Current Approaches to Retinopathy as a Predictor of Cardiovascular Risk

Abstract

Current guidelines emphasize the need for regular eye screening to detect retinopathy signs in patients with diabetes. This presents clinicians with a unique opportunity to visualize, assess and monitor the direct effects of diabetes and hyperglycemia on the microcirculation. Although the adverse impact of diabetic retinopathy on vision is well known, its clinical significance beyond the eye is less well recognized. Recent studies show that patients with diabetic retinopathy are more likely to have subclinical cardiovascular disease, and the presence of retinopathy signs is associated with increased risk of clinical stroke, coronary heart disease, heart failure and mortality. There is also emerging evidence to suggest that diabetic retinopathy may share common genetic linkages with many vascular diseases. These new data support the theory that retinopathy signs may reflect widespread microcirculatory disease not only in the eye but also in vital organs elsewhere in the body. Being a specific and noninvasive measure of diabetic microvascular damage, retinopathy signs may therefore also have a role in improving cardiovascular risk prediction in patients with diabetes.

Copyright © 2010 S. Karger AG, Basel

on vision is well known, the importance and significance of retinopathy signs beyond ocular morbidity is less well recognized. Two decades ago, the Framingham Heart and Eye Study proposed that diabetic retinopathy signs may reflect generalized microangiopathic processes that affect not only the eyes but also organs elsewhere in the body [1]. In recent years, with the use of standardized assessment of retinopathy signs based on retinal photographs [2], studies have more precisely quantified the associations of diabetic retinopathy with a range of subclinical and clinical cardiovascular diseases, suggesting that retinal assessment may have a role in improving cardiovascular risk prediction in patients with diabetes.

This chapter summarizes the evidence regarding the systemic associations of diabetic retinopathy and discusses their potential clinical and research implications.

Diabetic retinopathy is the most common and specific microvascular complication of diabetes and a leading cause of blindness in working aged adult people around the world. While its adverse impact

Diabetic Retinopathy and Mortality

It has long been observed that in persons with diabetes, the presence of retinopathy is associated with poorer survival [3]. Newer studies have

provided further insights into this association. There is now good evidence that this association is more consistently seen in patients with type 2 as compared to type 1 diabetes, reflecting older age and possibly higher prevalence of cardiovascular risk factors in type 2 diabetes.

In persons with type 2 diabetes, the Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) demonstrated that both nonproliferative (NPDR) and proliferative (PDR) diabetic retinopathies were associated with a 30–90% excess risk of death after 16 years of follow-up [4]. Importantly, this association was independent of age, sex, diabetes duration, glycemic control and other survival-related risk factors. Consistent with this finding are subsequent publications from other studies, mostly in Caucasian populations [5–9], but also in Asians [10] and MexicanAmericans [11].

In persons with type 1 diabetes, although some studies suggest that retinopathy also predicts mortality risk, the association may be chiefly explained by concomitant cardiovascular risk factors [4, 12, 13]. In the Early Treatment Diabetic Retinopathy Study, a large clinical trial with a relatively short follow-up, retinopathy was shown to have no association with mortality in type 1 diabetes [9]. Some [14, 15], but not all [8], investigators suggest that coexisting nephropathy (e.g. end-stage renal disease) is a major factor for the poorer survival in type 1 diabetic patients with retinopathy.

The association of diabetic retinopathy with mortality is mainly driven by an increased risk of cardiovascular disease in persons with retinopathy.TheWorldHealthOrganizationMultinational Study of Vascular Disease in Diabetes (WHOMSVDD) consists of a large cohort of type 1 and 2 diabetic persons who were followed up for 12 years for incidence of fatal and nonfatal cardiovascular outcomes [16]. In the WHO-MSVDD, the presence of diabetic retinopathy predicted higher risk of cardiovascular disease and mortality [16]. This association remained significant

even after adjusting for traditional cardiovascular risk factors, and was stronger in women than in men, and again confined to persons with type 2, but not type 1, diabetes [16].

While the presence of retinopathy itself seems to signify an increased mortality risk, studies have also shown a ‘dose-dependent’ association between increasing severity of diabetic retinopathy and increasing cardiovascular disease risk [5–8, 13, 17–20].

Diabetic Retinopathy and Cerebrovascular

Disease

Stroke is a major source of morbidity and mortality in people with diabetes. The significant progress made in stroke prevention and treatment has been confined to the management of strokes that are caused by large vessel disease (e.g. carotid atherosclerosis). However, up to one third of symptomatic strokes are now thought to be attributable to disease of the small arteries/arterioles in the cerebral circulation [21], and this is especially so in people with diabetes [22–26]. However, relatively little is known about these small vessel pathologies due to the paucity of simple and noninvasive methods to study the cerebral microcirculation [27, 28].

Since the retinal and cerebral vasculatures share similar embryological origin, anatomical features and physiological properties [29, 30], retinopathy lesions in persons with diabetes may mirror similar pathological disease processes in the cerebral microcirculation. Indeed, there is now a strong and consistent level of evidence that retinopathy signs are associated with both clinical and subclinical stroke, independent of cerebrovascular risk factors.

Dating back to the 1970s, physicians documented that the presence of retinopathy is associated with stroke, particularly in persons with hypertension [31–37]. Newer populationbased studies, using standardized photographic

evaluation of retinal images to ascertain retinopathy lesions, have confirmed these early observations (table 1). In the WESDR, PDR was associated with incident stroke mortality in both type 1 and 2 diabetes, independent of diabetes duration, glycemic control and other risk factors [4, 12, 15]. In type 1 diabetes, increasing retinopathy severity was also associated with higher stroke risk [15]. These findings are consistent with data from the WHO-MSVDD in both men and women with type 2 diabetes [16].

More recently, the Atherosclerosis Risk in Communities (ARIC) study, a large prospective cohort study of 1,617 middle-aged white and black Americans with type 2 diabetes, showed that the presence of NPDR, even of the mildest phenotype (presence of retinal microaneurysms and/or retinal hemorrhages only, level 14 or 15 on the ETDRS scale), was associated with a twoto three-fold higher risk of ischemic stroke (fig. 1) [38, 39]. In a substudy of the ARIC cohort in which participants had cranial magnetic resonance imaging (MRI) scans, a synergistic interaction between

Follow-up time (days)

Fig. 1. Stroke-free survival in participants with (dashed line) and without (solid line) diabetic retinopathy [38].

the presence of retinopathy and the presence of MRI-defined cerebral white matter lesions on subsequent risk of clinical stroke development was seen. Participants with retinopathy or white

matter lesions alone had about two-fold increase in stroke risk, but participants with both retinopathy and white matter lesions had more than eighteen times higher stroke risk than those without either finding [40]. This supports the theory that subclinical cerebrovascular disease may be more severe or extensive in persons with both cerebral and retinal markers of microvascular pathology compared to those without these markers. Findings from the ARIC study are further reinforced by the Cardiovascular Health Study (an older population) [41] and other studies reported similar findings [37, 42–44]. Finally, there is new evidence that retinopathy signs are associated with stroke risk even in persons without clinical diabetes [45] and in persons with impaired glucose tolerance [46].

The importance of these reported associations is that they directly support a possible contribution of small vessel disease, evident in the retina, in the pathogenesis of cerebrovascular disease in persons with diabetes. In addition, because diabetic retinopathy is usually the result of a disruption in the blood-retinal barrier, it is possible to infer that these cerebral conditions may also be related to a breakdown of the blood-brain barrier [47].

Diabetic Retinopathy and Heart Disease

Similar to stroke, microvascular dysfunction has also emerged as an important pathogenic factor in the development of diabetic heart disease [48]. However, there are no simple and noninvasive techniques for the assessment of coronary microcirculation [49], and studies that have traditionally evaluated the role of coronary microvascular dysfunction in diabetic heart disease have been limited to small clinic-based samples using highly specialized and invasive methods [50–54].

Data from the Framingham Heart and Eye Study conducted two decades ago suggest that retinopathy signs may reflect a generalized

Follow-up time (days)

Fig. 2. Coronary heart disease-free survival in participants with (dashed line) and without (solid line) diabetic retinopathy [59].

microangiopathic process that affects the myocardium in people with diabetes [1]. This hypothesis is supported by earlier studies, based on ophthalmoscopic examinations, linking retinopathy signs with ischemic T-wave changes on electrocardiogram [55, 56], severity of coronary artery stenosis on angiography [57], histological evidence of microvascular disease in the myocardium [50], and incident clinical coronary heart disease events [58].

Recent epidemiological studies using standardized photographic grading of retinopathy have produced more robust evidence in support of previous observations. It is now clear that diabetic retinopathy signs are associated with an increased risk of not only coronary artery disease (fig. 2) but also its major complication, congestive heart failure (fig. 3; table 2). The ARIC study showed that the presence of any retinopathy signs was associated with two-fold higher risk of incident coronary heart disease (and myocardial infarction), three-fold higher risk of fatal coronary heart disease, and four-fold higher risk of heart