Ординатура / Офтальмология / Английские материалы / Automated Image Detection of Retinal Pathology_Jelinek, Cree_2009

consistent evidence that retinal vascular changes are associated with both clinical and subclinical stroke and a variety of cerebrovascular conditions independent of traditional risk factors such as hypertension, diabetes, and cigarette smoking.

Since the 1970s, physicians have reported that in people with hypertension, the presence of retinopathy signs is associated with both subclinical and clinical stroke [34; 105–107]. Newer population-based studies, using standardized grading of digitized retinal photographs, have confirmed these early observations. In the ARIC study, among more than 10 000 individuals without a history of stroke, those with microaneurysms, retinal hemorrhages, and cotton wool spots were two to three times more likely to develop an incident clinical stroke in the next three years than those without these retinopathy signs, even after factoring the effects of multiple vascular risk factors [78]. Similar associations were seen in persons with type 2 diabetes [79]. Among the ARIC participants without clinical cerebrovascular disease, these retinal vascular abnormalities were also related to cognitive decline [108], and magnetic resonance imaging (MRI) detected structural abnormalities including cerebral white matter lesions [80] and atrophy [109]. Furthermore, the ARIC study suggests a possible synergistic interaction between the presence of retinal vascular abnormalities and subclinical white matter lesions on the subsequent risk of clinical stroke. Participants with both retinopathy and white matter lesions had a substantially higher stroke risk than those without either finding (relative risk 18.1, 95% confidence intervals, 5.9 to 55.4) [80]. Thus cerebrovascular pathology may be more severe or extensive in persons with both cerebral and retinal signs of microvascular disease.

The Cardiovascular Health Study, which examined older persons, found similar associations. In a cross-sectional analysis, after controlling for blood pressure and risk factors, participants with retinopathy were twice as likely to have a prevalent stroke as those without retinopathy (odds ratio 2.0, 95% confidence intervals, 1.1 to 3.6) [57]. In this older population, retinal arteriolar abnormalities were also associated with prevalent and incident MRI-defined cerebral infarcts, as well as presence and progression of white matter changes [76]. These observations are consistent with data from the Blue Mountains Eye Study in Australia, in which nondiabetic persons with retinopathy were 70% more likely to suffer stroke-related death than those without retinopathy [81]. Similarly, in a nested case-control study in the Beaver Dam Eye Study cohort, the presence of retinal microaneurysms, retinal hemorrhages, and retinal arteriolar narrowing was associated with an increased 10-year risk of stroke mortality [110]. Finally, there is new evidence that in persons with impaired glucose tolerance, retinopathy signs are associated with prevalent stroke [77].

In addition to retinopathy signs, variations in retinal vascular caliber have also been linked to stroke risk. The ARIC study previously showed that a smaller retinal AVR, interpreted as generalized retinal arteriolar narrowing, might be an independent predictor of incident stroke in middle-aged individuals. Smaller clinical investigations support this finding [111–113]. In a series of patients with symptomatic atherosclerotic disease (recent ischemic stroke, myocardial infarction, or peripheral arterial disease), retinal arteriolar narrowing and sclerosis, defined from retinal photographs, were related to presence of white matter lesions and lacunar infarcts de-

Retinal Vascular Changes as Biomarkers of Systemic Cardiovascular Diseases 193

tected on MRI [111]. Other researchers found that retinal microvascular flow is reduced in persons with cerebral small vessel disease [112; 114], and that retinal and cerebral arteriolar histopathology is similar in stroke decedents [113]. Subsequent discovery of the shortfalls relating to the use of retinal AVR prompted newer studies to evaluate the association of retinal arteriolar and venular calibers separately with stroke risk [64; 65]. Using this approach, both the Rotterdam Eye Study [95] and the Cardiovascular Health Study [93] showed that rather than narrower retinal arteriolar caliber, wider retinal venular caliber predicted the future risk of clinical stroke, independent of other stroke-related risk factors. Thus, the relative importance of arteriolar and venular caliber in stroke risk prediction remains to be determined

The importance of the reported associations of retinal vascular signs with stroke, white matter lesions, cerebral atrophy, and cognitive impairment is that it supports a contribution of small vessel disease to the pathogenesis of a wide range of cerebrovascular disorders. In addition, because the retinal signs (e.g., microaneurysms, retinal hemorrhages and cotton wool spots) that are most strongly related to cerebrovascular diseases are usually the result of a disruption in the blood-retinal-barrier, it may be possible to infer that a breakdown of the cerebral blood-brain-barrier may also be a key pathophysiological process in the pathogenesis of cerebrovascular diseases [115].

7.4.3Coronary heart disease and congestive heart failure

Similar to cerebrovascular disease, the current literature provides increasing evidence that retinal vascular changes are related to CHD and congestive heart failure development. Previous clinical studies based on ophthalmoscopic examinations have linked retinopathy signs with ischemic T-wave changes on electrocardiogram [25; 26], severity of coronary artery stenosis on angiography [116], and more recently, with incident clinical CHD events [117].

Newer population-based studies using retinal imaging techniques have produced stronger evidence supportive of these findings, demonstrating associations of various retinal vascular signs with CHD and CHD mortality. In the ARIC study, smaller AVR (initially interpreted as generalized retinal arteriolar narrowing and subsequently found to be due to generalized retinal venular dilatation) was shown to be an independent predictor of incident CHD in women (relative risk 2.2; 95% confidence intervals: 1.0–4.6), but not in men [90]. This gender difference was also present in the Blue Mountains Eye Study [94] and the National Health Examination Survey [33]. These important observations suggest a more prominent role of microvascular disease in the pathogenesis of CHD in women than in men [118], a theory that has been well described in the past [119]. However, gender difference in the relationship between retinopathy signs and risk of CHD may not be present in high-risk populations. For example, the Lipid Research Clinic’s Coronary Primary Prevention Trial provides evidence of an independent association of retinopathy with incident CHD in high-risk men. Additional analysis of the ARIC study data found that in persons with diabetes, CHD risk doubles in those with retinopathy signs as compared to those without retinopathy (relative risk 2.07; 95% confidence intervals: 1.38–3.11),

7.5.1Diabetes mellitus

The hypothesis that diabetes may have etiologic links with microvascular disease has been tested in recent studies using retinal vessel measurements. In the ARIC and Beaver Dam Eye studies, nondiabetic individuals with smaller AVR were shown to have about a 50% to 70% higher risk of incidence with diabetes, independent of other diabetes-related risk factor [143; 144]. The Beaver Dam Study showed that this association is noticeably stronger in individuals with hypertension at baseline (relative risk 3.41; 95% confidence intervals: 1.66–6.98) [144]. The Rotterdam Eye Study proposed that this association may be due to retinal venular dilatation instead of arteriolar narrowing and demonstrated an association of larger retinal venular caliber with impaired fasting glucose [145]. This finding is consistent with earlier findings of prevalence data from the ARIC study [137]. While the underlying biological mechanisms for these observations remain to be elucidated, experimental studies have shown that administration of intravenous dextrose can cause dilatation of retinal venules in normoglycemic patients [148]. Moreover, reduced vascular reactivity associated with endothelial dysfunction and inflammatory processes may also play an integral role in the development of wider retinal venules and diabetes [149].

Even though diabetic retinopathy is a classic example in which retinal vascular changes evidently reflect the status of a metabolic disorder, there has been inconsistent evidence to support the hypothesis that early retinopathy signs in nondiabetic persons are preclinical markers of diabetes. Epidemiological data from several crosssectional studies indicate that retinopathy signs are associated with impaired glucose metabolism [77; 137; 150; 151] and prevalent diabetes [56]. Some investigators speculated that retinopathy development may precede the onset of diabetes [152]. This theory, nevertheless, is unsupported by currently available prospective data. The ARIC study reported that the presence of typical retinopathy signs in persons without diabetes is not associated with subsequent development of diabetes over a period of 3.5 years [136], suggesting that these retinal lesions may reflect pathological conditions other than diabetes (e.g., hypertension). This is in agreement with findings from the Blue Mountain Eye Study [153]. Nonetheless, in stratified analysis, the ARIC study revealed a possible association of retinopathy with twofold increased risk of incident diabetes in those with a family history of diabetes [136]. The significance of this finding awaits further exploration.

7.5.2The metabolic syndrome

Apart from diabetes, metabolic syndrome, defined by the presence of three out of five clinical or biochemical features (abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, high blood pressure, and impaired fasting glucose), has also been associated with retinal vascular changes. The ARIC study found that persons with metabolic syndrome are more likely to have typical signs of retinopathy as well as larger retinal venules [137]. The prevalence of these retinal vascular changes also appears to be higher with an increasing number of metabolic syndrome components. These findings are further reinforced by data from the Multi-

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Ethnic Study of Atherosclerosis (MESA), reporting associations of larger retinal venular caliber with a number of metabolic syndrome components in a multi-ethnic population-based cohort [56].

7.5.3Overweight and obesity

Obesity may have a profound effect on the eye [154], but the retinal vascular manifestations of obesity are poorly understood. There is evidence that obesity increases the risk of retinopathy development in both diabetic and nondiabetic populations [149]. Interestingly, recent studies have shown that variations in retinal vascular caliber may also be associated with obesity correlates. The ARIC and Blue Mountain Eye studies both reported an association of larger retinal venular caliber with body mass index and prevalent obesity [137; 146]. Prospective data from the Blue Mountains Eye Study further indicated that larger retinal venular caliber may even predict the incidence of obesity over a 5-year period, suggesting the existence of altered microvascular function in the pathogenesis of obesity [146]. These findings are in keeping with data from a cohort of young healthy children [147], in which confounding effects of systemic and ocular disease processes are of less concern. Inflammation, oxidative stress, hyperleptinemia, and nitric oxide dysregulation have all been implicated as potential pathways in the link between larger retinal venules and obesity development [146; 147].

7.6Retinal Vascular Changes and Other Systemic Diseases

7.6.1Renal disease

Retinopathy and nephropathy are two well known microvascular complications of diabetes [155; 156]. Experimental studies show a high correlation of pathological changes in the retinal vessels with those that occur in the renal vasculature [157]. However, there have been few studies that have explored the independent association of retinal vascular abnormalities with nephropathy, particularly in people without diabetes. An earlier study of individuals with hypertension demonstrated a strong relationship of retinopathy grades with microalbuminuria, a preclinical marker of renal dysfunction [158]. This is supported by more recent studies of clinical renal disease in the general population. In the ARIC study, various retinopathy signs, such as AV nicking, retinal hemorrhages, microaneurysms, and cotton wool spots, were associated with a higher risk of renal dysfunction than those without these retinal lesions [84]. This association was independent of vascular risk factors and was seen in persons with and without diabetes or hypertension. Similarly, in the Cardiovascular Health Study, the presence of retinopathy was independently associated with an increased risk of incident renal dysfunction as well as progression of renal impairment [85]. These findings raise the possibility that retinopathy and nephropathy may share common pathogenic pathways (e.g., endothelial dysfunction, inflammation),

even in nondiabetic individuals, and highlight the need to monitor renal function in individuals with retinopathy.

7.6.2Atherosclerosis

Atherosclerosis, the key pathophysiological disease process of CHD and stroke, has been the focus of interest in studies of retinal vascular measurements (Table 7.3). The evidence of a link between direct measures of atherosclerosis and retinal vascular changes, however, has not been consistently demonstrated. In the ARIC study, factoring the effect of blood pressure and other risk factors, smaller AVR was associated with carotid artery plaque but not intima-media thickness (IMT), whereas AV nicking was associated with carotid artery IMT but not plaque [98]. The Rotterdam Eye Study, on the other hand, found an association of smaller AVR with carotid artery IMT [68]. Moreover, smaller AVR has also been independently associated with increased carotid artery stiffness, an early marker of atherosclerosis [159]. These findings, nevertheless, are contradictory to data from the Cardiovascular Health Study (CHS),which revealed no consistent independent association between smaller AVR and measures of large artery atherosclerosis [57].

Apart from retinal vessel measurements, retinopathy signs (e.g., microaneurysms) have also been related to atherosclerosis. For example, the CHS showed an independent association of retinopathy with carotid artery plaque and increased carotid IMT [57]. This is supported by data from the Chennai Urban Rural Epidemiology Study, which demonstrate independent associations of retinopathy signs with both increased carotid IMT and arterial stiffness in diabetic individuals [165]. Furthermore, newer data from the MESA indicate that retinopathy is positively associated with coronary artery calcification, a robust measure of coronary atherosclerotic burden, independent of blood pressure, diabetes, and other risk factors [129].

These data imply that while changes in retinal vascular caliber may be pathologically distinct from atherosclerotic processes [98], there is need to further understand the link between other retinopathy signs and atherosclerosis.

7.6.3Inflammation and endothelial dysfunction

Retinal vascular changes in diabetes, hypertension,and other systemic disease processes may be related to inflammation and/or endothelial dysfunction (Table 7.3). This concept is supported by data from three population-based studies, in which various inflammatory markers were demonstrated to be associated with larger retinal venules [56; 68; 164]. In the Beaver Dam Eye Study, indicators of endothelial dysfunction were also shown to be associated with larger retinal venular caliber [164]. These observations agree with findings from experimental studies, which demonstrated an increase in the diameter of retinal venules, but not arterioles, after administration of lipid hydroperoxide into the vitreous of rats with a resultant increase in the number of leukocytes in the retinal microvasculature [166]. Dilatation of retinal venules has been postulated to be a result of increased production of nitric oxide secondary to release of inflammatory mediators [167]. The collective data from these

studies suggest that both inflammation and endothelial dysfunction may play key mechanistic roles in interlinking retinal venular dilatation with systemic diseases.

7.6.4Subclinical cardiac morphology

Prospective data from the ARIC study indicate that retinopathy may predict clinical CHD and congestive heart failure events in the general population [83]. There is now evidence that retinal vascular changes may be associated with early geometric alterations in the heart prior to manifestation of clinical heart disease (Table 7.3). Previous studies have demonstrated strong correlations of retinopathy grades with left ventricular hypertrophy (LVH) in persons with hypertension [102; 168; 169]. In the ARIC study, both focal and generalized narrowing of retinal arterioles were associated with increased odds of LVH in middle-aged African-Americans, independent of blood pressure and other risk factors [162]. This is supported by recent analysis of the cross-sectional data from the MESA, showing that in the general population, narrower retinal arteriolar caliber is associated with left ventricular concentric remodeling, determined from cardiac MRI, even after adjusting for traditional risk factors (odds ratio 1.87; 95% confidence intervals: 1.41–2.48) [161]. This association remained significant in those without diabetes, hypertension,or significant coronary calcification, but was strongest in diabetic persons (odds ratio 4.02; 95% confidence intervals: 2.05–7.88) [161]. Therefore narrowing of retinal arterioles may be a marker of early subclinical myocardial abnormalities.

7.7Genetic Associations of Retinal Vascular Changes

The effects of genetic and environmental factors are intertwined in the development of cardiovascular diseases [170–173]. However, the genetic influence on the microvasculature is unclear. Utilizing new retinal image-analysis technology, emerging studies have begun exploring this important aspect.

For example, the Beaver Dam Eye Study reported that retinal vascular calibers were more highly correlated between relatives than between unrelated individuals, an observation proposed to be due to shared genes [174]. This is in keeping with data from a recent twin study, showing that 70% of the variance in retinal arteriolar caliber and 83% of the variance in retinal venular caliber were attributable to genetic factors [175]. Newer data from the Beaver Dam Eye Study, based on a genome-wide linkage scan, further reinforce the genetic contribution to the variation in retinal vascular calibers, independent of hypertension and other confounders [176]. The investigators showed that the linkage regions for retinal vascular caliber overlap with regions that have been previously associated with essential hypertension, coronary heart disease, endothelial dysfunction, and vasculogenesis [176]. These novel findings provide the first genetic evidence to support the clinical observations, as described in Section 7.4, that changes in retinal arteriolar and venular caliber may

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precede and contribute to the pathogenesis of cardiovascular disease (e.g., hypertension).

While the currently available data regarding the genetic basis of retinal vascular changes are limited, findings from recent studies clearly demonstrate the usefulness of retinal image analysis in advancing our understanding of the complex geneticenvironmental interaction pathways involved in the pathogenesis of cardiovascular disease. The exciting prospect of this expanding field of research opens many possibilities [177].

7.8Conclusion

There is increasing recognition that retinal vascular image analysis presents great potential to advance our understanding of the role of microvascular disease in the development of various systemic disorders. Retinal vascular changes have now been linked to a spectrum of clinical and subclinical cardiovascular and metabolic outcomes. The mounting evidence generated from recent studies supports the notion that the retinal vasculature may provide a lifetime summary measure of genetic and environmental exposure, and may therefore act as a valuable risk marker for future systemic diseases. Nonetheless, despite an increasing application of retinal image analysis in research settings, its clinical value remains to be determined. Epidemiological evidence that retinal vascular changes are significantly predictive of morbid events does not necessarily translate directly into clinical practice. Further research is clearly required, perhaps with a more directed focus in assessing the ability of retinal imaging to provide clinically useful information above and beyond currently available risk stratification methods to aid prevention and management of cardiovascular and metabolic diseases. Finally, there remain additional novel measures of retinal vascular structure [178–182] that may offer additive value to the existing traditional retinal vascular signs in predicting systemic diseases. The role of these new measures in retinal image analysis remains to be clarified.

7.A Appendix: Retinal Vessel Caliber Grading Protocol

IVAN is a semi-automated system used to measure retinal vessel widths from a digital retinal image. IVAN is operated off of a two-monitor workstation with the image files organized by reading lists. The software opens on the primary monitor with three windows: the image display window, the control window, and the vessel data parameters file.

The image display is viewed on the primary monitor (Figure 7.A.1) and the control panel is moved to the secondary monitor (Figure 7.A.2).