doi: 10.1161/CIRCIMAGING.108.784876
Advances in Cardiovascular Imaging |
Retinal Vascular Imaging
A New Tool in Microvascular Disease Research
From the Centre for Vision Research (G.L., J.J.W., P.M., T.Y.W.), University of Sydney, Australia; Centre for Eye Research Australia (J.J.W., T.Y.W.), University of Melbourne, Australia, and Singapore Eye Research Institute; Yong Loo Lin School of Medicine Westmead Millennium Institute, National University of Singapore, Singapore.
Correspondence to Jie Jin Wang, MMed, PhD, Centre for Vision Research, Department of Ophthalmology, University of Sydney, Westmead Hospital, Hawkesbury Rd, Westmead, NSW 2145, Australia. E-mail jiejin_wang{at}wmi.usyd.edu.au
Received April 8, 2008; accepted July 14, 2008.
 |
Abstract |
|---|
 Top Abstract IntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
The microcirculation is relatively inaccessible to direct visualization and investigation. Recent methods have been developed which use advanced retinal photographic imaging techniques and computer-assisted image analysis to characterize, measure and quantify subtle variations and abnormalities in the retinal vasculature. These quantitative and qualitative assessments demonstrate a close association of retinal vascular signs to both clinical and subclinical cerebrovascular, cardiovascular and metabolic outcomes. Retinal vascular imaging may thus offer potential as a noninvasive research tool to probe the role and pathophysiology of the microvasculature, and as a cardiovascular risk prediction tool. Key areas where retinal vascular imaging has contributed to increased understanding of microvascular pathology and major areas of current and new research are discussed in this review.
Key Words: arteriosclerosis • microcirculation • retinal vessels • cardiovascular disease • risk factors
|
Introduction |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
The microcirculation represents the bulk of the circulatory system; yet, its role in the cardiovascular disease is less clear than the role of the macrocirculation (ie, large vessel disease). This is partly because current methods to investigate the microvasculature are invasive and can be performed only in highly specialized settings, which limits their utility as tools to understand the clinical consequences of microvascular disease.
The retina is a unique site where the in vivo microvasculature can be directly visualized and monitored repeatedly over time. Recent advances in retinal photographic imaging techniques have facilitated the development of computer-assisted methods to measure and quantify subtle variations and abnormalities in the retinal microvasculature.1,2 These quantitative assessments have been applied to large populations, of both adults and children, and in community and clinic settings. Existing data now convincingly show links between a range of retinal microvascular signs and both clinical and subclinical cerebrovascular, cardiovascular, and metabolic outcomes.3 Thus, retinal vascular imaging offers the potential to provide information that summarizes the cumulative microcirculatory effects of an individual’s lifetime exposures to lifestyle and environmental factors, and the body’s responses to these exposures, which may in turn be modified by genetic predisposition.
Retinal vascular imaging is currently used in 2 broad areas of cardiovascular research. First, retinal imaging is a novel, noninvasive research tool to probe the role and pathophysiology of the microvasculature, typically defined as vessels between 100 and 300 µm in size, in the development of clinical cardiovascular disease.4 Second, retinal vascular imaging is explored in clinical settings as a risk stratification tool to aid clinicians in identifying patients with microvascular signs who are at high risk of future clinical cardiovascular and cerebrovascular events. A third possibility is under investigation: retinal vascular imaging has potential as a surrogate measure of the microvascular benefits of new therapeutic agents in early phase II or even phase III studies.5 Although this prospect has been raised, several critical issues must be addressed before retinal vascular imaging can be considered a valid surrogate for assessing outcomes in cardiovascular clinical trials. The unique perspective offered by retinal vascular image analysis is used by an increasing number of researchers and research groups to address scientific questions that are difficult to answer through other means. Some key questions this new technique has been applied to are described later, as are major issues that remain to be addressed.
|
Retinal Vascular Imaging Technologies |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
Several semiautomated programs to measure retinal vascular caliber have been developed and described. The most widely used program was developed and validated in the Atherosclerosis Risk in Communities Study to examine the retinal vascular signs of arteriosclerosis in 11 114 middle-aged adults6 and has since undergone further refinement and improvement.7 The program measures arteriolar and venular caliber from digital retinal photographs centered on the optic disc (or images digitized from photographic slides). Photographs of sufficient quality for grading can be obtained using nonmydriatic autofocus cameras, although higher quality images are taken if pharmacological pupil dilation is undertaken beforehand. With the assistance of a trained grader, the program identifies all retinal vessels greater than 25 µm in diameter that completely pass through the region between
and 1 disc diameter from the optic disc margin (zone B) and identifies their edges using a pixel density histogram (Figure 1). The cross-sectional diameter of retinal arterioles and venules is measured repeatedly and summarized using formulae to obtain values representing the average arteriolar and venular caliber of that particular eye.6,7 Reliability of this method is high, with intergrader reliability weighted kappa of 0.85 and 0.90, for arteriolar and venular caliber measurements, respectively, and intragrader reliability between 0.80 and 0.93 for both arteriolar and venular caliber measurements.8
|
|
Temporal Sequence of Microvascular Changes and Clinical Cardiovascular Disease |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
A key question in cardiovascular physiology is whether changes detected in the microvasculature are early markers of vascular disease secondary to the disease process or whether microvasculature changes represent the primary causes that contribute etiologically and mechanistically to the development of vascular disease. For example, a distinctive feature of hypertension is increased peripheral vascular resistance, which is determined largely by narrower arterioles in the systemic microcirculation.9 However, one of the central unresolved issues in understanding the pathophysiology of hypertension is whether arteriolar narrowing is antecedent to and contributes to the development of hypertension, or whether it is consequential to and represents a secondary adaptation to elevated blood pressure,10 or whether both processes occur.
It has been hypothesized that relatively modest decreases in internal arteriole lumen caliber, particularly in the renal preglomerular vasculature,11 occur early in the genesis of essential hypertension. These caliber changes then act to "reset" blood pressure to a higher level by altering hemodynamics in a manner similar to renal artery stenosis.11,12 By providing noninvasive means to measure arteriolar caliber, retinal vascular imaging provided the first prospective clinical evidence, which showed that narrower arteriolar caliber preceded the development of clinical hypertension and was not purely a secondary response to established hypertension (Figure 2).13 Subsequent studies have since demonstrated that retinal arteriolar narrowing precedes by years the development of hypertension in initially normotensive individuals (Table),8,13–15 which supports the hypothesis that microvascular changes have a primary role in the development and evolution of hypertension. Such data probing the anatomic substrate underlying the development of hypertension have clear implications for its treatment and prevention.8
|
|
|
Homology Between Retinal Microvasculature and Other Microvascular Beds |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
Retinal vascular imaging appears to have utility in the investigation of microcirculatory changes in cardiovascular disease, but there is an important caveat to insights obtained through this means. The extent to which the structure and function of the retinal microvasculature mirrors the cerebral microvasculature, and microvascular beds elsewhere, is not clear. Histopathologic studies suggest that retinal vascular signs16 are closely related to pathological microvascular changes in other organs (eg, hypertensive arteriolar changes in the brain17 and myocardium18). Other studies demonstrate that persons with lacunar stroke have functional alterations in the retinal vasculature19 including reduced retinal arteriolar-venule passage time.20 Pathological changes in the retinal arteries parallel changes in the small cerebral arteries that cause white matter lesions and lacunes.21–24 The close relationship between retinal and cerebral vascular changes is unsurprising given the embryological, morphological, and functional similarities due to their common origin from the internal carotid artery. What is perhaps more surprising is that there are also strong indications that retinal vascular changes parallel pathology in the coronary micro and macrocirculations, with retinal arteriolar narrowing strongly associated with the presence and severity of angiographically defined coronary artery occlusion,25,26 and reduced myocardial perfusion measures on cardiac MRI,27 whereas retinopathy is correlated with coronary artery calcification on cardiac computed tomography scanning.26,28
Although these lines of evidence support the hypothesis that retinal microvasculature changes provide insights into the vascular structure and function of the cerebral and coronary microcirculations, 4,29 direct autopsy evidence linking specific retinal microvascular signs with cerebral and coronary microvascular abnormalities is still needed to confirm the homology in these different microvascular beds. Determining the extent to which the retinal microvasculature is a surrogate for microvascular beds elsewhere will greatly strengthen the rationale for using retinal microvascular signs to probe the biology and pathophysiology of systemic diseases.
|
Role of the Venular Circulation in Cardiovascular Disease |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
Studies linking retinal microvascular signs to cardiovascular disease have discovered unexpected associations that give new insights into vascular pathophysiology, particularly the pathophysiology of venules, an area that has previously received little attention. For example, recent studies have revealed that venular dilation, rather than arteriolar narrowing, is the stronger predictor of clinical stroke,1 a relationship hitherto unsuspected (Figure 3). This surprising result was confirmed in a subsequent work1,7,30 and suggests that venules are not merely passive conductance vessels but represent a dynamic component responsive to changes in the microcirculation. Such findings have already stimulated an increased interest in venular physiology, with new studies reporting that wider retinal venules are linked to cerebral hypoxia,31 endothelial dysfunction, hyperglycemia,32 and inflammation,3,33 in contrast to narrower retinal arterioles, which are consistently and strongly related to elevated blood pressure and endothelial dysfunction.1,3 The prospect that both these retinal microvascular changes result from underlying endothelial dysfunction, and could thus represent a directly visible microvascular phenotype of endothelial dysfunction, is enticing and offers scope for further potential applications, for example, as a surrogate marker of endothelial function in clinical trials of new antihypertensive or vasoprotective agents. Nonetheless, this possibility is remote at present as it is not clear whether the changes detected on retinal vascular imaging are directly related to the causal pathways of cardiovascular disease or are associated epiphenomena. Future research in animal models and clinic settings to monitor these retinal vascular changes and their relationship to the onset, progression, and regression of cardiovascular disease is needed to validate this phenotype.
|
|
Retinal Microvasculature Is Accessible and Information Rich |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
There is a wealth of geometric and structural data present in the visible retinal microvasculature, only parts of which have been investigated in detail. Theoretical and experimental work supports the concept that the vascular architecture develops in a way that is optimized for efficient flow and that deviations from this optimal state occur in disease processes.34 These deviations are reflected in abnormal, or suboptimal, geometric parameters of retinal microvascular architecture that may translate into an increased risk of cardiovascular disease. For example, geometric parameters of the retinal vascular network, such as vessel tortuosity, the angle, and number of bifurcations, and the length to diameter ratio of vessels appear to convey prognostic information on the risk of hypertension and cardiovascular disease,35,36 but to date, this has only been investigated in small case-control series. A mutation in the basement membrane collagen gene COL4A1 leads to both an increased retinal vessel tortuosity and an increased risk of hemorrhagic stroke.37 This genotype could underlie certain microvascular phenotypes that increase risk of cerebrovascular disease. Importantly, retinal imaging may provide a means to directly detect, measure, and quantify these phenotypes and thus evaluate risk.
One such recent analysis is the fractal dimension of the retinal vasculature, a novel means of measuring the complexity or density of the retinal vessel branching network (Figure 4). A less complex, less dense, and lower fractal dimension indicates rarefaction or loss of vessels, whereas a more complex, denser, and higher fractal dimension indicates a microvascular proliferation. This measure has been used in a limited number of studies to provide insights into the embryology and development of microvasculature38 and has shown promise as a sensitive indicator of early vascular changes in diabetic retinopathy, other retinal diseases, and systemic cardiovascular disease.36,39 The fractal dimension may combine contributions of the individual vessel parameters (eg, retinal vessel caliber, bifurcation angle, length to diameter ratio) with the vascular branching pattern into a single global value that summarizes the geometric complexity of the retinal vasculature.36 The variation and change in the fractal dimension may, thus, be a sensitive indicator of deviation from normal or optimized architecture and, thus, early microvascular disease. Measurement of fractal dimension may track the microcirculatory response to the progression of hypertension or, conversely, the microvascular response to antihypertensive treatments. Despite this promise, only very few, mostly clinic-based studies, have examined the role of retinal vessel fractal analysis in cardiovascular disease.
|
|
Functional Measures of the Retinal Microvasculature Complement Structural Retinal Vascular Imaging |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
Most studies to date have examined the prognostic information conveyed by static structural features of the microcirculation, largely because these are the most amenable to analysis from retinal images. In contrast, dynamic functional measures of the retinal microcirculation (eg, flowmetry and dynamic vessel assessments) and their relationship to cardiovascular risk have had relatively little attention. Such functional changes in the retinal microcirculation may well be more relevant to the prediction of cardiovascular risk. Techniques such as scanning laser doppler flowmetry and scanning laser ophthalmoscopy40,41 permit in vivo measurement of microcirculatory blood flow that is inaccessible in any other microcirculation. When coupled with imaging of the retinal vessels, estimates of retinal vessel wall thickness may be obtained,40,41 providing a unique means of determining actual arteriolar and venular wall thickness, which is clearly of value in assessing the health of the microcirculation. Some studies have shown that these measures may track the microcirculatory response to therapy for hypertension and may identify increased cerebrovascular risk.40 Stimulating the retina with flickering light increases retinal arterial and venous diameters, indicating a tight coupling among neural activity, blood flow, and vasoreactivity.42 Such flicker-dependent vasodilation may be an indicator of healthy endothelial function and is diminished in systemic diseases like hypertension and diabetes.42 However, whether these functional measures of retinal vascular hemodynamics will help to identify those at risk of cardiovascular diseases is unexplored.
|
Retinal Vascular Imaging May Provide Insights Into the Genetics of Microvascular Disease |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
Considerable research is currently focused on the role of genetic factors in the development of vascular disease processes and risk of cardiovascular disease. However, most major genetic studies, such as the Wellcome Trust Case Control Consortium,43 have focused on the genetic associations of large vessel atherosclerosis. Data on the genetic determinants of microvascular disease are sparse. Much of the variability in arteriolar and venular calibers is believed to be related to genetic factors,44,45 and although a number of candidate genes have been postulated,44 to date, no strong evidence implicates specific genes. In twin studies,45 heritability estimates for retinal arteriolar caliber are higher than those for mean arterial blood pressure, suggesting that genetic influences may potentially be direct and potent for the retinal arteriolar phenotype and its responses to environmental insults. A recent genome-wide linkage analysis of retinal vascular caliber demonstrated a number of linkage signals for the arteriolar caliber trait,44 which deserve further scrutiny.
|
Potential for Retinal Vascular Imaging as a Clinical Tool for Cardiovascular Risk Prediction. |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
The intimate association of retinal vascular signs and cardiovascular risk factors has been shown repeatedly in numerous clinical and epidemiological studies. These are reviewed elsewhere.1–3 In brief, the pattern of association of arteriolar and venular caliber appears fairly distinct, with narrower arteriolar caliber related mainly to current and past elevated blood pressure and greater waist-to-hip ratio, whereas wider venular caliber is related to metabolic abnormalities such as hyperglycemia, hypertriglyceridemia, inflammatory markers, obesity, and renal disease.1–3. Many studies have demonstrated prospective associations of retinal microvascular signs with incident cardiovascular outcomes. Narrower retinal arteriolar caliber predicts coronary heart disease events as well as mortality, with some evidence of stronger associations in women; wider venular caliber appears to predict both coronary heart disease and stroke events, including mortality from these causes.1–3
Despite these strong and consistent associations, much more work remains before retinal vascular imaging can be translated into clinical practice. To be clinically useful, retinal microvascular signs must demonstrate an additional prognostic information for cardiovascular risk prediction, over contributions from traditional risk factors. Previous studies on novel cardiovascular risk markers did not add substantially to risk prediction over traditional risk factors,46 partly because traditional risk factors have already moderately high predictive ability.47 In this regard, there remains skepticism that a retinal vascular assessment will offer sufficient prognostic potential beyond traditional cardiovascular assessment strategies.48 Recent work in populations without diabetes suggest that retinal vascular caliber measurements provide slightly superior coronary heart disease risk prediction to the use of traditional risk factors alone, but the magnitude of this improvement was considered unlikely to be relevant in clinical practice.49
There are certain population subgroups, however, where retinal microvascular imaging may be more strongly predictive of risk. These are subgroups in which the microvascular contribution to cardiovascular disease is more prominent, for example, in women50 and in persons with diabetes, suggesting that the targeted application of retinal vascular imaging may be more productive. The cost-effectiveness of retinal vascular imaging must also be considered, especially as the measurement of traditional risk factors (eg, blood pressure, serum cholesterol) is relatively inexpensive and is widely available. Such issues need to be resolved before retinal microvascular imaging could be considered for clinical risk prediction.
|
Conclusions |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
Progress in retinal vascular imaging technologies in the last 2 decades has provided clinicians and researchers with a noninvasive means to measure and quantify subtle variations and abnormalities in the retinal microvasculature. These new technologies have linked retinal microvascular signs with a greater risk of a range of important clinical and subclinical cardiovascular outcomes. Data from these studies are providing unique insights into the microvascular contribution to hypertension and cardiovascular disease. However, further work is needed to determine whether retinal vascular imaging will live up to its promise and attain translation as a valuable new clinical modality of assessing cardiovascular disease.
|
Acknowledgments |
|---|
We thank Ava Tan for her assistance with images and we also thank the participants of the Blue Mountains Eye Study for their generous contribution to research.
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopAbstractIntroductionRetinal Vascular Imaging...Temporal Sequence of...Homology Between Retinal...Role of the Venular...Retinal Microvasculature Is...Functional Measures of the...Retinal Vascular Imaging May...Potential for Retinal Vascular...ConclusionsReferences |
|---|
1. Wong TY, Mitchell P. The eye in hypertension. Lancet. 2007; 369: 425–435.[CrossRef][Medline]
2. Wong TY, Mitchell P. Hypertensive retinopathy. N Engl J Med. 2004; 351: 2310–2317.
3. Nguyen TT, Wong TY. Retinal vascular manifestations of metabolic disorders. Trends Endocrinol Metab. 2006; 17: 262–268.[CrossRef][Medline]
4. Touyz RM. Vascular remodeling, retinal arteries, and hypertension. Hypertension. 2007; 50: 603–604.
5. Stolk RP, Vingerling JR, Cruickshank JK, Hughes AD, Stanton A, Juming L, Patel A, Thom SA, Grobbee DE. Rationale and design of the AdRem study: evaluating the effects of blood pressure lowering and intensive glucose control on vascular retinal disorders in patients with type 2 diabetes mellitus. Contemp Clin Trials. 2007; 28: 6–17.[CrossRef][Medline]
6. Hubbard LD, Brothers RJ, King WN, Clegg LX, Klein R, Cooper LS, Sharrett AR, Davis MD, Cai J. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology. 1999; 106: 2269–2280.[CrossRef][Medline]
7. Wang JJ, Liew G, Klein R, Rochtchina E, Knudtson MD, Klein BE, Wong TY, Burlutsky G, Mitchell P. Retinal vessel diameter and cardiovascular mortality: pooled data analysis from two older populations. Eur Heart J. 2007; 28: 1984–1992.
8. Wang JJ, Rochtchina E, Liew G, Tan AG, Wong TY, Leeder SR, Smith W, Shankar A, Mitchell P. The long-term relation among retinal arteriolar narrowing, blood pressure, and incident severe hypertension. Am J Epidemiol. 2008; 168: 80–88.
9. Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HA. Microcirculation in hypertension: a new target for treatment? Circulation. 2001; 104: 735–740.
10. Mulvany MJ. Are vascular abnormalities a primary cause or secondary consequence of hypertension? Hypertension. 1991; 18 (3 Suppl): I52–I57.[Medline]
11. Norrelund H, Christensen KL, Samani NJ, Kimber P, Mulvany MJ, Korsgaard N. Early narrowed afferent arteriole is a contributor to the development of hypertension. Hypertension. 1994; 24: 301–308.
12. Anderson WP, Kett MM, Stevenson KM, Edgley AJ, Denton KM, Fitzgerald SM. Renovascular hypertension: structural changes in the renal vasculature. Hypertension. 2000; 36: 648–652.
13. Wong TY, Klein R, Sharrett AR, Duncan BB, Couper DJ, Klein BE, Hubbard LD, Nieto FJ. Retinal arteriolar diameter and risk for hypertension. Ann Intern Med. 2004; 140: 248–255.
14. Wong TY, Shankar A, Klein R, Klein BE, Hubbard LD. Prospective cohort study of retinal vessel diameters and risk of hypertension. BMJ. 2004; 329: 79.
15. Ikram MK, Witteman JC, Vingerling JR, Breteler MM, Hofman A, de Jong PT. Retinal vessel diameters and risk of hypertension: the Rotterdam Study. Hypertension. 2006; 47: 189–194.
16. Tso MO, Jampol LM. Pathophysiology of hypertensive retinopathy. Ophthalmology. 1982; 89: 1132–1145.[Medline]
17. Goto I, Katsuki S, Ikui H, Kimoto K, Mimatsu T. Pathological studies on the intracerebral and retinal arteries in cerebrovascular and noncerebrovascular diseases. Stroke. 1975; 6: 263–269.
18. Tanaka M, Fujiwara H, Onodera T, Wu DJ, Matsuda M, Hamashima Y, Kawai C. Quantitative analysis of narrowings of intramyocardial small arteries in normal hearts, hypertensive hearts, and hearts with hypertrophic cardiomyopathy. Circulation. 1987; 75: 1130–1139.
19. Schneider R, Rademacher M, Wolf S. Lacunar infarcts and white matter attenuation. Ophthalmologic and microcirculatory aspects of the pathophysiology. Stroke. 1993; 24: 1874–1879.
20. Korber N, Schneider R, Brockmann M. Circulatory parameters of the retina in patients with lacunar stroke. J Neurol. 1986; 233: 30–33.[CrossRef][Medline]
21. Kwa VI, van der Sande JJ, Stam J, Tijmes N, Vrooland JL. Retinal arterial changes correlate with cerebral small-vessel disease. Neurology. 2002; 59: 1536–1540.
22. Longstreth W, Jr, Larsen EK, Klein R, Wong TY, Sharrett AR, Lefkowitz D, Manolio TA. Associations between findings on cranial magnetic resonance imaging and retinal photography in the elderly: the Cardiovascular Health Study. Am J Epidemiol. 2007; 165: 78–84.
23. Cooper LS, Wong TY, Klein R, Sharrett AR, Bryan RN, Hubbard LD, Couper DJ, Heiss G, Sorlie PD. Retinal microvascular abnormalities and MRI-defined subclinical cerebral infarction: the Atherosclerosis Risk in Communities Study. Stroke. 2006; 37: 82–86.
24. Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao DP, Hubbard LD, Mosley TH. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA. 2002; 288: 67–74.
25. Michelson EL, Morganroth J, Nichols CW, MacVaugh H III. Retinal arteriolar changes as an indicator of coronary artery disease. Arch Intern Med. 1979; 139: 1139–1141.
26. Tedeschi-Reiner E, Strozzi M, Skoric B, Reiner Z. Relation of atherosclerotic changes in retinal arteries to the extent of coronary artery disease. Am J Cardiol. 2005; 96: 1107–1109.[CrossRef][Medline]
27. Wang L, Wong TY, Sharrett AR, Klein R, Folsom AR, Jerosch-Herold M. Relationship between retinal arteriolar narrowing and myocardial perfusion: multi-ethnic study of atherosclerosis. Hypertension. 2008; 51: 119–126.
28. Wong TY, Cheung N, Islam FM, Klein R, Criqui MH, Cotch MF, Carr JJ, Klein BE, Sharrett AR. Relation of retinopathy to coronary artery calcification: the multi-ethnic study of atherosclerosis. Am J Epidemiol. 2008; 167: 51–58.
29. Wong TY. Is retinal photography useful in the measurement of stroke risk? Lancet Neurol. 2004; 3: 179–183.[CrossRef][Medline]
30. Wong TY, Kamineni A, Klein R, Sharrett AR, Klein BE, Siscovick DS, Cushman M, Duncan BB. Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study. Arch Intern Med. 2006; 166: 2388–2394.
31. de Jong FJ, Vernooij MW, Ikram MK, Ikram MA, Hofman A, Krestin GP, van der Lugt A, de Jong PT, Breteler MM. Arteriolar oxygen saturation, cerebral blood flow, and retinal vessel diameters: the Rotterdam Study. Ophthalmology. 2008; 115: 887–892.[CrossRef][Medline]
32. Ikram MK, Janssen JA, Roos AM, Rietveld I, Witteman JC, Breteler MM, Hofman A, van Duijn CM, de Jong PT. Retinal vessel diameters and risk of impaired fasting glucose or diabetes: the Rotterdam study. Diabetes. 2006; 55: 506–510.
33. Klein R, Klein BE, Knudtson MD, Wong TY, Tsai MY. Are inflammatory factors related to retinal vessel caliber? The Beaver Dam Eye Study. Arch Ophthalmol. 2006; 124: 87–94.
34. Zamir M. Optimality principles in arterial branching. J Theor Biol. 1976; 62: 227–251.[CrossRef][Medline]
35. Witt N, Wong TY, Hughes AD, Chaturvedi N, Klein BE, Evans R, McNamara M, Thom SA, Klein R. Abnormalities of retinal microvascular structure and risk of mortality from ischemic heart disease and stroke. Hypertension. 2006; 47: 975–981.
36. Patton N, Aslam TM, MacGillivray T, Deary IJ, Dhillon B, Eikelboom RH, Yogesan K, Constable IJ. Retinal image analysis: concepts, applications and potential. Prog Retin Eye Res. 2006; 25: 99–127.[CrossRef][Medline]
37. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Bousser MG, Heutink P, Miner JH, Tournier-Lasserve E, John SW. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med. 2006; 354: 1489–1496.
38. Mainster MA. The fractal properties of retinal vessels: embryological and clinical implications. Eye. 1990; 4 (Pt 1): 235–241.[Medline]
39. Macgillivray TJ, Patton N, Doubal FN, Graham C, Wardlaw JM. Fractal analysis of the retinal vascular network in fundus images. Conf Proc IEEE Eng Med Biol Soc. 2007; 1: 6455–8.
40. Harazny JM, Ritt M, Baleanu D, Ott C, Heckmann J, Schlaich MP, Michelson G, Schmieder RE. Increased wall:lumen ratio of retinal arterioles in male patients with a history of a cerebrovascular event. Hypertension. 2007; 50: 623–629.
41. Michelson G, Warntges S, Baleanu D, Welzenbach J, Ohno-Jinno A, Pogorelov P, Harazny J. Morphometric age-related evaluation of small retinal vessels by scanning laser Doppler flowmetry: determination of a vessel wall index. Retina. 2007; 27: 490–498.[CrossRef][Medline]
42. Riva CE, Logean E, Falsini B. Visually evoked hemodynamical response and assessment of neurovascular coupling in the optic nerve and retina. Prog Retin Eye Res. 2005; 24: 183–215.[CrossRef][Medline]
43. Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, Dixon RJ, Meitinger T, Braund P, Wichmann HE, Barrett JH, Konig IR, Stevens SE, Szymczak S, Tregouet DA, Iles MM, Pahlke F, Pollard H, Lieb W, Cambien F, Fischer M, Ouwehand W, Blankenberg S, Balmforth AJ, Baessler A, Ball SG, Strom TM, Braenne I, Gieger C, Deloukas P, Tobin MD, Ziegler A, Thompson JR, Schunkert H, the WTCCC and the Cardiogenics Consortium. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007; 357: 443–453.
44. Xing C, Klein BE, Klein R, Jun G, Lee KE, Iyengar SK. Genome-wide linkage study of retinal vessel diameters in the Beaver Dam Eye Study. Hypertension. 2006; 47: 797–802.
45. Taarnhoj NC, Larsen M, Sander B, Kyvik KO, Kessel L, Hougaard JL, Sorensen TI. Heritability of retinal vessel diameters and blood pressure: a twin study. Invest Ophthalmol Vis Sci. 2006; 47: 3539–3544.
46. Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 1997; 96: 1102–1108.
47. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97: 1837–1847.
48. van den Born BJ, Hulsman CA, Hoekstra JB, Schlingemann RO, van Montfrans GA. Value of routine funduscopy in patients with hypertension: systematic review. BMJ. 2005; 331: 73.
49. McGeechan K, Liew G, Macaskill P, Irwig L, Klein R, Sharrett AR, Klein BE, Wang JJ, Chambless LE, Wong TY. Risk prediction of coronary heart disease based on retinal vascular caliber (from the Atherosclerosis Risk in Communities [ARIC] Study). Am J Cardiol. 2008; 102: 58–63.[CrossRef][Medline]
50. Cordero A, Alegria E. Sex differences and cardiovascular risk. Heart. 2006; 92: 145–146.
This article has been cited by other articles:
 |
|
 |
|
  C. C.A. Sng, C. Sabanayagam, E. L. Lamoureux, E. Liu, S. C. Lim, H. Hamzah, J. Lee, E. S. Tai, and T. Y. Wong Fractal analysis of the retinal vasculature and chronic kidney disease Nephrol. Dial. Transplant., February 1, 2010; (2010): gfq007v1 - gfq007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Yim-Lui Cheung, T. Y. Wong, E. L. Lamoureux, C. Sabanayagam, J. Li, J. Lee, and E. S. Tai C-Reactive Protein and Retinal Microvascular Caliber in a Multiethnic Asian Population Am. J. Epidemiol., January 15, 2010; 171(2): 206 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. McGeechan, G. Liew, P. Macaskill, L. Irwig, R. Klein, B. E. K. Klein, J. J. Wang, P. Mitchell, J. R. Vingerling, P. T. V. M. de Jong, et al. Prediction of Incident Stroke Events Based on Retinal Vessel Caliber: A Systematic Review and Individual-Participant Meta-Analysis Am. J. Epidemiol., December 1, 2009; 170(11): 1323 - 1332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Lesage, T. H. Mosley, T. Y. Wong, M. Szklo, D. Knopman, D. J. Catellier, S. R. Cole, R. Klein, J. Coresh, L. H. Coker, et al. Retinal microvascular abnormalities and cognitive decline: The ARIC 14-year follow-up study Neurology, September 15, 2009; 73(11): 862 - 868. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||