rior ciliary artery supplying the choroid a negative correla- tion between blood flow velocities and age was observed with. CDL3 Moreover, a small increase in ...
Age Dependence of Choroidal Blood Flow Susanne Dallinger, MD,' Oliver Findl, MD,t Karin Strenn, MD,t Hans-Georg Eichler, MD,* Michael Wolxt, MD, * and Leopold Schmetterer, PhD'#
OBJECTIVE: To investigate the age dependence of choroidal blood flow. DESIGN A cross-sectional study. SETTING: Department of Clinical Pharmacology, Vienna University. PARTICIPANTS:A total of 130 healthy volunteers between the ages of 19 and 83 years. MEASUREMENTS:Fundus pulsation amplitude (FPA)with a recently developed laser interferometric method, mean arterial pressure (MAP) with an automated oscillometric device, intraocular pressure (IOP) with an applanation tonometer, and ocular perfusion pressure (OPP) as calculated from MAP and IOP. RESULTS: There was a significant correlation of FPA with age I = -0.242 (P = .005).MAP, IOP, and OPP showed a significant positive correlation with age. Multiple regression analysis showed that FPA is associated with age but not with MAP, IOP, or OPP. CONCLUSION: Choroidal blood flow is reduced in older subjects, which argues in favor of an increase in ocular vascular resistance with age. This may be a risk factor in the development of common ocular diseases such as age-related macular degeneration or glaucoma J Am Geriatr SOC 46:484-487, 1998. ~
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here is evidence that several ocular diseases, such as age-related macular degeneration and glaucoma, are associated with ocular blood flow abnormalities. Both pathologic states are associated with a high incidence of visual impairment in older patients. However, relatively few studies have focused on the age dependence of ocular blood flow. The results of the effect of aging on retinal blood flow are contradictory. Grunwald et al.' reported a decrease in retinal macular blood flow in older subjects as evidenced by a blue field entoptic study. Yoshida et al.,' however, observed an increased retinal blood flow with laser Doppler velocimetry in normal middle-aged subjects compared with young subjects. Blood flow velocities in the central retinal artery do not show age de endence, as evidenced from color Doppler imaging (CDI).P From the 'Department of Clinical Pharmacology, tDepartmenr of Ophrhalmology B, and *Institute of Medical Physics, Vienna University, Vienna, Austria. Address correspondence to L. Schmetterer, Department of Clinical Pharmacology, Wahringer Giirtel 18-20, A-1090 Vienna, Austria
JAGS 4 6 : 4 8 4 4 8 7 , 1 9 9 8 0 1998 by the American Geriatrics Society
Investigations of choroidal circulation are difficult because only a few methods are available for the assessment of hemodynamic parameters in this vascular bed. In the posterior ciliary artery supplying the choroid a negative correlation between blood flow velocities and age was observed with CDL3 Moreover, a small increase in resistive index was observed with increasing a e, which is indicative of an increased vascular resistance.Is Ravalico et aL4 reported a decrease in pulsatile ocular blood flow (POBF) with age as measured with pneumatic tonometry. However, both CDI and pneumatic tonometry have important limitations in assessing choroidal blood flow. CDI measures blood flow velocities in retrobulbar vessels without any information on vessel diameter. POBF, as calculated from pneumatic tonometry, is dependent on ocular rigidity, which cannot be measured in vivo. In contrast, laser interferometric measurement of fundus pulsation, a recently developed noninvasive procedure, provides a more direct measure of pulsatile ocular blood flow.' We have applied this method to investigate the age dependence of choroidal blood flow.
MATERIALS AND METHODS One hundred thirty eyes of 130 nonsmoking subjects were included in the present study. One hundred three subjects were male and 27 were female. All subjects gave written informed consent to participate. An ophthalmic examination, including slit lamp biomicroscopy, indirect funduscopy, and applanation tonometry was performed. Inclusion criteria were ametropia of less than 3 diopters and an intraocular pressure (IOP)of less than 21 mm Hg. Exclusion criteria were any evidence of ocular vascular disease, a visual acuity of less than 0.7, systemic hypertension (defined as systolic blood pressure > 160 mm Hg or diastolic blood pressure > 90 mm Hg), and diabetes mellitus. The eyes were divided into three groups with almost equal age spans. The younger group (n = 52) included subjects between 19 and 39 years of age (28.0 -+ 5.4 years), the group of middle aged subjects (n = 42) included subjects between 40 and 59 years of age (48.1 2 5.0 years), and the group of older patients (n = 36) included subjects between ages 60 and 83 (70.9 -+ 5.5 years). Systolic, diastolic, and mean blood pressures were measured on the upper arm by an automated oscillometric device. Pulse rate was recorded automatically from a finger pulseoxymetric device (HP-CMS patient monitor, Hewlett Packard, Palo Alto, CA). Pulse synchronous pulsations of the ocular fundus were assessed by laser interferometry. The method is described in
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detail by Schmetterer et al.' Briefly, the eye is illuminated by the beam of a single mode laser diode with a wave length ( A ) of 783 nm. The light is reflected at both the front side of the cornea and the retina. The reflection from the retina most likely occurs from Bruch's membrane.6 The two re-emitted waves produce interference fringes from which the distance changes between cornea and retina during a cardiac cycle can be calculated. Distance changes between cornea and retina lead to a corresponding variation of the interference order (AN(t)).This change in interference order can be evaluated by counting the fringes moving inward and outward during the cardiac cycle. Changes in optical distance (AL(t)), corresponding to the cornea-retina distance changes, can then be calculated by AL(t) = AN(t).M2. The maximum distance change is called fundus pulsation amplitude (FPA) and estimates the local pulsatile blood flow. The short-term and day-to-day variability of the method is small,' which allows detection of even small drug-induced changes in local pulsatile blood f l o ~ . In ~ .contrast ~ to systems recording ocular pressure pu1se,10-13 information about ocular circulation can be obtained with high topographical resolution. To obtain information on choroidal blood flow, the macula, where the retina lacks vasculature, was chosen for measurement^.'^"^ A slit-lamp-mounted Goldmann applanation tonometer was used to measure intraocular pressure (IOP). Before each measurement, 1 drop of 0.4% benoxinate hydrochloride combined with 0.25% fluorescein sodium was used for local anesthesia of the cornea. Ocular perfusion pressure (OPP) was calculated as OPP = 2/3*MAP-IOP (MAP = mean arterial pressure).'6 Statistical analysis was done with CSS Statistica for Windows@(Statsoft Inc., Tusla, CA). Results are presented as arithmetic mean 1standard deviation. FPA, MAP, IOP, and OPP were chosen as outcome variables. Analysis of variance was used to compare the outcome variables in the three study groups. Linear regression analysis was performed to determine correlations among the outcome variables and age. Multiple regression analysis was performed to determine correlations among FPA and the other variables. The level of significance was set at P = .05. RESULTS The results of hemodynamic parameters and 1OP in the three study groups are presented in Table 1. FPA declined significantly with age (P = .026).The FPA was smaller in the middle-aged subjects (group 2), than in the group of younger subjects (group 1). MAP increased with age (P < .001) although the difference between group 2 and group 3 was small. There was also a significant age-associated increase in IOP ( P = .004)and OPP (P= .006).
There was a significant negative correlation between FPA and age (Figure 1 , upper panel). The correlation coefficient was Y = -.242 ( P = ,005).In contrast, MAP, IOP, and OPP showed a significant positive correlation with age. The correlation coefficient was highest for MAP ( Y = .405,P < .001). The correlation was also highly significant for IOP ( I = .396, P < .001) and OPP ( I = .235, P = ,007, Figure 1, lower panel). The correlation between OPP and age was, however, weaker than the correaltion of MAP with age because the calculated values of OPP are also dependent on IOP. Pulse rate did not correlate with age (data not shown). The results of multiple regression analysis are shown in Table 2. FPA values showed a significant correlation with age. In contrast, FPA was not dependent on MAP, IOP, or OPP.
DISCUSSION The present study provides evidence that choroidal blood flow is reduced in older subjects. Our multiple regression analysis shows that FPA was significantly associated with age but not with OPP or IOP. In a previous study in patients with diabetic retinopathy, we did not observe an age dependence of ocular fundus pulsation." In this earlier study we also included patients with systemic hypertension and found a significant correlation between MAP and FPA, which we did not observe in the present study in normotensive subjects. Because we also observed a significant positive correlation between MAP and age in the diabetic study cohort, we may have missed the age dependence of fundus pulsations in these patients. In the present study we observed a significant positive correlation between MAP and age and between IOP and age. Moreover, OPP, as calculated from brachial artery blood pressure and IOP, was correlated to age. As in other vascular beds, choroidal blood flow is determined by perfusion pressure and vascular resistance. Taken together, the positive correlation of OPP with age and the negative correlation of FPA with age argue in favor of an increased ocular vascular resistance in older subjects. There is a high incidence of age-related macular degeneration and glaucoma in older patient^.'^.'^ Several studies have shown that reduced ocular blood flow is associated with age-related macular degeneration2Os2' and g l a u c ~ m a . ~ ~ - ~ Therefore the age dependence of choroidal blood flow may well be a risk factor for the development of these ocular diseases in older subjects. The reason for this age dependence of ocular blood flow is not clear, but it may be associated with an altered endothelial function. It has been shown that aging is associated with reduced endothelium-dependent relaxations to vasoactive
Table 1. Fundus Pulsation Amplitude, Mean Blood Pressure, Intraocular Pressure, and Ocular Perfusion Pressure in the Three Study Groups. Data Are Given as Mean SD
Fundus pulsation amplitude (pm) Mean arterial pressure (mm Hg) lntraocular pressure (mm Hg) Ocular perfusion pressure (mm Hg)
Group 1 (age 20-39 years)
Group 2 (age 40-59 years)
Group 3 (age 60-83 years)
3.81 2 1.10 91 + 9 14.1 2 2.2 47 2 7
3.59 + 1.02 99 7 15.3 2 2.0 51 2 5
3.27 2 0.90 100 f 6 16.4 It 1.9 50 4
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Figure 1. Association between fundus pulsation amplitude (FPA) and age (upper panel) and ocular perfusion pressure (OPP)and age (lower panel). The solid lines represent the correlation lines, the dotted lines represent the 95% confidence intervals. Table 2. Multiple Regression Analysis Between Fundus Pulsation Amplitude and Age, Mean Arterial Pressure, Intraocular Pressure, and Ocular Perfusion Pressure P Value Age Mean arterlal pressure lntraocular pressure Ocular petfusion pressure
.004 .095 .142 .231
substances such as acetylcholine and h i ~ t a m i n eMoreover, .~~ the choroidal blood flow is strongly dependent on endothelial-derived vasoactive substances such as nitric o ~ i d e ’ ~ ,and ~’ endothelin-1 .28*29 A negative correlation between pulsatile ocular blood flow and age was observed previously with pneumotonometric technique^.^^^' Moreover, blood flow velocities in the posterior ciliary arteries are reduced in older subject^.^*^* In contrast, no age dependence of choroidal blood flow has been evidenced from fluorescein a n g i ~ g r a p h y . ~ ~
It must be noted that none of the methods discussed measures volumetric choroidal blood flow. Even in animals, as recently reviewed by Kiel, there is no gold standard for choroidal blood flow m e a s ~ r e m e n tHence, . ~ ~ it is difficult to validate noninvasive techniques, which are applicable in humans, using comparative blood flow studies in animals. With respect to CDI, it must be emphasized that only blood flow velocities, not vessel diameters, can be measured. Hence, a reduction in flow velocity can be caused by two distinct phenomena: (1)a decrease in blood flow through the vessel or (2) a dilation of the vessel without a concomitant change in blood flow. Which of these two possibilities applies to older patients cannot be decided absolutely. Extraction of choroidal hemodynamic parameters from fluorescein angiograms is difficult, and this method has several limitation^.^^ Finally, pneumotonometric measurement of POBF is based on the recording of the ocular pressure pulse, which is the change in IOP during the cardiac cycle. For the calculation of volume changes during the cardiac cycle, the scleral rigidity, which cannot yet be measured in vivo, has to be known. Therefore, an average scleral rigidity is used for the calculation, and this may introduce considerable error. In addition, although previous studies did not observe age de-
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pendence with scleral rigidity, it cannot be excluded that the mechanical properties change with age.35 In contrast, fundus pulsation amplitude is a more direct measure, of changes in blood volume during the cardiac cycle. The absolute value of FPA in the macula is, however, influenced by the choroidal angioarchitecture, which shows a considerable degree of interindividual ~ a r i a t i o n . ”This ~ does not limit our results because an age dependence of choroidal angioarchitecture seems very unlikely. Moreover, it must be emphasized that FPA only estimates the pulsatile component of ocular blood flow. The pulsatile blood flow may comprise SO3’ to 80%” of the total blood flow in the choroid, but no conclusions on total blood flow can be drawn when the flow pulsatility cannot be predicted. Previous CDI experiments in the posterior ciliary arteries, which supply the choroid, show that flow pulsatility is increased in older patients.3331Hence, FPA measurements may underestimate the dependence of choroidal blood flow on age. In conclusion, we have shown that there is a significant negative correlation between fundus pulsation amplitude and age. This indicates that choroidal blood flow is reduced in older subjects, which may be a risk factor for the development of common ocular diseases such as age-related macular degeneration or glaucoma.
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