The ARIC study has well documented data on a range of systemic cardiovascular risk factors and digitized retinal images, from which we measured retinal arteriolar (CRAE) and venular caliber (CRVE). In an earlier report, our group examined the association of cardiovascular risk factors with arteriole to venule ratio, a measure of arteriolar narrowing which has since been shown to have several limitations.21
Our findings are consistent with those from our earlier report and provide further insight into the vascular processes driving changes in the arteriole to venule ratio
Our study expands on earlier work examining the specific relationships of cardiovascular, metabolic, inflammatory, and lifestyle risk factors with retinal vascular caliber,17
including reports from the Multi-Ethnic Study of Atherosclerosis (MESA),3
Beaver Dam Eye Study (BDES),4
Blue Mountains Eye Study (BMES),6;11
Cardiovascular Health Study,7
and the Funagata study.8
All studies consistently found that high blood pressure was associated with narrower arteriolar caliber, and that smoking and body mass index were associated with wider venular caliber. Some studies have also reported high blood pressure associated with narrower venular caliber, and smoking associated with wider arteriolar caliber, which our analyses now show disappear with adjustment for natural anatomic variation and measurement error.5
In the case of both MABP and smoking, findings from models with additional adjustment may be more congruent with clinical experience and existing biological knowledge. For example, wider retinal venules with increasing MABP may be explained as a response to chronic retinal hypoxia or hypoperfusion 23;24
from chronic hypertensive damage to the microcirculation, whereas it is less biologically apparent why narrower venules should be associated with increasing MABP. Similarly, a lack of influence of smoking on arteriolar caliber is more consistent with the literature that smoking has little effect on arteriolar caliber, or causes only mild arteriolar narrowing25;26
rather than widening.
An important concern in controlling for anatomy and measurement error using the fellow vessel caliber is the potential for over-adjustment where anatomic factors common to both arteriolar and venular caliber may be inappropriately adjusted for. This is particularly relevant in determining the associations of age, gender and race on vascular caliber. Increasing age was a major contributor to narrower arteriolar and venular caliber. Other researchers have reported that men have narrower arterioles than women,3;27
which could be related to the higher blood pressure in men (with higher arteriolar resistance).27
In animal experiments, male gender is associated with narrower arterioles than female gender at the same blood pressure level.28;29
The associations of male gender and black race with wider venular caliber were reported in the BDES4
respectively, but the underlying mechanisms are not known. These differences may reflect genetic or cardiovascular influences not examined in this report.
We observed that the main determinants of narrower arteriolar caliber (other than demographic factors) were higher current MABP, lower serum albumin, and current alcohol consumption. In longitudinal analyses, both current and past MABP were strongly associated with narrower arteriolar caliber. All studies to date have consistently demonstrated that current,3–8
and past blood pressure30;31
are strongly associated with narrower arteriolar caliber, confirming retinal arteriolar narrowing as a marker of current and longer-term blood pressure levels. The association of lower serum albumin with narrower retinal arterioles was also observed in the BDES,4
although it was not statistically significant in that population. Lower serum albumin may be a non-specific marker of inflammation or chronic kidney disease, and the association with narrower arterioles may reflect these disease processes The markers of endothelial dysfunction examined in this report, vWF and factor VIII levels, made at most small or negligible contributions to arteriolar caliber, consistent with results from the BDES,4
and Hoorn studies32
which found no association of retinal arteriolar caliber with other more specific serum markers of endothelial dysfunction (e.g. serum soluble intercellular adhesion molecule-1, sICAM-1). However, we did not have data on other markers of endothelial dysfunction, such as plasma asymmetric dimethylarginine.33
The association with current alcohol consumption has been reported in some studies (MESA),3
but not others (Rotterdam),5
and may reflect impaired vasodilation with chronic alcohol ingestion, which is associated with impaired vasodilation in the cerebral 34;35
and systemic microcirculations.36
The main determinants of wider venular caliber in this population (other than demographic factors) were current smoking and higher current MABP, followed by increasing white cell count. Smoking has consistently been associated with wider retinal venules in the Rotterdam study, 5
the Wisconsin Epidemiologic Study of Diabetic Retinopathy,10
, and we now additionally show a temporal association of past smoking with wider retinal venules that is independent of current smoking status. Retinal venule widening in smokers has been observed clinically, and may be due to reduced oxyhemoglobin and tissue hypoxia, nicotine-induced changes in vessel autoregulation, and secondary polycythaemia.38;39
Chronic smoking also promotes inflammation (see below) and endothelial dysfunction,40–42
which may lead to disruptions of microvascular autoregulatory vasomotor function and venular widening.43;44
Wider retinal venules may thus be a lasting microvascular marker of damage from long-standing smoking.
Higher white cell count was a major contributor to wider venular caliber, with lesser contributions from other nonspecific markers of inflammation (fibrinogen and serum albumin).3–5
A range of inflammatory markers has now been consistently linked with wider retinal venules in all the major population-based studies,3–5;45
strongly implicating a role for inflammation in influencing retinal venular caliber. Inflammation may cause venular widening through mechanisms such as damage to the venular endothelial surface layer,5;45
resulting in loss of glycocalyx (and hence a wider blood column detected on retinal photography) or increased vasodilation.
We also examined for possible racial/ethnic and gender differences in associations. Associations were largely similar, but some systemic determinants appeared to vary by race or gender e.g. BMI, alcohol consumption and markers of endothelial dysfunction. These findings should be interpreted with caution as they may be chance associations, were not specified apriori, most interactions were not strongly statistically significant, and the mechanisms which may underlie them are not known.
he vascular risk factors examined in this report explain more of the variation in retinal arteriolar caliber than in retinal venular caliber, highlighting the lack of knowledge about the determinants of venular caliber. It was earlier assumed that venular calibers remain relatively static in the presence of vascular disease, but this is now shown to be clearly not the case. Some recent studies indicate that venular widening may be a marker of other processes such as endothelial dysfunction,3
hypoperfusion and cerebral hypoxia.46
However, it should be borne in mind that associations with venular widening may actually reflect associations with arteriolar widening, but due to the strong concomitant association of arteriolar narrowing with blood pressure this possibility is difficult to determine, and our method of adjusting for the fellow vessel caliber may be an overadjustment.
Strengths of this study include the use of well-measured cardiovascular risk factors, adjustment for many potential confounders and large sample size permitting subgroup analyses. As the main analyses were cross-sectional, care must be taken in interpreting the temporal sequence of effect. Although many associations were observed, most contributed only marginally to differences in vascular caliber. Although a high proportion of subjects had ungradeable photographs, we do not believe this influenced the associations we observed, as it is unlikely that persons with ungradeable photographs had retinal vessel calibers different from persons with gradeable photographs.
In summary, findings from the ARIC population suggest distinct patterns of systemic associations with arteriolar and venular caliber. The major systemic determinants of narrower arteriolar caliber were higher current blood pressure, lower serum albumin and current alcohol consumption. The major determinants of wider venular caliber were current smoking and higher blood pressure, with contributions from inflammatory processes. Past blood pressure and past smoking were associated with narrower arteriolar caliber and wider venular caliber respectively. Our results also indicate that spurious associations from shared anatomy and measurement error may occur with regards to associations with blood pressure and smoking. However, with regards to other systemic variables, spurious associations do not appear to be a major issue. These data show clearly the deleterious effects of elevated blood pressure, smoking, alcohol, obesity, dyslipidemia and inflammation on the microcirculation and emphasize again the importance of controlling these risk factors in preventing and treating cardiovascular disease. More research is needed into whether close monitoring of the retinal microvasculature using retinal imaging techniques permits clinicians to quantify the efficacy of treatments for elevated blood pressure and other vascular risk factors.