Ann Thorac Surg 2008;85:681-689. doi:10.1016/j.athoracsur.2007.07.066
© 2008 The Society of Thoracic Surgeons
Review
Diabetic Retinopathy and Coronary Artery Disease From the Cardiac Surgeon’s Perspective
Takayuki Ohno, MD*,
Shinichi Takamoto, MD,
Noboru Motomura, MD
Department of Cardiothoracic Surgery, The University of Tokyo, Tokyo, Japan
* Address correspondence to Dr Ohno, Department of Cardiothoracic Surgery, The University of Tokyo, 7-3-1, Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan (Email: takohno-tky{at}umin.net).
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Abstract
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Coronary artery disease is the leading cause of death in diabetics; therefore, the main purpose of managing coronary artery disease in diabetics should be to lengthen life expectancy. Recent evidence demonstrates that the severity of diabetic retinopathy is associated with a graded, increased risk of death from coronary artery disease and myocardial infarction. Recently, we found that the survival benefit of coronary artery bypass grafting over percutaneous coronary intervention is more apparent in patients with diabetic retinopathy than in diabetic patients without it. In this article, we review published studies evaluating the association between diabetic retinopathy and coronary artery disease, and we propose that coronary artery bypass surgery should be the first choice for revascularization of patients with diabetic retinopathy, especially in its early stage. Furthermore, coronary artery disease complicating diabetic retinopathy is often underdiagnosed, and all diabetic retinopathy patients should undergo screening for coronary artery disease followed by coronary artery bypass grafting. Future studies will probably comprise carefully performed cost-effective analyses of treatment effectiveness and prospective randomized studies comparing survival after coronary artery bypass grafting with that of survival after percutaneous coronary intervention, stratified by the stage of retinopathy.
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Introduction
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The lifestyle and diet of the Japanese population have changed significantly since the end of World War II. The Japanese have become much more sedentary and consume more fat than in the past. As a result, the prevalence of diabetes is increasing explosively. In 2002, the Japanese Ministry of Heath, Labor, and Welfare announced that in Japan 7.4 million people were strongly suspected of having diabetes mellitus, and already 8.8 million Japanese people were almost certainly diabetic [1]. In the United States, the prevalence of diagnosed diabetics increased to 7.9% in 2001 from 4.9% in 1990, an increase of 61%. Thus, in 2001, an estimated 16.7 million adults in the United States were diagnosed as having diabetes [2]. Diabetes confers a risk equivalent to aging by 15 years, and more deaths from diabetes are directly due to coronary artery disease (CAD) than to any other cause [3]. The risk of a myocardial infarction in diabetic patients with no evidence of CAD matches that in patients without diabetes who have had a previous myocardial infarction, supporting the idea of diabetes as a coronary equivalent [4]. Myocardial infarction is more likely to develop in diabetic patients presenting with unstable angina, and diabetic patients with myocardial infarction are more likely to die than nondiabetic patients. In the Organization to Assess Strategies for Ischemic Syndromes registry, diabetes with unstable angina and non-Q wave myocardial infarction increased mortality by 57% [5]. The SHOCK trial, which examined revascularization, found a 36% increased risk of death in diabetic patients with cardiogenic shock complicating myocardial infarction [6].
The important issue in managing CAD in a diabetic population is that the risk of CAD events varies widely from patient to patient and even in one diabetic patient as the disease progresses. Recent evidence strongly suggests that the severity of diabetic retinopathy is closely associated with the risk of CAD events. Therefore, we propose that diabetic retinopathy may be a useful guide for developing an appropriate treatment strategy for CAD in a diabetic population. As follows, we have reviewed published studies evaluating the association between diabetic retinopathy and CAD, and we propose that coronary artery bypass grafting (CABG) should be the first choice for revascularization in patients with diabetic retinopathy.
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Literature Search
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We included all cohort, case-controlled, cross-sectional, and experimental studies that evaluated the association between diabetic retinopathy and CAD, and we researched the MEDLINE database for reports published from January 1, 1966 to July 31, 2007 by using the following medical subject headings: "diabetic retinopathy and retinopathy," in combination with each of the following terms: "survival, mortality, heart disease, coronary artery disease, myocardial infarction, angina, myocardial ischemia, congestive heart failure, cardiac function, and ventricular function." This strategy was supplemented by a manual search of secondary sources, including selected citations in primary articles and proceedings of relevant conferences. The search was limited to English-language publications.
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Diabetic Retinopathy
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Many studies evaluate the association between nephropathy and CAD [7–9]. In diabetic patients, however, nephropathy is a late sign of microvascular complication of diabetes mellitus, and the risk of nephropathy is genetically determined [10]. Microalbuminuria affects 20% to 40% of patients 10 to 15 years after the onset of diabetes. Progression to microalbuminuria, or overt nephropathy, occurs in 20% to 40% of patients during a period of 15 to 20 years after the onset of diabetes [11]. In contrast, diabetic retinopathy is a frequent and early sign of microvascular complication of diabetes mellitus and the stage of retinopathy is directly related to the duration of diabetes and the degree to which the blood glucose concentration has been elevated [12]. Within 5 or 10 years of diagnosis, about 58% of type 1 diabetic patients and 80% of type 2 diabetic patients have retinopathy. After 15 to 20 years of the disease, more than 90% of patients have some evidence of retinopathy; after diabetes has been present for 20 years, almost all patients have retinopathy, with about half of these having proliferative retinopathy. In addition, more than 25% of patients with type 2 diabetes have retinopathy within 2 years of diagnosis. Furthermore, of all of the complications of diabetes, retinopathy presents the physician with the unique opportunity to directly visualize and grade the progression of the disease. Recent research has shown that inflammation plays a key role in diabetic retinopathy as well as in coronary heart disease [13].
Patients with diabetic retinopathy are grouped into two major categories: (1) those with nonproliferative diabetic retinopathy (NPDR) and (2) those with proliferative diabetic retinopathy (PDR) (Fig 1). Nonproliferative diabetic retinopathy is defined as the presence of fundus abnormalities located within the retina. Proliferative diabetic retinopathy is defined as the presence of new vessels or fibrous tissue, or both, arising from the retina or optic disc and extending along the inner surface of the retina or disc or into the vitreous cavity. The fundus findings commonly seen among patients with NPDR are retinal microaneurysms, retinal hemorrhage, hard exudates, soft exudates, intraretinal microvascular abnormalities, and venous beading. These intraretinal abnormalities always precede, as well as accompany, any proliferative changes that develop in front of the retina or within the vitreous cavity. Nonproliferative diabetic retinopathy is further classified into mild, moderate, and severe, according to the presence and extent of these abnormalities. The severe stage of NPDR is characterized as the presence of soft exudates, intraretinal microvascular abnormalities, venous beading, and extensive retinal hemorrhage or microaneurysms. In our experience, 23% of diabetic patients undergoing coronary revascularization (either CABG or percutaneous coronary intervention [PCI]) had NPDR, and 18% had PDR [14–16]. Therefore, diabetic retinopathy deserves more attention, both from cardiac surgeons and from interventional cardiologists.
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Fig 1. (A) Nonproliferative (ie, early stage of) diabetic retinopathy. Patients with nonproliferative retinopathy usually have no visual symptoms. (B) Proliferative (ie, advanced stage of) diabetic retinopathy. Patients with proliferative retinopathy often have impaired vision due to vitreous hemorrhage or retinal detachment.
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Increased Risk of Coronary Events in Patients with Diabetic Retinopathy
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Ophthalmologists know well that patients with advanced diabetic retinopathy have a poor life expectancy. In a retrospective review of 128 diabetics followed-up at the Radcliffe Infirmary, Oxford, England, the 5-year mortality was 45% for those with PDR, 8% for those with only microaneurysms, and 8% for those without any retinopathy [17]. In a prospective study of 709 patients with type 2 diabetes taking insulin and followed-up for up to 13 years, Davis and colleagues [18] reported a 5-year mortality of 44% for those with PDR, 19% for those with moderate NPDR, and 1% for those with no or minimal retinopathy at baseline. Helbig and colleagues [19] reported that half of diabetic patients with evidence of heart disease undergoing vitrectomy had died within 3.5 years, whereas those without heart disease had a 5-year survival rate of 90%.
The main clinical significance of CAD in patients with diabetic retinopathy is its association with increased risk of coronary events including CAD mortality and myocardial infarction (Table 1) [20–28]. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) based on an 8.5-year follow-up of 1,370 persons with older-onset diabetes mellitus, the age-adjusted and sex-adjusted hazard ratios for CAD mortality were 1.50 (95% confidence interval, 1.22–1.85) in patients with mild NPDR, 1.93 (95% confidence interval, 1.43–2.61) in those with moderate NPDR, and 2.07 (95% confidence interval, 1.48–2.91) in those with PDR [20]. The WESDR study involving 996 persons with type 1 diabetes mellitus demonstrates that severity of diabetic retinopathy is associated with incidence of myocardial infarction; the 20-year cumulative incidences of self-reported myocardial infarction were 6.0% for diabetic patients without retinopathy, 9.5% for early NPDR, 21.0% for moderate to severe NPDR, and 26.9% for PDR [21]. Recently, the Atherosclerosis Risk in Communities Study demonstrated that among patients with type 2 diabetes, the presence of diabetic retinopathy is associated with a twofold higher risk of CAD events, and a threefold higher risk of CAD death, independent of cardiovascular risk factors, diabetes duration and control, and large-vessel atherosclerosis [28]. This association is graded according to retinopathy severity.
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Increased Risk of Congestive Heart Failure in Patients with Diabetic Retinopathy
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"Diabetic cardiomyopathy" is a clinical condition, diagnosed when cardiac dysfunction develops in diabetic patients in the absence of coronary heart disease and hypertension. Five experimental studies assessed the association between diabetic retinopathy and cardiac function in patients with type 1 [29, 30] or type 2 diabetes [31–33]. Cardiac function was evaluated in different methods, including echocardiography [30–33] and radionuclide angiography [29]. In type 1 diabetes with unknown CAD, the resting left ventricular ejection fraction did not differ significantly between diabetic patients with and without retinopathy [29, 30], but at peak exercise, those with diabetic retinopathy had significantly lower ejection fractions than those without diabetic retinopathy [29]. One study demonstrated that patients with retinopathy had a higher prevalence of decreased ejection fraction (< 50%) than those without retinopathy in type 2 diabetes without any clinical evidence of heart disease [33]. Another study demonstrated that the ejection fraction did not differ significantly between the two groups with a positive exercise treadmill test and an angiographically normal left anterior descending coronary artery [32]. Three studies reported the decreased ratio of early-to-late diastolic mitral inflow velocities in patients with diabetic retinopathy in both type 1 diabetes [30] and type 2 diabetes [31, 33]. In the population-based, prospective cohort study involving 627 diabetic persons without pre-existing coronary heart disease, the 7-year incidence of congestive heart failure for persons with retinopathy was 19.9% compared with 8.2% for those without it (adjusted relative risk, 4.32; 95% confidence interval, 2.13–8.76) [34].
Congestive heart failure is more likely to develop in patients with diabetic retinopathy experiencing acute myocardial infarction than in those patients without retinopathy. Brown and colleagues [35] studied 64 diabetics admitted to the coronary care units with a diagnosis of acute myocardial infarction. Of 24 diabetics with retinopathy, 7 (29%) died, but of 40 diabetics without retinopathy, only 1 (3%) died (p < 0.01). Either cardiogenic shock or heart failure developed in 18 diabetics with retinopathy (75%) and in 10 diabetics without retinopathy (25%; p < 0.001). Fava and colleagues [36] studied 196 type 2 diabetics with acute myocardial infarction admitted to the coronary care unit and demonstrated that the presence of retinopathy treated by panretinal photocoagulation was correlated with congestive heart failure (22.7% vs 10.7%; p < 0.05), but not with mortality (23.5% vs 13.6%; not significant).
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Underdiagnosis of CAD in Patients With Diabetic Retinopathy
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Definitive data on the incidence and prevalence of CAD among patients with diabetic retinopathy are difficult to obtain. A study using questionnaires revealed that 15% of patients with sight-threatening diabetic retinopathy had reported themselves as having angina-like symptoms and 9% had a self-reported history of myocardial infarction [37]. However, these figures probably greatly underestimate the true burden of CAD in patients with diabetic retinopathy, because the disease is often asymptomatic until the catastrophic events of overt heart failure or sudden death (Fig 2). Between 1966 and 2007, six cross-sectional studies assessed the association between diabetic retinopathy and the incidence of coronary atherosclerotic disease (Table 2). Of these, three were studies of asymptomatic patients with normal electrocardiographic findings or normal left ventricular function [39, 41, 42], whereas two studies investigated patients with suspected CAD [40, 43], and the remaining study did not specify between asymptomatic or suspected CAD [38]. These findings indicate that approximately 20% of asymptomatic patients with diabetic retinopathy and normal resting electrocardiograms have CAD.
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Fig 2. Delayed diagnosis of coronary artery disease in patients with diabetic retinopathy. Many patients with advanced retinopathy have limited physical activity due to impaired vision. Limited physical activity reduces the appreciation of ischemic pain and is attributed to delayed diagnosis until a catastrophic event, such as overt heart failure or sudden death.
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Patients with sight-threatening diabetic retinopathy forego many important aspects of life, such as work, reading, and sports [44]. Bailey and Sparrow [45] demonstrated that only 25% of patients requiring retinal photocoagulation for macular edema and 17% of those for PDR were asymptomatic in terms of reading, seeing the television screen, recognizing faces, or utilizing night vision. Furthermore, retinal photocoagulation has side effects that include reduced visual acuity, poor night vision, deterioration of the visual field, reduced contrast sensitivity, and impaired color vision [46]. After treatment, 10% of patients with diabetic maculopathy were aware of new central scotomas. Thirteen percent of patients with PDR had given up driving due to poor eyesight and 19% had become aware of new peripheral field defects since the treatment. Furthermore, impaired vision such as visual acuity, contrast sensitivity, and stereopsis is a potential risk factor for impaired ability to implement a medication regimen. For severely affected patients, diabetic care activities (eg, exercise training, reading medication labels, preparing insulin and glucose testing) were difficult to accomplish [47]. It is clear that limited physical activity reduces the appreciation of ischemic pain and might delay appropriate timing of coronary revascularization, thereby worsening the outcome.
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Survival Benefit of CABG Over PCI in Patients with Diabetic Retinopathy
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Coronary revascularization (either with CABG or PCI) is the mainstay of treatment for CAD. Data from the Bypass Angioplasty Revascularization Investigation (BARI) study showed 15 excess deaths at 5-year follow-up for every 100 diabetic patients revascularized by PCI as opposed to CABG, and 20 excess deaths at 7 years and 22 excess deaths at 10 years, respectively [48–50]. In addition, strong evidence from several meta-analyses indicates that PCI, even with drug-eluting stents, does not offer any benefit in terms of avoiding death and myocardial infarction [51, 52]. Nevertheless, the advantage of PCI is obvious for the patients; it is performed under local anesthetic and postprocedural morbidity is minimal. Therefore, in "the real world" the presence of diabetes does not influence treatment decisions regarding revascularization in patients with stable CAD [53]. Under these circumstances, it is crucial to find a more specific subgroup of patients who will greatly benefit from CABG in the diabetic population. Recently, we found that the survival benefit of CABG over PCI is more apparent in patients with diabetic retinopathy than in diabetic patients without it [16]. Percutaneous coronary intervention directly targets "culprit" lesions. In contrast, CABG sidesteps most of the epicardial vessels including the "future" culprits, which are responsible for most coronary events, and it may render these events less fatal [54]. It would be reasonable for patients with diabetic retinopathy who are at high risk of myocardial infarction development and CAD death to benefit greatly from CABG, rather than PCI.
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Coronary Implantation of Sirolimus-Eluting Stents in Patients with Diabetic Retinopathy
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Currently, the number of patients with diabetes who undergo PCI with drug-eluting stents is increasing. Furthermore, Nargaz and colleagues [43] demonstrated that the diffuse nature of CAD is associated with the severity of diabetic retinopathy. Therefore, CAD with nonproliferative retinopathy is more amenable to PCI than to proliferative retinopathy. Recently, however, we demonstrated that patients with NPDR have a greater risk of target-vessel failure (ie, defined as a composite of death from cardiac causes, myocardial infarction, and target-vessel revascularization) after coronary implantation of sirolimus-eluting stents in comparison with diabetic patients without retinopathy [55]. After adjustment for the differences of patient characteristics, the number of stents, and their diameters, the association between NPDR and target-vessel failure remained statistically significant.
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Long-Term Prognosis After CABG
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We consider that patients with diabetic retinopathy and CAD should undergo CABG during the early stage of retinopathy, because the outcome of CABG in patients with advanced retinopathy is not satisfactory [14]. In our retrospective study of the 223 diabetic patients undergoing CABG, 12-year survival was 82% for diabetic patients without retinopathy, 56% for patients with mild-to-moderate NPDR, 36% for patients with severe NPDR, and 12% for those with PDR. One reason for the poor prognosis was that patients with advanced retinopathy are likely to have heart failure develop even after CABG [15]. These findings suggest that CABG alone rarely improves cardiac function in patients with advanced retinopathy who often have diabetic cardiomyopathy and diabetic nephropathy.
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Diabetic Retinopathy as a Guide for Developing an Appropriate Coronary Revascularization Strategy
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Our review demonstrated that the severity of diabetic retinopathy is closely related to the risk of future CAD events. Therefore, the treatment effect of coronary revascularization might vary according to severity of retinopathy, and the coronary revascularization strategy according to the severity of retinopathy is warranted. For diabetic patients during the stage that is free of retinopathy, PCI might be a preferable treatment method because these patients are a group in which the risk of having development of future CAD is low. For diabetic patients experiencing retinopathy, however, CABG would be the first choice, because there is a high risk of coronary events occurring in these patients (Fig 3). In the real world, however, for many patients with NPDR who have a high risk of target-vessel failure after drug-eluting stent implantation, PCI is selected and repeat PCI is vigorously performed, because the cardiac and renal functions of these patients are not impaired yet. Some patients with NPDR would proceed to the stage of PDR within 5 to 10 years and their cardiac and renal functions decrease gradually as severity of retinopathy progresses. The life expectancy of patients with PDR who have lowered cardiac and renal function is poor even after CABG; therefore CABG rather than PCI might be strongly indicated during the early stage of retinopathy.
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Fig 3. Diabetic retinopathy as a guide for appropriate timing of coronary artery bypass grafting (CABG). The risk of a coronary event is higher during nonproliferative diabetic retinopathy (NPDR) than during the "no diabetic retinopathy" (NDR) stage. Heart failure becomes an added risk during the proliferative diabetic retinopathy (PDR) stage. Also, CABG may be strongly indicated during early retinopathy. (DM = diabetes mellitus.)
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Future Directions
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The main purpose of managing CAD in a diabetic population should be to lengthen life expectancy. Therefore, in patients with diabetic retinopathy who are at high risk of developing CAD death and myocardial infarction, CABG is strongly indicated. In Japan, 3 million people have been reported with diabetic retinopathy. If, at the very least of these 3 million patients, 20% have CAD and 80% have left anterior descending coronary artery disease, it can be expected that CABG will be strongly indicated in 480,000 patients. On the other hand, approximately 20,000 patients in Japan undergo CABG annually, which corresponds to 4,000 patients with diabetic retinopathy undergoing CABG per year. A large proportion of patients with diabetic retinopathy in whom CABG can improve survival are underdiagnosed. Therefore, asymptomatic patients with diabetic retinopathy should have stress testing, computed tomographic coronary angiography, or cardiac catheterization followed by surgical revascularization. In our institute, we opened a new clinic in April 2007, which was named the "Diabetic Retino-coronary Clinic" for the purpose of early diagnosis and treatment of CAD in patients with diabetic retinopathy. Future studies should include the treatment effects of carefully performed cost-effective analyses and prospective randomized studies comparing survival after CABG with that of survival after PCI, stratified by retinopathy stage.
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Comment
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In summary, coronary artery disease is the leading cause of death in diabetic patients. Evidence indicates that diabetic retinopathy is associated with an increased risk of death from coronary artery disease and myocardial infarction. Cardiac surgeons should have a commitment to improving the life expectancy of diabetic patients by performing CABG when there is a high risk of myocardial infarction and CAD death. Patients with diabetic retinopathy could benefit greatly from CABG. However, those with advanced diabetic retinopathy most often have concomitant diabetic cardiomyopathy and nephropathy. These patients are likely to have persistent or recurrent heart failure after CABG, and their long-term prognosis is poor. Coronary artery bypass grafting may be strongly indicated before an advanced stage of retinopathy is reached. Prospective randomized studies are warranted to compare survival after CABG with survival after PCI, stratified by different stages of retinopathy.
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Abstract
Introduction
