contribution of small vessel disease (evident in the retina) in the pathogenesis of a wide spectrum of cerebrovascular conditions in persons with diabetes. In addition, because diabetic retinopathy is usually the end result of a disruption in the blood–retinal barrier, it is possible to infer that these cerebral conditions may also be related to breakdown of the blood–brain barrier (49).

DIABETIC RETINOPATHY AND HEART DISEASE

Microvascular dysfunction is now recognized as an important pathogenic factor in the development of heart disease in persons with diabetes. However, similar to cerebral circulation, there are no simple and noninvasive techniques for the assessment of coronary microcirculation (50), and studies that have traditionally evaluated the role of coronary microvascular dysfunction in diabetic heart disease have been limited by small clinic-based samples using highly specialized methods (51–55).

More than two decades ago, the Framingham Heart and Eye Study proposed that retinopathy signs may reflect a generalized microangiopathic process that affects organs elsewhere in the body, such as the heart, in people with diabetes (56). This hypothesis is consistent with earlier clinical studies based on ophthalmoscopic examinations linking retinopathy signs with ischemic T-wave changes on electrocardiogram (57, 58), severity of coronary artery stenosis on angiography (59), and more recently, with incident clinical coronary heart disease vents (60).

Recent population-based studies using standardized photographic grading of retinopathy have produced stronger evidence in support of these previous observations. It is now clear that diabetic retinopathy signs are associated with risk of coronary heart disease and congestive heart failure (Table 4). In the ARIC study, the presence of retinopathy was associated with twofold higher risk of incident coronary heart disease, threefold higher risk of fatal coronary heart disease, and fourfold higher risk of congestive heart failure, independent of diabetes duration, glycemic control, smoking, lipid profile, and other risk factors (61, 62). The population-attributable risk of retinopathy to congestive heart failure has been estimated to be 30.5% (62). In addition, there is a graded, dose-dependent association of increasing diabetic retinopathy severity with increasing coronary heart disease risk (61). These findings are consistent with data from the WHO-MSVDD (21) and other studies showing associations of not only NPDR but also PDR with coronary heart disease (12, 63, 64).

As for associations with cardiovascular mortality and stroke, the association of retinopathy with coronary heart disease risk is not consistently present in younger persons with type 1 diabetes. In the WESDR type 1 diabetes cohort, while NPDR, PDR, and retinopathy severity were all associated with an excess risk of deaths from ischemic heart disease, ascertained from death certificates, these associations were not significant after adjusting for cardiovascular risk factors, including nephropathy (9, 17, 20). The authors have suggested that misclassification of cause of death could have limited their study (9). In the EURODIAB study of type 1 diabetes, retinopathy was also not significantly associated with incident CHD after multivariate analysis (65).

Apart from epidemiological studies, there are clinical studies that suggest the presence of retinopathy can be used as an indicator of silent myocardial ischemia and help guide investigative approaches in diabetic patients with suspected heart disease (66–71).

Furthermore, retinopathy may also be a valuable prognostic predictor for diabetic patients undergoing cardiac revascularization procedures. For instance, studies show that compared with patients without diabetic retinopathy, patients with retinopathy are more likely to sustain major adverse cardiac events or complications (e.g., death, myocardial infarction, heart failure, in-stent restenosis) after percutaneous coronary intervention or coronary artery bypass surgery, even after factoring effects of age, gender, diabetes duration, insulin use, and other factors that may affect prognosis after these procedures (72–75). Thus, it may be useful to assess retinopathy status when making clinical decision regarding the need for revascularization in diabetic patients with established coronary heart disease (76).

The associations of retinopathy with cardiac morbidity and mortality are consistent with other observations that diabetic retinopathy is associated with subclinical coronary microand macrovascular pathology. Studies showed that persons with retinopathy are more likely to have myocardial arteriolar abnormalities (51), coronary perfusion defects (71, 77, 78), poorer coronary flow reserve (79), and lower coronary collateral score (80), than those without retinopathy. The presence of retinopathy signs has also been associated with higher degrees of coronary artery calcification (unpublished data from the Multi-Ethnic Study of Atherosclerosis, Wong TY 2007) (81) and more diffuse/severe coronary artery stenosis on angiograms (70), two robust measures of coronary atherosclerotic burden. Nevertheless, the fundamental question of whether the association of retinopathy with heart disease is driven by microor macrovascular disease remains unclear but it is likely that a mixture of microand macrovascular disease processes, mediated by common pathogenic pathways, contributes to the observed associations.

DIABETIC RETINOPATHY, NEPHROPATHY, AND NEUROPATHY

Nephropathy is another well-known microvascular complication of diabetes. Experimental studies show a high correlation of pathological changes in the retinal vasculature with those that occur in the renal vasculature (82, 83). This is in keeping with epidemiological studies consistently demonstrating an association between diabetic retinopathy and nephropathy, independent of shared risk factors (Table 5). Studies of individuals with hypertension show that retinopathy signs are strongly related to microalbuminuria, a preclinical marker of renal dysfunction (84). More recent studies of clinical kidney disease support this observation. In the WESDR, more severe diabetic retinopathy was associated with an increased 4-year risk of nephropathy in persons with type 1 diabetes (17, 85). Moreover, the presence of specific retinopathy signs, such as retinal hemorrhages, microaneurysms, and cotton wool spots, was associated with higher risk of renal dysfunction, even in persons without clinical diabetes (86). Similarly, in the Cardiovascular Health Study, the presence of retinopathy was independently associated with prevalent gross protenuria (23) and an increased risk of progression of renal impairment (87). These findings suggest that retinopathy and nephropathy share pathogenic pathways (e.g., inflammation, endothelial dysfunction) and highlight the need to monitor renal function in diabetic persons with retinopathy.

There is also evidence that retinopathy may be related to risk of neuropathy in people with diabetes (88, 89) or abnormal glucose metabolism (90). In a longitudinal study of

264 diabetic individuals, the presence of more severe microvascular diseases, including retinopathy, was associated with more severe diabetic polyneuropathy. Recently, the Australian Diabetes Obesity and Lifestyle Study, a population-based study of Australian adults aged 25 years or more, reported a strong association between retinopathy and neuropathy in persons without clinical diabetes but with abnormal glucose metabolism (90). Furthermore, in the WESDR, participants with PDR had a higher risk of incident lower leg amputation, a complication of diabetic peripheral neuropathy, as compared to those with no or minimal retinopathy at baseline (17).

PATHOGENIC BASIS BETWEEN DIABETIC RETINOPATHY

AND SYSTEMIC DISEASE

Although epidemiological and clinical studies have now clearly demonstrated associations of diabetic retinopathy with a range of systemic complications, the exact underlying pathophysiological mechanisms remain unclear. In part, this is due to several unresolved issues regarding the basic pathogenesis of diabetic retinopathy (1).

Nonetheless, several mechanisms have been hypothesized. First, the excess risk of systemic complications in persons with diabetic retinopathy has been suggested to be due to the more adverse cardiovascular profile in diabetic individuals. However, most studies have accounted in statistical analyses for the potential confounding effects of cardiovascular risk factors.

Second, it is important to note that diabetic retinopathy is related not only to microvascular complications (e.g., nephropathy), but also macrovascular diseases. For example, retinopathy has been associated with several direct measures of atherosclerosis, including carotid artery intima-media thickness or carotid plaque, arterial stiffness (a measure of early atherosclerosis), coronary artery calcification, as well as atherosclerotic lesions detected on angiograms (23, 41, 70, 81, 91). This later observation raises the possibility that common pathophysiological processes may underlie the development of both microand macrovascular disease in diabetes. These common pathways may include inflammation, endothelial dysfunction, and advanced glycation end products (10, 61, 92).

Third, it has been suggested, based on the Steno hypothesis, that retinopathy may reflect generalized vascular dysfunction caused by endothelial dysfunction (93) and genetically determined alterations in the basement membrane metabolism (94) associated with hyperglycemia. These diabetic vascular insults increase arterial/arteriolar wall permeability and leakage. In small arteriolar/capillary beds, retinopathy and nephropathy develop as a result. In large arterial wall, increased permeability facilitates entry and accumulation of lipids, thus promoting the pathogenic cascade of atherosclerosis formation. Such hypothesis, though attractive, remains to be further validated.

CLINICAL SIGNIFICANCE OF RETINOPATHY IN SYSTEMIC

DISEASE SCREENING

The relationships of diabetic retinopathy with systemic vascular diseases are clinically important to ophthalmologists and other healthcare providers who treat and counsel patients with diabetes. Current cardiovascular risk prediction for diabetic populations is inaccurate (95–97). As a recent systematic review of data from more than 70,000