@article {674, title = {The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study.}, journal = {Br J Ophthalmol}, volume = {86}, year = {2002}, month = {2002 Jan}, pages = {84-90}, abstract = {

AIMS: To describe the association of retinopathy with atherosclerosis and atherosclerotic risk factors in people with diabetes.

METHODS: 296 of the 558 people classified as having diabetes by the American Diabetes Association criteria, from a population based cohort of adults (ranging in age from 69 to 102 years) living in four United States communities (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were studied from 1997 to 1998. Lesions typical of diabetic retinopathy were determined by grading a 45 degrees colour fundus photograph of one eye of each participant, using a modification of the Airlie House classification system.

RESULTS: Retinopathy was present in 20\% of the diabetic cohort, with the lowest prevalence (16\%), in those 80 years of age or older. Retinopathy was detected in 20.3\% of the 296 people with diabetes; 2.7\% of the 296 had signs of proliferative retinopathy and 2.1\% had signs of macular oedema. The prevalence of diabetic retinopathy was higher in black people (35.4\%) than white (16.0\%). Controlling for age, sex, and blood glucose, retinopathy was more frequent in black people than white (odds ratio (OR) 2.26, 95\% confidence interval (CI) 1.01, 5.05), in those with longer duration of diabetes (OR (per 5 years of diabetes) 1.42, 95\% CI 1.18, 1.70), in those with subclinical cardiovascular disease (OR 1.49, 95\% CI 0.51, 4.31), or coronary heart disease or stroke (OR 3.23, 95\% CI 1.09, 9.56) than those without those diseases, in those with higher plasma low density lipoprotein (LDL) cholesterol (OR (per 10 mg/dl of LDL cholesterol) 1.12, 95\% CI 1.02, 1.23), and in those with gross proteinuria (OR 4.76, 95\% CI 1.53, 14.86).

CONCLUSION: Data from this population based study suggest a higher prevalence of retinopathy in black people than white people with diabetes and the association of cardiovascular disease, elevated plasma LDL cholesterol, and gross proteinuria with diabetic retinopathy. However, any conclusions or explanations regarding associations described here must be made with caution because only about one half of those with diabetes mellitus were evaluated.

}, keywords = {Age of Onset, Aged, Aged, 80 and over, Arteriosclerosis, Black People, Blood Pressure, Cohort Studies, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Female, Humans, Longitudinal Studies, Male, Odds Ratio, Prospective Studies, Regression Analysis, Risk Factors, Time Factors, White People}, issn = {0007-1161}, doi = {10.1136/bjo.86.1.84}, author = {Klein, Ronald and Marino, Emily K and Kuller, Lewis H and Polak, Joseph F and Tracy, Russell P and Gottdiener, John S and Burke, Gregory L and Hubbard, Larry D and Boineau, Robin} } @article {718, title = {Early age-related maculopathy in the cardiovascular health study.}, journal = {Ophthalmology}, volume = {110}, year = {2003}, month = {2003 Jan}, pages = {25-33}, abstract = {

OBJECTIVE: To describe the prevalence of early age-related maculopathy (ARM) and its relation to atherosclerosis, lipids, hypertension, and inflammatory factors in a population studied for cardiovascular disease risk factors and outcomes.

DESIGN: Population-based cohort study.

PARTICIPANTS: A biracial population of 2361 adults (ranging from 69-97 years of age; 1998 whites and 363 blacks) living in four US counties (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were examined during the interval from 1997 to 1998.

METHODS: Drusen and other lesions typical of ARM were identified by examining a 45 degrees color fundus photograph of one eye of each participant and classified by means of a modification of the Wisconsin Age-Related Maculopathy Grading System.

MAIN OUTCOME MEASURES: Early ARM.

RESULTS: Early ARM was present in 15.5\% and late ARM in 1.3\% of the cohort. The overall prevalence of any ARM was lower in blacks (9.1\%) compared with whites (18.2\%). While controlling for age, race, gender, and total calories consumed in the diet, factors associated with ARM were cerebral white matter disease as detected by magnetic resonance imaging (odds ratio [OR], 1.50; 95\% confidence interval [CI], 1.05, 2.16, P = 0.027), and lower serum total cholesterol (OR, per 10 mg/dl increase 0.95; 95\% CI, 0.91, 0.98, P = 0.02). There were no associations between hypertension, blood pressure, common carotid artery plaque, or any systemic inflammatory factors studied and early ARM.

CONCLUSIONS: This population-based study documents the higher prevalence of ARM in whites compared with blacks. Although an association was found between signs of white matter disease and early ARM, there was no evidence of an association of ARM with either hypertension or inflammatory factors.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Arteriosclerosis, Blood Pressure, C-Reactive Protein, California, Cohort Studies, Diet, European Continental Ancestry Group, Female, Humans, Hypertension, Leukocyte Count, Longitudinal Studies, Macular Degeneration, Male, Mid-Atlantic Region, North Carolina, Prevalence, Prospective Studies, Risk Factors, Serum Albumin}, issn = {0161-6420}, doi = {10.1016/s0161-6420(02)01565-8}, author = {Klein, Ronald and Klein, Barbara E K and Marino, Emily K and Kuller, Lewis H and Furberg, Curt and Burke, Gregory L and Hubbard, Larry D} } @article {734, title = {The prevalence and risk factors of retinal microvascular abnormalities in older persons: The Cardiovascular Health Study.}, journal = {Ophthalmology}, volume = {110}, year = {2003}, month = {2003 Apr}, pages = {658-66}, abstract = {

PURPOSE: To describe the prevalence of retinal microvascular characteristics and their associations with atherosclerosis in elderly, nondiabetic persons.

DESIGN AND PARTICIPANTS: Population-based, cross-sectional study comprising 2050 men and women aged 69 to 97 years without diabetes, living in four communities.

METHODS: Participants underwent retinal photography and standardized grading of retinal microvascular characteristics, including retinopathy (e.g., microaneurysms, retinal hemorrhages), focal arteriolar narrowing, and arteriovenous nicking. In addition, calibers of retinal arterioles and venules were measured on digitized photographs to obtain an estimate of generalized arteriolar narrowing. Atherosclerosis and its risk factors were obtained from clinical examination and laboratory investigations.

MAIN OUTCOME MEASURES: Prevalence of retinal microvascular abnormalities and their associations with measures of atherosclerosis.

RESULTS: The prevalence of retinal microvascular abnormalities was 8.3\% for retinopathy, 9.6\% for focal arteriolar narrowing, and 7.7\% for arteriovenous nicking. All retinal lesions were associated with hypertension (odds ratios [OR] were 1.8 for retinopathy, 2.1 for focal arteriolar narrowing, 1.5 for arteriovenous nicking, and 1.7 for generalized arteriolar narrowing). After controlling for age, gender, race, mean arterial blood pressure, and antihypertensive medication use, retinopathy was associated with prevalent coronary heart disease (OR, 1.7), prevalent myocardial infarction (OR, 1.7), prevalent stroke (OR, 2.0), presence of carotid artery plaque (OR, 1.9), and increased intima-media thickness of the common carotid (OR, 2.3; fourth vs. first quartile) and internal carotid (OR, 1.8; fourth vs. first quartile) arteries. In contrast, focal arteriolar narrowing, arteriovenous nicking, and generalized arteriolar narrowing were not associated with any measures of atherosclerosis.

CONCLUSIONS: Retinal microvascular abnormalities are common in older persons without diabetes and are related to hypertension. Retinopathy is associated with prevalent coronary heart disease, stroke, and carotid artery thickening, but focal and generalized arteriolar narrowing and arteriovenous nicking are not related to most measures of atherosclerosis. These data suggest that retinal microvascular abnormalities reflect processes associated with hypertension but distinct from atherosclerosis.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, Coronary Artery Disease, Cross-Sectional Studies, Female, Humans, Hypertension, Male, Prevalence, Retinal Diseases, Retinal Vessels, Risk Factors, United States}, issn = {0161-6420}, doi = {10.1016/S0161-6420(02)01931-0}, author = {Wong, Tien Yin and Klein, Ronald and Sharrett, A Richey and Manolio, Teri A and Hubbard, Larry D and Marino, Emily K and Kuller, Lewis and Burke, Gregory and Tracy, Russell P and Polak, Joseph F and Gottdiener, John S and Siscovick, David S} } @article {794, title = {The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study.}, journal = {Am J Kidney Dis}, volume = {44}, year = {2004}, month = {2004 Jul}, pages = {25-34}, abstract = {

BACKGROUND: Microalbuminuria is a risk factor for coronary heart disease (CHD). It occurs most commonly in the settings of diabetes and hypertension. The mechanisms by which it increases CHD risk are uncertain.

METHODS: We examined the cross-sectional association of microalbuminuria with a broad range of CHD risk factors in 3 groups of adults aged 65 years or older with and without microalbuminuria: those with (1) no diabetes or hypertension (n = 1,098), (2) hypertension only (n = 1,450), and (3) diabetes with or without hypertension (n = 465).

RESULTS: Three factors were related to microalbuminuria in all 3 groups: age, elevated systolic blood pressure, and markers of systemic inflammation. In patients with neither diabetes nor hypertension, increasing C-reactive protein levels were associated with microalbuminuria (odds ratio per 1-mg/L increase, 1.46; 95\% confidence interval [CI], 1.15 to 1.84). Among those with diabetes, an increase in white blood cell (WBC) count was associated with microalbuminuria (odds ratio per 1,000-cell/mL increase, 2.57; 95\% CI, 1.12 to 5.89). Among those with hypertension, an increase in WBC count (odds ratio per 1,000-cell/mL increase, 1.83; 95\% CI, 1.04 to 3.23) and fibrinogen level (odds ratio per 10-mg/dL increase, 1.02; 95\% CI, 1.00 to 1.05) were significantly associated with microalbuminuria. In all 3 groups, prevalent CHD was related to an elevated WBC count. In none of the 3 groups was brachial artery reactivity to ischemia, an in vivo marker of endothelial function, related to microalbuminuria.

CONCLUSION: Microalbuminuria is associated with age, systolic blood pressure, and markers of inflammation. These associations reflect potential mechanisms by which microalbuminuria is related to CHD risk.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Albuminuria, Biomarkers, Brachial Artery, Comorbidity, Coronary Disease, Cross-Sectional Studies, Diabetes Mellitus, Female, Humans, Hypertension, Inflammation, Logistic Models, Male, Multivariate Analysis, Odds Ratio, Risk Factors, Smoking, Ultrasonography}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2004.03.022}, author = {Barzilay, Joshua I and Peterson, Do and Cushman, Mary and Heckbert, Susan R and Cao, Jie J and Blaum, Caroline and Tracy, Russell P and Klein, Ronald and Herrington, David M} } @article {782, title = {Sleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the Sleep Heart Health Study.}, journal = {Sleep}, volume = {27}, year = {2004}, month = {2004 May 01}, pages = {467-73}, abstract = {

STUDY OBJECTIVE: Sleep apnea and milder forms of sleep-disordered breathing (SDB) have been associated with overt clinical cardiovascular disease, but it is unknown whether SDB is associated with arterial microvascular pathology. We examined the relation between SDB and retinal microvascular abnormalities.

DESIGN: Cross-sectional study.

PARTICIPANTS: Subjects were 2,927 men and women, aged 51 to 97 years, who participated in the Sleep Heart Health Study and had retinal photographs taken within approximately 3 years of overnight, unattended, at-home polysomnography.

MEASUREMENTS AND RESULTS: A respiratory disturbance index (RDI), calculated as the average number of apneas and hypopneas per hour of sleep, was used as an indicator of SDB in analysis. The overall prevalence of retinopathy was slightly higher in people with higher RDI values (5.4\%, 4.9\%, 8.6\%, and 7.6\%, respectively, in increasing quartiles of RDI), but after adjustment for age, body-mass index, hypertension, diabetes, and other factors, the presence of retinopathy was not associated with SDB. With the possible exceptions of microaneurysms and generalized arteriolar narrowing, as measured by lower arteriole-to-venule ratio, specific retinal abnormalities were not associated consistently with the RDI. Relative to the first quartile of RDI, the adjusted odds ratios (95\% confidence interval) for the presence of microaneurysm in the second, third, and fourth quartiles of RDI were 1.05 (0.44-2.55), 1.97 (0.89-4.37), and 1.79 (0.78-4.10), respectively. An increase of RDI from 0 to 10 was associated with a predicted decrease in arteriole-to-venule ratio of 0.01. Results were similar when analyses were conducted in normotensive and nondiabetic persons separately.

CONCLUSIONS: These data do not demonstrate a notable relation between SDB and retinal abnormalities. However, since this is the first investigation of a link between retinopathy and SDB, similar studies should be conducted in other population samples to demonstrate either consistency or inconsistency of our findings across studies.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Coronary Disease, Cross-Sectional Studies, Female, Humans, Hypoxia, Middle Aged, Polysomnography, Positive-Pressure Respiration, Retina, Retinal Vessels, Sleep Apnea Syndromes}, issn = {0161-8105}, doi = {10.1093/sleep/27.3.467}, author = {Boland, Lori L and Shahar, Eyal and Wong, Tien Y and Klein, Ronald and Punjabi, Naresh and Robbins, John A and Newman, Anne B} } @article {854, title = {Associations between retinal microvascular abnormalities and declining renal function in the elderly population: the Cardiovascular Health Study.}, journal = {Am J Kidney Dis}, volume = {46}, year = {2005}, month = {2005 Aug}, pages = {214-24}, abstract = {

BACKGROUND: Microvascular abnormalities in the kidney are common histopathologic findings in individuals with chronic kidney disease or renal failure. These abnormalities may represent one manifestation of ongoing systemic microvascular damage. We hypothesized that retinal microvascular abnormalities, when present, would be associated with progressive renal dysfunction in elderly individuals.

METHODS: The Cardiovascular Health Study (CHS) is a prospective, multicenter, cohort study initiated in 1989 designed to examine cardiovascular risk factors, morbidity, and mortality in elderly Americans. As part of an ancillary study, CHS participants underwent retinal photography in 1997 and 1998. Retinal microvascular abnormalities were assessed and graded by using standardized measures. Retinal microvascular abnormalities were defined as retinopathy (hard and soft exudates, hemorrhages, or microaneurysms) and/or retinal arteriolar abnormalities (arteriovenous nicking, focal arteriolar narrowing, or lowest quartile arteriole-venule ratio). Associations between these abnormalities and observed 4-year changes in serum creatinine levels and estimated glomerular filtration rates (eGFRs) from study years 5 to 9 (encompassing years 1994 to 2001) were examined by using regression modeling.

RESULTS: A total of 1,394 CHS participants had retinal and serum creatinine data. After adjustments for age, race, sex, weight, diabetes, hypertension, angiotensin-converting enzyme inhibitor use, and proteinuria, participants with retinopathy showed a significant increase in serum creatinine level and decline in eGFR compared with those without retinopathy during the 4-year study period (+0.24 mg/dL [+21 micromol/L] versus -0.21 mg/dL [-19 micromol/L] and -0.48 mL/min/1.73 m2 [-0.01 mL/s/1.73 m2] versus +1.74 mL/min/1.73 m2 [+0.03 mL/s/1.73 m2], respectively). Participants with retinopathy also were significantly more likely to have an observed significant deterioration in renal function, defined as a 0.3-mg/dL (27-micromol/L) increase in serum creatinine level or 20\% or greater decline in eGFR (odds ratio, 3.20; 95\% confidence interval, 1.58 to 6.50; and odds ratio, 2.84; 95\% confidence interval, 1.56 to 5.16, respectively). These associations remained in separate stratified analyses of patients with and without diabetes. The presence of retinal arteriolar abnormalities was not associated with deteriorating renal function.

CONCLUSION: Retinal microvascular abnormalities defined as retinopathy were significantly associated with renal function deterioration. The observed findings were independent of effects of any associated diabetes or hypertension. These findings suggest that systemic microvascular disease may be associated with progressive renal dysfunction in the elderly population.

}, keywords = {African Americans, Aged, Aged, 80 and over, Aging, Antihypertensive Agents, Capillaries, Cohort Studies, Comorbidity, Creatinine, Diabetes Mellitus, Disease Progression, European Continental Ancestry Group, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney, Male, Photography, Prospective Studies, Proteinuria, Retina, Retinal Diseases, Retinal Vessels}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2005.05.005}, author = {Edwards, Matthew S and Wilson, David B and Craven, Timothy E and Stafford, Jeanette and Fried, Linda F and Wong, Tien Y and Klein, Ronald and Burke, Gregory L and Hansen, Kimberley J} } @article {826, title = {Cardiovascular risk factors for retinal vein occlusion and arteriolar emboli: the Atherosclerosis Risk in Communities \& Cardiovascular Health studies.}, journal = {Ophthalmology}, volume = {112}, year = {2005}, month = {2005 Apr}, pages = {540-7}, abstract = {

OBJECTIVE: To examine the associations of retinal vein occlusion and arteriolar emboli with cardiovascular disease.

DESIGN: Population-based cross-sectional study.

PARTICIPANTS: Pooled from the Atherosclerosis Risk in Communities Study (n = 12,642; mean age, 60 years) and the Cardiovascular Health Study (n = 2824; mean age, 79 years).

METHODS: Retinal vein occlusion and arteriolar emboli were identified from a single nonmydriatic retinal photograph using a standardized protocol. Photographs were also graded for arteriovenous nicking and focal arteriolar narrowing. All participants had a comprehensive systemic evaluation, including standardized carotid ultrasonography.

MAIN OUTCOME MEASURES: Retinal vein occlusion and arteriolar emboli.

RESULTS: Prevalences of retinal vein occlusion and arteriolar emboli were 0.3\% (n = 39 cases) and 0.2\% (n = 34 cases), respectively. After adjusting for age, retinal vein occlusion was associated with hypertension (odds ratio [OR], 2.96; 95\% confidence interval [CI], 1.43-6.14), systolic blood pressure (BP) (OR, 4.12; 95\% CI, 1.40-12.16; highest quartile vs. lowest), diastolic BP (OR, 2.64; 95\% CI, 1.07-6.46; highest quartile vs. lowest), carotid artery plaque (OR, 5.62; 95\% CI, 2.60-12.16), body mass index (OR, 3.88; 95\% CI, 1.23-12.18; highest quartile vs. lowest), plasma fibrinogen (OR, 3.29; 95\% CI, 1.08-10.02; highest quartile vs. lowest), arteriovenous nicking (OR, 4.09; 95\% CI, 2.00-8.36), and focal arteriolar narrowing (OR, 5.17; 95\% CI, 2.59-10.29). After adjusting for age, retinal arteriolar emboli were associated with hypertension (OR, 3.14; 95\% CI, 1.44-6.84), systolic BP (OR, 3.46; 95\% CI, 1.13-10.65; highest quartile vs. lowest), prevalent coronary heart disease (OR, 2.33; 95\% CI, 1.01-5.42), carotid artery plaque (OR, 4.62; 95\% CI, 1.85-11.57), plasma lipoprotein (a) (OR, 3.69; 95\% CI, 1.20-11.41; highest quartile vs. lowest), plasma fibrinogen (OR, 3.09; 95\% CI, 0.98-9.76; highest quartile vs. lowest), and current cigarette smoking (OR, 3.08; 95\% CI, 1.47-6.47). Approximately a quarter of participants with retinal vein occlusion and arteriolar emboli had evidence of carotid artery plaque as defined from ultrasound.

CONCLUSIONS: Retinal vein occlusion and retinal arteriolar emboli are associated with carotid artery disease, hypertension, and other cardiovascular risk factors.

}, keywords = {Aged, Aged, 80 and over, Arterioles, Blood Pressure, Cardiovascular Diseases, Carotid Stenosis, Coronary Artery Disease, Cross-Sectional Studies, Embolism, Female, Fibrinogen, Humans, Hypertension, Lipoprotein(a), Male, Meta-Analysis as Topic, Middle Aged, Retinal Artery, Retinal Vein Occlusion, Risk Factors}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2004.10.039}, author = {Wong, Tien Yin and Larsen, Emily K Marino and Klein, Ronald and Mitchell, Paul and Couper, David J and Klein, Barbara E K and Hubbard, Larry D and Siscovick, David S and Sharrett, A Richey} } @article {920, title = {CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses.}, journal = {Hum Mol Genet}, volume = {15}, year = {2006}, month = {2006 Nov 01}, pages = {3206-18}, abstract = {

Age-related maculopathy (ARM) is an important cause of visual impairment in the elderly population. It is of crucial importance to identify genetic factors and their interactions with environmental exposures for this disorder. This study was aimed at investigating the CFH, ELOVL4, PLEKHA1 and LOC387715 genes in independent cohorts collected using different ascertainment schemes. The study used a case-control design with subjects originally recruited through the Cardiovascular Health Study (CHS) and the Age-Related Eye Disease Study (AREDS). CFH was significantly associated with ARM in both cohorts (P}, keywords = {Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Complement Factor H, Eye Proteins, Female, Genetic Predisposition to Disease, Humans, Intracellular Signaling Peptides and Proteins, Macular Degeneration, Male, Membrane Proteins, Proteins}, issn = {0964-6906}, doi = {10.1093/hmg/ddl396}, author = {Conley, Yvette P and Jakobsdottir, Johanna and Mah, Tammy and Weeks, Daniel E and Klein, Ronald and Kuller, Lewis and Ferrell, Robert E and Gorin, Michael B} } @article {929, title = {Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study.}, journal = {Arch Intern Med}, volume = {166}, year = {2006}, month = {2006 Nov 27}, pages = {2388-94}, abstract = {

BACKGROUND: Small vessel disease may contribute to the risk of cardiovascular disease in older persons. We describe the relation of retinal vascular caliber to incident coronary heart disease (CHD) and stroke in elderly persons.

METHODS: Prospective population-based cohort study composed of 1992 men and women aged 69 to 97 years living in 4 US communities. Retinal arteriolar and venular calibers were measured from retinal photographs using a computer-assisted method. Incident CHD and stroke events were ascertained using standardized methods.

RESULTS: After 5 years of follow-up, there were 115 incident CHD events and 113 incident stroke events. Participants with larger retinal venular caliber had a higher incidence of CHD (11.7\%; 95\% confidence interval [CI], 8.7\%-15.8\%, vs 8.1\%; 95\% CI, 5.7\%-11.6\%), comparing largest with smallest venular caliber quartiles, and stroke (8.4\%; 95\% CI, 6.0-11.7, vs 5.8\%; 95\% CI, 3.9-8.4). At multivariable analysis, controlling for age, sex, race, arteriolar caliber, systolic and diastolic blood pressure, diabetes, glucose concentration, cigarette smoking, pack-years of smoking, and high-density-lipoprotein and low-density lipoprotein cholesterol levels, larger retinal venular caliber was associated with incident CHD (rate ratio, 3.0; 95\% CI, 1.6-5.7, comparing largest with smallest venular caliber quartiles; P(trend) = .001) and incident stroke (rate ratio, 2.2; 95\% CI, 1.1-4.3; P(trend) = .02). Additional adjustment for C-reactive protein and common and internal carotid artery intimal-media thickness had minimal effect on these associations. At multivariable analysis, smaller retinal arteriolar caliber was associated with incident CHD (rate ratio, 2.0; 95\% CI, 1.1-3.7, comparing largest with smallest arteriolar caliber quartiles; P = .03) but not stroke (rate ratio,1.1; 95\% CI, 0.5-2.2; P = .73).

CONCLUSION: Larger retinal venular caliber is independently associated with risk of cardiovascular disease in elderly persons.

}, keywords = {Aged, Aged, 80 and over, Algorithms, Cardiovascular Diseases, Cohort Studies, Female, Humans, Image Processing, Computer-Assisted, Incidence, Male, Photography, Prospective Studies, Retinal Diseases, Retinal Vein, Retinal Vessels, Risk Factors, Stroke, United States}, issn = {0003-9926}, doi = {10.1001/archinte.166.21.2388}, author = {Wong, Tien Yin and Kamineni, Aruna and Klein, Ronald and Sharrett, A Richey and Klein, Barbara E and Siscovick, David S and Cushman, Mary and Duncan, Bruce B} } @article {935, title = {Apolipoprotein e gene and age-related maculopathy in older individuals: the cardiovascular health study.}, journal = {Arch Ophthalmol}, volume = {125}, year = {2007}, month = {2007 Jan}, pages = {68-73}, abstract = {

OBJECTIVE: To examine the association between the apolipoprotein E (APOE) gene and age-related maculopathy (ARM) in an older population.

METHODS: Two thousand one hundred seventy persons 65 years and older sampled from 4 US communities had ARM signs assessed from retinal photographs using a modified Wisconsin Age-Related Maculopathy Grading System. DNA extracted from blood samples was analyzed for common APOE alleles.

RESULTS: After controlling for age, sex, cigarette smoking, and other factors, white participants carrying the epsilon2 allele had an increased risk of late ARM (odds ratio, 2.53 [95\% confidence interval, 1.08-5.90]) while carriers of the epsilon4 allele had a lower risk of late ARM (odds ratio, 0.69 [95\% confidence interval, 0.19-2.50]). There were too few late ARM cases in African American individuals for analysis.

CONCLUSION: APOE polymorphism is associated with late ARM in older white persons 65 years and older. Consistent with previous studies, the APOE epsilon2 allele is associated with a significant increased risk of late ARM development, whereas the epsilon4 allele may confer some protection.

}, keywords = {African Americans, Aged, Aged, 80 and over, Alleles, Apolipoprotein E2, Apolipoprotein E3, Apolipoprotein E4, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genotype, Humans, Macular Degeneration, Male, Odds Ratio, Polymorphism, Genetic, Risk Factors}, issn = {0003-9950}, doi = {10.1001/archopht.125.1.68}, author = {Tikellis, Gabriella and Sun, Cong and Gorin, Michael B and Klein, Ronald and Klein, Barbara E K and Larsen, Emily K Marino and Siscovick, David S and Hubbard, Larry D and Wong, Tien Y} } @article {1003, title = {Apolipoprotein E gene and retinal microvascular signs in older people: the Cardiovascular Health Study.}, journal = {Mol Vis}, volume = {13}, year = {2007}, month = {2007 Nov 12}, pages = {2105-11}, abstract = {

PURPOSE: To examine the association between apolipoprotein E (APOE) gene polymorphism and retinal microvascular signs in an older population.

METHODS: Retinal photographs were taken of 2,152 participants (1,831 whites, and 321 African-Americans), aged 69-96 years, who were participating in a population-based study of four United States communities. We used standardized protocols to assess photographs for the presence of retinal microvascular signs (retinopathy, arterio-venous nicking, and focal arteriolar narrowing) and a computer-assisted method to measure retinal vessel diameters. We analyzed DNA extracted from blood samples of participants for common allelic variants of the APOE gene.

RESULTS: After adjusting for age, gender, systolic blood pressure, smoking, total serum cholesterol, and other risk factors, we found white participants carrying the epsilon2 and epsilon4 alleles were more likely to have arterio-venous nicking than the epsilon3/epsilon3 homozygotes, with odds ratio (OR) of 1.70 and confidence interval (CI) 95\% (1.03-2.83) for the epsilon2 carriers and OR 1.74 (95\% CI 1.06-2.84) for the epsilon4 carriers. Among white participants without hypertension, the associations remained significant for the epsilon4 carriers (OR 2.32, 95\% CI 1.18-4.57). Whites, normotensive carriers of the epsilon2 allele had significantly narrower retinal arteriolar diameters (adjusted mean arteriolar diameter of 163.5 mum, 95\% CI 160.1-167.0, p=0.03) compared to the epsilon3/epsilon3 homozygotes (167.8 mum, 95\% CI 166.0-169.6). APOE gene polymorphism was not associated with retinopathy, focal narrowing, or retinal venular diameters in white participants. There were insufficient numbers of African-Americans for separate multivariate analysis.

CONCLUSIONS: This study provides little evidence that the APOE gene polymorphism plays a significant role in the pathogenesis of retinal microvascular changes in the general population. In the older white population, APOE epsilon2 and epsilon4 allele carriers were more likely to have arterio-venous nicking. Other retinal signs, however, were not related to APOE gene polymorphism.

}, keywords = {Aged, Aged, 80 and over, Apolipoprotein E2, Apolipoprotein E4, Apolipoproteins E, European Continental Ancestry Group, Female, Gene Frequency, Genotype, Heterozygote, Homozygote, Humans, Male, Microcirculation, Polymorphism, Genetic, Retinal Diseases, Retinal Vessels}, issn = {1090-0535}, author = {Sun, Cong and Tikellis, Gabriella and Liew, Gerald and Klein, Ronald and Larsen, Emily K Marino and Wong, Tien Y} } @article {949, title = {Are microvascular abnormalities in the retina associated with depression symptoms? The Cardiovascular Health Study.}, journal = {Am J Geriatr Psychiatry}, volume = {15}, year = {2007}, month = {2007 Apr}, pages = {335-43}, abstract = {

OBJECTIVE: Depression has been linked with vascular risk factors and stroke. The authors examined the relationship between retinal microvascular abnormalities and depression symptoms in an elderly population.

METHODS: The Cardiovascular Health Study is a population-based study conducted in four U.S. communities initiated in 1989-1990. A total of 2,420 persons aged 65 years and older were included in the current analyses. During the 1997-1998 examination, retinal photographs were performed and assessed for retinal microvascular abnormalities (retinopathy, focal arteriolar narrowing, arteriovenous nicking, generalized retinal arteriolar narrowing, and generalized retinal venular dilation) according to standardized methods. Depression symptoms were assessed by a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale annually from 1989 through 1997-1998 and was defined as a CES-D score of >9.

RESULTS: Participants with retinal microvascular abnormalities were not more likely to have depression symptoms, with adjusted odds ratio (OR) (95\% confidence intervals) of 1.08 (0.71-1.65) for retinopathy, OR 1.09 (0.71-1.68) for focal arteriolar narrowing, OR 0.85 (0.52-1.40) for arteriovenous nicking, OR 0.97 (0.70-1.34) for generalized arteriolar narrowing, and OR 0.79 (0.56-1.12) for generalized venular dilation. Retinal microvascular abnormalities were not related to depression symptoms in multinomial logistic regression comparing the three top quartiles of the depression CES-D scores with the lowest quartile.

CONCLUSIONS: Our study did not find an association between retinal microvascular abnormalities and depression symptoms in older people.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Cohort Studies, Comorbidity, Cross-Sectional Studies, Depression, Female, Fluorescein Angiography, Humans, Male, Microcirculation, Personality Inventory, Retinal Artery Occlusion, Retinal Diseases, Retinal Vein Occlusion, Risk Factors, Statistics as Topic, United States}, issn = {1064-7481}, doi = {10.1097/01.JGP.0000247161.98311.0f}, author = {Sun, Cong and Tikellis, Gabriella and Klein, Ronald and Steffens, David C and Larsen, Emily K Marino and Siscovick, David S and Klein, Barbara E K and Wong, Tien Y} } @article {921, title = {Associations between findings on cranial magnetic resonance imaging and retinal photography in the elderly: the Cardiovascular Health Study.}, journal = {Am J Epidemiol}, volume = {165}, year = {2007}, month = {2007 Jan 01}, pages = {78-84}, abstract = {

Associations between findings on cranial magnetic resonance imaging (MRI) and retinal photographs have been described mostly in middle-aged people. In the Cardiovascular Health Study, 1,717 elderly participants underwent MRI and retinal photography between 1991 and 1999. Associations were sought between MRI findings and four findings of retinal microvascular disease: retinopathy, focal arteriolar narrowing, arteriovenous nicking, and the arteriovenous ratio--the last based upon semiautomated measurements of arterioles and venules. After controlling for age and gender, the authors found associations between MRI findings and the smaller arteriovenous ratio (per standard deviation decrease): prevalent infarcts (odds ratio = 1.18, 95\% confidence interval: 1.05, 1.34; p = 0.007), white matter grade (regression coefficient, 0.093; p = 0.011), incident infarct (odds ratio = 1.26, 95\% confidence interval: 1.09, 1.46; p = 0.002), and worsening white matter grade (odds ratio = 1.12, 95\% confidence interval: 0.98, 1.29; p = 0.09). Arteriovenous nicking was also associated with prevalent (odds ratio = 1.84, 95\% confidence interval: 1.23, 2.76; p = 0.003) and incident (odds ratio = 1.84, 95\% confidence interval: 1.15, 2.94; p = 0.011) infarcts. Adjustment for hypertension and diabetes had minimal effect. Evidence of small vessel disease in the retina increases the likelihood of finding it in the brain. Associations were less prominent in this elderly population than have been described in middle-aged people.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Arteriosclerosis, Cerebral Infarction, Female, Humans, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Microcirculation, Photography, Retina, Retinal Diseases, Retinal Vessels, Risk Assessment, Risk Factors}, issn = {0002-9262}, doi = {10.1093/aje/kwj350}, author = {Longstreth, Wt and Larsen, Emily K Marino and Klein, Ronald and Wong, Tien Yin and Sharrett, A Richey and Lefkowitz, David and Manolio, Teri A} } @article {968, title = {Depressive symptoms and age-related macular degeneration in older people: the cardiovascular health study.}, journal = {Ophthalmic Epidemiol}, volume = {14}, year = {2007}, month = {2007 May-Jun}, pages = {127-33}, abstract = {

PURPOSE: To examine the association between age-related macular degeneration (AMD) and depressive symptoms.

METHODS: Population-based, cross-sectional study. A total of 2,194 persons aged 69-97 years were included in the current analyses. During the 1997-1998 examination, retinal photography from one randomly selected eye was graded for presence of early and late AMD using a modified Wisconsin AMD by Grading System. Depressive symptoms were assessed via a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale annually from 1989 through 1997-1998. Depressive symptoms were defined as a CES-D score of >9 (top quartile of CES-D score) at the 1997-1998 examination.

RESULTS: There were 338 (15.6\%) individuals with early AMD and 29 (1.3\%) with late AMD. Among them, 368 (16.8\%) persons had depressive symptoms at the 1997-1998 examination. Depressive symptoms were not associated with early AMD (multivariable adjusted odds ratio [OR]: 0.97; 95\% confidence intervals [CI]: 0.69-1.36) or late AMD (OR: 1.15; 95\% CI: 0.38-3.46). Including persons using anti-depressive medications did not alter these associations (OR: 0.98; 95\% CI: 0.74-1.32 for early AMD and OR: 0.97; 95\% CI: 0.35-2.67 for late AMD). There was no association in multinomial logistic regression models of increasing quartiles of the CES-D scores with early or late AMD status.

CONCLUSIONS: Our study did not find an association between early AMD and depressive symptoms in older people.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cross-Sectional Studies, Depressive Disorder, Female, Health Surveys, Humans, Intelligence Tests, Macular Degeneration, Male, Photography, United States}, issn = {0928-6586}, doi = {10.1080/09286580601186742}, author = {Sun, Cong and Tikellis, Gabriella and Klein, Ronald and Steffens, David C and Larsen, Emily K Marino and Wong, Tien Y} } @article {965, title = {Retinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {38}, year = {2007}, month = {2007 Jul}, pages = {2041-7}, abstract = {

BACKGROUND AND PURPOSE: Cerebral microvascular disease may be a risk factor for the development of dementia in elderly persons. We describe the association of retinal microvascular signs with cognitive function and dementia among older individuals.

METHODS: In the population-based Cardiovascular Health Study, 2211 persons aged 69 to 97 years at recruitment had retinal photography. Photographs were evaluated for retinopathy (eg, microaneurysms, retinal hemorrhages), focal arteriolar narrowing, arteriovenous nicking, and retinal arteriolar and venular caliber. Cognitive status was determined from the Digit-Symbol Substitution Test and Modified Mini-Mental State Examination. Participants were also further evaluated for the presence of dementia with detailed neuropsychological testing. Persons with a prior stroke or taking antipsychotic or antidepressant medications were excluded.

RESULTS: After adjusting for age, gender, race, field center, education level, internal carotid intima-media thickness, body mass index, hypertension, diabetes, and cigarette smoking status, persons with retinopathy had lower mean Digit-Symbol Substitution Test scores but not Modified Mini-Mental State Examination than those without retinopathy (39 versus 41, P=0.002). In hypertensive persons, retinopathy (multivariable-adjusted OR, 2.10; 95\% CI, 1.04 to 4.24) and focal arteriolar narrowing (OR, 3.02; 95\% CI, 1.51 to 6.02) were associated with dementia. These associations were not present in individuals without hypertension.

CONCLUSIONS: In older persons, our study shows a modest cross-sectional association between retinopathy signs with poorer cognitive function and, in persons with hypertension, with dementia. These data support a possible role of cerebral microvascular disease in the pathogenesis of impaired cognitive function and dementia in older hypertensive persons.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cognition, Cross-Sectional Studies, Dementia, Female, Humans, Longitudinal Studies, Male, Microcirculation, Neuropsychological Tests, Retinal Vessels, Risk Factors}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.107.483586}, author = {Baker, Michelle L and Marino Larsen, Emily K and Kuller, Lewis H and Klein, Ronald and Klein, Barbara E K and Siscovick, David S and Bernick, Charles and Manolio, Teri A and Wong, Tien Yin} } @article {1111, title = {Age-related macular degeneration and risk of coronary heart disease and stroke: the Cardiovascular Health Study.}, journal = {Ophthalmology}, volume = {116}, year = {2009}, month = {2009 Oct}, pages = {1913-9}, abstract = {

PURPOSE: To examine the associations of age-related macular degeneration (AMD) with incident coronary heart disease (CHD) and stroke in the Cardiovascular Health Study.

DESIGN: Population-based prospective cohort study.

PARTICIPANTS: A total of 1786 white and African-American participants free of CHD or 2228 participants free of stroke, aged 69 to 97 years.

METHODS: AMD was evaluated from photographs taken in 1997 and 1998.

MAIN OUTCOME MEASURES: Incident CHD and stroke ascertained using standardized methods.

RESULTS: Of the 1786 persons free of CHD, 303 developed incident CHD over 7 years. Participants with early AMD (n = 277) had a higher cumulative incidence of CHD than participants without early AMD (25.8\% vs. 18.9\%, P = 0.001). By adjusting for age, gender, race, systolic and diastolic blood pressure, hypertension status, fasting glucose, triglyceride, low-density lipoprotein cholesterol, cigarette smoking, pack years of smoking, and C-reactive protein, the presence of early AMD was associated with an increased risk of incident CHD (hazard ratio 1.57; 95\% confidence interval, 1.17-2.22). Late AMD (n = 25) was not associated with incident CHD (hazard ratio 0.78; 95\% confidence interval, 0.25-2.48). Among 2228 persons at risk, 198 developed incident stroke; neither early nor late AMD was associated with incident stroke.

CONCLUSIONS: This study suggests persons with early AMD have a higher risk of CHD but not stroke in a population aged 69 to 97 years. This provides further support that AMD is associated with underlying systemic vascular disease.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Blood Pressure, Cholesterol, LDL, Coronary Disease, European Continental Ancestry Group, Female, Humans, Incidence, Macular Degeneration, Male, Prospective Studies, Risk Factors, Sex Factors, Stroke, Triglycerides, United States}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2009.03.046}, author = {Sun, Cong and Klein, Ronald and Wong, Tien Y} } @article {1100, title = {Early age-related macular degeneration, cognitive function, and dementia: the Cardiovascular Health Study.}, journal = {Arch Ophthalmol}, volume = {127}, year = {2009}, month = {2009 May}, pages = {667-73}, abstract = {

OBJECTIVE: To describe the association of cognitive function and dementia with early age-related macular degeneration (AMD) in older individuals.

METHODS: This population-based study included 2,088 persons aged 69 to 97 years who participated in the Cardiovascular Health Study. The AMD was assessed from retinal photographs based on a modified Wisconsin AMD grading system. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination. Participants were also evaluated for dementia using detailed neuropsychological testing.

RESULTS: After controlling for age, sex, race, and study center, persons with low DSST scores (lowest quartile of scores, < or =30) were more likely to have early AMD (odds ratio, 1.38; 95\% confidence interval, 1.03-1.85) than were persons with higher DSST scores. In analyses further controlling for education, systolic blood pressure, total cholesterol level, diabetes mellitus, smoking status, and apolipoprotein E genotype, this association was stronger (odds ratio, 2.00; 95\% confidence interval, 1.29-3.10). There was no association of low Modified Mini-Mental State Examination scores, dementia, or Alzheimer disease with early AMD.

CONCLUSIONS: In this older population, cognitive impairment may share common age-related pathogenesis and risk factors with early AMD.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cognition Disorders, Dementia, Female, Humans, Intelligence Tests, Macular Degeneration, Male, Neuropsychological Tests, Odds Ratio, Prospective Studies, Risk Factors, United States}, issn = {1538-3601}, doi = {10.1001/archophthalmol.2009.30}, author = {Baker, Michelle L and Wang, Jie Jin and Rogers, Sophie and Klein, Ronald and Kuller, Lewis H and Larsen, Emily K and Wong, Tien Yin} } @article {1129, title = {Meta-analysis: retinal vessel caliber and risk for coronary heart disease.}, journal = {Ann Intern Med}, volume = {151}, year = {2009}, month = {2009 Sep 15}, pages = {404-13}, abstract = {

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.

}, keywords = {Adult, Aged, Arterioles, Biomarkers, Coronary Disease, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Retinal Vessels, Risk Factors, Sex Factors, Venules}, issn = {1539-3704}, author = {McGeechan, Kevin and Liew, Gerald and Macaskill, Petra and Irwig, Les and Klein, Ronald and Klein, Barbara E K and Wang, Jie Jin and Mitchell, Paul and Vingerling, Johannes R and Dejong, Paulus T V M and Witteman, Jacqueline C M and Breteler, Monique M B and Shaw, Jonathan and Zimmet, Paul and Wong, Tien Y} } @article {1142, title = {Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis.}, journal = {Am J Epidemiol}, volume = {170}, year = {2009}, month = {2009 Dec 01}, pages = {1323-32}, abstract = {

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.

}, keywords = {Aged, Fluorescein Angiography, Humans, Middle Aged, Predictive Value of Tests, Proportional Hazards Models, Retinal Artery, Retinal Vein, Retinal Vessels, Risk Factors, Stroke}, issn = {1476-6256}, doi = {10.1093/aje/kwp306}, author = {McGeechan, Kevin and Liew, Gerald and Macaskill, Petra and Irwig, Les and Klein, Ronald and Klein, Barbara E K and Wang, Jie Jin and Mitchell, Paul and Vingerling, Johannes R and de Jong, Paulus T V M and Witteman, Jacqueline C M and Breteler, Monique M B and Shaw, Jonathan and Zimmet, Paul and Wong, Tien Y} } @article {1243, title = {Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.}, journal = {PLoS Genet}, volume = {6}, year = {2010}, month = {2010 Oct 28}, pages = {e1001184}, abstract = {

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0{\texttimes}10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0\%-3.2\% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61{\texttimes}10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25{\texttimes}10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15{\texttimes}10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32{\texttimes}10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Cohort Studies, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Microcirculation, Middle Aged, Polymorphism, Single Nucleotide, Retinal Vessels, Young Adult}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001184}, author = {Ikram, M Kamran and Sim, Xueling and Xueling, Sim and Jensen, Richard A and Cotch, Mary Frances and Hewitt, Alex W and Ikram, M Arfan and Wang, Jie Jin and Klein, Ronald and Klein, Barbara E K and Breteler, Monique M B and Cheung, Ning and Liew, Gerald and Mitchell, Paul and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Hofman, Albert and de Jong, Paulus T V M and van Duijn, Cornelia M and Kao, Linda and Cheng, Ching-Yu and Smith, Albert Vernon and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Jonasson, Fridbert and Eiriksdottir, Gudny and Aspelund, Thor and Harris, Tamara B and Launer, Lenore J and Taylor, Kent D and Li, Xiaohui and Iyengar, Sudha K and Xi, Quansheng and Sivakumaran, Theru A and Mackey, David A and Macgregor, Stuart and Martin, Nicholas G and Young, Terri L and Bis, Josh C and Wiggins, Kerri L and Heckbert, Susan R and Hammond, Christopher J and Andrew, Toby and Fahy, Samantha and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Islam, F M Amirul and Rotter, Jerome I and McAuley, Annie K and Boerwinkle, Eric and Tai, E Shyong and Gudnason, Vilmundur and Siscovick, David S and Vingerling, Johannes R and Wong, Tien Y} } @article {1567, title = {Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe).}, journal = {Invest Ophthalmol Vis Sci}, volume = {52}, year = {2011}, month = {2011 Sep 29}, pages = {7593-602}, abstract = {

PURPOSE: To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).

METHODS: Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades >= 14 and >= 30. The χ{\texttwosuperior} analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.

RESULTS: Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 {\texttimes} 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.

CONCLUSIONS: Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.

}, keywords = {Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Diabetic Retinopathy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Iduronidase, Odds Ratio, P-Selectin, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1552-5783}, doi = {10.1167/iovs.11-7510}, author = {Sobrin, Lucia and Green, Todd and Sim, Xueling and Jensen, Richard A and Tai, E Shyong and Tay, Wan Ting and Wang, Jie Jin and Mitchell, Paul and Sandholm, Niina and Liu, Yiyuan and Hietala, Kustaa and Iyengar, Sudha K and Brooks, Matthew and Buraczynska, Monika and Van Zuydam, Natalie and Smith, Albert V and Gudnason, Vilmundur and Doney, Alex S F and Morris, Andrew D and Leese, Graham P and Palmer, Colin N A and Swaroop, Anand and Taylor, Herman A and Wilson, James G and Penman, Alan and Chen, Ching J and Groop, Per-Henrik and Saw, Seang-Mei and Aung, Tin and Klein, Barbara E and Rotter, Jerome I and Siscovick, David S and Cotch, Mary Frances and Klein, Ronald and Daly, Mark J and Wong, Tien Y} } @article {1283, title = {Retinal microvascular signs and functional loss in older persons: the cardiovascular health study.}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Jun}, pages = {1589-95}, abstract = {

BACKGROUND AND PURPOSE: We hypothesized that retinal microvascular signs are associated with executive dysfunction, slow gait, and depressive mood, which are characteristic features of microvascular disease affecting frontal subcortical regions of the brain.

METHODS: In the Cardiovascular Health Study, 1744 participants (mean age, 78) free of stroke had retinal photographs and carotid ultrasound during the 1997 to 1998 visit. We examined the cross-sectional association of retinal signs with the digit-symbol substitution test (DSST) score, gait speed, the Center for Epidemiologic Studies-Depression score, and depressive mood, defined as Center for Epidemiologic Studies-Depression score >9 or antidepressant use.

RESULTS: After adjusting for potential confounders, retinal signs were associated with lower DSST score (generalized arteriolar narrowing and arteriovenous nicking), slower gait (retinopathy), and depressive mood (generalized arteriolar narrowing). A higher number of retinal signs was associated with lower DSST score (-0.76 and -2.79 points for 1 sign and >=2 signs versus none; P<0.001) and slower gait (-0.009 and -0.083 m/s; P=0.047), but not with the square root of Center for Epidemiologic Studies-Depression score (0.079 and -0.208; P=0.072). In addition, coexistence of retinal signs (generalized arteriolar narrowing and arteriovenous nicking) and carotid atherosclerosis was associated with lower DSST score compared with either process alone (P for interaction <0.01). Notably, further adjustment for ventricular size, white matter disease, and infarcts on MRI did not attenuate the association.

CONCLUSIONS: Retinal signs are associated with executive dysfunction and slow gait, and possibly with depressive mood, suggesting a common process involving small vessels.

}, keywords = {Aged, Cardiovascular Diseases, Depressive Disorder, Frontal Lobe, Humans, Microcirculation, Neuropsychological Tests, Retinal Diseases, Retinal Vessels, Risk Factors}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.110.605261}, author = {Kim, Dae Hyun and Newman, Anne B and Hajjar, Ihab and Strotmeyer, Elsa S and Klein, Ronald and Newton, Elizabeth and Sarnak, Mark J and Burke, Gregory L and Lipsitz, Lewis A} } @article {1351, title = {Retinal microvascular signs and disability in the Cardiovascular Health Study.}, journal = {Arch Ophthalmol}, volume = {130}, year = {2012}, month = {2012 Mar}, pages = {350-6}, abstract = {

OBJECTIVE: To study the associations of retinal microvascular changes, which are associated with systemic conditions and cognitive decline, with disability in performing activities of daily living (ADL).

DESIGN: Prospective cohort study of 1487 community-dwelling participants in the Cardiovascular Health Study (mean age, 78 years) who were free of ADL disability and had available data on retinal signs and carotid intima-media thickness at the 1998-1999 visit. Main outcome measures were incident ADL disability, defined as self-reported difficulty in performing any ADL, by the presence of retinal signs and advanced carotid atherosclerosis, defined by carotid intima-media thickness in the 80th percentile or more or 25\% or more stenosis, and potential mediation by cerebral microvascular disease on brain imaging or by executive dysfunction, slow gait, and depressive mood, which are symptoms of frontal subcortical dysfunction.

RESULTS: During the median follow-up of 3.1 years (maximum, 7.8 years), participants with 2 or more retinal signs had a higher rate of disability than those with fewer than 2 retinal signs (10.1\% vs 7.1\%; adjusted hazard ratio, 1.45; 95\% confidence interval, 1.24-1.69; P~<~.001). There was no evidence of interaction by advanced carotid atherosclerosis (P~>~.10). The association seemed to be partially mediated by executive dysfunction, slow gait, and depressive symptoms but not by cerebral microvascular disease on brain imaging.

CONCLUSIONS: These results provide further support for the pathophysiologic and prognostic significance of microvascular disease in age-related disability. However, it remains to be determined how to best use retinal photography in clinical risk prediction.

}, keywords = {Activities of Daily Living, Aged, Carotid Artery Diseases, Cognition Disorders, Diagnostic Techniques, Ophthalmological, Disability Evaluation, Follow-Up Studies, Humans, Hypertension, Incidence, Kaplan-Meier Estimate, Microcirculation, Predictive Value of Tests, Prevalence, Prognosis, Prospective Studies, Retinal Diseases, Risk Factors, Smoking}, issn = {1538-3601}, doi = {10.1001/archophthalmol.2011.360}, author = {Kim, Dae Hyun and Chaves, Paulo H M and Newman, Anne B and Klein, Ronald and Sarnak, Mark J and Newton, Elizabeth and Strotmeyer, Elsa S and Burke, Gregory L and Lipsitz, Lewis A} } @article {6027, title = {Genetic loci for retinal arteriolar microcirculation.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e65804}, abstract = {

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{\texttimes}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{\texttimes}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.

}, keywords = {Aged, Aged, 80 and over, Arterioles, Chromosomes, Human, Pair 5, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Male, MEF2 Transcription Factors, Microcirculation, Middle Aged, Models, Genetic, Retinal Vessels}, issn = {1932-6203}, doi = {10.1371/journal.pone.0065804}, author = {Sim, Xueling and Jensen, Richard A and Ikram, M Kamran and Cotch, Mary Frances and Li, Xiaohui and Macgregor, Stuart and Xie, Jing and Smith, Albert Vernon and Boerwinkle, Eric and Mitchell, Paul and Klein, Ronald and Klein, Barbara E K and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and de Jong, Paulus T V M and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Launer, Lenore J and Attia, John and Baird, Paul N and Harrap, Stephen and Holliday, Elizabeth G and Inouye, Michael and Rochtchina, Elena and Scott, Rodney J and Viswanathan, Ananth and Li, Guo and Smith, Nicholas L and Wiggins, Kerri L and Kuo, Jane Z and Taylor, Kent D and Hewitt, Alex W and Martin, Nicholas G and Montgomery, Grant W and Sun, Cong and Young, Terri L and Mackey, David A and van Zuydam, Natalie R and Doney, Alex S F and Palmer, Colin N A and Morris, Andrew D and Rotter, Jerome I and Tai, E Shyong and Gudnason, Vilmundur and Vingerling, Johannes R and Siscovick, David S and Wang, Jie Jin and Wong, Tien Y} } @article {6072, title = {Genome-wide association study of retinopathy in individuals without diabetes.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e54232}, abstract = {

BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.

METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.

RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3{\textpm}0.23 (beta {\textpm} standard error), p = 6.6{\texttimes}10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (\~{}2\%), the quality of the imputation was moderate (r(2) \~{}0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.

CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

}, keywords = {Aged, Aged, 80 and over, Female, Genome-Wide Association Study, Genotype, Histone Deacetylases, Humans, Hypertension, Male, Polymorphism, Single Nucleotide, Repressor Proteins, Retinal Diseases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0054232}, author = {Jensen, Richard A and Sim, Xueling and Li, Xiaohui and Cotch, Mary Frances and Ikram, M Kamran and Holliday, Elizabeth G and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Klein, Barbara E K and Launer, Lenore J and Smith, Albert Vernon and Boerwinkle, Eric and Cheung, Ning and Hewitt, Alex W and Liew, Gerald and Mitchell, Paul and Wang, Jie Jin and Attia, John and Scott, Rodney and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Taylor, Kent and Hofman, Albert and de Jong, Paulus T V M and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Tay, Wan-Ting and Teo, Yik Ying and Seielstad, Mark and Liu, Jianjun and Cheng, Ching-Yu and Saw, Seang-Mei and Aung, Tin and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Nalls, Mike A and Wiggins, Kerri L and Kuo, Jane Z and van Duijn, Cornelia M and Gudnason, Vilmundur and Klein, Ronald and Siscovick, David S and Rotter, Jerome I and Tai, E Shong and Vingerling, Johannes and Wong, Tien Y} } @article {5875, title = {Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e53830}, abstract = {

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5{\texttimes}10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3{\texttimes}10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1{\texttimes}10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9{\texttimes}10(-6)) and upstream of GLI2 (rs6721654; P = 6.5{\texttimes}10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5{\texttimes}10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

}, keywords = {Apolipoproteins E, Complement Factor H, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Kruppel-Like Transcription Factors, Macular Degeneration, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Proteins, Risk Factors, Zinc Finger Protein Gli3}, issn = {1932-6203}, doi = {10.1371/journal.pone.0053830}, author = {Holliday, Elizabeth G and Smith, Albert V and Cornes, Belinda K and Buitendijk, Gabri{\"e}lle H S and Jensen, Richard A and Sim, Xueling and Aspelund, Thor and Aung, Tin and Baird, Paul N and Boerwinkle, Eric and Cheng, Ching Yu and van Duijn, Cornelia M and Eiriksdottir, Gudny and Gudnason, Vilmundur and Harris, Tamara and Hewitt, Alex W and Inouye, Michael and Jonasson, Fridbert and Klein, Barbara E K and Launer, Lenore and Li, Xiaohui and Liew, Gerald and Lumley, Thomas and McElduff, Patrick and McKnight, Barbara and Mitchell, Paul and Psaty, Bruce M and Rochtchina, Elena and Rotter, Jerome I and Scott, Rodney J and Tay, Wanting and Taylor, Kent and Teo, Yik Ying and Uitterlinden, Andr{\'e} G and Viswanathan, Ananth and Xie, Sophia and Vingerling, Johannes R and Klaver, Caroline C W and Tai, E Shyong and Siscovick, David and Klein, Ronald and Cotch, Mary Frances and Wong, Tien Y and Attia, John and Wang, Jie Jin} } @article {7019, title = {Genetic determinants of age-related macular degeneration in diverse populations from the PAGE study.}, journal = {Invest Ophthalmol Vis Sci}, volume = {55}, year = {2014}, month = {2014 Sep 9}, pages = {6839-50}, abstract = {

PURPOSE: Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci.

METHODS: Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study.

RESULTS: Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05{\texttimes}10(-8) and P=6.36{\texttimes}10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing.

CONCLUSIONS: While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.

}, keywords = {Adult, Aged, Aged, 80 and over, Complement Factor H, DNA, Ethnic Groups, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Macular Degeneration, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Prevalence, Prospective Studies, Proteins, Risk Factors, United States}, issn = {1552-5783}, doi = {10.1167/iovs.14-14246}, author = {Restrepo, Nicole A and Spencer, Kylee L and Goodloe, Robert and Garrett, Tiana A and Heiss, Gerardo and B{\r u}zkov{\'a}, Petra and Jorgensen, Neal and Jensen, Richard A and Matise, Tara C and Hindorff, Lucia A and Klein, Barbara E K and Klein, Ronald and Wong, Tien Y and Cheng, Ching-Yu and Cornes, Belinda K and Tai, E-Shyong and Ritchie, Marylyn D and Haines, Jonathan L and Crawford, Dana C} } @article {6363, title = {Prognostic implications of microvascular and macrovascular abnormalities in older adults: cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Dec}, pages = {1495-502}, abstract = {

BACKGROUND: Microvascular and macrovascular abnormalities are frequently found on noninvasive tests performed in older adults. Their prognostic implications on disability and life expectancy have not been collectively assessed.

METHODS: This prospective study included 2,452 adults (mean age: 79.5 years) with available measures of microvascular (brain, retina, kidney) and macrovascular abnormalities (brain, carotid, coronary, peripheral artery) in the Cardiovascular Health Study. The burden of microvascular and macrovascular abnormalities was examined in relation to total, activity-of-daily-living disability-free, and severe disability-free life expectancies in the next 10 years (1999-2009).

RESULTS: At 75 years, individuals with low burden of both abnormalities lived, on average, 8.71 years (95\% confidence interval: 8.29, 9.12) of which 7.67 years (7.16, 8.17) were without disability. In comparison, individuals with high burden of both abnormalities had shortest total life expectancy (6.95 years [6.52, 7.37]; p < .001) and disability-free life expectancy (5.60 years [5.10, 6.11]; p < .001). Although total life expectancy was similarly reduced for those with high burden of either type of abnormalities (microvascular: 7.96 years [7.50, 8.42] vs macrovascular: 8.25 years [7.80, 8.70]; p = .10), microvascular abnormalities seemed to have larger impact than macrovascular abnormalities on disability-free life expectancy (6.45 years [5.90, 6.99] vs 6.96 years [6.43, 7.48]; p = .016). These results were consistent for severe disability-free life expectancy and in individuals without clinical cardiovascular disease.

CONCLUSIONS: Considering both microvascular and macrovascular abnormalities from multiple noninvasive tests may provide additional prognostic information on how older adults spend their remaining life. Optimal clinical use of this information remains to be determined.

}, keywords = {Aged, Aged, 80 and over, Aging, Ankle Brachial Index, Disability Evaluation, Electrocardiography, Female, Follow-Up Studies, Forecasting, Humans, Life Expectancy, Magnetic Resonance Imaging, Male, Microcirculation, Prognosis, Prospective Studies, Risk Factors, Vascular Malformations}, issn = {1758-535X}, doi = {10.1093/gerona/glu074}, author = {Kim, Dae Hyun and Grodstein, Francine and Newman, Anne B and Chaves, Paulo H M and Odden, Michelle C and Klein, Ronald and Sarnak, Mark J and Patel, Kushang V and Lipsitz, Lewis A} } @article {6852, title = {Microvascular and Macrovascular Abnormalities and Cognitive and Physical Function in Older Adults: Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {63}, year = {2015}, month = {2015 Sep}, pages = {1886-93}, abstract = {

OBJECTIVES: To evaluate and compare the associations between microvascular and macrovascular abnormalities and cognitive and physical function

DESIGN: Cross-sectional analysis of the Cardiovascular Health Study (1998-1999).

SETTING: Community.

PARTICIPANTS: Individuals with available data on three or more of five microvascular abnormalities (brain, retina, kidney) and three or more of six macrovascular abnormalities (brain, carotid artery, heart, peripheral artery) (N = 2,452; mean age 79.5).

MEASUREMENTS: Standardized composite scores derived from three cognitive tests (Modified Mini-Mental State Examination, Digit-Symbol Substitution Test, Trail-Making Test (TMT)) and three physical tests (gait speed, grip strength, 5-time sit to stand)

RESULTS: Participants with high microvascular and macrovascular burden had worse cognitive (mean score difference = -0.30, 95\% confidence interval (CI) = -0.37 to -0.24) and physical (mean score difference = -0.32, 95\% CI = -0.38 to -0.26) function than those with low microvascular and macrovascular burden. Individuals with high microvascular burden alone had similarly lower scores than those with high macrovascular burden alone (cognitive function: -0.16, 95\% CI = -0.24 to -0.08 vs -0.13, 95\% CI = -0.20 to -0.06; physical function: -0.15, 95\% CI = -0.22 to -0.08 vs -0.12, 95\% CI = -0.18 to -0.06). Psychomotor speed and working memory, assessed using the TMT, were only impaired in the presence of high microvascular burden. Of the 11 vascular abnormalities considered, white matter hyperintensity, cystatin C-based glomerular filtration rate, large brain infarct, and ankle-arm index were independently associated with cognitive and physical function.

CONCLUSION: Microvascular and macrovascular abnormalities assessed using noninvasive tests of the brain, kidney, and peripheral artery were independently associated with poor cognitive and physical function in older adults. Future research should evaluate the usefulness of these tests in prognostication.

}, keywords = {Aged, Aged, 80 and over, Cognition, Cross-Sectional Studies, Female, Humans, Male, Neuropsychological Tests, Vascular Malformations}, issn = {1532-5415}, doi = {10.1111/jgs.13594}, author = {Kim, Dae Hyun and Grodstein, Francine and Newman, Anne B and Chaves, Paulo H M and Odden, Michelle C and Klein, Ronald and Sarnak, Mark J and Lipsitz, Lewis A} } @article {7597, title = {Association of Diabetic Macular Edema and Proliferative Diabetic Retinopathy With Cardiovascular Disease: A Systematic Review and Meta-analysis.}, journal = {JAMA Ophthalmol}, volume = {135}, year = {2017}, month = {2017 Jun 01}, pages = {586-593}, abstract = {

Importance: Previous studies on the relationship between diabetic retinopathy (DR) and cardiovascular disease (CVD) focused on the early stages of DR. Understanding whether patients with type 2 diabetes and severe stages of DR (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]) have a higher risk of CVD will allow physicians to more effectively counsel patients.

Objective: To examine the association of severe stages of DR (DME and PDR) with incident CVD in patients with type 2 diabetes.

Data Sources: English-language publications were reviewed for articles evaluating the relationship of DR and CVD in MEDLINE, EMBASE, Current Contents, and the Cochrane Library from inception (January 1, 1950) to December 31, 2014, using the search terms diabetic retinopathy OR macular edema AND stroke OR cerebrovascular disease OR coronary artery disease OR heart failure OR myocardial infarction OR angina pectoris OR acute coronary syndrome OR coronary artery disease OR cardiomyopathy.

Study Selection: Among 656 studies screened for eligibility, 7604 individuals were included from 8 prospective population-based studies with data on photographic-based DR grading, follow-up visits, and well-defined incident CVD end point.

Data Extraction and Synthesis: Two independent reviewers conducted a systematic search of the 4 databases, and a single pooled database was developed. Incidence rate ratios (IRRs) were estimated for patients with DME, PDR, and vision-threatening DR, compared with persons without these conditions, by using individual participant data followed by a standard inverse-variance meta-analysis (2-step analysis). The review and analyses were performed from January 1, 2009, to January 1, 2017.

Main Outcome and Measures: Incident CVD, including coronary heart disease, stroke, or death from cardiovascular causes.

Results: Among 7604 patients with type 2 diabetes, the prevalence of DME was 4.6\% and PDR, 7.4\%. After a mean follow-up of 5.9 years (range, 3.2-10.1 years), 1203 incident CVD events, including 916 coronary heart disease cases, were reported. Persons with DME or PDR were more likely to have incident CVD (IRR, 1.39; 95\% CI, 1.16-1.67) and fatal CVD (IRR, 2.33; 95\% CI, 1.49-3.67) compared with those without DME or PDR.

Conclusions and Relevance: Patients with type 2 diabetes and DME or PDR have an increased risk of incident CVD, which suggests that these persons should be followed up more closely to prevent CVD.

}, keywords = {Cardiovascular Diseases, Diabetic Retinopathy, Global Health, Humans, Incidence, Macular Edema, Risk Factors}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2017.0988}, author = {Xie, Jing and Ikram, M Kamran and Cotch, Mary Frances and Klein, Barbara and Varma, Rohit and Shaw, Jonathan E and Klein, Ronald and Mitchell, Paul and Lamoureux, Ecosse L and Wong, Tien Yin} } @article {7590, title = {Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.}, journal = {Diabetes}, volume = {66}, year = {2017}, month = {2017 12}, pages = {3130-3141}, abstract = {

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

}, keywords = {Aged, Diabetic Retinopathy, Female, Genome-Wide Association Study, Humans, Lipids, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Risk}, issn = {1939-327X}, doi = {10.2337/db17-0398}, author = {Sobrin, Lucia and Chong, Yong He and Fan, Qiao and Gan, Alfred and Stanwyck, Lynn K and Kaidonis, Georgia and Craig, Jamie E and Kim, Jihye and Liao, Wen-Ling and Huang, Yu-Chuen and Lee, Wen-Jane and Hung, Yi-Jen and Guo, Xiuqing and Hai, Yang and Ipp, Eli and Pollack, Samuela and Hancock, Heather and Price, Alkes and Penman, Alan and Mitchell, Paul and Liew, Gerald and Smith, Albert V and Gudnason, Vilmundur and Tan, Gavin and Klein, Barbara E K and Kuo, Jane and Li, Xiaohui and Christiansen, Mark W and Psaty, Bruce M and Sandow, Kevin and Jensen, Richard A and Klein, Ronald and Cotch, Mary Frances and Wang, Jie Jin and Jia, Yucheng and Chen, Ching J and Chen, Yii-Der Ida and Rotter, Jerome I and Tsai, Fuu-Jen and Hanis, Craig L and Burdon, Kathryn P and Wong, Tien Yin and Cheng, Ching-Yu} }