Showing papers by "Ronald Klein published in 2007"
TL;DR: The 15-year cumulative incidence of late AMD in people > or = 75 years of age (8%) indicates a public health problem of significant proportions because the United States population this age is expected to increase by 54% between 2005 and 2025.
601 citations
TL;DR: Retinal vessel diameter may predict risk of CHD and stroke deaths in middle-aged persons and is associated with an increased risk of stroke-mortality among persons aged 43-69.
Abstract: Aims The retinal microvasculature may reflect pre-clinical changes in the cerebral and coronary microcirculations. We assessed whether smaller retinal arterioles and larger venules predicted coronary heart disease (CHD)- and stroke-mortality. Methods and results We pooled data from the Beaver Dam Eye Study (n ¼ 4926, aged 43–86) and the Blue Mountains Eye Study (n ¼ 3654, aged 49–97). Retinal vessel diameters were measured from digitized retinal photographs. Change point models were used to assess and document the existence of threshold effects. We defined smaller arterioles as diameters within the narrowest quintile and larger venules as diameters within the widest quintile, with other quintiles as the reference. Of 8550 participants, 7494 (88%) with complete data were included, of whom 653 died from CHD and 299 from stroke over 10–12 years follow-up. After multivariable adjustment, each standard deviation (SD) increase in arteriolar diameter, or SD decrease in venular diameter, was not found to be significantly associated with either CHD-mortality or stroke-mortality. However, smaller arterioles [hazard ratio (HR) 1.34, 95% confidence interval (CI) 1.11–1.62] and larger venules (HR 1.24, CI 1.02–1.52), predicted increased risk of CHD-mortality. These associations were mainly evident among persons aged 43–69 (smaller arterioles: HR 1.70, CI 1.27–2.28; larger venules: HR 1.41, CI 1.06–1.89). Smaller arterioles (HR 1.64, CI 1.00–2.67) and larger venules (HR 1.53, CI 0.94–2.47) were also associated with an increased risk of stroke-mortality among persons aged 43–69. Conclusion Retinal vessel diameter may predict risk of CHD and stroke deaths in middle-aged persons.
298 citations
TL;DR: The data support the role of microvascular disease in the pathogenesis of CHD in diabetes and in individuals with type 2 diabetes, the presence of retinopathy signifies an increased CHD risk, independent of known risk factors.
Abstract: Objective: To examine the relation of diabetic retinopathy to incident coronary heart disease (CHD).
Research Design and Methods: A population-based, prospective cohort study consisting of 1,524 middle-aged persons with type 2 diabetes without prevalent CHD and stroke at baseline. Diabetic retinopathy signs were graded from retinal photographs according to the Early Treatment for Diabetic Retinopathy Severity Scale. Incident CHD events (myocardial infarction, fatal CHD or coronary revascularization) were identified and validated following standardized protocols.
Results: In our study, 214 (14.7%) participants had diabetic retinopathy. Over an average follow-up of 7.8 years, there were 209 (13.7%) incident CHD events. After controlling for age, gender, race, study center, fasting glucose, glycosylated hemoglobin, duration of diabetes, blood pressure, anti-hypertensive treatment, cigarette smoking, body mass index and lipid profile, the presence of diabetic retinopathy was associated with a two-fold higher risk of incident CHD events (Hazard rate ratios [HR] 2.07, 95% confidence interval [CI]: 1.38-3.11) and a three fold higher risk of fatal CHD (HR 3.35; 95% CI: 1.40-8.01). Further adjustments for inflammatory markers, carotid artery intima-media thickness or nephropathy had minimal impact on the association. The increased risk of CHD was significant in both men (HR 1.89; 95% CI: 1.08-3.31) and women (HR 2.16; 95% CI: 1.16-4.02) with diabetic retinopathy.
Conclusions: In persons with type 2 diabetes, the presence of retinopathy signifies an increased CHD risk, independent of known risk factors. Our data support the role of microvascular disease in the pathogenesis of CHD in diabetes.
239 citations
TL;DR: Retinal vessel caliber is independently associated with risk of incident nephropathy, lower extremity amputation, and stroke mortality in persons with type 2 diabetes.
173 citations
TL;DR: Retinal vein occlusion in persons aged 43 to 69 years may signal a doubling of the risk of cardiovascular mortality, and in people aged less than 70 years, baseline RVO was associated with higher cardiovascular mortality.
170 citations
TL;DR: The findings suggest AVR provides less information with regards to predicting systemic outcomes than its two components, arteriolar and venular calibers, while modeling both simultaneously appears to provide unbiased, biologically plausible results.
Abstract: PURPOSE. The arteriole to venule ratio (AVR) is widely used in studies of the associations of retinal microvascular disease with systemic and ocular outcomes. This is a discussion of the limitations of AVR; a comparison of its predictive information with that of its components, arteriolar and venular caliber; and a description of a suggested alternative method of modeling arteriolar and venular calibers directly. METHODS. Data from the population-based Blue Mountains Eye Study were used to compare the predictive information in models using AVR with models using arteriolar and venular calibers directly. Determination was made of how the apparent relationship between vessel caliber and two systemic outcomes (blood pressure [BP] and white blood cell count [WBC]) was influenced by the choice of regression model. These findings were interpreted with reference to the known biological relationship among vessel calibers, BP, and WBC. RESULTS. Models using arteriolar and venular calibers directly had more predictive information than models using AVR. The apparent relationship of vessel caliber to BP and WBC differed substantially, depending on the model chosen. For example, after adjustment for age, sex, and other covariates, decreasing venular caliber was associated with higher systolic BP when modeled separately, but was associated with lower systolic BP when modeled simultaneously with arteriolar caliber. CONCLUSIONS. The findings suggest AVR provides less information with regards to predicting systemic outcomes than its two components. Modeling arteriolar and venular calibers separately could be biased by confounding, while modeling both simultaneously appears to provide unbiased, biologically plausible results. The use of this approach is recommended in future research relating retinal vascular caliber to systemic or ocular outcomes.
151 citations
TL;DR: Narrower retinal arteriolar caliber is associated with LV concentric remodeling independent of traditional risk factors and coronary atherosclerotic burden, supporting the hypothesis that microvascular disease may contribute to cardiac remodeling.
139 citations
TL;DR: Diabetic retinopathy predicts incident ischemic stroke in people with diabetes, independent of other risk factors, and is associated with an increased risk of isChemic stroke.
Abstract: Background and Purpose— The relationship between diabetic retinopathy and ischemic stroke is uncertain and examined in this study. Methods— A population-based, prospective cohort study of 1617 middle-aged persons with diabetes. Diabetic retinopathy signs were ascertained from retinal photographs, and incident ischemic stroke events were prospectively identified and validated. Results— Over an average follow-up of 7.8 years, there were 75 ischemic stroke events. After adjustment for age, gender, race, center, 6-year mean arterial blood pressure, anti-hypertensive treatment use, fasting glucose, insulin treatment, duration of diabetes, high-density lipoprotein and low-density lipoprotein cholesterol levels and cigarette smoking status, diabetic retinopathy was associated with an increased risk of ischemic stroke (hazard rate ratio, 2.34; 95% CI, 1.13 to 4.86). Conclusions— Diabetic retinopathy predicts incident ischemic stroke in people with diabetes, independent of other risk factors.
139 citations
TL;DR: In this paper, the authors used the Medical Outcomes Study Short Form Health Survey (SF-36) to assess the impact of tinnitus on quality of life in older adults.
Abstract: Few population-based data exist to assess the impact of tinnitus on quality of life. As part of the Epidemiology of Hearing Loss Study, self-reported data on tinnitus and quality of life were obtained by interview at the first follow-up examination (1998-2000; N = 2800; ages 53-97 years). The Medical Outcomes Study Short Form Health Survey (SF-36) was used to assess quality of life. Adjusted mean SF-36 scores decreased (worsened) with increasing tinnitus severity (None, Mild, Moderate, Severe) for the Role-Physical, Bodily Pain, Vitality, and Mental Health domains, and the Physical Component Summary scale (F-tests for linear trend, p < .05). Scores tended to be lower for those who first reported tinnitus at the follow-up (five-year incidence of tinnitus) compared to those who reported tinnitus at the baseline and follow-up examinations (prevalent tinnitus). This study documents clear associations between tinnitus and reduced quality of life in this large cohort of older adults.
129 citations
TL;DR: It is concluded that increased aortic stiffness is associated with retinal arteriolar narrowing, independent of measured blood pressure levels and vascular risk factors, and changes in the microvasculature may play a role linking aorti stiffness with clinical cardiovascular events.
Abstract: Increased aortic stiffness and retinal arteriolar narrowing are subclinical vascular effects of chronic hypertension and predict future cardiovascular events. The relationship between these 2 vascular measures is uncertain and is examined in the Multi-Ethnic Study of Atherosclerosis. This cross-sectional analysis involves 3425 participants (aged 45 to 85 years) free of clinical cardiovascular disease. Retinal vascular caliber was quantified from digital retinal photographs using standardized protocols. Aortic distensibility was determined from chest MRI. After controlling for age, squared age, gender, race, study center, height, weight, heart rate, cigarette smoking, past and current systolic blood pressure, use of antihypertensive medications, diabetes, fasting glucose, lipid profile, and C-reactive protein, reduced aortic distensibility (first versus fourth distensibility quartile) was associated with increased odds of retinal arteriolar narrowing (odds ratio: 1.72; 95% CI: 1.15 to 2.58, comparing lowest to highest quartile of arteriolar caliber). Further adjustments for atherosclerotic measures (carotid intima-media thickness, coronary calcium score, and ankle brachial index) had minimal impact on this association (odds ratio: 1.70; 95% CI: 1.13 to 2.55). Reduced aortic distensibility was not associated with retinal venular caliber. We conclude that increased aortic stiffness is associated with retinal arteriolar narrowing, independent of measured blood pressure levels and vascular risk factors. These data suggest that changes in the microvasculature may play a role linking aortic stiffness with clinical cardiovascular events.
129 citations
TL;DR: AMD is associated with older age, female gender, being white, and having a history of MI, hypertension, and diabetes, and these findings suggest the possibility of shared common antecedents between MI and AMD.
University of Wisconsin-Madison1, University of Michigan2, Stony Brook University3, Massachusetts Eye and Ear Infirmary4, Wayne State University5, University of Iowa6, University of California, Irvine7, Geisinger Health System8, University of Pittsburgh9, University of Nevada, Reno10, University of Tennessee Health Science Center11
TL;DR: Results suggest that smoking, use of calcium channel blockers, diabetes, and obesity are risk factors for late AMD in women, however, the association of late AMD with systolic blood pressure and the effects of other CVD risk factors on early AMD need to be further explored.
TL;DR: In older persons, this study shows a modest cross-sectional association between retinopathy signs with poorer cognitive function and, in persons with hypertension, with dementia.
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 ...
TL;DR: Despite remarkable progress in understanding AMD, many questions remain that can only be addressed by continuation of longitudinal population-based studies.
Abstract: Purpose: To provide an over-view of progress in the epidemiology of age-related macular degeneration. Methods: Review of epidemiological and clinical trial findings regarding AMD since initial National Eye Institute sponsored epidemiology meeting in 1982. Results: A growing number new epidemiological studies have provided data on the prevalence and long-term incidence of AMD. Despite a similar prevalence of early AMD in whites, blacks, and hispanics, whites have higher prevalence of late AMD. An age-period cohort effect has been shown in the Beaver Dam Eye Study suggesting that AMD incidence may be declining among younger birth cohorts. Genetic factors such as complement factor H have been shown to be strongly associated with AMD. Smoking is strongly related to risk of AMD. Randomized controlled clinical trials have shown the benefits of zinc-antioxidant supplementation in preventing visual loss in persons with signs of early AMD and anti-vascular endothelial growth factor agents in restoring vision in ey...
TL;DR: These data provide no evidence of an association between early AMD signs with incident CHD and all-cause mortality in middle-aged persons and individuals with late AMD appear to have a higher rate of CHD events than those without late AMD, but this finding should be interpreted cautiously.
TL;DR: It is proposed that an area on chromosome 1 may harbor a gene or genes conferring susceptibility to diabetic retinopathy, as well as other areas of suggestive linkage, which are found using variance components modeling.
Abstract: Hyperglycemia and long duration of diabetes are widely recognized risk factors for diabetic retinopathy, but inherited susceptibility may also play a role because retinopathy aggregates in families. A genome-wide linkage analysis was conducted in 211 sibships in which > or =2 siblings had diabetes and retinal photographs were available from a longitudinal study. These sibships were a subset of 322 sibships who had participated in a previous linkage study of diabetes and related traits; they comprised 607 diabetic individuals in 725 sibpairs. Retinal photographs were graded for presence and severity of diabetic retinopathy according to a modification of the Airlie House classification system. The grade for the worse eye was adjusted for age, sex, and diabetes duration and analyzed as a quantitative trait. Heritability of diabetic retinopathy in this group was 18% (95% CI 2-36). A genome-wide linkage analysis using variance components modeling found evidence of linkage on chromosome 1p. Using single-point analysis, the peak logarithm of odds (LOD) was 3.1 for marker D1S3669 (34.2 cM), whereas with multipoint analysis the peak LOD was 2.58 at 35 cM. No other areas of suggestive linkage were found. We propose that an area on chromosome 1 may harbor a gene or genes conferring susceptibility to diabetic retinopathy.
TL;DR: The study showed that the high risk of DR in adult Latinos is independently associated with both nonmodifiable and modifiable risk factors, and suggests that controlling hyperglycemia and hypertension in this ethnic group may reduce the highrisk of having DR associated with T2DM.
TL;DR: This study provides additional support for the CFH and LOC387715 genes in ARM susceptibility via the evaluation of cohorts that had different ascertainment schemes regarding ARM status and through the meta-analyses.
TL;DR: It is shown that retinopathy signs are independently associated with CAC, supporting the concept that common pathophysiologic processes may underlie both micro- and macrovascular disease.
Abstract: Microvascular disease, reflected by retinal vascular changes, has been shown to predict clinical coronary heart disease. Whether retinal vascular changes are associated with subclinical coronary artery disease is unclear and was examined in this study. The authors conducted a multiethnic, population-based study of 6,147 persons aged 45-84 years, sampled from six US communities in 2002-2004, who were free of clinical cardiovascular disease. Coronary artery calcification (CAC), a noninvasive measure of subclinical coronary artery disease, was assessed by cardiac computed tomography scanning and categorized into three groups of increasing severity: none (average CAC score = 0), mild (1-100), and moderate-to-severe (>100). Retinopathy signs and retinal vascular caliber were graded from retinal photographs following standardized protocols. After adjustment for age, gender, race/ethnicity, blood pressure, diabetes, lipid profile, smoking, and other risk factors, retinopathy was associated with having a moderate-to-severe CAC score (odds ratio = 1.43, 95% confidence interval: 1.18, 1.75). This association remained significant in both men and women and in persons with and without diabetes or hypertension. Variations in retinal vascular caliber were not significantly associated with CAC score. This study shows that retinopathy signs are independently associated with CAC, supporting the concept that common pathophysiologic processes may underlie both micro- and macrovascular disease.
TL;DR: Elevated glycosylated hemoglobin levels were associated with all-cause and cardiovascular mortality, independent of duration of diabetes, smoking, hypertension, and proteinuria, and this association was present among both sexes and persisted in subgroup analyses by categories of diabetes duration,smoking, body mass index, proteinuria and retinopathy.
Abstract: Hyperglycemia is implicated in the development and progression of microvascular complications in type 1 diabetes. In contrast, the association between hyperglycemia and macrovascular complications or mortality in type 1 diabetes is not clear. The authors studied a population-based cohort of 879 individuals with type 1 diabetes from Wisconsin, free of cardiovascular disease and end-stage renal disease at the baseline examination (1980-1982). The main outcome of interest was all-cause (n=201) and cardiovascular (n=132) mortality as of December 31, 2001. Elevated glycosylated hemoglobin levels were associated with all-cause and cardiovascular mortality, independent of duration of diabetes, smoking, hypertension, and proteinuria. The multivariable relative risks comparing the highest quartile of glycosylated hemoglobin (>or=12.1%) with the lowest quartile (
TL;DR: In this article, the authors investigated whether composite measures of chronic glycemia correlate or predict complications better than individual components, while Orchard et al. reported evidence against the hypothesis, while we reported evidence for the hypothesis.
Abstract: We are pleased to respond to the letter by Orchard et al. (1), especially since they first raised the following question: Do composite measures of chronic glycemia correlate or predict complications better than individual components? Orchard et al. reported evidence against the hypothesis, while we (2) reported evidence for the hypothesis. Having considered their suggestions, we offer an explanation for why their conclusions differed from ours.
Orchard et al. (3) compared the fit from two models, one consisting …
TL;DR: In this article, the effect of baseline dietary glycemic index (dGI) on the progression of age-related macular degeneration (AMD) was evaluated using multivariate Cox proportional-hazards regression.
TL;DR: The authors conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least two diabetic siblings.
Abstract: We conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least two diabetic siblings. The sample included 567 retinopathy case subjects comprising 282 affected sibling pairs. Retinopathy was classified as none, early nonproliferative, moderate-to-severe nonproliferative, or proliferative. Using 360 polymorphic markers (average spacing 9.4 cM), we conducted nonparametric linkage analysis followed by ordered-subset analysis (OSA) ranking families by average age of diabetes diagnosis. For any retinopathy, the highest LOD scores including all families were on chromosomes 3 (2.41 at 117 cM) and 12 (2.47 at 15.5). OSA logarithm of odds (LOD) scores >2 for any retinopathy occurred on chromosomes 12 (4.47 at 13.2 cM), 15 (3.65 at 100.6), and 20 (2.67 at 54.1). Scores >2 for either moderate-to-severe nonproliferative or proliferative retinopathy occurred on chromosomes 5 (2.53 at 11.2 cM), 6 (2.28 at 30.6), and 19 (2.21 at 100.6). Thus, unconditional linkage analysis revealed suggestive evidence of linkage with retinopathy on two chromosomes, whereas OSA revealed strong evidence of linkage on two chromosomes, and suggestive evidence on four. Candidate genes were identified in most implicated regions.
TL;DR: Middle-aged persons with migraine and other headaches were more likely to have retinopathy signs, supporting the hypothesis that neurovascular dysfunction may underlie vascular headaches.
Abstract: Rose and colleagues concluded that “persons with migraine and other headaches were more likely to have retinopathy signs.”1 They divided the study population into four groups: migraine/other headache with aura; migraine without aura; other headache without aura; and no headache. The names of the last two groups may be misleading because they pertain only to headaches lasting more than 4 hours. This was not mentioned in the Discussion or Conclusion.
Furthermore, the authors used the heading “no headache” group yet several subjects assigned to this group had different headaches—lasting < 4 hours—as a control for the three remaining headache groups. There are several headache types that may last <4 hours and tension-type headache (TTH) is the most common. According to International Headache Society (IHS) criteria,2 episodic TTH duration …
TL;DR: The relationship between arterial stiffness and retinal vascular caliber is examined and it is found that arterIAL stiffness is a newly recognized risk factor for stroke.
Abstract: Objective
Arterial stiffness is a newly recognized risk factor for stroke. Whether this is mediated by small- or large-artery disease is unknown. In this study, we examined the relationship between arterial stiffness and retinal vascular caliber.
Methods
A cross-sectional, population-based study of 5,731 participants (aged 45–84 years) who were free of clinical cardiovascular disease (the Multi-Ethnic Study of Atherosclerosis). Retinal arteriolar and venular calibers were measured from retinal photographs according to standardized protocols. Small- and large-artery compliance was determined from pulse contour analysis.
Results
After adjusting for age, sex, blood pressure, diabetes, smoking, lipid profile, and other risk factors, reduced large-artery compliance was associated with smaller retinal arteriolar caliber; each standard deviation decrease in large-artery compliance was associated with a 0.70μm (p = 0.002) decrease in retinal arteriolar caliber. After adjusting for the same set of risk factors, reduced small-artery compliance was associated with wider retinal venular caliber; each standard deviation decrease in small artery compliance was associated with a 1.43μm (p = 0.001) increase in retinal venular caliber. These associations remained significant after further adjustments for large-vessel atherosclerosis (carotid intima-media thickness, coronary artery calcium, and ankle–arm index).
Interpretation
Reduced arterial wall compliance in large arterial beds is associated with retinal arteriolar narrowing, whereas reduced arterial wall compliance in small arterial beds is associated with retinal venular widening. These data may provide further insights into the effects of altered arterial stiffness on the cerebral microcirculation. Ann Neurol 2007
TL;DR: Higher CRP levels are associated with PAD among US adults free of CVD, diabetes, and hypertension, and these results suggest that inflammatory mechanisms related to atherosclerosis may be operative even among clinically healthy adults.
TL;DR: Retinopathy signs occur frequently in middle-aged people, even in those without diabetes, and Hypertension and hyperglycemia are risk factors for incident retinopathy.
TL;DR: This work confirms a previously reported linkage region on 22q and identifies 2 novel regions of linkage on 1q and 7p, both of which were previously linked to myopia.
Abstract: Objective To localize genes influencing ocular refraction in subjects in the Beaver Dam Eye Study. Previous studies establish that myopia clusters within families and linkage to myopia has been demonstrated on 2q, 4q, 12q, 17q, 18q, 22q, and Xq. Few studies have examined genetic effects across the entire range of refraction, though linkages to 1p, 3q, 4q, 8p, and 11p have been reported, and our previous analysis of the Beaver Dam Eye Study demonstrated substantial heritability for refraction (68%). Methods We conducted nonparametric sibling-pair and genome-wide linkage analyses on spherical equivalent adjusting for age, education, and nuclear sclerosis, in 834 sibling pairs in 486 extended pedigrees. Results We identified a novel region of suggestive linkage on 1q (multipoint, P P = .0033) previously linked to myopia. Additionally, there was some evidence of linkage to 7p (multipoint, P = .0023). Conclusion Refraction is a complex trait influenced by both genes and environment. Our work confirms a previously reported linkage region on 22q and identifies 2 novel regions of linkage on 1q and 7p. Clinical Relevance Further, genetic research is needed to finemap this trait to identify the causative gene. Modifying the actions of such a gene might lead to a reduction in the risk of refractive error.
TL;DR: Findings do not show an association between statin use and the incidence or progression of AMD over a five-year period.