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Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

Background: Microvascular changes have been associated with the metabolic syndrome., Methods: We included 869 participants aged ≥ 40 years from the High-risk for Diabetes Changfeng Study, who had gradable fundus photographs. On digital photographs sum retinal arteriolar and venular calibers were measured with a semi-automated system. Metabolic syndrome was defined according to the International Diabetes Federation consensus., Results: A total of 286 (32.9%) participants was diagnosed with metabolic syndrome. Participants with narrower retinal arteriolar caliber were more often diagnosed with metabolic syndrome (odds ratio 1.78, 95% confidence interval 1.02 – 3.10; lowest vs highest quintile). Additionally adjusting for age, gender, education, smoking and weekly activity, and adding arteriolar and venular caliber simultaneously in the same models did not alter these associations. In the component analyses, participants with narrower retinal arteriolar caliber were more likely to have central obesity, dyslipidaemia or raised blood pressure, and less likely to have raised fasting plasma glucose. The association between wider venular caliber and metabolic syndrome was less pronounced and non-significant (odds ratio 1.34; 95% confidence interval 0.79 – 2.38; highest vs lowest quintile)., Conclusion: Retinal arteriolar narrowing and, to a lesser extent, retinal venular dilatation were associated with metabolic syndrome in this Chinese population. These vascular changes, although small in magnitude, may still be important in the pathophysiological mechanisms involved in the metabolic syndrome.

Background: Retinal vessels provide a unique opportunity to study both systemic and cerebrovascular disease. Smaller retinal arteriolar calibers are strongly related to hypertension, whereas larger retinal venular calibers are more related to inflammation, cerebral hypoperfusion, and cerebrovascular disease. Whether retinal vessel calibers are related to dementia remains unclear., Methods: We investigated whether retinal arteriolar and venular calibers are associated with risk of dementia, and its subtypes Alzheimer disease (AD) and vascular dementia, in the prospective population-based Rotterdam Study. Digitized retinal images were available in 5,553 participants aged 55 years or over and dementia-free at baseline (1990-1993). Participants were re-examined in 1993-1994, 1997-1999, and 2002-2004 and were continuously monitored for development of dementia., Results: During a mean follow-up of 11.6 years, 655 participants developed dementia. AD was diagnosed in 519 and vascular dementia in 73 participants. Larger venular calibers were associated with an increased risk of dementia, in particular vascular dementia (age- and sex-adjusted hazard ratio per SD increase: 1.31; 95% confidence interval 1.06-1.64), but not AD. The association remained significant after adjustment for stroke and cardiovascular risk factors. Smaller arteriolar calibers were also associated with an increased risk of vascular dementia, yet only when adjusted for venular calibers., Conclusions: Retinal venular widening is associated with an increased risk of vascular dementia. Our findings are in line with previous observations in stroke and cerebral small-vessel disease and suggest that the association between larger retinal venular calibers and dementia may reflect cerebral hypoperfusion and subsequent ischemia.

Background and Purpose: Narrower retinal arteriolar calibers and wider venular calibers are associated with cardiovascular disease, including cerebral infarction. We investigated the association between retinal vascular calibers and the long-term risk for stroke and its subtypes with particular focus on intracerebral hemorrhage., Methods: We included 5518 participants (aged ≥ 55 years) from the prospective population-based Rotterdam Study who were stroke-free at baseline (1990-1993) and of whom digital retinal images were available. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally for potential confounders. Arteriolar and venular calibers were entered both separately and simultaneously in the models., Results: During an average follow-up of 11.5 years, 623 participants developed a first-ever stroke (50 hemorrhagic, 361 ischemic, 212 unspecified). Larger venular caliber was independently associated with an increased risk for stroke (hazard ratio [HR] per SD increase: 1.20; 95% confidence interval [CI]: 1.09 to 1.33), cerebral infarction (HR: 1.28; 95% CI: 1.13 to 1.46), and intracerebral hemorrhage (HR: 1.53; 95% CI: 1.09 to 2.15). Much weaker, only borderline significant associations were found between arteriolar caliber and risk for stroke (HR per SD decrease: 1.12; 95% CI: 0.99 to 1.23), cerebral infarction (HR: 1.12; 95% CI, 0.98 to 1.27), and intracerebral hemorrhage (HR: 1.25; 95% CI: 0.87 to 1.79). Retinal vascular calibers were strongly associated with lobar hemorrhages and oral anticoagulant-related hemorrhages., Conclusions: Larger retinal venular caliber is associated with an increased risk for stroke in the general population and, in particular, with an increased risk for intracerebral hemorrhage.

Objectives: To test the "vascular depression" hypothesis, the authors investigated whether smaller retinal arteriolar or larger venular calibers, which are markers of cerebral microvascular disease, were associated with incident late-life depression., Methods: The authors included 3,605 participants (age > or =55 years) from the population-based Rotterdam Study with no depression at baseline (1993-1995) and fundus photographs gradable for retinal vascular caliber measurements. The authors identified persons with incident depressive symptoms and syndromes using psychiatric interviews during follow-up visits and continuous monitoring. The follow-up was complete until October 2005., Results: After a mean follow-up of 9.0 years, 555 participants developed incident depression, including 312 with depressive syndrome. Neither smaller arteriolar (age- and sex-adjusted hazard ratio: 1.01; 95% confidence interval: 0.93-1.10), nor larger venular calibers (hazard ratio: 1.02; 95% confidence interval: 0.94-1.12) were associated with incident depressive syndromes., Conclusions: Our data showed no evidence of an association between retinal vascular calibers and incident late-life depression.

The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5-12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95% confidence interval: 1.05, 1.25 per 20-micron increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.

Background: Retinal vessel caliber may be a novel marker of coronary heart disease (CHD) risk. However, the sex-specific effect, magnitude of association, and effect independent of traditional CHD disease risk factors remain unclear., Purpose: To determine the association between retinal vessel caliber and risk for CHD., Data Sources: Relevant studies in any language identified through MEDLINE (1950 to June 2009) and EMBASE (1950 to June 2009) databases., Study Selection: Studies were included if they examined a general population, measured retinal vessel caliber from retinal photographs, and documented CHD risk factors and incident CHD events., Data Extraction: 6 population-based prospective cohort studies provided data for individual participant meta-analysis., Data Synthesis: Proportional hazards models, adjusted for traditional CHD risk factors, were constructed for retinal vessel caliber and incident CHD in women and men. Among 22,159 participants who were free of CHD and followed for 5 to 14 years, 2219 (10.0%) incident CHD events occurred. Retinal vessel caliber changes (wider venules and narrower arterioles) were each associated with an increased risk for CHD in women (pooled multivariable-adjusted hazard ratios, 1.16 [95% CI, 1.06 to 1.26] per 20-microm increase in venular caliber and 1.17 [CI, 1.07 to 1.28] per 20-microm decrease in arteriolar caliber) but not in men (1.02 [CI, 0.94 to 1.10] per 20-microm increase in venular caliber and 1.02 [CI, 0.95 to 1.10] per 20-microm decrease in arteriolar caliber). Women without hypertension or diabetes had higher hazard ratios., Limitation: Error in the measurement of retinal vessel caliber and Framingham variables was not taken into account., Conclusion: Retinal vessel caliber changes were independently associated with an increased risk for CHD events in women.

Background: Retinal vessels may provide information on cerebral vascular pathology, because they share many features with cerebral vessels. A smaller ratio of the retinal arteriolar-to-venular diameters reportedly predicts the risk of stroke. It is unclear if this is due to arteriolar narrowing or venular dilation., Objective: To investigate whether smaller arteriolar or larger venular diameters are related to the risk of stroke and cerebral infarction., Methods: This study was based on the prospective population-based Rotterdam Study and included 5,540 participants of 55 years or over, who had gradable fundus transparencies and were free of stroke at baseline (1990 to 1993). For each participant, retinal arteriolar and venular diameters were measured on digitized images of one eye. Follow-up for first-ever stroke was complete until January 1, 2002., Results: After a mean follow-up of 8.5 years, 411 participants had a stroke, of whom 259 had cerebral infarction. Larger venular diameters were associated with an increased risk of stroke (hazard ratio [HR] adjusted for age and sex per SD increase: 1.12 [95% CI: 1.02 to 1.24]) and cerebral infarction (HR: 1.15 [95% CI: 1.02 to 1.29]). Smaller arteriolar diameters were neither related to the risk of stroke (HR per SD decrease: 1.02 [95% CI: 0.93 to 1.13]) nor to the risk of cerebral infarction (HR: 1.02 [95% CI: 0.90 to 1.15]). After additional adjustment for other cardiovascular risk factors, the results did not change., Conclusions: Larger retinal venular diameters are associated with an increased risk of stroke and cerebral infarction. The role of venules in cerebrovascular disease warrants further exploration.

Generalized retinal arteriolar narrowing is an important sign of systemic hypertension, and a lower arteriolar:venular diameter ratio predicts the risk of hypertension. We investigated whether this association was based on arteriolar or venular diameters or both. This study was based on the prospective population-based Rotterdam Study (1990-1993) and included 1900 participants (> or =55 years of age) of whom 739 persons had normal blood pressure (systolic <120 mm Hg and diastolic <80 mm Hg) and 1161 prehypertension (systolic 120 to 139 mm Hg or diastolic 80 to 89 mm Hg). For each participant, retinal arteriolar and venular diameters were measured on digitized images of 1 eye. After a mean follow-up of 6.6 years, 808 persons developed hypertension, defined as either systolic blood pressure > or =140 mm Hg or diastolic blood pressure > or =90 mm Hg or use of antihypertensive medication. Adjusted for age, gender, follow-up time, body mass index, smoking, diabetes mellitus, total and high-density lipoprotein cholesterol, C-reactive protein, and intima-media thickness, arteriolar narrowing was associated with an increased risk of hypertension (odds ratio per SD: 1.38; 95% CI, 1.23 to 1.55); for venular narrowing this was less striking (OR: 1.17; 95% CI, 1.04 to 1.32). Each SD decrease in the arteriolar:venular diameter ratio significantly increased the risk of hypertension by 24%. To examine the effect of baseline blood pressure, we stratified persons into those with "normal blood pressure" or "prehypertension." Within these strata, arteriolar narrowing was still related to incident hypertension. These data show that both retinal arteriolar and venular narrowing may precede the development of systemic hypertension.

Purpose: To study the relationship between retinal vessel diameters and incident age-related macular disease (iAMD)., Design: Prospective population-based cohort study., Participants: Persons (55 years and older) from the Rotterdam Study, who participated at the baseline (1990-1993) and 1 of 2 follow-up examinations (1993-1994 and 1997-1999)., Methods: In the current analysis, 4345 participants who were free of AMD at baseline and had gradable macular transparencies at both baseline and follow-up examination were included. Also, arteriolar and venular diameters were measured on digitized baseline images. Stereoscopic transparencies of the macular region were graded according to the International Classification and Grading System for AMD. Incidence of AMD was defined as the development of soft distinct drusen with pigmentary changes or indistinct or reticular drusen with or without pigmentary changes (early iAMD) or atrophic or neovascular AMD (late iAMD). Logistic regression models were used to assess these associations, adjusting for age, gender, and follow-up time and, additionally, for smoking, body mass index, intima-media thickness, systolic blood pressure, and total and high-density lipoprotein cholesterol levels., Main Outcome Measure: Incidence of AMD., Results: After a mean follow-up time of 5.2 years, a total of 374 persons developed early and late iAMD. Neither arteriolar nor venular diameters were related to the risk of iAMD. The odds ratio (OR) per standard deviation (SD) decrease in arteriolar diameter was 1.03 (95% confidence interval [CI], 0.93-1.15), and the OR per SD increase in venular diameter was 1.04 (95% CI, 0.93-1.16). After categorizing the retinal vessel diameters into quintiles, there was no trend. After stratifying on age, only persons 75 years and older with smaller arteriolar diameters were at a borderline significant increased risk of iAMD: OR/SD decrease in arteriolar diameters adjusted for age, gender, follow-up time, and other cardiovascular risk factors, 1.24 (95% CI, 0.94-1.63)., Conclusion: Overall retinal vessel diameters were not related to the risk of iAMD in this general elderly population.