. Moreover, systolic but not diastolic blood
pressure or mean arterial pressure was found to be negatively
related to the percent increase of retinal capillary blood flow
to flicker light exposure, independently of other cardiovascular risk factors. Thus, the assessment of changes of retinal
capillary blood flow to flicker light exposure might be an
interesting noninvasive in vivo tool for detection of early
vascular changes in arterial hypertension.
It might be rational to hypothesize that either constricted
vessels with increased vascular resistance in arterial hypertension might be associated with decreased capillary blood flow and
to suggest that changes in baseline capillary blood flow before
the flicker light exposure may result in altered relative changes
in capillary blood flow after the flicker light exposure; however,
in our study, retinal capillary blood flow at baseline (ie, before
flicker light exposure) did not differ significantly between the
hypertensive and the normotensive group. Moreover, neither in
univariate correlation analysis nor in multiple linear regression
analysis, a significant relationship between retinal capillary
blood flow at baseline and the increase of retinal capillary blood
flow to flicker light exposure was found.
The underlying mechanisms explaining the impaired increase
of retinal capillary blood flow to flicker light exposure in our
patients with hypertension compared with normotensive controls
remains unclear. Reduced production and/or action of vasorelaxing factors such as nitric oxide, endothelial-derived hyperpolarizing factor, and prostacyclin or increased production or
activity of vasoconstrictor factors such as prostanoids (endoperoxides, thromboxane A2), superoxide anions, and endothelin
increases vascular tone, leads to chronic vasoconstriction of
peripheral vessels, and might impair vasodilatory properties in
arterial hypertension.20–22 Impairment of peripheral vasodilatory
properties were found to represent early vascular changes in
arterial hypertension.12,13 Moreover, remodeling of smallresistance arteries and arterioles, which also occurs early in
arterial hypertension23 and can be characterized by changes in
the wall (media)-to–lumen ratio of these vessels, might also
impact on vasodilatory properties. Remodeled small-resistance
arteries and arterioles frequently reveal deposition of extracellular matrix proteins (in particular, collagen) and restructuring of
smooth muscle cells in their vessel walls, which might lead to
embedding of the contracted vessel in a remodeled extracellular
matrix and impairment of vasodilatory properties of the vessels
in arterial hypertension.24 As small-resistance arteries and arterioles act as major gatekeepers of tissue perfusion, impairment of
vasodilatory properties of these vessels might further lead to
reduction in the capillary perfusion reserve of corresponding
tissue. In line, we had previously found an inverse relationship
between wall-to–lumen ratio of retinal arterioles and the increase
of retinal capillary blood flow to flicker light exposure in
patients with arterial hypertension but not in normotensive
controls.25 Another group had observed an inverse relationship
between the media-to–lumen ratio of isolated subcutaneous
small arteries and arterioles and coronary vasodilatory response
to adenosine infusion in patients with arterial hypertension.26
In a subgroup of the total study cohort, concomitant infusion
of nitric oxide synthase inhibitor L-NMMA did not reduce the
Ritt et al
Table 2. Multiple Linear Regression Analysis Assessing the
Quantitative Impact of Various Cardiovascular Risk Factors on
the Percent Change of Retinal Capillary Blood Flow to Flicker
Light Exposure
Change of Retinal
Capillary Blood
Flow to Flicker
Light Exposure (%)
␤
Characteristics
P Value
Model 1
Age (y)
0.055
0.639
BMI (kg/m2)
0.103
0.292
⫺0.216
0.023
Heart rate (beats/minute)
0.040
0.658
Fasting glucose (mg/dl)
0.035
0.696
LDL-cholesterol (mg/dl)
⫺0.123
0.224
Estimated creatinine clearance (ml/min/1.73 m )
⫺0.041
0.726
Retinal capillary blood flow at baseline
(ie, before flicker light exposure) (AU)
⫺0.064
0.506
Systolic blood pressure (mm Hg)
2
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Model 2
Age (y)
0.098
0.435
BMI (kg/m2)
0.069
0.484
⫺0.117
0.243
Heart rate (beats/minute)
0.010
0.908
Fasting glucose (mg/dl)
0.025
0.785
LDL-cholesterol (mg/dl)
⫺0.122
0.235
Estimated creatinine clearance (ml/min/1.73 m2)
⫺0.038
0.750
Retinal capillary blood flow at baseline
(ie, before flicker light exposure) (AU)
⫺0.101
0.292
Diastolic blood pressure (mm Hg)
Model 3
Age (y)
0.099
0.417
BMI (kg/m2)
0.090
0.361
⫺0.178
0.073
Heart rate (beats/minute)
0.029
0.751
Fasting glucose (mg/dl)
0.028
0.757
LDL-cholesterol (mg/dl)
⫺0.122
0.234
Estimated creatinine clearance (ml/min/1.73 m2)
⫺0.042
0.723
Retinal capillary blood flow at baseline,
i.e. before flicker light exposure (AU)
⫺0.080
0.406
Mean arterial pressure (mm Hg)
y indicates years; BMI, body mass index; LDL, low-density lipoprotein.
Characteristics under model 1, 2, and 3 are characteristics that were
included in that particular model.
increase of retinal capillary blood flow to flicker light. This
result does not support the hypothesis of a major impact of nitric
oxide on the increase of retinal capillary blood flow to flicker
light exposure at first glance; however, in contrast to our study,
Dorner et al16 reported a reduced increase of major retinal
arteriolar diameters in response to flicker light exposure during
concomitant infusion of 3 mg/kg body weight of L-NMMA, a
dosage comparable to the dosage used in our current study, in a
cohort of 12 young (mean⫾ SD age of 25.6⫾2.1 years) healthy,
nonsmoking subjects. The reasons for the discrepancy between
the 2 studies might be owing to differences in the methodologies
used: Dorner et al16 measured changes in major retinal arteriolar
diameter in reflexion images (by digital retinal photography),
Retinal Vasodilatory Capacity in Hypertension
875
while we measured true changes in perfusion of the retinal
capillary bed by scanning laser Doppler flowmetry. Second,
Dorner et al16 used a frequency of the flicker light of 8 Hz, while
we used a frequency of flicker light of 10 Hz. Previous data
indicate that the frequency of flicker light might indeed impact
on retinal capillary blood flow response to flicker light exposure.27 Third, Dorner et al16 used a much shorter flicker light
duration of up to 64 seconds compared with a 3-minute flicker
period in our current study. Furthermore, most of the patients in
our substudy revealed cardiovascular risk factors such as arterial
hypertension, metabolic syndrome, or obesity that might have
resulted in decreased basal nitric oxide activity.20 Thus, to
clearly address the role of nitric oxide in the increase of retinal
capillary blood flow to flicker light exposure under physiological conditions, a cohort of healthy volunteers who do not reveal
any cardiovascular risk factors will need to be examined.
Our study has limitations. First, although the readers of retinal
vasculature were blinded to the clinical data (including blood
pressure levels and history of arterial hypertension, among
others), they might have been biased by detecting signs of
hypertensive retinopathy, such as focal arteriolar narrowing
among others; however, such signs of hypertensive retinopathy
might also be detectable in patients with prehypertension7 that,
in case of the current study, have been grouped into the
normotensive group. Second, owing to inclusion criteria, our
study cohort comprised only male subjects. Hormone levels, that
potentially impact on microvascular function, differ between
women and men.28 Therefore, results of our study might not be
extensible to women. Third, all subjects in our current study
were white. It cannot be excluded that the impact of blood
pressure on the flicker light-induced changes in retinal capillary
blood flow might differ between different ethnic groups. Fourth,
owing to the cross-sectional design of our study, we can only
describe associations but cannot give any information with
respect to a causal role.
Perspectives
We found that the increase of retinal capillary blood flow to
flicker light is impaired in subjects with arterial hypertension.
Systolic but not diastolic blood pressure or mean arterial
pressure was negatively related to the increase of retinal
capillary blood flow to flicker light, independently of other
cardiovascular risk factors. Thus, the noninvasive measurement of increases of retinal capillary blood flow to flicker
light exposure might represent an interesting research and
potentially clinical tool to assess early microvascular changes
in vivo in arterial hypertension.
Acknowledgments
We thank U. Heinritz, S. Avendano, I. Fleischmann, S. Pejkovic, I.
Birmann, and D. Bader-Schmieder for their excellent technical
assistance.
Sources of Funding
This work was supported by grants from the German Hypertension
League and ELAN-Fund of the University of Erlangen-Nüremberg.
Disclosures
None.
876
Hypertension
September 2012
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Novelty and Significance
What Is New?
●
The increase of retinal capillary blood flow to flicker light exposure,
assessed by scanning laser Doppler flowmetry, is lower in hypertensive compared to normotenisve subjects and negatively related to
systolic blood pressure, independently of possible confounders.
●
Assessment of changes in retinal capillary blood flow to flicker light
exposure by scanning laser Doppler flowmetry allows detection of early
microvascular changes in hypertension.
What Is Relevant?
Summary
Our current study introduces a new, safe, and elegant noninvasive
in vivo tool for detection of early microvascular changes in
hypertension, which might be of great interest for future research,
as well as patient management.
Impaired Increase of Retinal Capillary Blood Flow to Flicker Light Exposure in Arterial
Hypertension
Martin Ritt, Joanna M. Harazny, Christian Ott, Ulrike Raff, Philipp Bauernschubert, Marina
Lehmann, Georg Michelson and Roland E. Schmieder
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Hypertension. 2012;60:871-876; originally published online July 9, 2012;
doi: 10.1161/HYPERTENSIONAHA.112.192666
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