Can Ophthalmoscope Predict Silent Coronary Artery Disease in Patients with Type 2 Diabetes Mellitus ?

Background & Aim: Diabetic retinopathy (DR) and Coronary Artery Disease (CAD) share similar pathophysiological background of vascular damage. So we aimed to study the relationship between DR and silent CAD in patients with type 2 diabetes mellitus (T2DM). Subject & Methods: A cross sectional study was performed on 40 patients with T2DM from diabetic outpatient clinic in Ain Shams University Hospitals, Cairo, Egypt from June 2012 to December 2012. All patients were subjected to data collection, laboratory analysis and imaging studies. Patients with known CAD, abnormal resting or stress ECG, abnormal ejection fraction or segmental wall motion abnormalities, smoking history, hypertension, or abnormal lipid profile were excluded. Results: Mean age is 62.35 ± 1.38 years, 75% (n = 30) were females, 75% (n = 30) had DR, and 77.50% (n = 31) had positive Tc99 scan. There is a significant positive association between Tc99 scan and DR (p value = 0.029) as 86.7% of patients with DR had positive Tc99 scan. Resting and stress perfusion TC99 scan were significantly worse (91.77% vs 100%; 86.48% vs 96.27%, p value = 0.008, 0.005 respectively) and microalbuminuria were significantly higher (207 ± 29.65 vs 36 ± 10.66 mg/dl, p value =< 0.001) in patients with DR. By binary logistic regression, DR was an independent predictor for CAD (OR was 16.377, 95% CI was 1.017 263.586, p value = 0.049) after adjustment of SBP and albuminuria. Conclusion: 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. More multi-centric prospective studies are needed to elucidate the effect of the degree of DR on CAD risk.


Introduction
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.

Study Design and Setting
A cross-sectional study was performed on patients with T2DM attending consequently to diabetic outpatient clinic in Ain Shams University Hospitals, Cairo, Egypt from June 2012 to December 2012.
For the purpose of the study, exclusion criteria were patients with a well-known history of cardiac disease including CAD, any abnormal echocardiography finding or abnormal resting or stress electrocardiograph; hypertension, elevated systolic blood pressure (SBP) > 130 mmHg or diastolic blood pressure (DBP) > 80 mmHg, or on antihypertensive drugs.Also patients with acute or chronic kidney disease or abnormal creatinine, hyperlipidemia, or abnormal lipid profile or on lipid lowering agents; or past or current history of smoking or current urinary tract infections, cerebrovascular disease, peripheral artery disease were excluded.Moreover, patients who declined from participation during the study or refused to participate were also excluded.The study had been approved by the local ethical committees of Ain Shams University and all patients or their next kin provided informed consent to the work.Because of exclusion criteria of the study, only 10% (n = 40) of patients were eligible.75% (n = 300) of patients were excluded due to smoking, CAD, elevated blood pressure, elevated lipid profile, elevated serum creatinine and acute or chronic kidney disease.15% (n = 60) of patients were also excluded either due to refusal to participate, or withdrawal from the study.

Data Collection
All patients were subjected to data collection including personal characteristics, detailed medical history with especial focus on diabetes mellitus and its complications, and physical examination including standardized blood pressure measurement, screening for peripheral neuropathy using vibration sense perception examination and superficial pain sensation; and anthropometric assessment for weight, height, and body mass index (BMI).

Fundus Examination
Routine screening for diabetic retinopathy were done to all patients with T2DM as stated in the Clinical Practice Guidelines in the eye clinic by an experienced ophthalmologist specialized in retinal diseases using mydriatic indirect ophthalmoscopic examination and slit-lamp fundus examination with a precorneal lens.Diagnosis of DR was based on the International Clinical Diabetic Retinopathy Disease severity Scale [7] which depends on the presence of microaneurysms, intraretinal hemorrhage, venous beading, neovascularization, and vitreous/ preretinal hemorrhage [7].

Cardiac Assessment
Resting and stress Electrocardiograph were done to all participants to exclude patients with abnormal finding such as abnormal Q waves or deep T wave inversions, Left Bundle Branch Block, non-specific ST-T changes. 2 D Echocardiography was also done to exclude patients with segmental wall motion abnormalities, abnormal ejection fraction, or cardiac chamber dilation or hypertrophy.Nuclear cardiac imaging by Single Photon Emission Computed Tomography (SPECT) is a modality to assess myocardial perfusion especially in diabetics at risk of CAD.The presence of reversible defects in SPECT despite other normal cardiac tests is defined as silent CAD [8].SPECT is the most commonly used and well-documented noninvasive method for diagnosis and risk stratification of coronary artery disease (CAD) [9].It was evaluated by highly qualified nuclear medicine professors.It has good specificity 75% -82% [10] to assess myocardial ischemia.The specificity of SPECT scans can be improved up to 90% by using attenuation correction algorithms as well as incorporating the gated left ventricular ejection fraction and regional wall motion into test interpretations [11] which had been used in our study.

Laboratory Investigations
For each participant, 12 hours fasting blood sample was collected for fasting blood glucose, total cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), glycosylated hemoglobin (HB A1c) and serum creatinine.Another 2 h postprandial blood sample was collected for glucose.For microalbuminuria, 24 hours urine samples collections were done to all participants to determine the urinary albumin excretion rate (UAER).All laboratory investigations were analyzed using standard laboratory techniques.Criteria of lipid profile values used for low risk DM without overt CAD were according to American diabetic association, 2011.Total cholesterol < 4 mmol/L, LDL-C < 2.6 mmol/L, HDL-C cholesterol > 1.0 mmol/L in males and >1.3 mmol/L in females.Triglycerides < 1.7 mmol/L.Serum creatinine < 1.5 mg/dl (<132 µmol/L).

Statistical Analysis
Data collected were revised, coded, tabulated and introduced into a personal computer.Qualitative data were presented in the form of number and percent.Quantitative data were presented in the form of means and SD.All data manipulation and analysis were performed using the 17th version of SPSS (Statistical Package for Social Science).The level of significance was established as p value less than 0.05.Comparison between quantitative variables was done using Student t-test for parametric data and Mann-Whitney test for non-parametric data to compare two groups.Comparison between qualitative variables was done using Pearson's Chi square test or Fisher's Exact when the cell count < 5%.
Adjustment of the significant covariates was done to detect if DR is an independent predictor of preclinical cardiac ischemia by Tc 99 scan using binary logistic regression analysis.

Discussion
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].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  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].

Conclusion
DR is an independent predictor of asymptomatic CAD even with normal stress ECG and echocardiography.Routine screening for CAD using Tc 99 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.

Table 1 .
Descriptive characteristics of the studied population.

Table 2 .
Comparison between diabetic patients with and without diabetic retinopathy regarding personal characteristics, laboratory investigations and Tc 99 scan.

Table 3 .
Comparison between diabetic patients with and without silent CAD regarding personal characteristics, laboratory investigations and Tc 99 scan.

Table 4 .
Logistic regression analysis for independent predictor of cardiac ischemia using Tc 99 scan.