http://informahealthcare.com/cot ISSN: 1556-9527 (print), 1556-9535 (electronic) Cutan Ocul Toxicol, Early Online: 1–5 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2014.950380
RESEARCH ARTICLE
Effects of cigarette smoking on choroidal and retinal thickness and ocular pulse amplitude Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by University of Connecticut on 10/11/14 For personal use only.
Mehmet Serdar Dervi¸sog˘ulları, Yu¨ksel Totan, Aylin Tenlik, and Aslihan Yuce ¨ zal University, Ankara, Turkey Department of Ophthalmology, Medical School, Turgut O
Abstract
Keywords
Background: In our study, we aimed to show the effects of smoking on choroidal thickness and ocular pulse amplitude. It is known that the anatomy and physiologic functions of the choroid is important in ocular diseases like glaucoma and age-related macular degeneration. Choroidal thickness is measured by the spectral domain optical coherence tomography (SD-OCT). The ocular pulse amplitude (OPA) is the difference between the systolic and diastolic intraocular pressure (IOP) and it is an index of choroidal perfusion. Design: This was a cross-sectional prospective observational study at the Turgut Ozal University Hospital setting. Participants: The test subjects were divided into two groups: the smokers group which consisted in 24 participants (20 male, 4 female) and the control group with 22 participants (16 male, 6 female). Methods: The participants underwent full ophthalmological examination including best-corrected visual acuity (BCVA), spherical equivalent (SE) values of refractive errors, intraocular pressure (IOP), ocular pulse amplitude (OPA), central corneal thickness (CCT), axial length (AL) and choroidal thickness. The IOP and the OPA were measured with the dynamic contour tonometer. The CCT and the AL were measured with the Nidek AL-Scan (Nidek Co., Ltd., Gamagori, Japan). The choroidal thickness was measured by the Cirrus high-definition optical coherence tomography (Cirrus Version 6.0; Carl Zeiss Meditec, Dublin, CA). Results: Gender did not differ significantly between the groups (p ¼ 0.12). The age, SE, IOP, OPA, CCT and AL did not differ significantly in smokers and control groups (p ¼ 0.12, p ¼ 0.37, p ¼ 0.54, p ¼ 0.80, p ¼ 0.56 and p ¼ 0.82, respectively). The nasal, temporal, central retinal (p ¼ 021, p ¼ 021, p ¼ 0.11) and nasal, temporal, central choroidal thicknesses (p ¼ 0.80, p ¼ 0.39, p ¼ 0.75) did not differ significantly between smokers and control groups. Conclusions: We could not find a significant difference in OPA, retinal and choroidal thicknesses between smokers and non smokers. Further studies including histopathological changes in larger groups are needed to show the effect of smoking on choroidal thickness especially in patients with ocular diseases like age-related macular degeneration.
Choroidal thickness, ocular pulse amplitude, smoking
Introduction One of the risk factors that are important in developing systemic and ocular vascular diseases is cigarette smoking1. It is known that smoking is especially associated with anatomical alterations of the arterial system including an increase in arterial wall thickness and atherosclerosis, both in the microvasculary and macrovasculary structures2,3. Although the exact pathogenesis is not identified yet, it is known that smoking can cause a decrease in the retinal blood flow4–6. It is also shown that an acute significant decrease occurred in choroidal thickness within the first couple of hours following smoking7.
Address for correspondence: Mehmet Serdar Dervi¸sog˘ulları, Department ¨ zal University, Ankara, of Ophthalmology, Medical School, Turgut O Turkey. E-mail: [email protected]
History Received 3 June 2014 Revised 15 July 2014 Accepted 26 July 2014 Published online 29 August 2014
The choroid is a highly vascularized tissue. It provides oxygen and nourishment to the outer retinal layers and regulates heat at the foveal region. Nearly 90% of the ophthalmic artery blood flow is received by the choroid8,9. It has been shown that the anatomy and physiologic functions of the choroid is quite important in the development of ocular diseases like glaucoma10. Several studies have reported noninvasive in vivo measurements of the choroidal thickness with the spectral domain optical coherence tomography (SD-OCT) in normal subjects and choroidal or retinal diseases11–22. The choroidal thickness can be measured by the high definition optical coherence tomography. The image size is doubled, foveally centered and the subfoveal choroidal thickness can be measured manually from the outer portion of the hyper reflective line corresponding to the retina pigment epithelium to the inner surface of sclera by the linear measuring tool of Cirrus software. The difference between the
2
M. S. Dervi¸sog˘ulları et al.
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systolic and diastolic intraocular pressure (IOP) is called the ocular pulse amplitude (OPA) and it is caused by cardiovascular pulsations and ocular blood flow. The OPA is an index of choroidal perfusion23,24. There are many different methods for measuring the OPA and choroidal perfusion25. The dynamic contour tonometer (DCT; Swiss Microtechnology AG, Port, Switzerland) is a relatively new technology that allows the measurement of both intraocular pressure (IOP) and ocular pulse amplitude. In this study, we aimed to show the effects of smoking on choroidal thickness and OPA as most of the ophthalmic artery blood flow is received by the choroid and OPA is the index of choroidal perfusion.
Materials and methods This cross-sectional prospective observational study was carried out with the participants recruited from the patients, patients’ relatives and hospital staff of the Turgut Ozal University Hospital from 1 May to 1 November 2013. This study was performed in adherence with the tenets of the Declaration of Helsinki and was approved by the local ethics committee. Informed consent was obtained from all of the study participants. The study participants were divided into two groups. The smokers group was formed by participants who were healthy cigarette smokers for more than10 years with no other systemic or ocular disease. The control group consisted of age- and gender-matched healthy non-smokers and these participants of the control group never smoked. The smokers group was also gender balanced. The smokers group consisted of 48 eyes of 24 participants (20 male, 4 female). In the control group, 44 eyes of 22 participants (16 male, 6 female) were investigated. Both eyes were evaluated. The participants underwent full ophthalmological examination including best corrected visual acuity (BCVA), spherical equivalent (SE) values of refractive errors, IOP, OPA, central corneal thickness (CCT), axial length (AL) and choroidal thickness. The IOP and the OPA were measured with the DCT by an experienced operator (MSD) after administering topical anesthesia. The CCT and the AL was measured using the Nidek AL-Scan (Nidek Co., Ltd., Gamagori, Japan). The choroidal thickness was measured by the Cirrus high definition optical coherence tomography (HD-OCT, Cirrus Version 6.0; Carl Zeiss Meditec, Dublin, CA). Participants with any ocular disease that prevents the examination of the cornea and retina, a history of any ocular surgery, ocular or systemic disease and taking any medication within the last 3 months in both groups, a history of smoking or alcohol intake in the control group, a history of alcohol intake in the smokers group were excluded from the study. Patients with 25–50 years of age, spherical refractive error smaller than 3 diopters (D), cylindrical refractive error smaller then 1 D, best corrected visual acuity of 20/20 or better, no history of chronic ocular disease, normal blood pressure (brachial systolic/diastolic blood pressure smaller than 140/90 mmHg) and normal blood parameters were included. Blood parameters included complete blood count, clinical chemistry (glucose, sodium, potassium, creatinine,
Cutan Ocul Toxicol, Early Online: 1–5
uric acid, total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, total bilirubin and total protein) and thyroid function test (thyrotropin, free T4 and total T3). It was ascertained that the participants in the control group were not passive smokers and were not exposed to cigarette smoke at home or work. The standard pack year method was used to measure the incidence and degree of smoking and participants with minimum 10-years of smoking history with at least one pack of cigarettes per day for 1 year were included. The subjects who can not meet any of the screening criteria were excluded. All OCT scans were performed by the same experienced technician the day after the examination between 8:00 and 9:00 am and after pupil dilation. Smokers were not allowed to smoke until the test that morning. Each participant’s head was fixed on the sustainer with the eye focusing on the international fixation target without blinking and moving the eye while six radial retinal scans were performed. The scans were only accepted if they were completed, well centered, had signal strength of at least 6 and had no motion or blinking artifacts. After each examination, three independent masked graders (MSD, AT, AY) evaluated the best image that is projected on a computer screen. The image was accepted and used for analysis when two or more graders determined that both inner and outer borders of the choroid were clearly distinguishable. The choroidal image was obtained according to the previous method26. The protocol of HD 5 Line Raster centered foveally and spaced at 0.25 mm was performed. This protocol consisted of 6 mm parallel lines with 1024 A-scans/B-scans and averaging 4 B-scans per image. As the inversion of the image by using the Cirrus software results in a pixelated and low resolution image, the images were not inverted to bring the choroid into closer proximity to the zero delay line. The image of the thinnest point of the macula was chosen to prevent the affect of positioning on the measured thickness of the fovea. The image size was doubled, foveally centered and the subfoveal choroidal thickness was measured manually from the outer portion of the hyper reflective line corresponding to the retina pigment epithelium to the inner surface of sclera by the linear measuring tool of Cirrus software. The thickness of the choroid at the areas 1500 mm nasal and 1500 mm temporal to the fovea was also examined (Figure 1). Two independent raters (MSD, YT) measured images without the information of the eye or other observer, as described previously27 and the average of the two measurements was taken; the differences between readings of the masked physicians were found to be within 10% of the mean. Statistical analysis was performed using the statistical package SPSS V.20.0 (SPSS Inc., IBM Corp., Chicago, IL). For general statistical reporting, the mean values from each data set were calculated with the standard deviation (SD). For each continuous variable, normality was checked using the Kolmogorov–Smirnov test. For all the measured values, the p value for the Kolmogorov–Smirnov test was 40.05. Independent samples t-test, repeated measures analysis of variance (ANOVA) and Pearson’s correlation analysis were used for the statistical analysis of the data. Values of p50.05 were considered statistically significant
Smoking and choroid
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DOI: 10.3109/15569527.2014.950380
3
Figure 1. Choroidal thickness measurements of the right and left eyes of a participant.
Results The smokers group consisted of 48 eyes of 24 patients (20 male, 4 female). In the control group 44 eyes of 22 patients (16 male, 6 female) were investigated. Gender distribution did not differ significantly between the groups (p ¼ 0.12). The demographic and clinical characteristics of the groups and their statistical significances are shown in Table 1. The intraocular pressure and ocular pulse amplitude values and their statistical significances are shown in Table 2. The age, SE, AL, CCT, IOP and OPA did not differ significantly in smokers and control groups. The smokers had smoked an average of 23.3 ± 2.87 cigarettes per day for 1 year (range, 20–30). The mean smoking duration of the smokers was 19.4 ± 3.36 years (range, 10–35 years). The retinal and choroidal thicknesses did not differ significantly between smokers and control groups (Table 3). Repeated measures ANOVA test did not reveal a significant difference between central (p ¼ 0.086), nasal (p ¼ 0.069) and temporal (p ¼ 0.088) retinal thicknesses. There was also not a significant difference between subfoveal (p ¼ 0.75), nasal (p ¼ 0.80) and temporal (p ¼ 0.39) choroidal thicknesses with the repeated measures ANOVA test. Pearson’s correlation coefficient test did not reveal any significant correlation between age, gender, SE, AL, CCT, IOP, OPA, central retinal and choroidal thicknesses in both smokers(r values ranged between 0.31 and 0.35 and p values ranged between 0.35 and 0.65) and control(r values ranged between 0.36 and 0.57 and p values ranged between 0.48 and 0.56) groups.
Table 1. Demographical and clinical characteristics of the control and smokers groups.
Age (years) SE (diopter) IOP (mmHg) OPA (mmHg) CCT (mm) AL (mm)
Group
Mean
SD
SEM
Range
p*
Control Smokers Control Smokers Control Smokers Control Smokers Control Smokers Control Smokers
34.40 38.62 0.4 0.21 17.4 18.1 2.64 2.56 543.67 545.07 23.70 23.76
8.76 8.86 0.79 0.52 3.19 4.14 1.03 0.87 29.47 31.22 0.84 0.71
0.51 0.47 0.17 0.1 0.71 0.84 0.23 0.17 5.07 4.96 0.23 0.17
22–50 25–50 1.00–1.00 0.50–0.00 10–21 10–21 1–3 1–3 500–585 495–575 22–25 22–25
0.12 0.37 0.54 0.80 0.56 0.82
AL, axial length; CCT, central corneal thickness; CT, choroidal thickness; IOP, intraocular pressure; OPA, ocular pulse amplitude; RT, retinal thickness; SD, standard deviation; SE, spherical equivalent; SEM, standard error of the mean. *Independent samples t-test.
Table 2. Intraocular pressure and ocular pulse amplitude of the control and smokers groups.
IOP (mmHg) OPA (mmHg)
Group
Mean
SD
SEM
Range
p*
Control Smokers Control Smokers
17.4 18.1 2.64 2.56
3.19 4.14 1.03 0.87
0.71 0.84 0.23 0.17
10–21 10–21 1–3 1–3
0.54 0.80
IOP, intraocular pressure; OPA, ocular pulse amplitude; SD, standard deviation; SEM, standard error of the mean. *Independent samples t-test.
Discussion In this study, the chronic effects of smoking on choroidal thickness in otherwise healthy smokers were investigated. According to the results of our study, chronic smoking did not significantly decrease the retinal and choroidal thicknesses in healthy subjects aged 20–50 years. According to the regression analysis subfoveal choroidal thickness, OPA and DCT were not significant predictors of smoking status. Pathological factors (polypoidal choroidal vasculopathy28 and central serous chorioretinopathy13), pharmaceutical factors (intravitreal ranibizumab29), age16,30, axial length16,30, refractive status16,30, diurnal rhythm30 and perfusion
pressure31 are known to cause differences in choroidal thickness, but most of the factors that affect the subfoveal choroidal thickness are still not known. In our study chronic smoking did not seem to affect choroidal thickness significantly. We performed our study in the morning because it is known that choroidal thickness decreases progressively after getting up in the morning30. Although the flicker-induced hemodynamic response of retinal veins is reduced in chronic smokers, and this reduction supports the hypothesis that chronic smoking leads to vascular dysfunction in the eye32, there were no signs of an impaired
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Cutan Ocul Toxicol, Early Online: 1–5
Table 3. Retinal and choroidal thicknesses of the groups. Group Control Smokers Temporal RT (mm) Control Smokers Nasal RT (mm) Control Smokers Central CT (mm) Control Smokers Temporal CT (mm) Control Smokers Nasal CT (mm) Control Smokers
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Central RT (mm)
Mean 257.90 249.70 322.85 327.93 346.13 359.27 308.20 304.04 281.60 271.04 276.95 273.83
SD
SEM
Range
p*
20.61 4.61 205–288 0.11 9.01 1.84 201–267 13.59 2.21 282–359 0.21 16.05 2.97 287–366 10.12 1.59 312–365 0.21 16.54 2.73 314–373 44.97 10.05 207–420 0.75 42.01 8.57 205–412 41.38 9.25 214–407 0.39 40.48 8.26 211–422 41.39 9.25 201–403 0.80 42.31 8.63 204–405
CT, choroidal thickness; RT, retinal thickness; SD, standard deviation; SEM, standard error of the mean. *Independent samples t-test.
retinal or choroidal vascular function in smokers as there was not a significant difference in the choroidal and retinal thicknesses of the smokers and control groups. It was shown that smoking causes acute hemodynamic and vascular changes, but chronic smokers did not differ from non smokers in hemodynamic variables and vascular properties33. Ula¸s et al. reported that smoking causes an increase in choroidal thickness at 5 min of smoking that gradually returned to baseline values after 60 min in habitual smokers, but the baseline choroidal and retinal thicknesses in habitual smokers were similar to those of age- and sex-matched non smokers34. Ulas et al. reported an acute increase in choroidal thickness but in our study, participants were not allowed to smoke before HD-OCT test in that morning. Sizmaz et al. showed that smoking one cigarette causes a significant decrease in choroidal thickness that persisted for at least 3 h but the baseline choroidal thickness measurements did not show significant difference between smokers and non smokers and in non smokers, choroidal thickness remained unchanged7. These results are in good agreement with our data, which revealed similar choroidal thickness, except for the acute phase in smokers and non smokers. In our study, smokers were not allowed to smoke in the morning before the HD-OCT test, so the acute effect was not evaluated. The opposite acute effect results between Ulas and Sizmaz may be related to the balance between nitric oxide and carbon monoxide. Garhofer et al. reported that nitric oxide synthase activity is reduced in chronic smokers and decreased nitric oxide production may decrease the ocular blood flow in chronic smokers32. In contrary, acute smoking increases blood flow velocity in the optic nerve head and in the choroid of habitual smokers35 but this is possibly related with the carbon monoxide as it is a major component of cigarette smoke and it is reported that retinal and choroidal blood flow increased during inhalation of carbon monoxide36. OPA is caused by cardiovascular pulsations and ocular blood flow. The OPA is an index of choroidal perfusion23,24. There are many different methods for measuring the OPA and choroidal perfusion including DCT25. We could not determine a relationship between age, smoking duration and OPA in our study and further studies with larger samples, are needed to determine the relationship between these parameters.
One of the limitations of our study may be that we included the subjects with normal serum lipid levels. It is known that smoking could affect lipid profiles and smokers are reported to have higher serum triglyceride, cholesterol and low-density lipoprotein levels but lower high density lipoprotein than non smokers37 and choroidal thickness of smokers with abnormal serum lipid profile may be different. Another limitation was performing choroidal thickness measurements manually as no software is used for choroidal segmentation, but this limitation is currently for all studies involved with choroidal thickness measurements and OCT38. As a conclusion, we could not find a significant difference in OPA, retinal and choroidal thicknesses between smokers and non smokers. To the best of our knowledge, our study is the first to investigate the effect of chronic smoking on choroidal thickness and OPA in such a large sample size, but further studies in larger groups are needed to show the effect of smoking on choroidal thickness and OPA, especially in patients with ocular diseases like age-related macular degeneration and glaucoma. It should be kept in mind that choroidal thickness measurements cannot show the ultrastructural changes and further studies including histopathological changes may enlighten the tissue changes better in smokers.
Declaration of interest The authors declare no conflict of interest.
References 1. Benowitz NL. The role of nicotine in smoking-related cardiovascular disease. Prev Med 1997;26:412–417. 2. van den Berkmortel FW, Smilde TJ, Wollersheim H, et al. Intimamedia thickness of peripheral arteries in asymptomatic cigarette smokers. Atherosclerosis 2000;150:397–401. 3. Fielding JE. Smoking: health effects and control (1). N Engl J Med 1985;313:491–498. 4. Wimpissinger B, Resch H, Berisha F, et al. Response of choroidal blood flow to carbogen breathing in smokers and non-smokers. Br J Ophtalmol 2004;88:776–781. 5. Hara K. Effect of cigarette smoking on ocular circulation. Immediate effect on retinal circulation. Folia Ophthalmol Jpn 1991;42:263–267. 6. Steigerwalt Jr RD, Laurora G, Incandela L, et al. Ocular and orbital blood flow in cigarette smokers. Retina 2000;20:394–397. 7. Sizmaz S, Ku¨c¸u¨kerdo¨nmez C, Pinarci EY, et al. The effect of smoking on choroidal thickness measured by optical coherence tomography. Br J Ophthalmol 2013;97:601–604. 8. Hayreh SS. Segmental nature of the choroidal vasculature. Br J Ophthalmol 1975;59:631–648. 9. Flu¨gel C, Tamm ER, Mayer B, Lu¨tjen-Drecoll E. Species differences in choroidal vasodilative innervation: evidence for specific intrinsic nitrergic and VIP-positive neurons in the human eye. Invest Ophthalmol Vis Sci 1994;35:592–599. 10. Kubota T, Jonas JB, Naumann GO. Decreased choroidal thickness in eyes with secondary angle-closure glaucoma: an aetiological factor for deep retinal changes in glaucoma? Br J Ophthalmol 1993;77:430–432 11. Spaide RF, Koizumi H, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. 12. Fujiwara T, Imamura Y, Margolis R, et al. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthalmol 2009;148:445–450. 13. Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina 2009;29:1469–1473.
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14. Ikuno Y, Tano Y. Retinal and choroidal biometry in highly myopic eyes with spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 2009;50:3876–3880. 15. Grover S, Murthy RK, Brar VS, Chalam KV. Normative data for macular thickness by high-definition spectral-domain optical coherence tomography (Spectralis). Am J Ophthalmol 2009;148: 266–271. 16. Ikuno Y, Kawaguchi K, Nouchi T, Yasuno Y. Choroidal thickness in healthy Japanese subjects. Invest Ophthalmol Vis Sci 2010;51: 2173–2176. 17. Mwanza JC, Hochberg JT, Banitt MR, et al. Lack of association between glaucoma and macular choroidal thickness measured with enhanced depth-imaging optical coherence tomography. Invest Ophthalmol Vis Sci 2011;52:3430–3435. 18. Rahman W, Chen FK, Yeoh J, et al. Repeatability of manual subfoveal choroidal thickness measurements in healthy subjects using the technique of enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci 2011;52: 2267–2271. 19. Ikuno Y, Maruko I, Yasuno Y, et al. Reproducibility of retinal and choroidal thickness measurements in enhanced depth imaging and high-penetration optical coherence tomography. Invest Ophthalmol Vis Sci 2011;52:5536–5540. 20. Wood A, Binns A, Margrain T, et al. Retinal and choroidal thickness in early age-related macular degeneration. Am J Ophthalmol 2011;152:1030–1038. 21. Usui S, Ikuno Y, Miki A, et al. Evaluation of the choroidal thickness using high-penetration optical coherence tomography with long wavelength in highly myopic normal-tension glaucoma. Am J Ophthalmol 2012;153:10–16. 22. Branchini L, Regatieri CV, Flores-Moreno I, et al. Reproducibility of choroidal thickness measurements across three spectral domain optical coherence tomography systems. Ophthalmology 2012;119: 119–123. 23. Walker RE, Litovitz TL. An experimental and theoretical study of pneumatictonometer. Exp Eye Res 1972;13:14–23. 24. Walker RE, Langham ME. Pneumatic applanation tonometer studies. Analysis of pulsatile response. Exp Eye Res 1975;20: 245–253. 25. Schmetterer L, Dallinger S, Findl O, et al. Noninvasive investigations of the normal ocular circulation in humans. Invest Ophthalmol Vis Sci 1998;39:1210–1220.
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26. Manjunath V, Taha M, Fujimoto JG, Duker JS. Choroidal thickness in normal eyes measured using Cirrus HD optical coherence tomography. Am J Ophthalmol 2010;150:325–329. 27. Branchini L, Regatieri CV, Flores-Moreno I, et al. Reproducibility of choroidal measurements across three spectral domain optical coherence tomography systems. Ophthalmology 2012;119: 119–123. 28. Koizumi H, Yamagishi T, Yamazaki T, et al. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2011;249:1123–1128. 29. Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S. Subfoveal choroidal thickness after ranibizumab therapy for neovascular agerelated macular degeneration: 12-month results. Ophthalmology 2012;119:1621–1627. 30. Tan CS, Ouyang Y, Ruiz H, Sadda SR. Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:261–266. 31. Kiel JW, van Heuven WA. Ocular perfusion pressure and choroidal blood flow in the rabbit. Invest Ophthalmol Vis Sci 1995;36:579–585. 32. Garhofer G, Resch H, Sacu S, et al. Effect of regular smoking on flicker induced retinal vasodilatation in healthy subjects. Microvasc Res 2011;82:351–355. 33. Kool MJ, Hoeks AP, Struijker Boudier HA, et al. Short- and longterm effects of smoking on arterial wall properties in habitual smokers. J Am Coll Cardiol 1993;22:1881–1886. ¨ , C¸elebi S. Effect of smoking on 34. Ula¸s F, C¸elik F, Dog˘an U choroidal thickness in healthy smokers. Curr Eye Res 2014;39: 504–511. 35. Tamaki Y, Araie M, Nagahara M, Tomita K. Acute effects of cigarette smoking on tissue circulation in human optic nerve head and choroid-retina. Ophthalmology 1999;106:564–569. 36. Resch H, Zawinka C, Weigert G, et al. Inhaled carbon monoxide increases retinal and choroidal blood flow in healthy humans. Invest Ophthalmol Vis Sci 2005;46:4275–4280. 37. Craig WY, Palomaki GE, Haddow JE. Cigarette smoking and serum lipid and lipoprotein concentrations: an analysis of published data. BMJ 1989;298:784–788. 38. Kim YT, Kang SW, Bai KH. Choroidal thickness in both eyes of patients with unilaterally active central serous chorioretinopathy. Eye 2011;25:1635–1640.
RESEARCH ARTICLE
Effects of cigarette smoking on choroidal and retinal thickness and ocular pulse amplitude Cutaneous and Ocular Toxicology Downloaded from informahealthcare.com by University of Connecticut on 10/11/14 For personal use only.
Mehmet Serdar Dervi¸sog˘ulları, Yu¨ksel Totan, Aylin Tenlik, and Aslihan Yuce ¨ zal University, Ankara, Turkey Department of Ophthalmology, Medical School, Turgut O
Abstract
Keywords
Background: In our study, we aimed to show the effects of smoking on choroidal thickness and ocular pulse amplitude. It is known that the anatomy and physiologic functions of the choroid is important in ocular diseases like glaucoma and age-related macular degeneration. Choroidal thickness is measured by the spectral domain optical coherence tomography (SD-OCT). The ocular pulse amplitude (OPA) is the difference between the systolic and diastolic intraocular pressure (IOP) and it is an index of choroidal perfusion. Design: This was a cross-sectional prospective observational study at the Turgut Ozal University Hospital setting. Participants: The test subjects were divided into two groups: the smokers group which consisted in 24 participants (20 male, 4 female) and the control group with 22 participants (16 male, 6 female). Methods: The participants underwent full ophthalmological examination including best-corrected visual acuity (BCVA), spherical equivalent (SE) values of refractive errors, intraocular pressure (IOP), ocular pulse amplitude (OPA), central corneal thickness (CCT), axial length (AL) and choroidal thickness. The IOP and the OPA were measured with the dynamic contour tonometer. The CCT and the AL were measured with the Nidek AL-Scan (Nidek Co., Ltd., Gamagori, Japan). The choroidal thickness was measured by the Cirrus high-definition optical coherence tomography (Cirrus Version 6.0; Carl Zeiss Meditec, Dublin, CA). Results: Gender did not differ significantly between the groups (p ¼ 0.12). The age, SE, IOP, OPA, CCT and AL did not differ significantly in smokers and control groups (p ¼ 0.12, p ¼ 0.37, p ¼ 0.54, p ¼ 0.80, p ¼ 0.56 and p ¼ 0.82, respectively). The nasal, temporal, central retinal (p ¼ 021, p ¼ 021, p ¼ 0.11) and nasal, temporal, central choroidal thicknesses (p ¼ 0.80, p ¼ 0.39, p ¼ 0.75) did not differ significantly between smokers and control groups. Conclusions: We could not find a significant difference in OPA, retinal and choroidal thicknesses between smokers and non smokers. Further studies including histopathological changes in larger groups are needed to show the effect of smoking on choroidal thickness especially in patients with ocular diseases like age-related macular degeneration.
Choroidal thickness, ocular pulse amplitude, smoking
Introduction One of the risk factors that are important in developing systemic and ocular vascular diseases is cigarette smoking1. It is known that smoking is especially associated with anatomical alterations of the arterial system including an increase in arterial wall thickness and atherosclerosis, both in the microvasculary and macrovasculary structures2,3. Although the exact pathogenesis is not identified yet, it is known that smoking can cause a decrease in the retinal blood flow4–6. It is also shown that an acute significant decrease occurred in choroidal thickness within the first couple of hours following smoking7.
Address for correspondence: Mehmet Serdar Dervi¸sog˘ulları, Department ¨ zal University, Ankara, of Ophthalmology, Medical School, Turgut O Turkey. E-mail: [email protected]
History Received 3 June 2014 Revised 15 July 2014 Accepted 26 July 2014 Published online 29 August 2014
The choroid is a highly vascularized tissue. It provides oxygen and nourishment to the outer retinal layers and regulates heat at the foveal region. Nearly 90% of the ophthalmic artery blood flow is received by the choroid8,9. It has been shown that the anatomy and physiologic functions of the choroid is quite important in the development of ocular diseases like glaucoma10. Several studies have reported noninvasive in vivo measurements of the choroidal thickness with the spectral domain optical coherence tomography (SD-OCT) in normal subjects and choroidal or retinal diseases11–22. The choroidal thickness can be measured by the high definition optical coherence tomography. The image size is doubled, foveally centered and the subfoveal choroidal thickness can be measured manually from the outer portion of the hyper reflective line corresponding to the retina pigment epithelium to the inner surface of sclera by the linear measuring tool of Cirrus software. The difference between the
2
M. S. Dervi¸sog˘ulları et al.
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systolic and diastolic intraocular pressure (IOP) is called the ocular pulse amplitude (OPA) and it is caused by cardiovascular pulsations and ocular blood flow. The OPA is an index of choroidal perfusion23,24. There are many different methods for measuring the OPA and choroidal perfusion25. The dynamic contour tonometer (DCT; Swiss Microtechnology AG, Port, Switzerland) is a relatively new technology that allows the measurement of both intraocular pressure (IOP) and ocular pulse amplitude. In this study, we aimed to show the effects of smoking on choroidal thickness and OPA as most of the ophthalmic artery blood flow is received by the choroid and OPA is the index of choroidal perfusion.
Materials and methods This cross-sectional prospective observational study was carried out with the participants recruited from the patients, patients’ relatives and hospital staff of the Turgut Ozal University Hospital from 1 May to 1 November 2013. This study was performed in adherence with the tenets of the Declaration of Helsinki and was approved by the local ethics committee. Informed consent was obtained from all of the study participants. The study participants were divided into two groups. The smokers group was formed by participants who were healthy cigarette smokers for more than10 years with no other systemic or ocular disease. The control group consisted of age- and gender-matched healthy non-smokers and these participants of the control group never smoked. The smokers group was also gender balanced. The smokers group consisted of 48 eyes of 24 participants (20 male, 4 female). In the control group, 44 eyes of 22 participants (16 male, 6 female) were investigated. Both eyes were evaluated. The participants underwent full ophthalmological examination including best corrected visual acuity (BCVA), spherical equivalent (SE) values of refractive errors, IOP, OPA, central corneal thickness (CCT), axial length (AL) and choroidal thickness. The IOP and the OPA were measured with the DCT by an experienced operator (MSD) after administering topical anesthesia. The CCT and the AL was measured using the Nidek AL-Scan (Nidek Co., Ltd., Gamagori, Japan). The choroidal thickness was measured by the Cirrus high definition optical coherence tomography (HD-OCT, Cirrus Version 6.0; Carl Zeiss Meditec, Dublin, CA). Participants with any ocular disease that prevents the examination of the cornea and retina, a history of any ocular surgery, ocular or systemic disease and taking any medication within the last 3 months in both groups, a history of smoking or alcohol intake in the control group, a history of alcohol intake in the smokers group were excluded from the study. Patients with 25–50 years of age, spherical refractive error smaller than 3 diopters (D), cylindrical refractive error smaller then 1 D, best corrected visual acuity of 20/20 or better, no history of chronic ocular disease, normal blood pressure (brachial systolic/diastolic blood pressure smaller than 140/90 mmHg) and normal blood parameters were included. Blood parameters included complete blood count, clinical chemistry (glucose, sodium, potassium, creatinine,
Cutan Ocul Toxicol, Early Online: 1–5
uric acid, total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, total bilirubin and total protein) and thyroid function test (thyrotropin, free T4 and total T3). It was ascertained that the participants in the control group were not passive smokers and were not exposed to cigarette smoke at home or work. The standard pack year method was used to measure the incidence and degree of smoking and participants with minimum 10-years of smoking history with at least one pack of cigarettes per day for 1 year were included. The subjects who can not meet any of the screening criteria were excluded. All OCT scans were performed by the same experienced technician the day after the examination between 8:00 and 9:00 am and after pupil dilation. Smokers were not allowed to smoke until the test that morning. Each participant’s head was fixed on the sustainer with the eye focusing on the international fixation target without blinking and moving the eye while six radial retinal scans were performed. The scans were only accepted if they were completed, well centered, had signal strength of at least 6 and had no motion or blinking artifacts. After each examination, three independent masked graders (MSD, AT, AY) evaluated the best image that is projected on a computer screen. The image was accepted and used for analysis when two or more graders determined that both inner and outer borders of the choroid were clearly distinguishable. The choroidal image was obtained according to the previous method26. The protocol of HD 5 Line Raster centered foveally and spaced at 0.25 mm was performed. This protocol consisted of 6 mm parallel lines with 1024 A-scans/B-scans and averaging 4 B-scans per image. As the inversion of the image by using the Cirrus software results in a pixelated and low resolution image, the images were not inverted to bring the choroid into closer proximity to the zero delay line. The image of the thinnest point of the macula was chosen to prevent the affect of positioning on the measured thickness of the fovea. The image size was doubled, foveally centered and the subfoveal choroidal thickness was measured manually from the outer portion of the hyper reflective line corresponding to the retina pigment epithelium to the inner surface of sclera by the linear measuring tool of Cirrus software. The thickness of the choroid at the areas 1500 mm nasal and 1500 mm temporal to the fovea was also examined (Figure 1). Two independent raters (MSD, YT) measured images without the information of the eye or other observer, as described previously27 and the average of the two measurements was taken; the differences between readings of the masked physicians were found to be within 10% of the mean. Statistical analysis was performed using the statistical package SPSS V.20.0 (SPSS Inc., IBM Corp., Chicago, IL). For general statistical reporting, the mean values from each data set were calculated with the standard deviation (SD). For each continuous variable, normality was checked using the Kolmogorov–Smirnov test. For all the measured values, the p value for the Kolmogorov–Smirnov test was 40.05. Independent samples t-test, repeated measures analysis of variance (ANOVA) and Pearson’s correlation analysis were used for the statistical analysis of the data. Values of p50.05 were considered statistically significant
Smoking and choroid
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DOI: 10.3109/15569527.2014.950380
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Figure 1. Choroidal thickness measurements of the right and left eyes of a participant.
Results The smokers group consisted of 48 eyes of 24 patients (20 male, 4 female). In the control group 44 eyes of 22 patients (16 male, 6 female) were investigated. Gender distribution did not differ significantly between the groups (p ¼ 0.12). The demographic and clinical characteristics of the groups and their statistical significances are shown in Table 1. The intraocular pressure and ocular pulse amplitude values and their statistical significances are shown in Table 2. The age, SE, AL, CCT, IOP and OPA did not differ significantly in smokers and control groups. The smokers had smoked an average of 23.3 ± 2.87 cigarettes per day for 1 year (range, 20–30). The mean smoking duration of the smokers was 19.4 ± 3.36 years (range, 10–35 years). The retinal and choroidal thicknesses did not differ significantly between smokers and control groups (Table 3). Repeated measures ANOVA test did not reveal a significant difference between central (p ¼ 0.086), nasal (p ¼ 0.069) and temporal (p ¼ 0.088) retinal thicknesses. There was also not a significant difference between subfoveal (p ¼ 0.75), nasal (p ¼ 0.80) and temporal (p ¼ 0.39) choroidal thicknesses with the repeated measures ANOVA test. Pearson’s correlation coefficient test did not reveal any significant correlation between age, gender, SE, AL, CCT, IOP, OPA, central retinal and choroidal thicknesses in both smokers(r values ranged between 0.31 and 0.35 and p values ranged between 0.35 and 0.65) and control(r values ranged between 0.36 and 0.57 and p values ranged between 0.48 and 0.56) groups.
Table 1. Demographical and clinical characteristics of the control and smokers groups.
Age (years) SE (diopter) IOP (mmHg) OPA (mmHg) CCT (mm) AL (mm)
Group
Mean
SD
SEM
Range
p*
Control Smokers Control Smokers Control Smokers Control Smokers Control Smokers Control Smokers
34.40 38.62 0.4 0.21 17.4 18.1 2.64 2.56 543.67 545.07 23.70 23.76
8.76 8.86 0.79 0.52 3.19 4.14 1.03 0.87 29.47 31.22 0.84 0.71
0.51 0.47 0.17 0.1 0.71 0.84 0.23 0.17 5.07 4.96 0.23 0.17
22–50 25–50 1.00–1.00 0.50–0.00 10–21 10–21 1–3 1–3 500–585 495–575 22–25 22–25
0.12 0.37 0.54 0.80 0.56 0.82
AL, axial length; CCT, central corneal thickness; CT, choroidal thickness; IOP, intraocular pressure; OPA, ocular pulse amplitude; RT, retinal thickness; SD, standard deviation; SE, spherical equivalent; SEM, standard error of the mean. *Independent samples t-test.
Table 2. Intraocular pressure and ocular pulse amplitude of the control and smokers groups.
IOP (mmHg) OPA (mmHg)
Group
Mean
SD
SEM
Range
p*
Control Smokers Control Smokers
17.4 18.1 2.64 2.56
3.19 4.14 1.03 0.87
0.71 0.84 0.23 0.17
10–21 10–21 1–3 1–3
0.54 0.80
IOP, intraocular pressure; OPA, ocular pulse amplitude; SD, standard deviation; SEM, standard error of the mean. *Independent samples t-test.
Discussion In this study, the chronic effects of smoking on choroidal thickness in otherwise healthy smokers were investigated. According to the results of our study, chronic smoking did not significantly decrease the retinal and choroidal thicknesses in healthy subjects aged 20–50 years. According to the regression analysis subfoveal choroidal thickness, OPA and DCT were not significant predictors of smoking status. Pathological factors (polypoidal choroidal vasculopathy28 and central serous chorioretinopathy13), pharmaceutical factors (intravitreal ranibizumab29), age16,30, axial length16,30, refractive status16,30, diurnal rhythm30 and perfusion
pressure31 are known to cause differences in choroidal thickness, but most of the factors that affect the subfoveal choroidal thickness are still not known. In our study chronic smoking did not seem to affect choroidal thickness significantly. We performed our study in the morning because it is known that choroidal thickness decreases progressively after getting up in the morning30. Although the flicker-induced hemodynamic response of retinal veins is reduced in chronic smokers, and this reduction supports the hypothesis that chronic smoking leads to vascular dysfunction in the eye32, there were no signs of an impaired
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M. S. Dervi¸sog˘ulları et al.
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Table 3. Retinal and choroidal thicknesses of the groups. Group Control Smokers Temporal RT (mm) Control Smokers Nasal RT (mm) Control Smokers Central CT (mm) Control Smokers Temporal CT (mm) Control Smokers Nasal CT (mm) Control Smokers
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Central RT (mm)
Mean 257.90 249.70 322.85 327.93 346.13 359.27 308.20 304.04 281.60 271.04 276.95 273.83
SD
SEM
Range
p*
20.61 4.61 205–288 0.11 9.01 1.84 201–267 13.59 2.21 282–359 0.21 16.05 2.97 287–366 10.12 1.59 312–365 0.21 16.54 2.73 314–373 44.97 10.05 207–420 0.75 42.01 8.57 205–412 41.38 9.25 214–407 0.39 40.48 8.26 211–422 41.39 9.25 201–403 0.80 42.31 8.63 204–405
CT, choroidal thickness; RT, retinal thickness; SD, standard deviation; SEM, standard error of the mean. *Independent samples t-test.
retinal or choroidal vascular function in smokers as there was not a significant difference in the choroidal and retinal thicknesses of the smokers and control groups. It was shown that smoking causes acute hemodynamic and vascular changes, but chronic smokers did not differ from non smokers in hemodynamic variables and vascular properties33. Ula¸s et al. reported that smoking causes an increase in choroidal thickness at 5 min of smoking that gradually returned to baseline values after 60 min in habitual smokers, but the baseline choroidal and retinal thicknesses in habitual smokers were similar to those of age- and sex-matched non smokers34. Ulas et al. reported an acute increase in choroidal thickness but in our study, participants were not allowed to smoke before HD-OCT test in that morning. Sizmaz et al. showed that smoking one cigarette causes a significant decrease in choroidal thickness that persisted for at least 3 h but the baseline choroidal thickness measurements did not show significant difference between smokers and non smokers and in non smokers, choroidal thickness remained unchanged7. These results are in good agreement with our data, which revealed similar choroidal thickness, except for the acute phase in smokers and non smokers. In our study, smokers were not allowed to smoke in the morning before the HD-OCT test, so the acute effect was not evaluated. The opposite acute effect results between Ulas and Sizmaz may be related to the balance between nitric oxide and carbon monoxide. Garhofer et al. reported that nitric oxide synthase activity is reduced in chronic smokers and decreased nitric oxide production may decrease the ocular blood flow in chronic smokers32. In contrary, acute smoking increases blood flow velocity in the optic nerve head and in the choroid of habitual smokers35 but this is possibly related with the carbon monoxide as it is a major component of cigarette smoke and it is reported that retinal and choroidal blood flow increased during inhalation of carbon monoxide36. OPA is caused by cardiovascular pulsations and ocular blood flow. The OPA is an index of choroidal perfusion23,24. There are many different methods for measuring the OPA and choroidal perfusion including DCT25. We could not determine a relationship between age, smoking duration and OPA in our study and further studies with larger samples, are needed to determine the relationship between these parameters.
One of the limitations of our study may be that we included the subjects with normal serum lipid levels. It is known that smoking could affect lipid profiles and smokers are reported to have higher serum triglyceride, cholesterol and low-density lipoprotein levels but lower high density lipoprotein than non smokers37 and choroidal thickness of smokers with abnormal serum lipid profile may be different. Another limitation was performing choroidal thickness measurements manually as no software is used for choroidal segmentation, but this limitation is currently for all studies involved with choroidal thickness measurements and OCT38. As a conclusion, we could not find a significant difference in OPA, retinal and choroidal thicknesses between smokers and non smokers. To the best of our knowledge, our study is the first to investigate the effect of chronic smoking on choroidal thickness and OPA in such a large sample size, but further studies in larger groups are needed to show the effect of smoking on choroidal thickness and OPA, especially in patients with ocular diseases like age-related macular degeneration and glaucoma. It should be kept in mind that choroidal thickness measurements cannot show the ultrastructural changes and further studies including histopathological changes may enlighten the tissue changes better in smokers.
Declaration of interest The authors declare no conflict of interest.
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