infarction. In the Rotterdam scan study [84], adult persons with larger retinal venular diameters were more likely to progress in cerebral small vessel disease, and it was 70% higher risk for progression in peri-ventricular or sub-cortical WMLs and 59% increased risk for incident lacuna infarcts. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) [85], among persons with diabetes, retinal arteriolar narrowing was associated with 20% higher risk of the 22-year all-cause mortality and 50% higher risk of stroke mortality. Larger retinal venular calibre was also associated with 1.7 times higher risk of stroke mortality.

McGeechan et al. performed a meta-study with multiple epidemiologic study data and concluded that when retinal venular calibre was included in the traditional risk prediction models for stroke, it could reassign 10% of people at intermediate risk into lower-risk categories [86].

8.3.2.3 Risk of Coronary Heart Disease

Studies suggest that retinal vessel calibre predicts CHD more strongly in women than men, possibly reflecting the greater contribution of microvascular disease to CHD development in women. In the ARIC study [87], smaller retinal AVR was associated with increased risk of incident CHD and acute myocardial infarction in women, but not in men. In the CHS [82], larger retinal venular calibre was associated with threefold increased risk of incident CHD independent of cardiovascular risk factors. Smaller retinal arteriolar calibre was also associated with twofold risk of incident CHD, comparing largest with smallest arteriolar calibre quartiles. In 9 years follow-up analysis, women with wider retinal venular calibre or narrower retinal arteriolar calibre each had 30% higher risk of CHD even after adjusting for Framingham risk score variables [88]. In the BMES [89], middleaged persons of 49–75 years with wider venules had a twofold increased risk of CHD mortality after adjusting for traditional risk factors. Additionally, in women, narrower arterioles were associated with 1.5 times higher risk of CHD mortality. In combined analysis of the

BMES and the BDES [90], smaller arterioles and larger venules were associated with 20–30% increased risk of CHD mortality independent of cardiovascular risk factors. These associations were more evident in relatively younger persons aged <70 years.

In another meta-analysis, McGeechan et al. found that retinal vessel calibre changes of both wider venules and narrower arterioles were associated with increased risk for CHD in women, but not in men, and concluded that retinal vessel calibre changes were independently associated with an increased risk for CHD events in women [91].

8.3.2.4 Risk of Peripheral Artery Disease

There has been limited research examining associations between retinal signs and peripheral artery disease (PAD) in general population. In persons with type 1 diabetes in WESDR, 20-year cumulative incidence of lower extremity amputations was two times higher in persons with generalized arteriolar narrowing and more than 3.5 times higher in persons with focal narrowing independent of traditional risk factors.

8.3.3Newer Morphologic Features of Retinal Vasculature

There are now increasing data that other features of the retinal vasculature may provide information on CVD risk. Liew et al. have examined the fractal dimensions of retinal vascular patterns in the area surrounding the optic disc using a semiautomated imaging program and reported that the fractal dimensions of retinal vessel patterns measured with the box-counting method were inversely correlated with systolic blood pressure [57]. Other studies show that hypertension is associated with an increase in the arteriolar ‘length-to-diameter ratio’ and a marked reduction in the number of terminal branches [92]. In a nested case–control study of the BDES, suboptimal relationship of arteriolar diameters at bifurcation and decreased retinal arteriolar tortuosity was associated with increased risk of ischaemic heart disease mortality. Increased arteriolar