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American Journal of Epidemiology Advance Access originally published online on October 12, 2007
American Journal of Epidemiology 2007 166(11):1288-1297; doi:10.1093/aje/kwm255
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Long-term Effects of Smoking on Retinal Microvascular Caliber

Annette Kifley1, Gerald Liew1, Jie Jin Wang1, Shweta Kaushik1, Wayne Smith2, Tien Y. Wong3,4 and Paul Mitchell1

1 Centre for Vision Research, Westmead Millennium Institute, Department of Clinical Ophthalmology and Eye Health, Faculty of Medicine, University of Sydney, Sydney, Australia
2 Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, Australia
3 Centre for Eye Research Australia, Department of Ophthalmology, School of Medicine, University of Melbourne, Melbourne, Australia
4 Singapore Eye Research Institute, National University of Singapore, Singapore

Correspondence to Prof. Paul Mitchell, University of Sydney Centre for Vision Research, Eye Clinic, Westmead Hospital, Hawkesbury Road, Westmead, NSW 2145, Australia (e-mail: paul_mitchell{at}wmi.usyd.edu.au).

Received for publication October 10, 2006. Accepted for publication August 13, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Although cigarette smoking is a major cardiovascular risk factor, its microcirculatory effects are not well understood. The authors investigated cross-sectional and longitudinal relations between smoking and retinal microvascular caliber in an older Australian population. Retinal vessel calibers were measured from digitized retinal photographs at baseline (1992–1994; n = 3,006) and at 5-year follow-up examinations (1997–1999; n = 1,850) in the population-based Blue Mountains Eye Study. Smoking status and quantity and pack-years of smoking were defined from standardized questionnaires administered at both examinations. After adjustment for other factors, current and past smoking were associated with wider retinal venular caliber at baseline (p < 0.01). These cross-sectional findings were virtually identical at the 5-year follow-up examination (p < 0.001). Heavy smokers were more likely to have relatively large changes in venular caliber in either direction over the 5-year period (widening or narrowing more than 1 standard deviation greater than the mean change) than were nonsmokers (for continuous trend by pack-years or current amount smoked, p < 0.05). Weaker and less consistent associations between smoking and arteriolar caliber were observed. These results suggest long-term effects of smoking on venular caliber that may contribute to associations between smoking and cardiovascular disease.

arterioles; microcirculation; retina; retinal vessels; risk factors; smoking; venules

Abbreviations: CI, confidence interval; CRAE, central retinal arteriolar equivalent; CRVE, central retinal venular equivalent; SD, standard deviation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Cigarette smoking is a major modifiable risk factor for cardiovascular disease, and its effects on large-vessel atherosclerosis and thrombosis are well known (1). Because of difficulties in imaging microcirculation, the impact of smoking on the microvasculature is less clear (2). The retina is a unique site where microcirculation can be directly and noninvasively imaged, and recently developed computer-assisted techniques allow precise measurement of retinal vessels from high-resolution photographs (3). These methods provide accurate and reproducible summary measures of retinal arteriolar and venular caliber and have been used in recent studies to investigate associations with systemic cardiovascular diseases (e.g., hypertension, diabetes, stroke, coronary heart disease) (4–8). Narrower retinal arteriolar caliber, for example, has been associated with hypertension and may even precede clinical hypertension (5, 9). By contrast, wider retinal venular caliber is associated with markers of systemic inflammation and various components of the metabolic syndrome (obesity, dyslipidemia, hyperglycemia) (10–12) and also predicts stroke and cardiovascular events (8, 13, 14).

The effects of smoking on retinal microcirculation, however, remain incompletely understood. In particular, there are no reported longitudinal data on the relation between smoking and microvascular changes in the retina or other end organs. The cross-sectional associations between smoking and wider retinal arterioles reported in some studies (10, 11, 15) may have been confounded by shared factors that determine the caliber of both vessels, such as genetic factors or body size (16–18). Further, there is evidence of interaction between smoking and inflammation in their associations with large-vessel atherosclerosis risk (19, 20), but whether a similar interaction exists for small-vessel changes is unknown.

In this study, we investigated cross-sectional associations between cigarette smoking and retinal vessel caliber and longitudinal associations between smoking and changes in retinal vessel caliber over a period of 5 years. We specifically compared patterns of association for arterioles and venules after adjusting for the caliber of the fellow vessel. We also examined possible interactions between smoking and inflammatory markers in their effects on retinal vessel caliber.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The Blue Mountains Eye Study is a population-based survey of vision and common eye diseases in a suburban Australian population aged 49 years or older. Study methods have been described previously in detail (21). In brief, residents in two postcode regions west of Sydney, Australia, were invited to participate by door-to-door census. Of 4,433 eligible persons, 3,654 (82.4 percent) were examined at baseline in 1992–1994. The study was approved by the Western Sydney Area Health Service Human Research Ethics Committee, and informed written consent was obtained from all participants. Surviving participants were invited to attend follow-up examinations after 5 years (1997–1999), and 2,335 (75.1 percent of survivors) participated. Similar survey methods were used at the follow-up visit.

Eye examinations were performed and a detailed questionnaire was administered. Participants were asked for details on current and past smoking, including type of smoking (manufactured or hand-rolled cigarettes, cigars, or pipe tobacco), usual amount (current and past), time of commencement, and, where applicable, time of quitting. Blood pressure was measured once using a mercury sphygmomanometer and standard adult cuff, at least 10 minutes after the participant had been comfortably seated. Participants were asked to return for fasting blood tests within 6 weeks, and 89 percent complied. Fasting blood samples were collected at the study site and were analyzed the same day at the Institute of Clinical Pathology and Medical Research, Westmead Hospital (Westmead, Australia).

Measurement of general retinal vessel caliber
A computer-assisted grading method with high reproducibility was used to measure retinal vessel width from digitized images in 3,368 participants (92 percent). Methodological details have been published previously (22–24). All vessels passing completely through a zone 0.5–1 disc diameter around the optic disc were measured by a trained grader using a computer imaging program (Retinal Analysis; Optimate, Madison, Wisconsin). Arteriolar branches were also measured if the trunk vessel was ≥85 µm in width. Summary measures for average retinal arteriolar or venular caliber were then calculated using the Parr-Hubbard formula (25) and are presented as the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE). A magnification correction described by Bengtsson and Krakau (26) was applied to correct for magnification errors which result from refraction. The arteriovenous ratio was also examined.

Definitions
Cigarette smoking was defined from answers to a standardized interviewer-administered questionnaire that included the following questions:

  • Have you ever smoked cigarettes, cigars, or a pipe regularly? (yes/no/don't know)
  • At what age did you start smoking regularly?
  • Have you given up smoking? (yes/no)
  • When did you last give up smoking?

If the participant was currently smoking, he or she was also asked:

  • How much do you usually smoke? (number of manufactured cigarettes per day; number of grams of hand-rolled tobacco per day; number of cigars per week; number of grams of pipe tobacco per week)

If the participant had given up smoking, he or she was also asked:

  • How much did you usually smoke just before you stopped? (further details collected as above)

Participants who stated that they had never smoked cigarettes, cigars, or a pipe regularly were defined as nonsmokers. Participants who stated that they had ever smoked cigarettes, cigars, or a pipe regularly and that they had not given up smoking were defined as current smokers. Participants who stated that they had ever smoked cigarettes, cigars, or a pipe regularly and that they had given up smoking were defined as past smokers. Daily amount smoked was calculated as cigarette-equivalent daily intake (a cigar was considered equivalent to 10 manufactured cigarettes; a gram of hand-rolled cigarette or pipe tobacco was considered equivalent to half a manufactured cigarette). Pack-years of smoking were calculated from the total number of years the subject had smoked, multiplied by the daily cigarette-equivalent intake, and divided by 20.

Diabetes was defined using either self-reported history of diabetes or a fasting plasma glucose level ≥7 mmol/liter, in accordance with the World Health Organization classification (27). Hypertension was defined using the World Health Organization criteria for stage II hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) (28) or as a previous diagnosis of hypertension and use of antihypertensive medication.

Statistical analysis
Statistical analyses were performed using SAS, version 9.1 (SAS, Inc., Cary, North Carolina). All p values presented are two-sided.

Cross-sectional data analyses.
Multivariable linear regression was used to assess associations between retinal vessel caliber and current smoking, past smoking, pack-years of smoking, and daily amount of smoking, after adjusting for potential confounders. A multivariable model for significant systemic risk factors included age, gender, systolic blood pressure, smoking, alcohol intake, hemoglobin concentration, platelet count, white blood cell count, fibrinogen level, body mass index (weight (kg)/height (m)2), and lipid levels. Analyses were repeated after further adjustment for the caliber of the correlated fellow vessel as an additional explanatory factor. Previous studies exploring associations of vessel caliber with age and blood pressure have found more biologically plausible results after such adjustment (16, 18, 29). Interactions between smoking and other vascular risk factors were also assessed.

Longitudinal data analyses.
The association between baseline smoking status and retinal vessel caliber at 5 years was assessed. Changes in vessel caliber over 5 years were calculated and compared between smoking subgroups using linear regression. The odds of a widening or narrowing in vessel caliber beyond 1 standard deviation (SD) from the overall mean change were compared with the reference group of participants whose change in vessel caliber was within 1 SD of the mean.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The Blue Mountains Eye Study baseline population was predominantly of European origin (98 percent), with an age range of 49–97 years (mean = 66 years) and a reasonable gender balance (57 percent female).

Of the 3,654 baseline participants, those with diabetes (n = 284) were excluded from all analyses. Among the 3,368 participants with retinal vessel caliber measurements, 255 were excluded because of diabetes. Among the 3,113 participants with retinal vessel caliber measurements who did not have diabetes, 107 did not provide information on smoking status. This left us with 3,006 participants for analysis of the association between smoking status and retinal vessel caliber. The mean CRAE and CRVE were 190 µm (SD, 20) and 222 µm (SD, 20), respectively. CRAE and CRVE were highly correlated (r = 0.59).

A total of 428 participants (14 percent) were defined as current smokers and 1,109 (37 percent) as past smokers. Baseline characteristics of participants by smoking status are shown in table 1. Participants with a history of current or past smoking were more likely to be male and to report regular alcohol intake, had higher white blood cell counts, and tended to have more adverse lipid profiles but slightly lower blood pressures. In addition, current smokers were younger on average, had higher fibrinogen levels, hemoglobin levels, and platelet counts, and had a lower body mass index.


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  		TABLE 1. Characteristics (mean or %) of participants at baseline, by smoking status, Blue Mountains Eye Study, 1992–1994

 
Cross-sectional associations
Table 2 shows baseline cross-sectional associations of retinal vascular caliber with smoking and other systemic factors. CRVE narrowed significantly with increasing age and widened significantly with increasing body mass index, fibrinogen level, platelet count, and hemoglobin concentration. CRAE narrowed significantly with male gender and with increasing age, blood pressure, triglyceride level, high density lipoprotein cholesterol level, and alcohol intake (table 2). After adjustment for these factors, both CRAE and CRVE were significantly wider among current and past smokers than among persons who had never smoked. Associations with past smoking were stronger in persons who had quit within the last 5 years but were still present among those who had quit more than 5 years previously (data not shown). CRVE remained significantly wider in current and past smokers after adjustment for CRAE, whereas after adjustment for CRVE, associations between smoking status and wider CRAE became substantially weaker and remained significant only for current smokers (table 2). There were no significant differences in arteriovenous ratio between smoking subgroups.


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  		TABLE 2. Cross-sectional associations of smoking and other vascular risk factors with retinal venular and arteriolar caliber at baseline, Blue Mountains Eye Study, 1992–1994

 
Dose-dependent patterns of association between smoking and wider CRVE were seen with increasing numbers of cigarettes smoked and with increasing pack-years of smoking (table 3). These dose-dependent trends persisted after adjustment for CRAE (ptrend < 0.0001). The odds of having CRVE >1 SD wider than the mean were two- to threefold higher in current smokers and in persons reporting ≥25 pack-years of smoking than in those who had never smoked (p < 0.05; data not shown). There were similar dose-dependent associations between smoking and wider CRAE before, but not after, adjustment for CRVE.


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  		TABLE 3. Adjusted mean retinal venular and arteriolar caliber at baseline, by smoking status and amount smoked, Blue Mountains Eye Study, 1992–1994*

 
There was evidence of effect modification between smoking status and white blood cell count as explanatory factors for retinal venular dilation (pinteraction < 0.0001), whereby increasing white blood cell count was associated with wider CRVE only among current or past smokers, and the association of smoking with wider CRVE was stronger in persons with higher white blood cell counts than in those with relatively low white blood cell counts (table 4). There were no significant interactions between smoking status and fibrinogen level (p = 0.8) or between smoking status and platelet count (p = 0.1).


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  		TABLE 4. Combined effects of smoking and white blood cell count* on retinal venular caliber at baseline, Blue Mountains Eye Study, 1992–1994

 
Longitudinal associations
Longitudinal analysis was possible in 1,850 participants who had 5-year retinal vessel caliber measurements in addition to the baseline assessment (61 percent of the 3,006 participants included in the baseline analyses; 92 percent of 2,013 participants included at baseline who also attended the 5-year follow-up). On average, CRVE narrowed slightly but significantly over the 5-year period (mean change = –1.8 µm (95 percent confidence interval (CI): –2.4, –1.3); range, –46 to 71 µm; SD, 12.1), while changes in CRAE were not significantly different from 0 (mean change = –0.3 µm (95 percent CI: –1.0, 0.3); range, –62 to 54 µm; SD, 15.0).

Based on reported smoking status at the baseline and 5-year follow-up examinations, five smoking status categories were assigned: consistent current smoking, past smoking, and nonsmoking reported at both baseline and 5 years (n = 148, n = 651, and n = 912, respectively), recommencement of smoking between examinations (n = 69), and quitting smoking between examinations (n = 20). Fifty participants had incomplete smoking data and could not be categorized. The cross-sectional associations between smoking status and retinal vessel caliber seen at baseline persisted at the 5-year follow-up examination, with wider CRVE among past and current smokers than in never smokers and wider CRAE among current smokers than in never smokers (table 5). There were no significant differences in the mean change in CRAE or CRVE between subgroups for smoking status (table 5) or amount smoked (data not shown), except for a small increase in average CRAE among persons with ≥50 pack-years of smoking as compared with those who had never smoked (mean change = 2.9 µm (95 percent CI: 0.6, 5.3); p = 0.004).


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  		TABLE 5. Mean retinal venular and arteriolar caliber at baseline (1992–1994) and 5 years (1997–1999) and change over 5 years, by smoking status, Blue Mountains Eye Study

 
We then assessed the odds of relatively large changes in vessel caliber (beyond 1 SD from the mean difference in measurements between baseline and the 5-year examination). A relatively large change in CRVE was seen in 529 participants (28.6 percent), with narrowing of >1 SD in 264 cases and widening of >1 SD in 265 cases. Participants who smoked were more likely to have had a relatively large change in CRVE (data not shown). We found weakly significant dose-dependent trends toward increased odds for both a relatively large increase in CRVE and a relatively large decrease in CRVE over the 5-year period (ptrend < 0.05) across baseline smoking categories (table 6). There were no significant trends for the odds of a relatively large increase or decrease in CRAE.


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  		TABLE 6. Odds of relatively large widening and narrowing in retinal venular caliber over 5 years (from 1992–1994 to 1997–1999), by smoking status and amount smoked, Blue Mountains Eye Study*

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this population of older persons, we observed cross-sectional associations of cigarette smoking with wider venular caliber and, to a lesser extent, wider arteriolar caliber. These cross-sectional findings persisted at the 5-year follow-up examination and are consistent with previous studies (10, 11, 15). Second, we found a statistically significant interaction between cigarette smoking and elevated white blood cell count for widening of venular caliber in cross-sectional analyses. Third, we found a longitudinal association between cigarette smoking at baseline and relatively large temporal changes in retinal venular caliber (both widening and narrowing) over 5 years.

A unique aspect of the current analysis, as compared with previous studies, was the adjustment for fellow retinal vessel caliber. To minimize confounding due to shared underlying determinants of venular and arteriolar caliber, such as body size and genetic factors, we reassessed associations after adjusting for the caliber of the correlated fellow vessel as an additional explanatory factor in the models. Cross-sectional findings of wider venular caliber with cigarette smoking remained significant after controlling for arteriolar caliber, while associations between wider arteriolar caliber and smoking became weaker and less consistent after controlling for venular caliber. The apparent association between wider arteriolar caliber and smoking observed before adjustment for venular caliber is therefore likely to involve confounding due to shared underlying determinants of caliber for both vessel types, as has been reported for the relation between venular caliber and incident hypertension (16, 17). Investigators in earlier studies did not adjust for the caliber of the fellow vessel type (10, 15).

While the mechanisms involved in retinal vascular dilation in smokers are not yet known, venular widening has been observed clinically in smokers and may be due to reduced oxyhemoglobin and tissue hypoxia, nicotine-induced changes in vessel autoregulation, and secondary polycythemia (30, 31). Endothelial dysfunction is also a consequence of smoking (32–34) and could potentially explain our findings. Epidemiologic studies have suggested but not yet convincingly demonstrated that endothelial dysfunction is associated with retinal vessel caliber. In the Multi-Ethnic Study of Atherosclerosis, levels of plasminogen activator inhibitor 1 and soluble intercellular adhesion molecule 1 were weakly associated with wider venular caliber after adjustment for age, gender, and ethnicity, but the significance of the association was lost after adjustment for other factors, and there were no significant findings for von Willebrand factor or soluble E-selectin (15). In the Beaver Dam Eye Study, retinal vessel caliber was not significantly associated with either soluble intercellular adhesion molecule 1 or soluble E-selectin (11). Chronic low-level inflammation (indicated by high-normal levels of circulating inflammatory markers such as white blood cell count, C-reactive protein, and interleukin-6) in current smokers (35, 36) could also be partially responsible for the observed association, as inflammation has been linked to wider venules and arterioles (10, 11, 15), and adjustment for inflammatory markers attenuated the association somewhat.

We observed a statistically significant interaction between smoking and raised white blood cell count for retinal venular caliber. The association between smoking and wider venular caliber appeared stronger among persons with higher white blood cell counts. The positive association between venular caliber and white blood cell count was seen only among past or current smokers. The mechanism of this effect modification is unclear, but it could suggest that the link between smoking and wider venules operates partly via subtle, subclinical inflammatory processes. This interaction between smoking and raised white blood cell count is consistent with the hypothesis that damage to the vascular endothelial surface by activated leukocytes due to smoking may play a role in venular dilation (10). However, wider venules were also observed in persons who had quit smoking years previously, and smoking was associated with wider venules among persons in the lowest quintile of white blood cell count, which suggests that the association between smoking and wider venular caliber may also operate via mechanisms other than inflammation.

Our findings support the developing concept that retinal venular dilation may reflect cumulative lifetime exposure to risk factors such as smoking (10–12, 15). Of note, even persons who had stopped smoking between baseline and the 5-year follow-up examination had wider venules than persons who had never smoked or who had quit smoking prior to baseline, supporting the speculation that smoking may be associated with long-term structural changes in microcirculation (2). The exact consequences of venular dilation in microcirculation are unclear, although widening of retinal vessels has been associated with the incidence (37) and progression (38) of diabetic retinopathy in persons with type 1 diabetes. The effect of smoking on systemic microcirculation could be analogous to diabetic retinopathy and may have clinical implications, since it suggests a mechanism which may partly explain the otherwise puzzling associations between wider retinal venular caliber and risk of stroke and coronary heart disease (4, 6, 8, 13).

Our longitudinal data on change in retinal vessel caliber measurements did not confirm a specific direction of association between smoking and further retinal venular widening between the two time points. Rather, there was a dose-response relation between smoking and relatively large changes in venular caliber measurements in either direction (widening or narrowing) over 5 years. While the increased likelihood of a relatively large widening over time was expected and hypothesized a priori, an increased likelihood of a relatively large narrowing of venular caliber during the same period was not. Nevertheless, temporal changes in retinal venular caliber in both directions among smokers are consistent with existing literature which describes complex disruptions of microvascular autoregulatory vasomotor function with chronic smoking (39, 40).

This study had several limitations. First, there are distinct anatomic and physiologic differences between the retinal and peripheral microcirculations (lack of direct autonomic innervation and the presence of a blood-retina barrier in retinal microcirculation) (41); therefore, we cannot assume a complete correlation of changes in microvascular caliber in the retinal vessels with identical changes in systemic microcirculation. Second, selection bias could have occurred because a proportion of our population did not attend the 5-year follow-up examination. However, given that persons who smoke and have wider venules are likely to have higher mortality (6, 8, 13), loss to follow-up would have attenuated the observed association between smoking and wider venules. Third, the attenuation of the association between smoking and arteriolar dilation after adjustment for venular caliber may represent overadjustment, if smoking has a shared effect on both vessels. We found no significant differences in arteriovenous ratio between smokers and nonsmokers, which could support this possibility. Fourth, potential effects of measurement error in retinal vessel caliber measurement on the findings for temporal change in retinal vessel caliber are not clear.

In conclusion, we report cross-sectional associations between smoking and wider retinal venules and weaker, less consistent associations between smoking and wider arteriolar caliber in the Blue Mountains Eye Study. These baseline associations persisted at the 5-year follow-up examination. The smoking effect on venules was dose-dependent. Smoking also appeared to modify the association between white blood cell count and widening of retinal venules. Longitudinal associations between smoking and changes in retinal vessel caliber were weaker and less consistent. Current and heavy smoking appeared to be weakly associated with relatively large temporal changes in venular caliber in either direction (widening or narrowing). Such long-term effects of smoking on microcirculation are not yet well explored in the epidemiologic literature and require confirmation and clarification from future studies. Long-term effects of smoking on microcirculation may contribute to the association between smoking and cardiovascular disease, since wider retinal venular caliber has been found to be associated with increased risk of adverse cardiovascular outcomes.


   ACKNOWLEDGMENTS
 
This study was supported by grants 153948 and 302068 from the National Health and Medical Research Council of Australia.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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