The importance of understanding the relationship between diabetic retinopathy (DR) and vascular disease is crucial for the physicians as the prevalence of diabetes continues to increase worldwide. Diabetic retinopathy is the commonest microvascular complication of diabetes. DR may start to develop as early as 7 years before the diagnosis of type 2 diabetes (T2DM) [1] . More than 60% of type 2 diabetic patients will have some degree of retinopathy after 20 years of onset of DM [1] . DM increases the risk of development of cardiovascular disease [2] . Current guidelines highlighted the importance of routine fundus examination for patients with T2DM which represent a unique opportunity for the clinician to visualize, assess and monitor the direct effects of diabetes on the microcirculation [3] . Recently, it was noted that DR may be one of the early signs of an increased risk of life-threatening systemic vascular complications [4] [5] like coronary artery disease (CAD) [6] . It has been noted that signs of DR could be a mirror to generalized microangiopathic processes that affect every organ in the body [4] [6] not only the eyes. Despite the widespread interest in studying the link between DR and CAD, the precise underlying pathophysiological mechanism is still uncertain [3] .

The role of DR as a predictor for incident CAD is an interesting point of research as it allows both primary and secondary prevention of CAD through aggressive management of this complication. Till now, it is still unclear whether the presence of DR in Egyptian diabetic elderly patients is associated with silent CAD independent of other traditional cardiovascular factors like hypertension or smoking. Therefore, this study examined the association between the presence of DR and subclinical CAD using Single Photon Emission Computed Tomography (SPECT) in patients with T2DM in absence of other traditional risk factors and tested whether DR could act as a predictor for CAD or not.

In our study sample, females were 75% (n = 30) and males were 25% (n = 10). The mean age of patients was 62.35 ± 1.38 years. The prevalence of DR was 75% (n = 30), positive Tc⁹⁹ scan was seen in 77.5% (n = 31) of patients. The median amount of Albuminuria was 100 (20 - 337.5) mg/24h Table 1. There were no significant differences between patients with DR and those without DR regarding age, sex, duration of DM, type of treatment, DBP, BMI, peripheral neuropathy (p value = 0.167, 0.401, 0.100, 0.855, 0.071, 0.455, 0.337 respectively). There were also no significant differences between patients with DR and those without DR regarding diabetic control (p values of FBS, 2hPP, HB A1c were 0.793, 0.420, 0.103 respectively) or lipid profile (p values of TC, TG, LDL-C, HDL-C were 0.260, 0.087, 0.813, 0.521 respectively) Table 2.

Patients with DR had statically significant higher SBP (although still within normal range) (126.50 ± 6.84 vs 120.00 ± 6.67 mmHg) and more albuminuria [185 (35 - 362.50) vs 20 (20 - 40) mg/24h] than those without DR (p value 0.013, 0.001) Table 2. Concerning cardiac nuclear imaging, the present study showed statistical significant positive association between DR and cardiac ischemia by Tc⁹⁹ scan (86.7% (n = 26) vs 50.00% (n = 5), p value = 0.029) with lower resting and stress perfusion index in patients with DR (91.77% vs 100%; 86.48% vs 96.27%, p value = 0.008, 0.005 respectively) than those without DR (Table 3). In addition, there was no statis-

OHG: oral hypoglycemic, SBP: systolic blood pressure, DBP: diastolic blood pressure, FBS: fasting blood sugar, 2hPPBS: 2 hours postprandial blood sugar, HB A1c: hemoglobin A1c, TC: total cholesterol, TG: triglycerides, LDL-C: low density lipoprotein, HDL-C: high density lipoprotein, DR: Diabetic retinopathy. ^*Non-advanced DR: background and non-proliferative diabetic retinopathy; ^*Ad- vanced DR: proliferative DR either with or without maculopathy; ^**Mann Wittny test was done, median and interquartile range was expressed.

tical significant difference between patients with non-advanced and advanced DR in the risk of CAD (p value = 0.815).

Patients with positive Tc⁹⁹ scan had also statically significant longer T2DM duration (12.19 ± 4.71 vs 9.56 ± 2.55, p value 0.037), higher SBP and DBP (126.29 ± 7.30 vs 120.00 ± 5.00, 82.90 ± 6.93 vs 75.56 ± 5.27, p value = 0.008, 0.006) Table 3. By binary logistic regression, DR was an independent predictor of CAD (Odds ratio was 16.377, 95% CI was 1.017 - 263.586, p value = 0.049) after adjustment of SBP and albuminuria Table 4.

Understanding the association between DR and systemic vascular diseases is important for the physicians caring for diabetic patients. The presence of DR doesn’t only predict the higher risk of cardiovascular disease but also mortality. This association remained even after adjusting for other traditional risk factors [12] .

Microvascular dysfunction has been arisen as a significant pathogenic factor in the development of diabetic heart disease [13] . However, there is no simple non-invasive test for the assessment of coronary microcirculation [14] . Medical stress test with SPECT imaging to assess myocardial ischemia has sensitivity 91% - 96% and specificity 75% - 82% [10] and it is still the best predictor of cardiac events in stable ischemic heart disease [15] . This test has definite advantages over clinical, electrocardiographic, lab and resting echocardiographic data, as it describes the severity and extent of stress-induced myocardial perfusion abnormality [8] .

OHG: oral hypoglycemic, SBP: systolic blood pressure, DBP: diastolic blood pressure, FBS: fasting blood sugar, 2hPPBS: 2 hours postprandial blood sugar, HB A1c: hemoglobin A1c, TC: total cholesterol, TG: triglycerides, LDL-C: low density lipoprotein, HDL-C: high density lipoprotein. ^*Mann Wittny test was done, median and interquartile range were expressed.

Generally, the prevalence of silent CAD in diabetic patients is widely varied in literature from 4% - 70% [16] . In Greek and Spain population studies on asymptomatic diabetic patients without DR, the prevalence of silent CAD using SPECT were 27.66% [17] and 13% [18] respectively while in asymptomatic patients with DR were 75.86% and 50% respectively. This difference could be attributed to smaller sample size, longer duration of diabetes, higher fasting and postprandial blood sugar, higher glycosylated hemoglobin and body mass index in our sample compared to the previous studies [17] [18] .

In our study, we found that DR is an independent predictor of silent CAD although we excluded all patients with CAD and other traditional risk factors like hypertension, hyperlipidemia and smoking. Our findings are consistent with many clinical studies that diabetic retinopathy is associated with subclinical coronary pathology [4] - [6] [12] - [15] . In a prospective population based study, the authors found that even mild DR is associated with incident CAD independent of other traditional risk factors although this study didn’t exclude patients with abnormal lipid profile, high blood pressure, smoking or abnormal creatinine [13] . Another meta-analysis reported that persons with any degree of DR are at higher risk of CAD and all-cause mortality independent of other traditional risk factors [14] .

Current evidence suggests that the presence of retinopathy, even in its mildest form, is associated with two- to four folds increase in the risk of CAD and heart failure, independent of cardiovascular risk factors such as smoking, lipid profile, diabetes duration, and glycemic control [6] . This is in agreement with our results which

OHG: oral hypoglycemic, SBP: systolic blood pressure, DBP: diastolic blood pressure, FBS: fasting blood sugar, 2hPPBS: 2 hours postprandial blood sugar, HB A1c: hemoglobin A1c, TC: total cholesterol, TG: triglycerides, LDL-C: low density lipoprotein, HDL-C: high density lipoprotein. ^*Mann Wittny test was done, median and interquartile range were expressed.

SBP: systolic blood pressure, DR: diabetic retinopathy.

found no statistical significant difference between patients with and without advanced retinopathy in the risk of CAD. Despite the widespread interest in studying the link between DR and CAD, the precise underlying pathophysiological mechanism is still uncertain [3] . Studies have shown that diabetic persons with retinopathy are more likely to have myocardial arteriolar abnormalities [19] which affect coronary perfusion and decrease the coronary flow reserve [17] [20] . Moreover, DR has been associated with lower coronary collateral score, higher degrees of coronary calcification [21] leading to more diffuse/severe coronary artery stenosis [22] . These obser- vations, in conjunction with ours, support the concept that micro-and macrovascular complications of diabetes

share common pathogenic mechanisms beyond other traditional risk factors. Other biochemical pathways can also play a role in this link especially with increased activity of protein kinase C and glycation of key proteins that lead to formation of advanced glycation end products which predispose to cellular changes, enhanced permeability of retinal vasculature, alterations in retinal blood flow, basement membrane thickening leading to ocular neovascularization [3] [6] . This is support our opinion regarding the fundamental role of proper screening and diagnosis of CAD for the prevention and early treatment of coronary events.

Although many epidemiological studies didn’t find hypertension as a consistent risk factor for DR incidence and progression, but at the same time, many randomized control trials showed that a decrease in systolic blood pressure by 10 mmHg associated with parallel decrease in the risk of retinopathy progression by 35% and vision loss by 50% [5] . This is conceded with our results which revealed that patients with DR had statically significant higher SBP (although still within normal range) than patients without DR.

Many experimental studies found a high correlation between pathological changes in the retinal and renal vasculature [23] [24] . Epidemiological studies have constantly demonstrated that diabetic retinopathy is associated with microalbuminuria and clinical nephropathy, independent of hypertension and other shared risk factors [25] - [27] . This is in agreement with our results which found patients with DR had statically significant more albuminuria than those without DR. Even with the abundant evidence that DR is associated with a range of systemic vascular complications but still there is incomplete understanding of the pathogenesis of DR itself [28] .

DR is an independent predictor of asymptomatic CAD even with normal stress ECG and echocardiography. Routine screening for CAD using Tc⁹⁹ scan is recommended in patients with DR even if asymptomatic. Systolic blood pressure decreases even if normal is associated with less prevalence of DR. More multi-centric prospective studies are needed to elucidate the effect of the degree of DR on CAD risk that may have great impact on formulation of CAD screening guidelines in diabetic patients.

The authors have no financial interests or any other kind of conflicts or disclosure related to the material in the manuscript to report. There is no compliance with any research funding agency.