Hypertensive Retinopathy
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《新英格兰医药杂志》
Hypertensive retinopathy is a condition characterized by a spectrum of retinal vascular signs in people with elevated blood pressure.1 The detection of hypertensive retinopathy with the use of an ophthalmoscope has long been regarded as part of the standard evaluation of persons with hypertension.2,3,4 This clinical practice is supported by both previous5 and current6 reports of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), which list retinopathy as one of several markers of target-organ damage in hypertension. On the basis of the JNC criteria, the presence of retinopathy may be an indication for initiating antihypertensive treatment, even in people with stage 1 hypertension (blood pressure, 140 to 159/90 to 99 mm Hg) who have no other evidence of target-organ damage.
Despite the JNC recommendation, the clinical implications of hypertensive retinopathy are unclear. Many physicians do not regularly perform an ophthalmoscopic examination as part of the care they provide to hypertensive patients, nor do they include retinal findings when making decisions about treatment. Furthermore, there is no clear consensus regarding the classification of hypertensive retinopathy or whether a retinal examination is useful for risk stratification.
The evidence in support of the JNC guidelines on retinal findings in hypertension is based on earlier studies that may not have direct relevance to current clinical practice.7,8,9,10 These studies have several important limitations. First, because they involved patients who had uncontrolled and untreated hypertension, generalization to contemporary populations of patients with lower blood-pressure levels may be problematic. Second, retinopathy as defined in these studies was based on a direct ophthalmoscopic examination. This technique has been shown to be unreliable, with high rates of interobserver variability (20 to 42 percent) and intraobserver variability (10 to 33 percent) when used in persons with mild hypertension.11,12 Third, although many earlier studies cite increased mortality among persons with hypertensive retinopathy,8,9,10 few studies have demonstrated associations between hypertensive retinopathy and specific cardiovascular outcomes (e.g., incident stroke and coronary heart disease) or have adequately controlled for relevant confounding factors (e.g., hyperlipidemia and cigarette smoking). Thus, whether hypertensive retinopathy predicts the risk of cardiovascular outcomes independently of other risk indicators has not been examined until recently. The purpose of this review is to appraise recent studies (i.e., from 1990 onward) in regard to the pathophysiology, epidemiology, and cardiovascular associations of hypertensive retinopathy and the evidence that supports its use for risk stratification in persons with hypertension.
Historical Context and Classification
Hypertensive retinopathy was first described by Marcus Gunn in the 19th century in a series of patients with hypertension and renal disease.7 The retinal signs he observed included generalized and focal arteriolar narrowing, arteriovenous nicking, flame-shaped and blot-shaped retinal hemorrhages, cotton-wool spots, and swelling of the optic disk (Figure 1, Figure 2, and Figure 3). In 1939, Keith et al. showed that these signs of retinopathy were predictive of death in patients with hypertension.10 The authors described a widely used classification system that categorized these signs into four groups of increasing severity.
Figure 1. Examples of Mild Hypertensive Retinopathy.
Panel A shows arteriovenous nicking (black arrow) and focal narrowing (white arrow). Panel B shows arteriovenous nicking (black arrows) and widening or accentuation ("copper wiring") of the central light reflex of the arterioles (white arrows).
Figure 2. Examples of Moderate Hypertensive Retinopathy.
Panel A shows retinal hemorrhages (black arrows) and a cotton-wool spot (white arrow). Panel B shows cotton-wool spots (white arrows) and arteriovenous nicking (black arrows).
Figure 3. Example of Malignant Hypertensive Retinopathy.
Multiple cotton-wool spots (white arrows), retinal hemorrhages (black arrows), and swelling of the optic disk are visible.
However, several reviews of hypertensive retinopathy since 199613,14,15,16 have questioned the usefulness of the classification system by Keith et al. (subsequently modified by Scheie8) and its relevance to current clinical practice. The major criticisms of the original and modified classifications are that they do not enable the clinician to distinguish among low retinopathy grades (e.g., grade 1 signs are not easily distinguished from grade 2 signs) and that the retinopathy grades are not closely correlated with the severity of hypertension.17 Furthermore, a detailed categorization of retinopathy into four grades does not appear to be supported by retinal studies with the use of fluorescein angiography.18
Pathophysiology
The retinal circulation undergoes a series of pathophysiological changes in response to elevated blood pressure.19 In the initial, vasoconstrictive stage, there is vasospasm and an increase in retinal arteriolar tone owing to local autoregulatory mechanisms. This stage is seen clinically as a generalized narrowing of the retinal arterioles. Persistently elevated blood pressure leads to intimal thickening, hyperplasia of the media wall, and hyaline degeneration in the subsequent, sclerotic, stage. This stage corresponds to more severe generalized and focal areas of arteriolar narrowing, changes in the arteriolar and venular junctions (i.e., arteriovenous nicking or nipping), and alterations in the arteriolar light reflex (i.e., widening and accentuation of the central light reflex, or "copper wiring").
This is followed by an exudative stage, in which there is disruption of the blood–retina barrier, necrosis of the smooth muscles and endothelial cells, exudation of blood and lipids, and retinal ischemia. These changes are manifested in the retina as microaneurysms, hemorrhages, hard exudates, and cotton-wool spots. Swelling of the optic disk may occur at this time and usually indicates severely elevated blood pressure (i.e., malignant hypertension). Because better methods for the control of blood pressure are now available in the general population, malignant hypertension is rarely seen. In contrast, other retinal vascular complications of hypertension, such as macroaneurysms and branch-vein occlusions, are not uncommon in patients with chronically elevated blood pressure. The stages of hypertensive retinopathy described here, however, may not be sequential.18,19 For example, signs of retinopathy that reflect the exudative stage, such as retinal hemorrhage or microaneurysm, may be seen in eyes that do not have features of the sclerotic stage (e.g., arteriovenous nicking).19 The exudative signs are nonspecific, since they are seen in diabetes and other conditions.
Epidemiology
Since 1990, there have been seven population-based epidemiologic studies (involving a total of 26,477 participants) of various signs of hypertensive retinopathy.20,21,22,23,24,25,26,27 In all seven studies, retinal photographs were used to define specific signs of retinopathy without regard to a predetermined grading system. All of the studies were conducted in the general community and included persons with and those without a history of hypertension.
In general, these studies show that signs of hypertensive retinopathy can be reliably identified with a standardized examination of photographs of the fundus. Reproducibility was substantial for the grading of retinal hemorrhages and microaneurysms (e.g., =0.80 to 0.99) and fair to moderate for the grading of arteriovenous nicking and focal arteriolar narrowing (=0.40 to 0.79).25,28 In four populations, generalized arteriolar narrowing was estimated from an assessment of retinal vessel diameters with the use of digitized photographs.25,28,29,30,31 This technique appears to have substantial reproducibility (i.e., the intraclass correlation coefficient ranged from 0.80 to 0.99 in four studies).25,28,29,30,31
On the basis of photographic grading, these epidemiologic studies show that signs of hypertensive retinopathy are common in people 40 years of age or older, even in those without a history of hypertension. Prevalence rates ranged from 2 to 15 percent for various signs of retinopathy,20,21,22,23,24,25 in contrast to the earlier report from the Framingham Eye Study that found a prevalence of less than 1 percent among participants who underwent an ophthalmoscopic examination with dilation.32 The higher rates of prevalence in these more recent studies are probably due to a higher sensitivity of photography, as compared with clinical ophthalmoscopy, for detecting certain signs of retinopathy. However, there have been no studies that have directly compared the sensitivity or reliability of photography with that of ophthalmoscopy for the detection of hypertensive retinopathy, as there have been for diabetic retinopathy.
A higher prevalence of retinopathy has been reported among black persons than among whites, a difference that is explained in large part by the higher levels of blood pressure among blacks.21,33 The racial variation confirms the results of a previous population-based survey that used direct ophthalmoscopy34 and suggests that retinal examination may be particularly useful for risk stratification among blacks. Variations in the prevalence of specific signs of hypertensive retinopathy according to age and sex have not been consistently demonstrated.20,21,22,23,24,25 There have been fewer studies of the incidence of hypertensive retinopathy. Two studies indicate that the incidence of various signs of retinopathy over a period of five to seven years ranges from 6 to 10 percent.26,27
Blood Pressure
Numerous studies have confirmed the strong association between the presence of signs of hypertensive retinopathy and elevated blood pressure.20,21,23,24,25,26,27,29,30,31,35 Two studies have further evaluated the effect of a history of elevated blood pressure on the occurrence of specific retinal signs.36,37 In both studies, generalized retinal arteriolar narrowing and arteriovenous nicking were associated with an elevation in blood pressure that had been documented six to eight years before the retinal assessment; the studies were controlled for concurrent blood-pressure levels. This association suggests that generalized narrowing and arteriovenous nicking are markers of vascular damage from chronic hypertension. In contrast, other signs (focal arteriolar narrowing, retinal hemorrhages, microaneurysms, and cotton-wool spots) were related to current but not previous blood-pressure levels36,37 and may therefore be more indicative of the severity of recent hypertension.
Furthermore, the observation of signs of retinopathy in people without a known history of hypertension suggests that these signs may be markers of a prehypertensive state. For example, generalized and focal narrowing of the retinal arterioles has been shown to predict the risk of hypertension in normotensive persons.38 Other factors unrelated to hypertension (e.g., hyperglycemia,15,22 inflammation, and endothelial dysfunction24) may also be involved in the pathogenesis of retinopathy.
The Risk of Stroke
The strongest evidence of the usefulness of an evaluation of hypertensive retinopathy for risk stratification is based on its association with stroke. It is well known that the retinal circulation shares anatomical, physiological, and embryologic features with the cerebral circulation. An autopsy study of patients with stroke showed a close correlation between retinal and cerebral arteriolar findings.39 Functional alterations in retinal blood flow in patients with lacunar stroke have also been reported.40
Epidemiologic data from four large, population-based studies showed independent associations between signs of hypertensive retinopathy, as defined by the findings on retinal photographs, and the risk of stroke. The Atherosclerosis Risk in Communities study, a multisite cohort study, showed that some signs of retinopathy (e.g., retinal hemorrhages, microaneurysms, and cotton-wool spots) were associated with a risk of newly diagnosed clinical stroke that was two to four times as high as that for patients who did not have these signs, even when the analysis was controlled for the effects of long-term elevations in blood pressure, cigarette smoking, elevated lipid levels, and other risk factors for stroke.41 This study has also shown that signs of retinopathy are associated with reduced cognitive performance on standardized neuropsychological tests,42 cerebral white-matter lesions,43 and cerebral atrophy as defined on the basis of findings on magnetic resonance imaging (MRI).44
In the Atherosclerosis Risk in Communities study, the five-year relative risk of stroke among participants who had both hypertensive retinopathy and cerebral lesions on MRI, as compared with those who had neither of these findings, was 18.1 (95 percent confidence interval, 5.9 to 55.4); among participants who had white-matter lesions only, the relative risk of stroke was 3.4 (95 percent confidence interval, 1.5 to 7.7).43 This pattern appears to reflect more severe or extensive subclinical cerebral microvascular disease in persons with both cerebral and retinal markers of hypertensive end-organ damage. In the Cardiovascular Health Study, after the analysis was controlled for elevated blood pressure and risk factors, persons with similar signs of retinopathy (retinal hemorrhages, microaneurysms, and cotton-wool spots) were twice as likely to have a history of stroke as were those who did not have these signs (odds ratio, 2.0; 95 percent confidence interval, 1.1 to 3.6).25 Population-based studies in Wisconsin45 and in Japan46 have shown that the risks of fatal and nonfatal stroke are two to three times as high in persons with signs of retinopathy as they are in persons who do not have these signs — an association that is independent of cardiovascular risk factors.
These population-based studies also show substantially weaker and less consistent associations between other retinal changes (e.g., generalized and focal narrowing of the arterioles and arteriovenous nicking) and stroke,25,42 death from stroke,45 cognitive impairment,42 and cerebral changes on MRI.43,44 The retinal signs most strongly associated with stroke (i.e., retinal hemorrhages, microaneurysms, and cotton-wool spots) are correlated with a breakdown of the blood–retina barrier.18,19 The association of these signs with stroke may therefore suggest that disruption of the blood–brain barrier is a possible pathophysiological feature in the development of cerebrovascular disease. These findings also support the concept that an assessment of specific signs, rather than the presence or absence of hypertensive retinopathy, may be important for risk stratification.
The Risk of Coronary Heart Disease
There are fewer data regarding the association of hypertensive retinopathy and the risk of coronary heart disease. In the National Health Examination Survey, persons with retinal arteriolar narrowing, as detected on ophthalmoscopy, were two to six times as likely to have preexisting coronary heart disease as those without these changes, after the analysis was controlled for the presence or absence of hypertension and diabetes and for serum cholesterol levels.47 In a study of 560 men with hypertension and hyperlipidemia, the presence of hypertensive retinopathy predicted a doubling of the risk of coronary heart disease (relative risk, 2.1; 95 percent confidence interval, 1.0 to 4.2), and the presence of either generalized or focal narrowing of the arterioles predicted almost a tripling of this risk (relative risk, 2.9; 95 percent confidence interval, 1.3 to 6.2).48 In contrast, the Atherosclerosis Risk in Communities study showed that generalized narrowing of the retinal arterioles was associated with subsequent coronary heart disease in women (relative risk, 2.2; 95 percent confidence interval, 1.0 to 4.6) but not in men (relative risk, 1.1; 95 percent confidence interval, 0.7 to 1.8).49 This finding may reflect the higher risk of coronary microvascular disease among women than among men.
Treatment
Some experimental studies50,51 and clinical trials52,53 have shown that signs of hypertensive retinopathy regress with the control of blood pressure, although spontaneous resolution of these signs in the presence of high blood pressure has also been reported.54 It is unclear whether antihypertensive medications that are thought to have direct beneficial effects on the microvascular structure (e.g., angiotension-converting–enzyme inhibitors) would reduce the damage of retinopathy beyond the reduction effected by lowered blood pressure. In a small study of 28 patients with mild hypertension who were randomly assigned to receive treatment with enalapril or hydrochlorothiazide, opacification of the retinal arteriolar wall was significantly reduced after 26 weeks of treatment with enalapril; no other signs of retinopathy were reduced.53 In contrast, hydrochlorothiazide did not have any effect on the signs of retinopathy. However, to date, there are no data from prospective, controlled trials that demonstrate that the specific reduction of hypertensive retinopathy also reduces the morbidity and mortality associated with cardiovascular disease. It is also unclear whether the targeting of persons with hypertensive retinopathy for established risk-reducing interventions offers additional advantages over the use of strategies without regard to retinal findings.
Future Research
The recent data suggest that there are several lines of future research. First, a standardized classification system for hypertensive retinopathy should be developed that is relevant to contemporary clinical situations and reflects the recent data. Evidence from recent studies supports the development of a photographic classification system that would be similar to the photographic grading of diabetic retinopathy. However, it is not yet clear that retinal photography should be a routine part of the management of hypertension or that photography is superior to ophthalmoscopy for the detection of signs of hypertensive retinopathy.
Second, additional prospective studies are needed that demonstrate independent associations of hypertensive retinopathy with various cardiovascular outcomes. For example, there are no recent studies focusing on whether signs of retinopathy predict other hypertensive complications, such as renal dysfunction or congestive heart failure. It is also unclear whether a retinal examination would confer a greater benefit in specific subgroups of populations (e.g., younger people,45 women,49 and blacks33). An ongoing longitudinal study involving a multiethnic population will provide further insights into these issues.54
Third, it is important to compare the relative value of a retinal assessment (based on an ophthalmoscopic examination performed with or without the use of photography) with other strategies of risk stratification (e.g., the use of electrocardiography and echocardiography). Finally, there is a need to evaluate whether specific therapy that is focused on the retinal microcirculation can reverse changes in retinopathy, and, if so, whether this approach will also ultimately result in a reduced cardiovascular risk.
The Clinical Approach
How should the physician use the available evidence? This review provides compelling evidence that certain signs of hypertensive retinopathy are associated with an increased cardiovascular risk that is independent of other risk factors. On the basis of the strength of these reported associations, we propose a simplified classification of hypertensive retinopathy — none, mild, moderate, and malignant — according to the severity of the retinal signs (Table 1). The physician may continue to provide routine care for patients with no retinopathy, undertake more vigilant monitoring of the cardiovascular risk in patients with mild retinopathy (i.e., those who have retinal arteriolar signs only), or adopt an aggressive approach to risk reduction in patients with moderate retinopathy (Figure 4). The few patients who have swelling of both optic disks and very high blood pressure (i.e., malignant retinopathy) need urgent antihypertensive treatment. In hypertensive patients with swelling of the optic disk, the physician should rule out anterior ischemic optic neuropathy, which occurs more frequently than malignant hypertensive retinopathy and is typically manifested as unilateral disk swelling, visual loss, and defects of the sectorial visual fields.
Table 1. Classification of Hypertensive Retinopathy on the Basis of Recent Population-Based Data.
Figure 4. Evaluation and Management of Hypertensive Retinopathy.
There is insufficient evidence to recommend a routine ophthalmoscopic consultation for all patients with hypertension. If the initial clinical findings are equivocal (e.g., there is borderline or inconsistent hypertension with no other evidence of target-organ damage), an ophthalmoscopic consultation may be useful to supplement the risk assessment and treatment decisions. For some patients (e.g., those with diabetes or visual symptoms), referral may also be important to rule out other conditions such as diabetic retinopathy or retinal-vein occlusion.
Conclusions
Signs of hypertensive retinopathy are common and are correlated with elevated blood pressure. Recent studies show that some of these signs (e.g., retinal hemorrhages, microaneurysms, and cotton-wool spots) predict stroke and death from stroke independently of elevated blood pressure and other risk factors. Patients with these signs of retinopathy may benefit from close monitoring of cerebrovascular risk and intensive measures to reduce that risk.
Source Information
From the Centre for Eye Research Australia, University of Melbourne, East Melbourne, Australia, and the Singapore Eye Research Institute, National University of Singapore, Singapore (T.Y.W.); and the Centre for Vision Research, University of Sydney, Sydney, Australia (P.M.).
Address reprint requests to Dr. Wong at the Centre for Eye Research Australia, University of Melbourne, 32 Gisborne St., East Melbourne 3002, Australia, or at twong@unimelb.edu.au.
References
Walsh JB. Hypertensive retinopathy: description, classification, and prognosis. Ophthalmology 1982;89:1127-1131.
1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999;17:151-183.
Ramsay LE, Williams B, Johnston GD, et al. British Hypertension Society guidelines for hypertension management 1999: summary. BMJ 1999;319:630-635.
August P. Initial treatment of hypertension. N Engl J Med 2003;348:610-617.
The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-2446.
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.
Gunn RM. Ophthalmoscopic evidence of (1) arterial changes associated with chronic renal diseases and (2) of increased arterial tension. Trans Ophthalmol Soc U K 1892;12:124-125.
Scheie HG. Evaluation of ophthalmoscopic changes of hypertension and arteriolar sclerosis. AMA Arch Ophthalmol 1953;49:117-38.
Breslin DJ, Gifford RW Jr, Fairbairn JF II, Kearns TP. Prognostic importance of ophthalmoscopic findings in essential hypertension. JAMA 1966;195:335-338.
Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1939;197:332-343.
Dimmitt SB, West JN, Eames SM, Gibson JM, Gosling P, Littler WA. Usefulness of ophthalmoscopy in mild to moderate hypertension. Lancet 1989;1:1103-1106.
Kagan A, Aureli E, Dobree J. A note on signs in the fundus oculi and arterial hypertension: conventional assessment and significance. Bull World Health Organ 1966;34:955-960.
Dodson PM, Lip GY, Eames SM, Gibson JM, Beevers DG. Hypertensive retinopathy: a review of existing classification systems and a suggestion for a simplified grading system. J Hum Hypertens 1996;10:93-98.
Schubert HD. Ocular manifestations of systemic hypertension. Curr Opin Ophthalmol 1998;9:69-72.
Wong TY, Klein R, Klein BEK, Tielsch JM, Hubbard LD, Nieto FJ. Retinal microvascular abnormalities, and their relationship with hypertension, cardiovascular disease, and mortality. Surv Ophthalmol 2001;46:59-80.
Chatterjee S, Chattopadhyay S, Hope-Ross M, Lip PL, Chattopadhya S. Hypertension and the eye: changing perspectives. J Hum Hypertens 2002;16:667-675.
Fuchs FD, Maestri MK, Bredemeier M, et al. Study of the usefulness of optic fundi examination of patients with hypertension in a clinical setting. J Hum Hypertens 1995;9:547-551.
Pache M, Kube T, Wolf S, Kutschbach P. Do angiographic data support a detailed classification of hypertensive fundus changes? J Hum Hypertens 2002;16:405-410.
Tso MOM, Jampol LM. Pathophysiology of hypertensive retinopathy. Ophthalmology 1982;89:1132-1145.
Klein R, Klein BE, Moss SE, Wang Q. Hypertension and retinopathy, arteriolar narrowing, and arteriovenous nicking in a population. Arch Ophthalmol 1994;112:92-98.
Sharp PS, Chaturvedi N, Wormald R, McKeigue PM, Marmot MG, Young SM. Hypertensive retinopathy in Afro-Caribbeans and Europeans: prevalence and risk factor relationships. Hypertension 1995;25:1322-1325.
Stolk RP, Vingerling JR, de Jong PT, et al. Retinopathy, glucose, and insulin in an elderly population: the Rotterdam Study. Diabetes 1995;44:11-15.
Yu T, Mitchell P, Berry G, Li W, Wang JJ. Retinopathy in older persons without diabetes and its relationship to hypertension. Arch Ophthalmol 1998;116:83-89.
Klein R, Sharrett AR, Klein BEK, et al. Are retinal arteriolar abnormalities related to atherosclerosis? The Atherosclerosis Risk in Communities Study. Arterioscler Thromb Vasc Biol 2000;20:1644-1650.
Wong TY, Klein R, Sharrett AR, et al. The prevalence and risk factors of retinal microvascular abnormalities in older people: the Cardiovascular Health Study. Ophthalmology 2003;110:658-666.
Klein R, Klein BEK, Moss SE. The relation of systemic hypertension to changes in the retinal vasculature: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc 1997;95:329-350.
van Leiden HA, Dekker JM, Moll AC, et al. Risk factors for incident retinopathy in a diabetic and nondiabetic population: the Hoorn study. Arch Ophthalmol 2003;121:245-251.
Couper DJ, Klein R, Hubbard LD, et al. Reliability of retinal photography in the assessment of retinal microvascular characteristics: the Atherosclerosis Risk in Communities Study. Am J Ophthalmol 2002;133:78-88.
Wang JJ, Mitchell P, Leung H, Rochtchina E, Wong TY, Klein R. Hypertensive retinal vessel wall signs in a general older population: the Blue Mountains Eye Study. Hypertension 2003;42:534-541.
Hubbard LD, Brothers RJ, King WN, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology 1999;106:2269-2280.
Wong TY, Klein R, Klein BEK, Meuer SM, Hubbard LD. Retinal vessel diameters and their associations with age and blood pressure. Invest Ophthalmol Vis Sci 2003;44:4644-4650.
Leibowitz HM, Krueger DE, Maunder LR, et al. The Framingham Eye Study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol 1980;24:Suppl:335-610.
Wong TY, Klein R, Duncan BB, et al. Racial differences in the prevalence of hypertensive retinopathy. Hypertension 2003;41:1086-1091.
McDonough JR, Garrison GE, Hames CG. Blood pressure and hypertensive disease among Negroes and whites: a study in Evans County, Georgia. Ann Intern Med 1964;61:208-228.
Houben AJ, Canoy MC, Paling HA, Derhaag PJ, de Leeuw PW. Quantitative analysis of retinal vascular changes in essential and renovascular hypertension. J Hypertens 1995;13:1729-1733.
Sharrett AR, Hubbard LD, Cooper LS, et al. Retinal arteriolar diameters and elevated blood pressure: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 1999;150:263-270.
Wong TY, Hubbard LD, Klein R, et al. Retinal microvascular abnormalities and blood pressure in older people: the Cardiovascular Health Study. Br J Ophthalmol 2002;86:1007-1013.
Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar diameters and risk for hypertension. Ann Intern Med 2004;140:248-255.
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.
Schneider R, Rademacher M, Wolf S. Lacunar infarcts and white matter attenuation: ophthalmologic and microcirculatory aspects of the pathophysiology. Stroke 1993;24:1874-1879.
Wong TY, Klein R, Couper DJ, et al. Retinal microvascular abnormalities and incident strokes: the Atherosclerosis Risk in Communities Study. Lancet 2001;358:1134-1140.
Wong TY, Klein R, Sharrett AR, et al. Retinal microvascular abnormalities and cognitive impairment in middle-aged persons: the Atherosclerosis Risk in Communities Study. Stroke 2002;33:1487-1492.
Wong TY, Klein R, Sharrett AR, et al. Cerebral white matter lesion, retinopathy and incident clinical stroke. JAMA 2002;288:67-74.
Wong TY, Mosley TH Jr, Klein R, et al. Retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middle-aged people. Neurology 2003;61:806-811.
Wong TY, Klein R, Nieto FJ, et al. Retinal microvascular abnormalities and 10-year cardiovascular mortality: a population-based case-control study. Ophthalmology 2003;110:933-940.
Nakayama T, Date C, Yokoyama T, Yoshiike N, Yamaguchi M, Tanaka H. A 15.5-year follow-up study of stroke in a Japanese provincial city: the Shibata Study. Stroke 1997;28:45-52.
Gillum RF. Retinal arteriolar findings and coronary heart disease. Am Heart J 1991;122:262-263.
Duncan BB, Wong TY, Tyroler HA, Davis CE, Fuchs FD. Hypertensive retinopathy and incident coronary heart disease in high risk men. Br J Ophthalmol 2002;86:1002-1006.
Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and women: the Atherosclerosis Risk in Communities Study. JAMA 2002;287:1153-1159.
Hamada Y, Niisato E, Otori T, et al. Ocular fundus changes in malignant or precocious stroke-prone spontaneously hypertensive rats after administration of antihypertensive drugs. Clin Exp Pharmacol Physiol Suppl 1995;22:S132-S133.
Morishita R, Higaki J, Nakamura F, et al. Regression of hypertension-induced vascular hypertrophy by an ACE inhibitor and calcium antagonist in the spontaneously hypertensive rat. Blood Press Suppl 1992;3:41-47.
Bock KD. Regression of retinal vascular changes by antihypertensive therapy. Hypertension 1984;6:III-158.
Dahlof B, Stenkula S, Hansson L. Hypertensive retinal vascular changes: relationship to left ventricular hypertrophy and arteriolar changes before and after treatment. Blood Press 1992;1:35-44.
Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol 2002;156:871-881.(Tien Y. Wong, M.D., Ph.D.)
Despite the JNC recommendation, the clinical implications of hypertensive retinopathy are unclear. Many physicians do not regularly perform an ophthalmoscopic examination as part of the care they provide to hypertensive patients, nor do they include retinal findings when making decisions about treatment. Furthermore, there is no clear consensus regarding the classification of hypertensive retinopathy or whether a retinal examination is useful for risk stratification.
The evidence in support of the JNC guidelines on retinal findings in hypertension is based on earlier studies that may not have direct relevance to current clinical practice.7,8,9,10 These studies have several important limitations. First, because they involved patients who had uncontrolled and untreated hypertension, generalization to contemporary populations of patients with lower blood-pressure levels may be problematic. Second, retinopathy as defined in these studies was based on a direct ophthalmoscopic examination. This technique has been shown to be unreliable, with high rates of interobserver variability (20 to 42 percent) and intraobserver variability (10 to 33 percent) when used in persons with mild hypertension.11,12 Third, although many earlier studies cite increased mortality among persons with hypertensive retinopathy,8,9,10 few studies have demonstrated associations between hypertensive retinopathy and specific cardiovascular outcomes (e.g., incident stroke and coronary heart disease) or have adequately controlled for relevant confounding factors (e.g., hyperlipidemia and cigarette smoking). Thus, whether hypertensive retinopathy predicts the risk of cardiovascular outcomes independently of other risk indicators has not been examined until recently. The purpose of this review is to appraise recent studies (i.e., from 1990 onward) in regard to the pathophysiology, epidemiology, and cardiovascular associations of hypertensive retinopathy and the evidence that supports its use for risk stratification in persons with hypertension.
Historical Context and Classification
Hypertensive retinopathy was first described by Marcus Gunn in the 19th century in a series of patients with hypertension and renal disease.7 The retinal signs he observed included generalized and focal arteriolar narrowing, arteriovenous nicking, flame-shaped and blot-shaped retinal hemorrhages, cotton-wool spots, and swelling of the optic disk (Figure 1, Figure 2, and Figure 3). In 1939, Keith et al. showed that these signs of retinopathy were predictive of death in patients with hypertension.10 The authors described a widely used classification system that categorized these signs into four groups of increasing severity.
Figure 1. Examples of Mild Hypertensive Retinopathy.
Panel A shows arteriovenous nicking (black arrow) and focal narrowing (white arrow). Panel B shows arteriovenous nicking (black arrows) and widening or accentuation ("copper wiring") of the central light reflex of the arterioles (white arrows).
Figure 2. Examples of Moderate Hypertensive Retinopathy.
Panel A shows retinal hemorrhages (black arrows) and a cotton-wool spot (white arrow). Panel B shows cotton-wool spots (white arrows) and arteriovenous nicking (black arrows).
Figure 3. Example of Malignant Hypertensive Retinopathy.
Multiple cotton-wool spots (white arrows), retinal hemorrhages (black arrows), and swelling of the optic disk are visible.
However, several reviews of hypertensive retinopathy since 199613,14,15,16 have questioned the usefulness of the classification system by Keith et al. (subsequently modified by Scheie8) and its relevance to current clinical practice. The major criticisms of the original and modified classifications are that they do not enable the clinician to distinguish among low retinopathy grades (e.g., grade 1 signs are not easily distinguished from grade 2 signs) and that the retinopathy grades are not closely correlated with the severity of hypertension.17 Furthermore, a detailed categorization of retinopathy into four grades does not appear to be supported by retinal studies with the use of fluorescein angiography.18
Pathophysiology
The retinal circulation undergoes a series of pathophysiological changes in response to elevated blood pressure.19 In the initial, vasoconstrictive stage, there is vasospasm and an increase in retinal arteriolar tone owing to local autoregulatory mechanisms. This stage is seen clinically as a generalized narrowing of the retinal arterioles. Persistently elevated blood pressure leads to intimal thickening, hyperplasia of the media wall, and hyaline degeneration in the subsequent, sclerotic, stage. This stage corresponds to more severe generalized and focal areas of arteriolar narrowing, changes in the arteriolar and venular junctions (i.e., arteriovenous nicking or nipping), and alterations in the arteriolar light reflex (i.e., widening and accentuation of the central light reflex, or "copper wiring").
This is followed by an exudative stage, in which there is disruption of the blood–retina barrier, necrosis of the smooth muscles and endothelial cells, exudation of blood and lipids, and retinal ischemia. These changes are manifested in the retina as microaneurysms, hemorrhages, hard exudates, and cotton-wool spots. Swelling of the optic disk may occur at this time and usually indicates severely elevated blood pressure (i.e., malignant hypertension). Because better methods for the control of blood pressure are now available in the general population, malignant hypertension is rarely seen. In contrast, other retinal vascular complications of hypertension, such as macroaneurysms and branch-vein occlusions, are not uncommon in patients with chronically elevated blood pressure. The stages of hypertensive retinopathy described here, however, may not be sequential.18,19 For example, signs of retinopathy that reflect the exudative stage, such as retinal hemorrhage or microaneurysm, may be seen in eyes that do not have features of the sclerotic stage (e.g., arteriovenous nicking).19 The exudative signs are nonspecific, since they are seen in diabetes and other conditions.
Epidemiology
Since 1990, there have been seven population-based epidemiologic studies (involving a total of 26,477 participants) of various signs of hypertensive retinopathy.20,21,22,23,24,25,26,27 In all seven studies, retinal photographs were used to define specific signs of retinopathy without regard to a predetermined grading system. All of the studies were conducted in the general community and included persons with and those without a history of hypertension.
In general, these studies show that signs of hypertensive retinopathy can be reliably identified with a standardized examination of photographs of the fundus. Reproducibility was substantial for the grading of retinal hemorrhages and microaneurysms (e.g., =0.80 to 0.99) and fair to moderate for the grading of arteriovenous nicking and focal arteriolar narrowing (=0.40 to 0.79).25,28 In four populations, generalized arteriolar narrowing was estimated from an assessment of retinal vessel diameters with the use of digitized photographs.25,28,29,30,31 This technique appears to have substantial reproducibility (i.e., the intraclass correlation coefficient ranged from 0.80 to 0.99 in four studies).25,28,29,30,31
On the basis of photographic grading, these epidemiologic studies show that signs of hypertensive retinopathy are common in people 40 years of age or older, even in those without a history of hypertension. Prevalence rates ranged from 2 to 15 percent for various signs of retinopathy,20,21,22,23,24,25 in contrast to the earlier report from the Framingham Eye Study that found a prevalence of less than 1 percent among participants who underwent an ophthalmoscopic examination with dilation.32 The higher rates of prevalence in these more recent studies are probably due to a higher sensitivity of photography, as compared with clinical ophthalmoscopy, for detecting certain signs of retinopathy. However, there have been no studies that have directly compared the sensitivity or reliability of photography with that of ophthalmoscopy for the detection of hypertensive retinopathy, as there have been for diabetic retinopathy.
A higher prevalence of retinopathy has been reported among black persons than among whites, a difference that is explained in large part by the higher levels of blood pressure among blacks.21,33 The racial variation confirms the results of a previous population-based survey that used direct ophthalmoscopy34 and suggests that retinal examination may be particularly useful for risk stratification among blacks. Variations in the prevalence of specific signs of hypertensive retinopathy according to age and sex have not been consistently demonstrated.20,21,22,23,24,25 There have been fewer studies of the incidence of hypertensive retinopathy. Two studies indicate that the incidence of various signs of retinopathy over a period of five to seven years ranges from 6 to 10 percent.26,27
Blood Pressure
Numerous studies have confirmed the strong association between the presence of signs of hypertensive retinopathy and elevated blood pressure.20,21,23,24,25,26,27,29,30,31,35 Two studies have further evaluated the effect of a history of elevated blood pressure on the occurrence of specific retinal signs.36,37 In both studies, generalized retinal arteriolar narrowing and arteriovenous nicking were associated with an elevation in blood pressure that had been documented six to eight years before the retinal assessment; the studies were controlled for concurrent blood-pressure levels. This association suggests that generalized narrowing and arteriovenous nicking are markers of vascular damage from chronic hypertension. In contrast, other signs (focal arteriolar narrowing, retinal hemorrhages, microaneurysms, and cotton-wool spots) were related to current but not previous blood-pressure levels36,37 and may therefore be more indicative of the severity of recent hypertension.
Furthermore, the observation of signs of retinopathy in people without a known history of hypertension suggests that these signs may be markers of a prehypertensive state. For example, generalized and focal narrowing of the retinal arterioles has been shown to predict the risk of hypertension in normotensive persons.38 Other factors unrelated to hypertension (e.g., hyperglycemia,15,22 inflammation, and endothelial dysfunction24) may also be involved in the pathogenesis of retinopathy.
The Risk of Stroke
The strongest evidence of the usefulness of an evaluation of hypertensive retinopathy for risk stratification is based on its association with stroke. It is well known that the retinal circulation shares anatomical, physiological, and embryologic features with the cerebral circulation. An autopsy study of patients with stroke showed a close correlation between retinal and cerebral arteriolar findings.39 Functional alterations in retinal blood flow in patients with lacunar stroke have also been reported.40
Epidemiologic data from four large, population-based studies showed independent associations between signs of hypertensive retinopathy, as defined by the findings on retinal photographs, and the risk of stroke. The Atherosclerosis Risk in Communities study, a multisite cohort study, showed that some signs of retinopathy (e.g., retinal hemorrhages, microaneurysms, and cotton-wool spots) were associated with a risk of newly diagnosed clinical stroke that was two to four times as high as that for patients who did not have these signs, even when the analysis was controlled for the effects of long-term elevations in blood pressure, cigarette smoking, elevated lipid levels, and other risk factors for stroke.41 This study has also shown that signs of retinopathy are associated with reduced cognitive performance on standardized neuropsychological tests,42 cerebral white-matter lesions,43 and cerebral atrophy as defined on the basis of findings on magnetic resonance imaging (MRI).44
In the Atherosclerosis Risk in Communities study, the five-year relative risk of stroke among participants who had both hypertensive retinopathy and cerebral lesions on MRI, as compared with those who had neither of these findings, was 18.1 (95 percent confidence interval, 5.9 to 55.4); among participants who had white-matter lesions only, the relative risk of stroke was 3.4 (95 percent confidence interval, 1.5 to 7.7).43 This pattern appears to reflect more severe or extensive subclinical cerebral microvascular disease in persons with both cerebral and retinal markers of hypertensive end-organ damage. In the Cardiovascular Health Study, after the analysis was controlled for elevated blood pressure and risk factors, persons with similar signs of retinopathy (retinal hemorrhages, microaneurysms, and cotton-wool spots) were twice as likely to have a history of stroke as were those who did not have these signs (odds ratio, 2.0; 95 percent confidence interval, 1.1 to 3.6).25 Population-based studies in Wisconsin45 and in Japan46 have shown that the risks of fatal and nonfatal stroke are two to three times as high in persons with signs of retinopathy as they are in persons who do not have these signs — an association that is independent of cardiovascular risk factors.
These population-based studies also show substantially weaker and less consistent associations between other retinal changes (e.g., generalized and focal narrowing of the arterioles and arteriovenous nicking) and stroke,25,42 death from stroke,45 cognitive impairment,42 and cerebral changes on MRI.43,44 The retinal signs most strongly associated with stroke (i.e., retinal hemorrhages, microaneurysms, and cotton-wool spots) are correlated with a breakdown of the blood–retina barrier.18,19 The association of these signs with stroke may therefore suggest that disruption of the blood–brain barrier is a possible pathophysiological feature in the development of cerebrovascular disease. These findings also support the concept that an assessment of specific signs, rather than the presence or absence of hypertensive retinopathy, may be important for risk stratification.
The Risk of Coronary Heart Disease
There are fewer data regarding the association of hypertensive retinopathy and the risk of coronary heart disease. In the National Health Examination Survey, persons with retinal arteriolar narrowing, as detected on ophthalmoscopy, were two to six times as likely to have preexisting coronary heart disease as those without these changes, after the analysis was controlled for the presence or absence of hypertension and diabetes and for serum cholesterol levels.47 In a study of 560 men with hypertension and hyperlipidemia, the presence of hypertensive retinopathy predicted a doubling of the risk of coronary heart disease (relative risk, 2.1; 95 percent confidence interval, 1.0 to 4.2), and the presence of either generalized or focal narrowing of the arterioles predicted almost a tripling of this risk (relative risk, 2.9; 95 percent confidence interval, 1.3 to 6.2).48 In contrast, the Atherosclerosis Risk in Communities study showed that generalized narrowing of the retinal arterioles was associated with subsequent coronary heart disease in women (relative risk, 2.2; 95 percent confidence interval, 1.0 to 4.6) but not in men (relative risk, 1.1; 95 percent confidence interval, 0.7 to 1.8).49 This finding may reflect the higher risk of coronary microvascular disease among women than among men.
Treatment
Some experimental studies50,51 and clinical trials52,53 have shown that signs of hypertensive retinopathy regress with the control of blood pressure, although spontaneous resolution of these signs in the presence of high blood pressure has also been reported.54 It is unclear whether antihypertensive medications that are thought to have direct beneficial effects on the microvascular structure (e.g., angiotension-converting–enzyme inhibitors) would reduce the damage of retinopathy beyond the reduction effected by lowered blood pressure. In a small study of 28 patients with mild hypertension who were randomly assigned to receive treatment with enalapril or hydrochlorothiazide, opacification of the retinal arteriolar wall was significantly reduced after 26 weeks of treatment with enalapril; no other signs of retinopathy were reduced.53 In contrast, hydrochlorothiazide did not have any effect on the signs of retinopathy. However, to date, there are no data from prospective, controlled trials that demonstrate that the specific reduction of hypertensive retinopathy also reduces the morbidity and mortality associated with cardiovascular disease. It is also unclear whether the targeting of persons with hypertensive retinopathy for established risk-reducing interventions offers additional advantages over the use of strategies without regard to retinal findings.
Future Research
The recent data suggest that there are several lines of future research. First, a standardized classification system for hypertensive retinopathy should be developed that is relevant to contemporary clinical situations and reflects the recent data. Evidence from recent studies supports the development of a photographic classification system that would be similar to the photographic grading of diabetic retinopathy. However, it is not yet clear that retinal photography should be a routine part of the management of hypertension or that photography is superior to ophthalmoscopy for the detection of signs of hypertensive retinopathy.
Second, additional prospective studies are needed that demonstrate independent associations of hypertensive retinopathy with various cardiovascular outcomes. For example, there are no recent studies focusing on whether signs of retinopathy predict other hypertensive complications, such as renal dysfunction or congestive heart failure. It is also unclear whether a retinal examination would confer a greater benefit in specific subgroups of populations (e.g., younger people,45 women,49 and blacks33). An ongoing longitudinal study involving a multiethnic population will provide further insights into these issues.54
Third, it is important to compare the relative value of a retinal assessment (based on an ophthalmoscopic examination performed with or without the use of photography) with other strategies of risk stratification (e.g., the use of electrocardiography and echocardiography). Finally, there is a need to evaluate whether specific therapy that is focused on the retinal microcirculation can reverse changes in retinopathy, and, if so, whether this approach will also ultimately result in a reduced cardiovascular risk.
The Clinical Approach
How should the physician use the available evidence? This review provides compelling evidence that certain signs of hypertensive retinopathy are associated with an increased cardiovascular risk that is independent of other risk factors. On the basis of the strength of these reported associations, we propose a simplified classification of hypertensive retinopathy — none, mild, moderate, and malignant — according to the severity of the retinal signs (Table 1). The physician may continue to provide routine care for patients with no retinopathy, undertake more vigilant monitoring of the cardiovascular risk in patients with mild retinopathy (i.e., those who have retinal arteriolar signs only), or adopt an aggressive approach to risk reduction in patients with moderate retinopathy (Figure 4). The few patients who have swelling of both optic disks and very high blood pressure (i.e., malignant retinopathy) need urgent antihypertensive treatment. In hypertensive patients with swelling of the optic disk, the physician should rule out anterior ischemic optic neuropathy, which occurs more frequently than malignant hypertensive retinopathy and is typically manifested as unilateral disk swelling, visual loss, and defects of the sectorial visual fields.
Table 1. Classification of Hypertensive Retinopathy on the Basis of Recent Population-Based Data.
Figure 4. Evaluation and Management of Hypertensive Retinopathy.
There is insufficient evidence to recommend a routine ophthalmoscopic consultation for all patients with hypertension. If the initial clinical findings are equivocal (e.g., there is borderline or inconsistent hypertension with no other evidence of target-organ damage), an ophthalmoscopic consultation may be useful to supplement the risk assessment and treatment decisions. For some patients (e.g., those with diabetes or visual symptoms), referral may also be important to rule out other conditions such as diabetic retinopathy or retinal-vein occlusion.
Conclusions
Signs of hypertensive retinopathy are common and are correlated with elevated blood pressure. Recent studies show that some of these signs (e.g., retinal hemorrhages, microaneurysms, and cotton-wool spots) predict stroke and death from stroke independently of elevated blood pressure and other risk factors. Patients with these signs of retinopathy may benefit from close monitoring of cerebrovascular risk and intensive measures to reduce that risk.
Source Information
From the Centre for Eye Research Australia, University of Melbourne, East Melbourne, Australia, and the Singapore Eye Research Institute, National University of Singapore, Singapore (T.Y.W.); and the Centre for Vision Research, University of Sydney, Sydney, Australia (P.M.).
Address reprint requests to Dr. Wong at the Centre for Eye Research Australia, University of Melbourne, 32 Gisborne St., East Melbourne 3002, Australia, or at twong@unimelb.edu.au.
References
Walsh JB. Hypertensive retinopathy: description, classification, and prognosis. Ophthalmology 1982;89:1127-1131.
1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens 1999;17:151-183.
Ramsay LE, Williams B, Johnston GD, et al. British Hypertension Society guidelines for hypertension management 1999: summary. BMJ 1999;319:630-635.
August P. Initial treatment of hypertension. N Engl J Med 2003;348:610-617.
The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-2446.
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.
Gunn RM. Ophthalmoscopic evidence of (1) arterial changes associated with chronic renal diseases and (2) of increased arterial tension. Trans Ophthalmol Soc U K 1892;12:124-125.
Scheie HG. Evaluation of ophthalmoscopic changes of hypertension and arteriolar sclerosis. AMA Arch Ophthalmol 1953;49:117-38.
Breslin DJ, Gifford RW Jr, Fairbairn JF II, Kearns TP. Prognostic importance of ophthalmoscopic findings in essential hypertension. JAMA 1966;195:335-338.
Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1939;197:332-343.
Dimmitt SB, West JN, Eames SM, Gibson JM, Gosling P, Littler WA. Usefulness of ophthalmoscopy in mild to moderate hypertension. Lancet 1989;1:1103-1106.
Kagan A, Aureli E, Dobree J. A note on signs in the fundus oculi and arterial hypertension: conventional assessment and significance. Bull World Health Organ 1966;34:955-960.
Dodson PM, Lip GY, Eames SM, Gibson JM, Beevers DG. Hypertensive retinopathy: a review of existing classification systems and a suggestion for a simplified grading system. J Hum Hypertens 1996;10:93-98.
Schubert HD. Ocular manifestations of systemic hypertension. Curr Opin Ophthalmol 1998;9:69-72.
Wong TY, Klein R, Klein BEK, Tielsch JM, Hubbard LD, Nieto FJ. Retinal microvascular abnormalities, and their relationship with hypertension, cardiovascular disease, and mortality. Surv Ophthalmol 2001;46:59-80.
Chatterjee S, Chattopadhyay S, Hope-Ross M, Lip PL, Chattopadhya S. Hypertension and the eye: changing perspectives. J Hum Hypertens 2002;16:667-675.
Fuchs FD, Maestri MK, Bredemeier M, et al. Study of the usefulness of optic fundi examination of patients with hypertension in a clinical setting. J Hum Hypertens 1995;9:547-551.
Pache M, Kube T, Wolf S, Kutschbach P. Do angiographic data support a detailed classification of hypertensive fundus changes? J Hum Hypertens 2002;16:405-410.
Tso MOM, Jampol LM. Pathophysiology of hypertensive retinopathy. Ophthalmology 1982;89:1132-1145.
Klein R, Klein BE, Moss SE, Wang Q. Hypertension and retinopathy, arteriolar narrowing, and arteriovenous nicking in a population. Arch Ophthalmol 1994;112:92-98.
Sharp PS, Chaturvedi N, Wormald R, McKeigue PM, Marmot MG, Young SM. Hypertensive retinopathy in Afro-Caribbeans and Europeans: prevalence and risk factor relationships. Hypertension 1995;25:1322-1325.
Stolk RP, Vingerling JR, de Jong PT, et al. Retinopathy, glucose, and insulin in an elderly population: the Rotterdam Study. Diabetes 1995;44:11-15.
Yu T, Mitchell P, Berry G, Li W, Wang JJ. Retinopathy in older persons without diabetes and its relationship to hypertension. Arch Ophthalmol 1998;116:83-89.
Klein R, Sharrett AR, Klein BEK, et al. Are retinal arteriolar abnormalities related to atherosclerosis? The Atherosclerosis Risk in Communities Study. Arterioscler Thromb Vasc Biol 2000;20:1644-1650.
Wong TY, Klein R, Sharrett AR, et al. The prevalence and risk factors of retinal microvascular abnormalities in older people: the Cardiovascular Health Study. Ophthalmology 2003;110:658-666.
Klein R, Klein BEK, Moss SE. The relation of systemic hypertension to changes in the retinal vasculature: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc 1997;95:329-350.
van Leiden HA, Dekker JM, Moll AC, et al. Risk factors for incident retinopathy in a diabetic and nondiabetic population: the Hoorn study. Arch Ophthalmol 2003;121:245-251.
Couper DJ, Klein R, Hubbard LD, et al. Reliability of retinal photography in the assessment of retinal microvascular characteristics: the Atherosclerosis Risk in Communities Study. Am J Ophthalmol 2002;133:78-88.
Wang JJ, Mitchell P, Leung H, Rochtchina E, Wong TY, Klein R. Hypertensive retinal vessel wall signs in a general older population: the Blue Mountains Eye Study. Hypertension 2003;42:534-541.
Hubbard LD, Brothers RJ, King WN, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology 1999;106:2269-2280.
Wong TY, Klein R, Klein BEK, Meuer SM, Hubbard LD. Retinal vessel diameters and their associations with age and blood pressure. Invest Ophthalmol Vis Sci 2003;44:4644-4650.
Leibowitz HM, Krueger DE, Maunder LR, et al. The Framingham Eye Study monograph: an ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol 1980;24:Suppl:335-610.
Wong TY, Klein R, Duncan BB, et al. Racial differences in the prevalence of hypertensive retinopathy. Hypertension 2003;41:1086-1091.
McDonough JR, Garrison GE, Hames CG. Blood pressure and hypertensive disease among Negroes and whites: a study in Evans County, Georgia. Ann Intern Med 1964;61:208-228.
Houben AJ, Canoy MC, Paling HA, Derhaag PJ, de Leeuw PW. Quantitative analysis of retinal vascular changes in essential and renovascular hypertension. J Hypertens 1995;13:1729-1733.
Sharrett AR, Hubbard LD, Cooper LS, et al. Retinal arteriolar diameters and elevated blood pressure: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 1999;150:263-270.
Wong TY, Hubbard LD, Klein R, et al. Retinal microvascular abnormalities and blood pressure in older people: the Cardiovascular Health Study. Br J Ophthalmol 2002;86:1007-1013.
Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar diameters and risk for hypertension. Ann Intern Med 2004;140:248-255.
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.
Schneider R, Rademacher M, Wolf S. Lacunar infarcts and white matter attenuation: ophthalmologic and microcirculatory aspects of the pathophysiology. Stroke 1993;24:1874-1879.
Wong TY, Klein R, Couper DJ, et al. Retinal microvascular abnormalities and incident strokes: the Atherosclerosis Risk in Communities Study. Lancet 2001;358:1134-1140.
Wong TY, Klein R, Sharrett AR, et al. Retinal microvascular abnormalities and cognitive impairment in middle-aged persons: the Atherosclerosis Risk in Communities Study. Stroke 2002;33:1487-1492.
Wong TY, Klein R, Sharrett AR, et al. Cerebral white matter lesion, retinopathy and incident clinical stroke. JAMA 2002;288:67-74.
Wong TY, Mosley TH Jr, Klein R, et al. Retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middle-aged people. Neurology 2003;61:806-811.
Wong TY, Klein R, Nieto FJ, et al. Retinal microvascular abnormalities and 10-year cardiovascular mortality: a population-based case-control study. Ophthalmology 2003;110:933-940.
Nakayama T, Date C, Yokoyama T, Yoshiike N, Yamaguchi M, Tanaka H. A 15.5-year follow-up study of stroke in a Japanese provincial city: the Shibata Study. Stroke 1997;28:45-52.
Gillum RF. Retinal arteriolar findings and coronary heart disease. Am Heart J 1991;122:262-263.
Duncan BB, Wong TY, Tyroler HA, Davis CE, Fuchs FD. Hypertensive retinopathy and incident coronary heart disease in high risk men. Br J Ophthalmol 2002;86:1002-1006.
Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and women: the Atherosclerosis Risk in Communities Study. JAMA 2002;287:1153-1159.
Hamada Y, Niisato E, Otori T, et al. Ocular fundus changes in malignant or precocious stroke-prone spontaneously hypertensive rats after administration of antihypertensive drugs. Clin Exp Pharmacol Physiol Suppl 1995;22:S132-S133.
Morishita R, Higaki J, Nakamura F, et al. Regression of hypertension-induced vascular hypertrophy by an ACE inhibitor and calcium antagonist in the spontaneously hypertensive rat. Blood Press Suppl 1992;3:41-47.
Bock KD. Regression of retinal vascular changes by antihypertensive therapy. Hypertension 1984;6:III-158.
Dahlof B, Stenkula S, Hansson L. Hypertensive retinal vascular changes: relationship to left ventricular hypertrophy and arteriolar changes before and after treatment. Blood Press 1992;1:35-44.
Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol 2002;156:871-881.(Tien Y. Wong, M.D., Ph.D.)