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Vascular Dysregulation in the Choroid of Subjects With Acral Vasospasm
Pascal W. Hasler, MD;
Selim Orgül, MD;
Konstantin Gugleta, MD;
Holger Vogten, MD;
Xiaohui Zhao, MD;
Doina Gherghel, MD;
Josef Flammer, MD
Arch Ophthalmol. 2002;120:302-307.
ABSTRACT
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Objective To assess the relationship between ocular perfusion pressure and blood
flow in the choroid in subjects with acral vasospasm.
Patients and Methods Twenty otherwise healthy subjects with acral vascular dysregulation
and 55 age-matched nonvasospastic healthy volunteers were recruited. After
a 20-minute rest in a sitting position, intraocular pressure and choroidal
blood flow were determined by means of applanation tonometry and choroidal
laser Doppler flowmetry, respectively. The laser Doppler flowmetry variables
velocity, volume, and flux were assessed. The correlations between mean ocular
perfusion pressure ({ x [( x diastolic blood pressure) + ( x systolic blood pressure)]} - intraocular pressure) and
blood flow measures were determined by means of the Pearson linear correlation
factor. The t test was used to evaluate differences
between normal subjects and patients with vasospasm.
Results Apart from a slight difference in systolic blood pressure (mean ±
SD, 113.70 ± 11.88 mm Hg in the vasospastic group and 121.09 ±
14.58 mm Hg in the control group; P = .05), the 2
study groups were completely comparable. Velocity and flux correlated significantly
with the mean ocular perfusion pressure (r = 0.76, P<.001; r = 0.64, P = .002, respectively) in vasospastic subjects. Such correlations
did not occur in the control group, and the difference between vasospastic
patients and control subjects with regard to these correlations was statistically
significant (P<.001 and P
= .003, respectively).
Conclusions Choroidal blood flow seems, to some degree, to be independent of perfusion
pressure, but not in subjects with acral vasospasm.
INTRODUCTION
GLAUCOMA IS a progressive optic neuropathy involving characteristic
structural changes of the optic nerve and characteristic visual field defects.1 The level of intraocular pressure (IOP) is the risk
factor most often associated with glaucomatous optic neuropathy. However,
the substantial number of cases of open-angle glaucoma that continue to progress
in damage despite therapeutically lowered IOP as well as the existence of
patients who develop glaucoma with normal IOP has prompted the search for
risk factors other than increased IOP. In addition to neurotoxicity, reduced
ocular blood flow,2-7
ocular vascular dysregulation,8-10
and systemic blood pressure alterations11-17
have been suggested as possible contributing factors to the pathogenesis of
glaucoma.
Among the vascular factors, vascular dysregulation or a lack of autoregulation,
leading to transient vasoconstrictions or to a lack of appropriate vasodilation,
has recently been proposed as a more likely contributor to glaucomatous damage
than frank ischemia.8-10
The etiology or the pathophysiology of vascular dysregulation is not clear.
There is some evidence that vascular endothelial dysfunction might play an
important role.18-19 The most
typical clinical manifestation is a history of frequent cold hands, often
associated with vasospastic reactions to cold in the nailfold capillaries
as assessed by nailfold capillaroscopy.20 Some
parallelism between finger and ocular blood flow has also been suggested.21-22 Vasospasms in the ocular circulation,
namely the retinal vessels, have been observed in association with unstable
primary angina and with migraine.23 Furthermore,
vascular dysregulation has been described in the retrobulbar circulation of
otherwise healthy subjects with vasospasm9
and patients with glaucoma who have progressive damage despite lowered IOP.10
Although vascular dysregulation has been suggested to represent a potential
risk factor in various ocular conditions, including glaucoma,8, 10, 24
retinal venous occlusion,25 acute ischemic
optic neuropathy,26 and central serous chorioretinopathy,27 it is still not well understood how such dysregulative
phenomena might lead to structural ischemic lesions. Indeed, most patients
with vasospastic diathesis do not develop any disease. Furthermore, there
is only scarce information about the ocular vascular beds within which dysregulative
phenomena may be expected. Therefore, investigations confirming altered blood
flow regulatory mechanisms in the ocular circulation of vasospastic subjects
are warranted. The most recent findings suggest an altered relationship between
blood flow and perfusion pressure in the ocular circulation of vasospastic
subjects.9-10 However, the later
investigations pertain to retrobulbar blood flow, and no data on intraocular
blood flow are available. Consequently, the purpose of the present study was
to compare the relationship between choroidal blood flow variables and ocular
perfusion pressure between vasospastic subjects relating a history of frequent
cold hands and normal control subjects.
PATIENTS AND METHODS
Seventy-five healthy subjects were included in this study. A notification
in the University Eye Clinic Basel (Basel, Switzerland) informed potential
volunteers (collaborators, students, and parents and friends of patients)
of the opportunity to participate in a scientific research project.
After informed consent was obtained, subjects were screened for ocular
and systemic diseases. A detailed medical and ophthalmic history was recorded,
including a questionnaire containing queries about complaints of cold hands,
and all subjects completed an ophthalmologic examination. Subjects were not
included if they had a history of ocular or systemic disease, a family history
of glaucoma, a history of eye surgery, any chronic systemic or topical medication,
a best-corrected visual acuity worse than 20/25, an applanation IOP of 20
mm Hg or more, or any pathologic finding on ophthalmologic examination, including
slitlamp biomicroscopy and funduscopy.
Subjects were classified as vasospastic if they related a clear history
of frequent cold hands (answering "yes" to the questions, "Do you have always
cold hands, even during summertime?" and "Do other people tell you that you
have cold hands?") and as normal if they denied such a history. Subjects describing
sometimes cold hands were excluded from the present analysis. Because a simple
assessment of a clear history of cold hands has been suggested to be better
at distinguishing ocular features supposedly related to vascular dysregulation
than the more complex determination of vasospasm by methods such as finger
aser Doppler flowmetry (LDF), no objective assertion of acral vasospasm was
performed.28
All subjects underwent choroidal blood flow assessment by means of choroidal
LDF.29 In brief, a continuous laser light is
projected into the fovea and the back-scattered light is then analyzed. The
back-scattered laser light contains 2 components: light scattered by the relatively
stationary structures, such as vessel walls and tissue, and light scattered
by moving blood cells. Most of the light is back-scattered without shift of
the frequency. Moving particles, however, cause a Doppler shift on scattered
light in proportion to the velocity of the moving particle. The interference
of these 2 wave components leads to an alternating signal at the photodetector.
This signal is subjected to a fast Fourier transform algorithm to obtain the
power spectrum of the multiple frequency shift components. From this spectrum,
variables called flux, volume,
and velocity, which are related to blood flow, are
computed by means of an algorithm based on Bonner and Nossal's photodiffusion
theory.30-31 These flow variables
are related to each other through the following relationship: flux = constant
x volume x velocity. Each variable is linear with respect to changes.
For the present experiments, a new compact confocal (focal plane thickness
of approximately 300 µm) laser Doppler flowmeter (Choroidal Blood Flowmeter-ChBF;
IRO, Sion, Switzerland) was used.32-34
The subjects were asked to fixate on a diode laser beam (wavelength, 811 nm;
95 µW at the cornea) delivered to the undilated eye. The diameter of
the beam at the fundus of the emmetropic eye is about 10 to 20 µm. Light
scattered in the tissue volume sampled by the incident laser beam is detected
at the fundus image plane of the camera by a fiber-bundle photodetector system
organized with 6 fibers arranged circularly around the central fixation point,
all within the avascular zone of the fovea, favoring measurement of choroidal
blood flow.29, 32-33
For all subjects, the left eye was chosen arbitrarily as the experimental
eye. During a measurement, the subject's head was comfortably placed in a
slitlamp head rest. Care was taken to keep the direct current component of
the signal as constant as possible during the recording, which lasted at least
20 seconds. Data points were averaged in phase with the heart pulse, which
was continuously recorded. All data points with the same phase delay after
the start of the pulse were averaged together, and this procedure was repeated
for all phase delays, producing an average waveform representative of each
flow variable. A mean value during the heart cycle was computed for each variable.
The entire experimental procedure was standardized. After the presence
or absence of vasospasticity was established, the subjects rested for 20 minutes
in a sitting position. Before choroidal LDF, the IOP was measured by means
of applanation tonometry after 1 drop of 0.4% benoxinate hydrochloride was
applied and the tearfilm was stained with a strip of fluorescein sodium. Afterward,
LDF variables were obtained from the choroid. All LDF measurements were performed
by the same experienced technician (H.V.), who was masked to the history regarding
cold hands of the subjects and was not allowed to shake hands with them. Before
as well as immediately after choroidal blood flow measurement, systemic blood
pressure and heart rate were recorded by means of an automatic device (Profilomat;
Roche, Basel, Switzerland). This device measures blood pressure automatically,
on the same principle as the conventional mercury sphygmomanometer, with a
cuff and a microphone. Subjects with marked variations in blood pressure during
the examinations were excluded. The average of the 2 measurements was considered
for blood pressure and pulse rate for further analysis.
The blood pressure readings for systolic blood pressure (SBP) and diastolic
blood pressure (DBP) obtained during choroidal LDF were used to calculate
the mean arterial blood pressure (MABP) according to the following formula:
MABP = ( x DBP) + ( x SBP). The ophthalmic artery pressure (OAP) was calculated
according to the following formula: OAP = x MABP. The mean ocular perfusion pressure (MOPP) was calculated
as MOPP = OAP - IOP.
The correlation between MOPP and the choroidal blood flow variables
velocity, volume, and flux was assessed by means of the Pearson linear correlation
factor in both experimental groups. To evaluate differences in these correlations
between vasospastic patients and control subjects, the interaction by the
covariates velocity, volume, or flux (parallelism of regression lines) was
computed in a covariance analysis model comparing MOPP between the experimental
groups. Differences in hemodynamic variables such as SBP, DBP, MABP, OAP,
and MOPP, as well as IOP and choroidal LDF variables velocity, volume, and
flux, between the group of vasospastic subjects and the control group were
assessed by means of the t test for unpaired variables.
Sex distribution in the experimental groups was compared by means of Fisher
exact test. P values less than .05 were considered
statistically significant.
RESULTS
Among the 75 volunteers, 20 subjects (15 women and 5 men) had a history
of acral vasospasm and 55 (20 women and 35 men) did not. The difference in
sex distribution was statistically different between the experimental groups
(Fisher exact test: P = .003). The mean (±SD)
age was 46 ± 15 years for the 20 vasospastic subjects and 48 ±
12 years for the 55 control subjects (P = .56). Hemodynamic
variables such as SBP, DBP, MABP, OAP, and MOPP, as well as IOP, are outlined
in Table 1. These variables were
comparable between the 2 experimental groups except for SBP, which was statistically
significantly lower in vasospastic subjects (P =
.05). The choroidal LDF variables in the left eye of the vasospastic group
and the control group are shown in Table
2. These variables were statistically comparable between the vasospastic
subjects and the control group (Table 2).
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Table 1. Systemic Hemodynamic Variables and Intraocular Pressure (IOP)*
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Table 2. Choroidal Blood Flow Variables*
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The correlation between the MOPP and the choroidal LDF variables velocity,
volume, and flux among the 2 experimental groups are shown in Figure 1, Figure 2, and Figure 3. In the vasospastic group, the MOPP
correlated statistically significantly with the choroidal LDF variables velocity
(Figure 1) and flux (Figure 3), but not volume (Figure
2). The correlation factors for velocity, volume, and flux were
0.76 (P<.001), 0.30 (P
= .20), and 0.64 (P = .002), respectively, among
the vasospastic subjects. None of these correlations was statistically significant
in the control group. For the control group, the respective correlation factors
for velocity, volume, and flux were 0.02 (P = .90),
0.04 (P = .76), and 0.03 (P
= .84). The difference between vasospastic patients and control subjects with
regard to the correlation between MOPP and LDF variables (divergence of the
regression lines) was statistically significant for velocity (F = 13.71, P<.001) and flux (F = 9.85; P
= .003), but not for volume (F = 1.69; P = .20).
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Figure 1. Relationship between choroidal
blood flow velocity and mean ocular perfusion pressure (MOPP) in normal subjects
(A) and patients with vasospasm (B). Velocity correlated positively with ocular
perfusion pressure in vasospastic patients (r = 0.76, P<.001), but not in normal control subjects (r = 0.02, P = .90). The difference between
vasospastic patients and control subjects with regard to the correlation between
MOPP and choroidal blood flow velocity (divergence of the regression lines)
was statistically significant (P<.001).
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Figure 2. Relationship between choroidal
blood flow volume and mean ocular perfusion pressure (MOPP) in normal subjects
(A) and patients with vasospasm (B). Volume did not correlate with ocular
perfusion pressure in vasospastic patients (r = 0.30, P = .20) or in normal control subjects (r
= 0.04, P = .76). The difference between vasospastic
patients and control subjects with regard to the correlation between MOPP
and choroidal blood flow volume (divergence of the regression lines) was not
statistically significant (P = .20). AU indicates
arbitrary units.
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Figure 3. Relationship between choroidal
blood flow flux and mean ocular perfusion pressure (MOPP) in normal subjects
(A) and patients with vasospasm (B). Flux correlated positively with MOPP
in vasospastic patients (r = 0.64, P
= .002) but not in normal control subjects (r = 0.03, P = .84). The difference between vasospastic patients and
control subjects with regard to the correlation between MOPP and choroidal
blood flow velocity (divergence of the regression lines) was statistically
significant (P = .003). AU indicates arbitrary units.
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COMMENT
Choroidal LDF measurements were obtained in 20 vasospastic, otherwise
healthy subjects and in 55 age-matched controls. Mean ocular perfusion pressure
and choroidal LDF variables were statistically comparable between the 2 groups.
A linear parametric regression analysis disclosed significantly lower choroidal
blood flow variables (flux and velocity, but not volume) in vasospastic subjects
with lower ocular perfusion pressure. Similar correlations did not occur in
the control group. The difference between vasospastic patients and control
subjects with regard to the correlation between MOPP and choroidal blood flow
was statistically significant for the LDF variables flux and velocity. These
observations suggest that, in contrast to normal subjects, choroidal blood
flow is low in vasospastic subjects when ocular perfusion pressure is low,
suggesting an altered vascular regulation in the choroidal circulation of
vasospastic subjects.
The choroid plays an important role in the supply of nutrients to the
outer retina in humans, particularly in the avascular region of the fovea.
A high flow rate–low oxygen extraction system has been considered to
be necessary for the choroid, with the argument that choriocapillaris PO2 must be kept high to maintain normal photoreceptor oxidative metabolism.35 The essential factor controlling the requirement
for high flow rate seems to be the distance between the choroid and the photoreceptor
inner segments. The relatively long diffusion distance requires a high PO2 at the choroid so that there is a steep enough oxygen gradient (high
enough flux) between the choroid and the inner segment layer. A sufficient
supply, however, will depend on adequate adjusting mechanisms, counteracting
the negative effects of external perturbations. A number of regulatory systems
and factors, such as circulating hormones, as well as metabolic, myogenic,
and neurogenic factors, participate in the regulation of the vascular tone.36 Blood flow through an organ such as the eye depends
on the arterial and venous pressure difference, ie, the perfusion pressure.
A decrease in perfusion pressure produces a decrease in flow, unless this
decrease is counteracted by a similar decrease in vascular resistance. Autoregulation
is said to occur when the effect of the decrease in perfusion pressure is
compensated for by a decrease in vascular resistance; the flow remains constant,
and, thus, within certain limits, local perfusion remains largely independent
of the local perfusion pressure. In various vascular systems, this is accomplished
in two principal ways, metabolic and myogenic mechanisms.37
Myogenic responses may require several minutes to induce stable vessel diameters
after an acute intravascular pressure change.38-39
On the other hand, in the rabbit's brain circulation, for example, autoregulatory
responses, probably driven by metabolic mechanisms, seem to occur within approximately
3 to 13 seconds after a steep decrease in MABP, depending on the severity
of hypotension.40
Vascular autoregulation applies to various vascular systems, including
that of the heart, the brain, the retina, and the optic nerve. In the choroidal
circulation, however, studies pertaining to the effect of increased IOP on
choroidal blood flow have suggested a linear relationship between choroidal
blood flow and perfusion pressure in animal eyes, failing to show evidence
of autoregulation in this vascular bed.41-42
More recently, investigations in rabbits in which systemic blood pressure
had been manipulated demonstrated a nonlinear relationship between choroidal
blood flow and perfusion pressure, suggesting that the choroid may well have
some capability to autoregulate in this animal.43
Not only rabbits exhibit some autoregulation in the choroid. Recent experiments
suggested that, even in humans, the relationship between choroidal blood flow
and perfusion pressure is not linear across the whole range of perfusion pressures.44 The nonlinear relationship between genuine perfusion
pressure in the normal population examined in the present investigation also
is in concordance with some autoregulatory potency of the choroidal circulation.
The choroidal vasculature of vasospastic subjects, however, seems to be devoid
of such an autoregulation. The present findings seem to suggest that, in vasospastic
subjects, low blood flow is brought about by a reduction in perfusion pressure.
As an alternative explanation, however, systemic vascular dysregulation might
be manifesting itself through a low blood flow as well as a low ocular perfusion
pressure, both resulting from a common cause, but not being related through
a cause-and-effect relationship. The present study does not allow us to choose
between these two interpretations. Indeed, only baseline conditions were compared,
and no experimental manipulations of perfusion pressure supposed to cause
alterations in LDF variables were performed.
Choroidal blood flow was assessed by means of LDF technology. Measurements
of choroidal blood flow with the use of a fundus camera–based LDF system
strongly suggested that the LDF signal originates predominantly from the choriocapillaris,
rather than from the larger choroidal vessels behind this layer or the capillaries
of the macular region of the retina.29 In the
present study, the relative contribution of light scattered by the blood in
the choriocapillaris compared with that scattered from the larger vessels
should be even stronger, because the probing beam and detecting aperture were
confocal with the level of the photoreceptors. With regard to the contribution
from retinal capillaries, a recent study performed with this instrument demonstrated
no detectable change in choroidal blood flow in response to breathing 100%
oxygen, confirming the absence of a contribution from the retina.45 Indeed, studies assessing the response of choroidal
blood flow to changes in ocular perfusion pressure,44, 46
changes in arterial blood oxygen or carbon dioxide tensions,45
and the Valsalva maneuver29 support the assumption
that choroidal LDF measures change in choroidal blood flow in the foveal region.29 The sensitivity of choroidal blood flow measurements,
defined as the minimum change that can be detected on the basis of 11 subjects,
was found to be approximately 6% with this device.46
Only the LDF variables flux and velocity, but not volume, correlated
with ocular perfusion pressure in vasospastic subjects. A mechanism that could
have played a role in the maintenance of constant choroidal blood volume within
the narrow physiologic range of IOP is a passive increase in volume of the
choriocapillaris.44 This could be caused by
a slight engorgement of this blood layer in response to the moderate increases
in IOP as suggested by the positive correlation between IOP and choroidal
blood volume observed in a previous study in healthy subjects.34
Furthermore, the present measurements provide only information on choroidal
blood flow in the foveal region of the fundus. Other regions of the choroid
could present completely different features, especially with regard to the
relationship between perfusion pressure and blood flow. Regional differences
in the responsiveness of the cat's choroidal circulation support the assumption
that specific regulatory mechanisms may prevail in the foveal region.47-49 Indeed, a distinct
dense nitrergic innervation, localized in the temporal-central portion of
the choroid, has been described in humans but not in other species.50 This finding suggests that, especially in this region,
in addition to intrinsic vascular mechanisms, neural mechanisms distinct from
those seen elsewhere within the choroid may take a large part in local blood
flow control. Neural regulatory mechanisms could, therefore, be the origin
of autoregulatory behavior of the foveal choriocapillaris.
In the present study, choroidal blood flow correlated positively with
MOPP in vasospastic subjects, suggesting that ocular blood flow might also
decrease with decreasing perfusion pressure. Such a behavior was not observed
in the control group, suggesting that blood flow–regulating mechanisms
are different between vasospastic and nonvasospastic subjects. The findings
of the present study demonstrate that blood flow alterations occur in the
choroidal circulation or, more precisely, in the foveal choriocapillaris of
vasospastic subjects. Whether similar alterations exist in other ocular vessels,
such as those feeding the anterior optic nerve, is not known. Indeed, vasospasms
have been suggested to represent a risk factor for ophthalmic diseases such
as glaucoma,24 anterior ischemic optic neuropathy,26 venous thrombosis in young individuals,25
or central serous chorioretinopathy.27 Consequently,
whether subjects with such diseases present similar alterations in their choroidal
circulation would be of utmost interest.
In summary, the present study demonstrated an altered vascular regulation
in the choroidal circulation of vasospastic subjects. Such alterations might,
hypothetically, render the eye susceptible to variations in IOP or systemic
blood pressure.
AUTHOR INFORMATION
Submitted for publication March 22, 2001; final revision received July
23, 2001; accepted October 5, 2001.
This study was supported by grant 32-059094.99 from the Swiss National
Foundation, Bern, Switzerland.
Corresponding author and reprints: Selim Orgül, MD, University
Eye Clinic Basel, Mittlere Strasse 92, PO Box 4012, Basel, Switzerland (e-mail: sorgul{at}magnet.ch).
From the University Eye Clinic Basel, Basel, Switzerland.
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