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(Investigative Ophthalmology and Visual Science. 2003;44:1573-1580.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.02-0521
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Choroidal Vascular Reaction to Hand-Grip Stress in Subjects with Vasospasm and Its Relevance in Glaucoma

Konstantin Gugleta, Selim Orgül, Pascal W. Hasler, Thierry Picornell, Doina Gherghel, and Josef Flammer

From the University Eye Clinic, Basel, Switzerland.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To assess the impact of vascular dysregulation on choroidal blood flow response to the hand-grip test and the relevance of this response to glaucoma.

METHODS. Eighty healthy volunteers underwent a hand-grip test while choroidal blood flow was measured by means of laser Doppler flowmetry. Blood pressure, heart rate, and intraocular pressure (IOP) were monitored. Choroidal blood flow changes were compared between subjects with a positive history of cold hands and control subjects by means of analysis of variance. The relationship of the vascular response to the level of IOP at which progressive damage occurred was analyzed in 21 patients with primary open-angle glaucoma who had progressive damage despite normal or normalized IOP.

RESULTS. Blood pressure and heart rate increased and IOP decreased in response to a hand-grip test. Healthy subjects with a positive history of cold hands (n = 36) demonstrated a decrease in choroidal blood flow during the hand-grip test (mean ± SD: 13.5 ± 5.8, 12.2 ± 6.8, and 13.4 ± 6.9 AU, at baseline, during the test, and 3 minutes after release, respectively), whereas control subjects (n = 44) demonstrated an inverse (12.5 ± 8.3, 13.7 ± 9.4, and 11.9 ± 7.1 AU, respectively) response pattern (P = 0.039). Glaucoma patients with a decrease of at least 10% in choroidal blood flow during the hand-grip test had lower IOP (14.67 ± 3.83 and 13.50 ± 2.59 mm Hg in the right and the left eyes, respectively) compared (P = 0.032) with those without such a decrease (16.54 ± 3.85 and 16.92 ± 2.95 mm Hg in the right and the left eyes, respectively).

CONCLUSIONS. A hand-grip test elicits a different blood flow response in subjects with vasospasm compared with control subjects. Damage by glaucoma in patients with a decrease in choroidal blood flow during a hand-grip test may progress at a relatively lower IOP.

Intraocular pressure (IOP) represents the most important risk factor in glaucomatous optic neuropathy. Because progression of such damage correlates surprisingly weakly with the level of IOP,1 the involvement of factors other than IOP has been suggested to participate in the pathogenesis of glaucoma. Especially, microcirculatory impairment of the anterior optic nerve has been invoked as a potential causal factor or contributor to glaucomatous optic neuropathy.2 The exact nature of blood flow alterations in patients with glaucoma, however, is unclear.

Perfusion pressure and local resistance are major determinants of blood flow through an organ, ensuring an adequate supply of oxygen and nutrients to the tissue. Many systems, such as the autonomic nervous system, circulating hormones, and endothelial cell layer, among others, are involved in this regulation. Deficiencies within such a complex process may cause some dysregulation, manifesting itself as arterial constriction (vasospasm) or inadequate dilation. A condition in which dysregulation occurs globally, involving many different organs simultaneously or sequentially is termed vasospastic syndrome and can be classified as primary or secondary syndrome.3 Secondary vasospastic syndrome occurs as a consequence of other diseases, such as autoimmune diseases. Primary vasospastic syndrome occurs more often in females than males and is characterized by a tendency toward cold hands and low blood pressure. Its pathogenesis is not yet known, but there are indications that it is a consequence of a vascular endotheliopathy.4

The observation of parallel changes in peripheral blood flow (fingers) and visual field in patients with vasospasm5 led to the definition of an entity called "presumed ocular vasospastic syndrome."6 In some patients with peripheral vasospasms, visual-field defects have been shown to worsen after provocation by cold, and, often, both peripheral vasospasms and visual-field defects improved after calcium channel-blocker treatment.5 Newer observations7 8 suggest indeed some parallelisms in ocular and digital blood flow. Visual-field changes in persons with vasospasm have been suggested to be due to changes in choroidal blood flow.9 With the advent of modern techniques to measure ocular blood flow it has been made possible to demonstrate that the eye may indeed be involved in the vasospastic syndrome,10 11 that the choroidal circulation is not spared,12 and that such a dysregulation may be of relevance in glaucoma.13

The present study was undertaken to define a test based on the choroidal blood flow response to the hand-grip stress test, to assess the same response in persons with vasospasm, and to determine the relevance of such a test in patients with glaucoma.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Compact Choroidal Laser Doppler Flowmeter
Choroidal blood flow assessment was performed by means of choroidal laser Doppler flowmetry (LDF). In brief, a continuous laser light is projected into the fovea and the backscattered light is then analyzed. The backscattered laser light contains two 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 backscattered 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 two 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, parameters including flux, volume, and velocity, which are related to blood flow, are computed, using an algorithm based on the photon diffusion theory of Bonner and Nossal.14 Velocity is expressed in kilohertz, and volume and flux are expressed in arbitrary units (AU). These flow parameters are related to each other through the relationship flux = constant x volume x velocity, where the constant represents an instrumental factor. Each parameter behaves linearly in relation to changes in blood flow.15

In the present study, a new compact, confocal choroidal laser Doppler flowmeter (choroidal blood flowmeter, ChBF; IRO, Sion, Switzerland) was used. The optical system for the delivery of the laser beam and the detection of the scattered light is based on a confocal arrangement and has been described in detail elsewhere.16 Briefly, a polarized laser source ({lambda} = 785 nm, 100 µm) is relayed with a 1:1 optical system (laser beam at the cornea: width = 1.3 mm, power = 90 µW) and focused at the subject’s retina (spot in the retinal image plane = 10–20 µm in diameter, optical thickness of confocal layer = 300 µm). The point laser source, the point of illumination of the fovea and the detecting optical fiber are located in conjugated planes. The scattered light is collected by an optical system organized with six fibers arranged circularly around the central fixation point along a circle of diameter of 180 µm (within the avascular zone of the fovea).

Healthy Subjects
Eighty healthy nonsmoking subjects were selected. The procedures were approved by the local ethics committee, the research adhered to the tenets of the Declaration of Helsinki, and each subject signed an informed consent form before examination. A notification in the University Eye Clinic Basel informed potential volunteers (collaborators, students, parents, and friends of patients) of the opportunity to participate in a scientific research project. Subjects were screened for ocular and systemic diseases. A detailed medical and ophthalmic history was recorded, including a questionnaire containing queries about reports of cold hands, and all subjects underwent an ophthalmic examination. Included were only individuals with no history of ocular or systemic disease, no history of chronic or current systemic or topical medication, and no history of drug or alcohol abuse. Further inclusion criteria were normal systolic (100–140 mm Hg) and diastolic (60–90 mm Hg) blood pressure, best corrected visual acuity above 20/25 in both eyes, ametropia within -3 to +3 D of spherical equivalent and less than 1 D astigmatism in both eyes, a pupil diameter of at least 4 mm, an IOP lower than 20 mm Hg in both eyes by applanation tonometry, and no pathologic findings on a slit-lamp examination and indirect fundoscopy. Subjects were classified as having vasospasm if they related a clear history of frequently cold hands (answering yes to the questions: "do you always have cold hands, even during the summer?" and "do other people tell you that you have cold hands?") and as normal subjects if they reported no such history.12 Subjects describing "sometimes having 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 using methods such as finger LDF,17 no objective assertion of acral vasospasm was performed. Furthermore, an earlier study has shown that by defining vasospasm by a clear history of cold hands, it is possible to observe particular vascular features.12

Patients
Twenty-one patients with progressive primary open-angle glaucoma, including normal-tension glaucoma, were selected. Patients with closed iridocorneal angles, evidence of secondary glaucoma, pseudoexfoliation, pigmentary dispersion, a history of intraocular surgery (except trabeculectomy), any form of retinal or neuroophthalmic disease that could result in visual field defects, or with a history of chronic systemic medication or disease, especially diabetes mellitus, systemic hypertension, or occlusive vascular disorders, were not included. All patients had typical glaucomatous disc and visual field damage and had been referred by their ophthalmologists because of suspected progression of the damage. After informed consent for the use of their clinical data in a scientific publication was obtained from each patient, the patients with glaucoma underwent recording of a diurnal IOP curve (6:00 AM, before arising from bed, 8:00 AM, 11:00 AM, 4:00 PM, and 10:00 PM) during 2 days that showed no readings above 21 mm Hg among the selected patients. Retrospective information regarding visual field results was obtained from the clinical charts. Visual field examinations had been performed with the program G118 on a visual field analyzer (Octopus; Interzeag, Schlieren, Switzerland). The criteria for glaucomatous visual field defects were a cluster of three points (except rim points) in at least one hemifield reduced by 5 dB or greater, and including at least one point reduced by 10 dB or greater, a cluster of two points reduced by 10 dB or greater, or three adjacent points on the nasal horizontal meridian that differed by 5 dB or greater from their mirror points on the opposite side of the meridian. All patients had periodic visual field studies during follow-up for at least 2 years (mean ± SD: 3.6 ± 1.6 years). After the first fields were excluded to avoid learning effect, 5 to 13 examinations per eye (mean ± SD: 7.1 ± 2.3) were considered for the assessment of progression. Patients with poor visual field reliability (false-positive or false-negative errors exceeding 33%) were not enrolled. Enrolled patients had 3 mm or larger pupil diameters when their fields were plotted. Patients with lens changes (defined as loss of more than 1 line of visual acuity with a nuclear sclerotic cataract or the development of any degree of posterior subcapsular cataract) or who underwent cataract extraction with or without trabeculectomy during the follow-up period were excluded. Simple previous trabeculectomy was not considered an exclusion criterion. The definition of visual field progression consisted of a deepening of an existing scotoma, the expansion of an existing scotoma, or a fresh scotoma in a previously normal part of the visual field, at least in the penultimate and the last fields of the selected series per eye. A deepening or an expansion of an existing scotoma was diagnosed if two adjacent points had declined 10 dB from their original levels, and a new scotoma was diagnosed if an alteration meeting the criteria for a visual field defect occurred in a previously normal part of the field. Minimally, each patient underwent five reliable visual field examinations during the follow-up period. An additional visual field examination as a second confirmation of progression in damage was always obtained the day before choroidal LDF measurement, and this visual field examination had also to satisfy the criteria for progression outlined above.

Measurement of the Blood Flow Parameters
Subjects were studied after an overnight fast and were asked to refrain from alcohol and caffeine for 12 hours before the trial days. A resting period of at least 30 minutes was scheduled for each subject. Stable baseline conditions were established that were ensured by repeated measurements of blood pressure. The subjects were seated with the head stabilized in a slit lamp headrest. Care was taken to standardize the subject’s head position, which was held constant throughout the recordings by aligning marks on the headrest with anatomic landmarks on the forehead, the chin, and temporal orbital rim. They were asked to fixate the red light spot within the ocular and to adjust the focus by turning the ocular until the smallest possible size of the red light spot was obtained. The ocular-to-cornea distance was set between 1.5 and 2 cm and held constant throughout the recordings. In addition, a constant very low-level artificial room illumination was used throughout all the experiments. For the healthy subjects, the left eye was chosen arbitrarily as the experimental eye. A stable direct current (DC) during a recording was used as a criterion of proper fixation.19 The same experienced technician, who was masked to the history regarding cold hands of the subjects and was not allowed to shake hands with them, performed all LDF measurements. In patients with glaucoma, the eye with the progressive or the more marked progression was chosen as the experimental eye.

No attempt was made before the choroidal LDF measurement to wash out the topical medication used by the patients. However, patients using topical antiglaucoma medication had to use the same treatment in both eyes for at least 1 year. Previous surgery had to have been performed at least 1 year before the study.

Isometric Hand-Grip Test
An isometric hand-grip test was performed in healthy subjects and patients with glaucoma. The isometric hand-grip test is a specific, sensitive, reproducible, simple, and noninvasive test of sympathetic function with relatively well-studied reflex pathways.20 A bulb dynamometer (Martin Vigorimeter; BCB Ltd., Cardiff, Wales, UK) was used in the present study. The candidates were instructed to hold the ball in their dominant hand in line with the forearm and hanging by the thigh and to exert maximum compressive force on three separate occasions. Each squeezing period was followed by a rest period of 1 minute. The average measurement of the three was calculated as the maximal voluntary contraction. After 5 minutes of recovery, the patients were asked to maintain hand-grip contraction at 33% of the predetermined maximum voluntary contraction force. The grip was maintained for 2 minutes.

Experimental Setup
Before baseline choroidal LDF measurement, the IOP was measured by means of applanation tonometry after applying 1 drop of 0.4% benoxinate hydrochloride and staining the tear film with a strip of fluorescein sodium. After IOP 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 principal as the conventional mercury sphygmomanometer, with a cuff and a microphone. The average of three measurements was considered for blood pressure and pulse rate for further analysis. Afterward, an LDF parameter flux measurement was obtained from the choroid for 20 seconds. After baseline measurement, the subjects performed a hand-grip test for 2 minutes, and the parameters IOP, systemic blood pressure, heart rate, and the LDF parameter flux were assessed again. A final measurement of all the parameters was obtained 3 minutes after release of the hand-grip.

Statistics
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 formula: MABP = 2/3 x DBP + 1/3 x SBP. The ophthalmic artery pressure (OAP) was calculated according to the formula: OAP = 2/3 x MABP. The mean ocular perfusion pressure (MOPP) was calculated according to the formula: MOPP = OAP - IOP.

Differences between the groups in systemic and ocular hemodynamic parameters as well as IOP were assessed by means of Student’s t-test for unpaired variables. Sex distribution in the groups was compared by means of the Fisher exact test.

In healthy subjects, the changes in systemic hemodynamics, IOP, and choroidal blood flow and differences between the vasospastic and control groups in these changes during the hand-grip test was assessed in a two-way (repeated measurements of LDF parameter flux; two groups) analysis of variance (ANOVA) model with OPP as a changing covariate. The latter statistical computations were performed with a multivariate approach, to ascertain the conservation of sphericity (independence of the change at each step from the other changes in repeated-measures ANOVA models containing repeated-measurement factors with more than two levels).

In patients with glaucoma, the difference in IOP between patients showing a decrease of at least 10% (arbitrary limit) in the LDF parameter flux during the hand-grip test and those without such a response was analyzed in a multivariate ANOVA model.

All statistical tests were two-sided, and all tests for main effects or interaction effects with a corresponding P ≤ 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Healthy Subjects
Among the 80 healthy volunteers, 36 subjects (29 women and 7 men) related a history of acral vasospasm and 44 (15 women and 29 men) did not. The difference in sex distribution was statistically different between the experimental groups (Fisher exact test: P < 0.0001). The mean (±SD) age was 42 ± 12 years for the 36 with vasospasm and 46 ± 13 years for the 44 control (P = 0.18). Hemodynamic parameters such as SBP, DBP, MABP, OAP, MOPP, and IOP have been outlined in Table 1 . Systemic hemodynamic parameters were consistently lower among subjects with vasospasm, but IOP was comparable between the two groups. The choroidal LDF parameters in the left eye of the vasospasm and control groups have been outlined in Table 2 . These parameters were statistically comparable between the subjects with vasospasm and the control group, except for velocity at baseline (Table 2) .


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  		TABLE 1. Systemic Hemodynamic Parameters and Intraocular Pressure in Healthy Subjects

 

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  		TABLE 2. Choroidal LDF Parameters in Healthy Subjects

 
SBP, DBP, MABP, OAP, MOPP, and IOP varied significantly (P < 0.0001 for all parameters and in both experimental groups) during the hand-grip test, but this variation was comparable between the experimental groups (ANOVA: P = 0.96, P = 0.54, P = 0.70, P = 0.70, P = 0.54, and P = 0.69, respectively). When only the change between baseline and the period of maximal stimulation during isometric exercise was considered, SBP, DBP, MABP, OAP, MOPP, increased in the vasospasm (21.1%, 11.7%, 15.5%, 15.5%, and 24.0% respectively) and control (19.5%, 14.0%, 16.2%, 16.2%, and 24.1% respectively) groups, whereas IOP decreased in both groups (2.5% and 4.5% in the vasospasm and control groups, respectively). The observed changes between baseline and the period of maximal stimulation during isometric exercise were comparable between the experimental groups for all the parameters (two-way ANOVA: SBP: P = 0.98; DBP: P = 0.52; MABP: P = 0.62; OAP: P = 0.62; MOPP: P = 0.45; and IOP: P = 0.39). Mean pulse rate at baseline, after isometric exercise, and after recovery was 72.97 ± 9.21, 80.94 ± 11.91, and 73.44 ± 9.28 beats per minute, respectively, in the vasospasm group, and 70.80 ± 8.88, 78.50 ± 10.03, and 73.07 ± 8.50 beats per minute respectively in the control group. The variation in pulse during the hand-grip test was comparable between the experimental groups (two-way ANOVA: P = 0.18), indicating a comparable sympathetic arousal.

Comparing the change of the choroidal LDF parameters in a two-way ANOVA model with OPP as the changing covariate disclosed that the observed variation in velocity (P = 0.11) and volume (P = 0.21) were comparable between the experimental groups. When both groups were considered together, velocity decreased significantly (P = 0.035), whereas volume (P = 0.49) did not show a significant variation. The variation in the choroidal LDF parameter flux, however, was significantly (P = 0.039) different between the experimental groups (Fig. 1) . Planned comparisons in the latter model disclosed that the change between baseline blood flow and blood flow during isometric exercise (P = 0.022) and the change between blood flow during isometric exercise and blood flow after recovery (0.031) were significantly different between the two experimental groups, whereas the difference between blood flow at baseline and after recovery was comparable (P = 0.70). Consequently, subjects with a positive history of cold hands showed a decrease in blood flow during isometric exercise while control subjects showed an inverse response (Table 2) . Both groups recovered to baseline values at the end of the stimulation (Fig. 1) . To exclude that the difference between the groups was due to a difference in sex distribution, choroidal blood flow variation was compared between female and male subjects in a two-way ANOVA model with OPP as the changing covariate, disclosing that the choroidal LDF-determined flux varied comparably in women and men (P = 0.18).



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  		FIGURE 1. The choroidal LDF parameter flux (the variably sized central boxes represent the SEM and the whiskers represent the SD of the data) showed a statistically significant (P = 0.039) difference in response to the handgrip test in subjects with vasospasm compared with control subjects.

 
Patients
Based on the findings in healthy subjects, a decrease in the LDF-measured flux during the hand-grip test was considered abnormal, and the limit of relevance was set at a change of 10% or more.15 Among the 21 patients with glaucoma, 7 patients (4 women and 3 men) showed a decrease of 10% and more in choroidal blood flow during the hand-grip test and 14 patients (6 women and 8 men) did not. The difference in sex distribution was statistically comparable between the two groups (Fisher exact test: P = 0.66). The mean (±SD) age was 60 ± 17 years for the 7 patients showing a decrease of 10% in choroidal blood flow and 63 ± 12 years for the 14 patients who did not show such a decrease (P = 0.67). The topical treatment of the patients with glaucoma is detailed in Table 3 . Previous trabeculectomy had been performed in seven patients with open-angle glaucoma. Eight patients had no local treatment (six with normal-tension glaucoma and two with open-angle glaucoma who had a previous trabeculectomy), and treatment was not significantly different between the two groups of patients with glaucoma (Table 3) . Based on the clinical information available, five patients among those showing a decrease of 10% in choroidal blood flow had open-angle glaucoma and two patients had normal-tension glaucoma. Among the patients not showing a decrease of 10% in choroidal blood flow, 10 had open-angle glaucoma and 4 had normal-tension glaucoma (P = 1.0). The visual field index mean defect in the experimental eye was 6.16 ± 4.77 dB in the 7 patients showing a decrease of 10% in choroidal blood flow and 10.39 ± 6.70 dB in the 14 patients who did not show such a decrease (P = 0.15).


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  		TABLE 3. Number of Patients with Previous Trabeculectomy or Receiving Topical Medication

 
The Hemodynamic parameters SBP, DBP, MABP, OAP, MOPP, and IOP in the experimental eye in patients with glaucoma are outlined in Table 4 . These parameters were comparable between the two groups at all time points of the experiment, except for IOP (see separate analysis). The choroidal LDF parameters are outlined in Table 5 for the patients with glaucoma. These parameters were statistically comparable between the two groups at all time points of the experiment.


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  		TABLE 4. Systemic Hemodynamic Parameters in Patients with Glaucoma

 

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  		TABLE 5. Choroidal LDE Parameters in Patients with Glaucoma

 
SBP, DBP, MABP, OAP, MOPP, and IOP in the experimental eye varied significantly (P < 0.01 for all parameters) during the hand-grip test, but this variation was comparable between the experimental groups (ANOVA: P = 0.22, P = 0.30, P = 0.17, P = 0.17, P = 0.19, and P = 0.28, respectively). Pulse at baseline, after isometric exercise, and after recovery was 62.00 ± 11.39, 65.71 ± 10.73, and 61.00 ± 10.25 beats per minute, respectively, in patients showing a decrease of 10% in choroidal blood flow during the hand-grip test, and 75.44 ± 16.30, 80.67 ± 16.00, and 76.67 ± 15.48 beats per minute, respectively, in patients not showing such a decrease in choroidal blood flow. The variation of pulse during the hand-grip test was comparable between the two groups (two-way ANOVA: P = 0.46), indicating a comparable sympathetic arousal. However, patients showing a decrease of 10% in choroidal blood flow during the hand-grip test had on average a borderline significantly lower pulse rate (two-way ANOVA: P = 0.054).

The average IOP of the diurnal tension curves of both eyes was compared between patients showing a decrease of 10% in choroidal blood flow during the hand-grip test and those not showing such a decrease, using a multivariate model of analysis of variance. IOP in right and left eyes was 14.67 ± 3.83 and 13.50 ± 2.59 mm Hg, respectively, in patients showing a decrease of 10% in choroidal blood flow during the hand-grip test, and 16.54 ± 3.84 and 16.92 ± 2.96 mm Hg, respectively, in patients who did not show such a decrease in choroidal blood flow (Fig. 2) . This difference in IOP between the two groups was statistically significant (P = 0.032).



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  		FIGURE 2. IOP (the variably sized central boxes represent the SEM and the whiskers represent the SD of the data) was significantly lower (P = 0.032) in patients with progressive damage who showed a decrease of at least 10% in choroidal blood flow during the handgrip test, when compared with patients with glaucoma with progressive damage who did not.

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The present study assessed the response of choroidal blood flow to isometric exercise, and, seemingly, disclosed a qualitative difference in blood flow response pattern between otherwise healthy subjects with a positive history of cold hands and control subjects. Although choroidal blood flow decreased during the hand-grip test in healthy subjects with a positive history of cold hands, an inverse response pattern was observed in control subjects, although systemic parameters, especially perfusion pressure showed comparable alterations. It is not the change in blood flow that was statistically significant, but only the fact that blood flow changes occurred in opposite directions. A second study in patients with primary open-angle glaucoma with progressive damage despite normal or normalized IOP indicated that patients with a decrease of at least 10% in choroidal blood flow during the hand-grip test seem to have progression of visual field damage at lower levels of IOP, suggesting a higher sensitivity to IOP.

Despite significant changes in perfusion pressure during the hand-grip test, only slight, statistically nonsignificant, variations in choroidal blood flow were observed in subjects with a positive history of cold hands as well as control subjects. The isometric hand-grip test increases heart rate, arterial pressure, and sympathetic nerve activity.20 21 22 23 The protective role of the sympathetic nervous system in the vasoconstriction of the choroidal circulation in response to arterial hypertension has been studied in animals24 25 26 and humans.27 28 29 The current data, together with other investigations,27 28 29 indicate that the maintenance of constant choroidal blood flow during sympathetic stimulation in humans is achieved through an increase in ocular vascular resistance. The volume sampled by the laser, which contains mainly the choriocapillaris,15 did not change significantly during the hand-grip test, indicating that the change in resistance during the hand-grip test must occur proximal to the choriocapillaris, including larger choroidal vessels and/or branches of the ophthalmic artery feeding the foveal region of the choroidal circulation.

In a previous study, a positive correlation between choroidal blood flow in the foveal choriocapillaris and OPP was observed in subjects with vasospasm, whereas such a behavior was not observed in the control group.12 This study indicated that choroidal blood flow-regulating mechanisms may be different between those with and those without vasospasm. The present data confirm dissimilar choroidal vasoregulatory mechanisms between subjects with vasospasm and control subjects. Furthermore, those with vasospasm had a higher propensity to be female, to have low systemic blood pressure and low OPP, also confirming earlier results.10 Comparable variations in blood pressure and pulse rate in the present study indicate a comparable sympathetic arousal in both experimental groups of healthy subjects. The calculated change in vascular resistance (perfusion pressure divided by choroidal blood flow) during the isometric exercise, however, reached 25.96% and 57.54% in control subjects and subjects with a positive history of cold hands, respectively. These figures indicate that, rather than a qualitative difference in the vascular response, subjects with vasospasm seem to overreact to the hand-grip test with a disproportionate choroidal vasoconstriction, but with an increase in blood pressure not different from that in control subjects, leading to a decrease in choroidal blood flow. In addition to variations in systemic blood pressure and pulse, IOP decreased in healthy subjects and in patients with glaucoma during the isometric exercise, which was not surprising, because several studies had previously demonstrated reduction in IOP in the face of isotonic or isometric workload, explaining it by neural, osmotic, chemical, and vascular mechanisms.30 31 32 33 34 35

Although the major known risk factor in glaucoma is IOP, other factors have been suggested to participate in the pathogenesis of glaucoma. Recent findings indicate that very aggressive reduction in IOP may preserve visual fields in patients with glaucoma.36 In the latter study, the level of IOP close to orbital venous pressure in patients with stable visual fields suggests that prevention of perturbation of ocular blood flow by IOP may be important for the preservation of the optic nerve in glaucoma. An ocular vascular dysregulation has been postulated in glaucoma,37 and a dependence of ocular blood flow on perfusion pressure has been demonstrated in patients who have progressive glaucoma despite normalized IOP.13 The present data support the idea that some patients with glaucoma are more sensitive to IOP. All included patients with glaucoma had progressive damage despite normal or normalized IOP. However, patients exhibiting a decrease of at least 10% in choroidal blood flow during the hand-grip test seemed to progress at lower levels of IOP. How such reactivity might impinge on axonal survival is unclear. Differences in local treatment do not explain the observed effect (Table 3) . If a similarly altered vascular responsiveness occurs within the optic nerve circulation, the exaggerated vasoconstrictive response to sympathetic stimulation may perturb blood flow, affecting ocular blood flow in a manner comparable to the effect of low perfusion pressure and, thus, enhancing the detrimental effect of IOP. An alternative explanation may be the occurrence of ischemia-reperfusion damage in patients with exaggerated vasoconstrictive response to sympathetic stimulation. Although much is still unclear regarding ischemia-reperfusion damage in glaucoma, recent findings indicate an altered gene expression in patients with glaucoma suggesting, indeed, a reperfusion damage of the optic nerve in glaucoma.37 38 Most important, these two hypothesis are not necessarily mutually exclusive.

A defect in agonist-mediated release of endothelium-derived vasodilators has been described in peripheral vessels in patients with normal-tension glaucoma.39 40 In vivo studies in animals41 42 43 and humans44 45 have demonstrated the role endothelial factors play in the regulation of choroidal blood flow. Consequently, endothelial dysfunction may be the source of the observed alteration in the behavior of the choroidal circulation of some patients with glaucoma during the handgrip test. Although endothelin-1, a potent endothelial vasoconstrictor, does not seem to substantially contribute to the regulation of basal choroidal vascular tone in healthy humans,46 it must be considered that increased plasma levels of endothelin-1 have been described in some patients with glaucoma.47 Recently, it was demonstrated that administration of an endothelin-1 antagonist may enhance blood flow increase in the choroid during isometric exercise.48 It is, therefore, conceivable, but this is purely hypothetical, that increased levels of endothelin may enhance the vasoconstrictor response to sympathetic stimulation in some patients with glaucoma. Alternatively, a deficient release of endothelium-derived vasodilators39 40 may have altered choroidal blood flow during isometric exercise.49

Choroidal blood flow was assessed by means of LDF technology. Measurements of choroidal blood flow using 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.15 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. Regarding the contribution from retinal capillaries, a recent study performed with this instrument demonstrated no detectable change in choroidal blood flow in response to 100% oxygen breathing, confirming the absence of contribution from the retina.50 Indeed, studies assessing the response of choroidal blood flow to changes in OPP,28 29 51 arterial blood oxygen, or carbon dioxide tensions29 50 and Valsalva15 support the assumption that choroidal LDF measures changes in choroidal blood flow in the foveal region.15

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 response to alterations in perfusion pressure and sympathetic stimulation. Regional differences in the responsiveness of the cat’s choroidal circulation support the assumption that specific regulatory mechanisms may prevail in the foveal region.52 53 54 55 In the present study, it is also striking that baseline choroidal blood flow in patients with glaucoma is markedly higher than in normal subjects. However, the study was not designed to compare hemodynamic parameters between normal subjects and patients with glaucoma. The recording conditions were dissimilar and were obtained at different locations, and the two populations were not age matched. The inconsistent reports on the effect of age on the LDF parameters volume and flux,15 56 57 and the high sensitivity to recording conditions of the device used19 make any conjecture vain. In the absence of any study comparing measurements obtained with choroidal LDF between normal persons and patients with glaucoma, it is probably advisable not to rely on absolute measurements, but to limit interpretations to changes observed during the measurements.15

A further important limitation of the present study should be mentioned. The patients had been referred by their ophthalmologists because of suspected progression in glaucomatous damage. It seemed to be easier to obtain information on previous visual fields than on IOP measurements during the follow-up period. Therefore, we opted for selecting patients without change in treatment for at least 1 year, as an indication that IOP may have been under control, and obtained a diurnal IOP tension curve during 2 days. Although this was the best approximation of the patients’ level of IOP that we could obtain in this retrospective evaluation of the patients’ status, it may relatively imperfectly reflect the IOP level that may have contributed to the observed progression. Finally, the study design did not evaluate the response to the handgrip test in different types of patients with glaucoma. The present study design rather represents an exploratory approach. As opposed to traditional hypothesis testing designed to verify a priori hypotheses about relations between variables, exploratory data analysis is used to identify systematic relations between variables when there are no (or not complete) a priori expectations as to the nature of those relations. In this spirit, we assessed whether an altered response to the hand-grip test may discriminate different types of patients with glaucoma. The current results suggest indeed a potential discriminating ability of the test. However, exploratory data analysis can only be treated as tentative at best as long as the results are not confirmed, and the predictive validity of the handgrip test regarding susceptibility to IOP in patients with glaucoma will have to be evaluated in future studies.

In summary, otherwise healthy subjects with systemic vascular dysregulation may show an increased ocular vasoconstrictive response to sympathetic stimulation. In patients with glaucoma with a vasoconstrictive response inducing a choroidal blood flow reduction of at least 10%, the consecutive blood flow alterations may lead directly, through ischemia-reperfusion damage, or indirectly, through an increased sensitivity to IOP, to axonal damage, despite normal or normalized IOP. It remains to be determined whether the handgrip test may be helpful in determining target IOP in glaucoma treatment.


   Footnotes
 
Supported by the Swiss National Foundation Grant 32-059094.99.

Submitted for publication May 30, 2002; revised December 5, 2002; accepted December 16, 2002.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Selim Orgül, University Eye Clinic Basel, Mittlere Strasse 91, PO Box, 4012 Basel, Switzerland; sorgul{at}magnet.ch.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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