Follow-up time (days)

Fig. 3. Heart failure-free survival in participants with (dashed line) and without (solid line) diabetic retinopathy [Cheung, unpubl. data; the ARIC Study].

failure, independent of diabetes duration, glycemic control, smoking, lipid profile and other risk factors [59–61]. The population-attributable risk of retinopathy to heart failure has been estimated to be about 30% in people with diabetes without a previous history of myocardial infarction and hypertension. Thus, if retinopathy signs are a perfect reflection of coronary small vessel pathology, nearly one third of diabetic cardiomyopathy cases could be related to microvascular dysfunction [60]. There is a graded, dose-dependent association of increasing diabetic retinopathy severity with increasing coronary heart disease risk [59]. These findings are consistent with data from the WHO-MSVDD [16] and other studies showing associations of not only NPDR but also PDR with ischemic heart disease [7, 62, 63].

In addition to population-based 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 and potentially treatment in diabetic patients with suspected heart disease [64–69].

For example, retinopathy may be a valuable prognostic predictor for diabetic patients undergoing cardiac revascularization procedures. Studies show that compared to 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 in effects of age, gender, diabetes duration, insulin use and other factors that may affect prognosis after these procedures [70–73]. Thus, it may be important to assess retinopathy status to assist in clinical deci- sion-making for revascularization strategies in diabetic patients with established coronary heart disease [74].

The association of retinopathy with clinical heart disease is well supported by the observed links between diabetic retinopathy and subclinical coronary microand macrovascular pathology. Pathological and radiological studies have shown that persons with retinopathy are more likely to have myocardial arteriolar abnormalities [50], coronary perfusion defects [69, 75, 76], poorer coronary flow reserve [77] and lower coronary collateral score [78], than those without retinopathy. The presence of retinopathy signs has also been associated with higher degrees of coronary artery calcification [79, 80] and more diffuse/severe coronary artery stenosis on angiograms [68], two established measures of subclinical coronary atherosclerotic burden.

Retinal Venules and Cardiovascular Disease

Dilatation of the retinal venules has long been recognized as a characteristic clinical sign of severe diabetic retinopathy and as a possible marker of retinopathy progression [81]. However, this vascular feature has been less well described in comparison to other morphologically more distinct retinopathy lesions (e.g. microaneurysms,

blot hemorrhages, soft exudates), largely because of difficulties in quantifying retinal venular dilation based on clinical examination.

Recent advances in retinal image-analytical techniques have allowed precise measurements of retinal vascular caliber from retinal photographs [2, 82, 83]. Using this new approach, wider (or dilated) retinal venular caliber has been associated with higher risks of diabetic retinopathy progression and incident PDR in the WESDR [84, 85]. Furthermore, there is now evidence that wider retinal venules may also have associations with major cardiovascular outcomes [86–91]. Wider retinal venular caliber has been shown to predict higher risks of stroke and coronary heart disease in several population-based studies, even after factoring the effects of concomitant risk factors [87–89, 91, 92]. In addition, data from these

new studies suggest that wider retinal venular caliber is a marker of early retinal as well as systemic microvascular damage caused by hyperg- lycemia-related processes (e.g. impaired vascular tone autoregulation, inflammation, endothelial dysfunction) [93, 94]. These findings provide further support for the link between early retinal vascular changes and cardiovascular disease.

Pathogenic Links between Retinopathy and Cardiovascular Disease

Despite the increasingly abundant evidence from epidemiological and clinical studies that diabetic retinopathy is associated with cardiovascular disease, the underlying pathophysiological mechanisms remain uncertain [95]. This reflects,

at least in part, an incomplete understanding of the pathogenesis of diabetic retinopathy itself [81]. Nevertheless, several mechanisms have been hypothesized.

First, in people with type 2 diabetes, the presence of retinopathy may simply indicate a more adverse cardiovascular risk profile. It is known that compared to those without retinopathy, diabetic persons with retinopathy are more likely to have concomitant cardiovascular risk factors, such as hypertension and dyslipidemia, which can all increase their cardiovascular risk [18, 96–98]. However, this is unlikely the sole reason as many studies have demonstrated that traditional cardiovascular risk factors cannot fully explain the observed associations [4, 7, 15, 38, 59, 62], suggesting the existence of other biological mechanisms.

Second, it has been suggested that retinopathy is a manifestation of generalized vascular dysfunction caused by endothelial dysfunction or genetically determined alterations in the basement membrane metabolism associated with hyperglycemia (the Steno hypothesis) [99, 100]. These vascular effects increase arterial or arteriolar wall permeability and leakage. Therefore, in small arteriolar or capillary beds, retinopathy and nephropathy may develop as a result. In large arterial wall, increased permeability facilitates entry and accumulation of lipids, thus promoting the pathogenic cascade of atherosclerosis formation.

Third, another possibility is that microvascular disease, evident as retinopathy lesions in the eye, may be present in other tissues and play a causal role in the development of atherosclerotic disease in people with diabetes. This is based on the observations that diabetic retinopathy is related not only to classic microvascular complications (e.g. nephropathy), but also complications of predominantly macrovascular etiology (e.g. coronary heart disease; table 2). There is now a large body of literature indicating that retinopathy is associated with several direct subclinical measures of large artery atherosclerosis, including

carotid artery intima-media thickness or carotid plaque, arterial stiffness, coronary artery calcification as well as atherosclerotic lesions detected on angiograms [18, 41, 68, 79, 80, 101]. Based on the complex pathophysiological interactions between diabetic microvascular and macrovascular disease [95, 102], a possible mechanism that may causally link retinopathy to the development of atherosclerosis is shown in figure 4 [103].

Finally, there is a circulatory mechanism hypothesis that may also provide a causal link for diabetic retinopathy and cardiovascular disease [104, 105]. Microvascular disease is known to play an important role in the pathogenesis of diabetic cardiomyopathy, a complex and unique disease entity that is independent of coronary atherosclerosis and hypertension [106]. Recently, in the Multi-Ethnic Study of Atherosclerosis, diabetic retinopathy was found to be associated with left ventricular concentric remodeling, a known precursor for heart failure development [104]. This finding is consistent with the ARIC study, which demonstrated a strong association of retinopathy with clinical congestive heart failure in people with diabetes [60]. Both studies offer good support for a pathogenic link between diabetic retinopathy and cardiomyopathy. It is possible that diabetic retinopathy may represent widespread systemic microcirculatory (resistance vessel) disease, which places an increased impedance burden, in part through reflected pulse waves, on the diabetic heart. The excess load may in turn compromise the efficiency of cardiac performance (e.g. ventricular emptying and cardiac contractility), predisposing the development and manifestation of diabetic cardiomyopathy [104, 105].

Genetic Links between Retinopathy and Cardiovascular Disease

There is a great deal of interest in identifying genetic factors involved in the development of cardiovascular disease, as knowledge of these genes

Cardiovascular risk factors

(e.g. hyperglycemia, hypertension, dyslipidemia)

Increased oxidative stress and impaired endothelial dysfunction in microcirculation

Local inflammation causes microvascular disease (e.g. retinopathy) (leukocyte adhesion, platelet recruitment, cytokine release)

Systemic inflammatory milieu

Activated blood cells gain access to systemic circulation (TNF- , sCD40L, IL-6, IFN- , IL-12, sP-sel, CRP)

AGEs

PKC

may open new avenues for preventative and therapeutic strategies. However, previous studies have largely focused on the genetic associations of large vessel atherosclerotic disease [107, 108]. There is less research on the genetic determinants of small vessel microvascular disease.

Thus, understanding the genetic basis of diabetic retinopathy may uncover important insights into the genetic etiology of systemic diabetic microangiopathy.

Twin studies and family-based analyses of diabetic populations have shown significant