David Couper

Retinal arteriolar diameter and risk for hypertension.

Context Does narrowing of small arterioles lead to or result from hypertension? Contribution This large prospective study measured diameters of small retinal vessels using digitized photographs in people without preexisting hypertension. After 3 years, more people with narrowed arterioles at baseline had hypertension than did people without any arteriolar narrowing. Implications Smaller arteriolar diameters are independently associated with development of hypertension. Cautions Rather than leading to hypertension, reduced arteriolar diameters at baseline might have reflected elevated blood pressure in persons who did not yet meet diagnostic criteria for hypertension. The Editors Hypertension affects up to 50 million people in the United States and is the single most important modifiable risk factor for stroke (1). Despite extensive research, much remains to be elucidated about the risk factors and pathogenesis of hypertension. A key characteristic of hypertension is the presence of narrowing and vasoconstriction of the small arteries and arterioles in the peripheral circulation (2-4). However, it is uncertain whether reduced arteriolar caliber, by increasing peripheral vascular resistance, contributes to the subsequent development of hypertension (5-7). Prospective clinical data demonstrating a link between smaller arteriolar caliber and risk for hypertension are unavailable, largely because the microcirculation is difficult to evaluate outside of experimental settings (5-7). As a result, the value of specific antihypertensive treatment targeted at the peripheral microcirculation remains questionable (7). The retinal arterioles offer a unique opportunity to noninvasively investigate the relation of arteriolar characteristics to the development of cardiovascular disease (8). We recently developed a method to quantify retinal arteriolar diameters from digitized retinal photographs (9). In this study, we examine whether retinal arteriolar narrowing is related to incident hypertension in a cohort of middle-aged normotensive persons. Methods Study Sample The Atherosclerosis Risk in Communities (ARIC) study is a population-based cohort study with 4 examinations (10). The ARIC study examined 15792 participants 45 to 64 years of age at baseline from 1987 to 1989 (10). The study sample was selected by probability sampling from 4 U.S. communities: Forsyth County, North Carolina; Jackson, Mississippi; suburbs of Minneapolis, Minnesota; and Washington County, Maryland. The Jackson sample included African-American persons only; in the other field centers, samples were representative of the populations in these communities (that is, mostly white persons in the suburbs of Minneapolis and Washington County and about 15% African-American persons in Forsyth County). Initial participation rates were 46% in Jackson and approximately 65% in the other communities. Participants were examined every 3 years; the second examination was done between 1990 and 1992 (n = 14348 [93% of 15440 survivors]), the third examination was done between 1993 and 1995 (n = 12887 [86% of 14944 survivors]), and the fourth examination was done between 1996 and 1998 (n = 11656 [81% of 14485 survivors]). Retinal photographs were taken at the third examination. Of the 12887 persons who returned for this examination, we excluded 38 whose race was neither African American nor white and 42 nonwhite residents in the suburbs of Minneapolis and Washington County, 1009 with no photographs or ungradable photographs, and 1434 who did not participate in the fourth examination. We further excluded 4464 persons with prevalent hypertension diagnosed at the first, second, or third examination and 272 persons with missing hypertension data. The remaining cohort consisted of 5628 normotensive persons at the third examination (Figure 1). Excluded participants (n = 7259) were older and more likely to be African American; had higher systolic and diastolic blood pressures, body mass indexes, waist-to-hip ratios, and fasting glucose and triglyceride levels; had lower high-density lipoprotein cholesterol levels; and were more likely to currently smoke and drink alcohol compared with participants included in the study (data not shown). Figure 1. Study design and population. Institutional review boards at each study site and at the Fundus Photograph Reading Center at the University of Wisconsin, Madison, Wisconsin, approved the study. Informed consent was obtained from all participants. Measurement of Retinal Arteriolar Diameters The retinal photography procedure has been reported in detail (9). Briefly, photographs of the retina of one randomly selected eye were taken after 5 minutes of dark adaptation. To estimate a generalized reduction in arteriolar diameters (referred to as generalized retinal arteriolar narrowing in this paper), the photographs were digitized, and the diameters of all arterioles and venules coursing through a specified area surrounding the optic disc were measured on the computer by graders who were blinded to participant identity. The individual arteriolar and venular diameters were combined into summary measures (in m) and combined as an arteriole-to-venule ratio on the basis of formulas described elsewhere (9). The arteriole-to-venule ratio accounts for magnification differences among photographs and is distributed normally. An arteriole-to-venule ratio of 1.0 indicates that retinal arteriolar diameters were, on average, the same as venular diameters, whereas a smaller ratio represents narrower arterioles, because venular diameters vary little (9). Figure 2 shows examples of retinas with low and high arteriole-to-venule ratios. The intra- and intergrader reliability coefficients for the arteriole-to-venule ratio were 0.84 and 0.79, respectively (9). Figure 2. Retinal photographs with arteriole-to-venule ratios. Top. Bottom. Trained graders who were blinded to retinal vessel measurements also evaluated photographs for the presence of localized areas of arteriolar constriction (referred to as focal retinal arteriolar narrowing) as well as other retinal microvascular characteristics (arteriovenous nicking, microaneurysms, and retinal hemorrhages) by using a standard protocol. Intra- and intergrader statistics ranged from 0.61 to 1.00 (9). Definition of Incident Hypertension Trained technicians performed a standard evaluation of blood pressure at each examination (11). Blood pressure was taken with a random-zero sphygmomanometer, and the mean of the last 2 measurements was used. Hypertension was defined as systolic blood pressure of 140 mm Hg or higher, diastolic blood pressure of 90 mm Hg or higher, or use of antihypertensive medication during the previous 2 weeks (11). Persons without preexisting hypertension at the first, second, or third examination who met these criteria at the fourth examination were defined as having incident hypertension. To examine the effect of current and previous blood pressure on these associations, we defined a persons 6-year average systolic and diastolic blood pressures as the mean of the blood pressure measurements taken at the first, second, and third examinations. The 6-year average systolic and diastolic blood pressures were then included as covariates in the assessment of the independence of retinal arteriolar narrowing with incident hypertension. We categorized a person as having normal blood pressure for systolic values averaging less than 130 mm Hg and diastolic values averaging less than 85 mm Hg and as having high normal blood pressure for systolic values averaging 130 to 139 mm Hg or diastolic values of 85 to 90 mm Hg, according to the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure classification (12). Definition of Other Variables Height and weight were measured with participants dressed in scrub suits. Body mass index, defined as weight/height2, was then computed. We calculated waist-to-hip ratio as the circumference of the waist (umbilical level) divided by the circumference of the hips (maximum circumference of the buttocks). We characterized physical activity by using a sports index; scores ranged from 1 (low) to 5 (high) (13). Diabetes mellitus was defined as a fasting glucose level of 7.0 mmol/L (126 mg/dL) or higher, a nonfasting glucose level of 11.1 mmol/L (200 mg/dL) or higher, or a history of physician-diagnosed diabetes or treatment for diabetes. Blood collection and processing for total and high-density lipoprotein cholesterol levels, triglyceride level, and fasting glucose level are described elsewhere (14). All variables were based on data from the third examination. Statistical Analysis For analysis of generalized retinal arteriolar narrowing, the arteriole-to-venule ratio was categorized into quintiles (with the first quintile indicating the largest arteriolar diameters and the fifth representing the smallest diameters). We also analyzed the ratio as a continuous variable (per SD reduction). Focal retinal arteriolar narrowing and other lesions were defined as binary variables. We used analysis of covariance to compare the arteriole-to-venule ratio and its components (summary measures of retinal arteriolar and venular diameters) between persons who did and did not subsequently develop hypertension. We used multiple logistic regression to calculate the odds ratio of incident hypertension by comparing a given arteriole-to-venule ratio quintile with the first quintile and the presence versus the absence of focal narrowing and other lesions. In these models, we adjusted for age, sex, race, field center, 6-year average systolic and diastolic blood pressures (mm Hg), body mass index (kg/m2), waist-to-hip ratio, sports activity index (1 to 5), diabetes (yes or no), cigarette smoking and alcohol consumption (current, former, or never), total cholesterol level, high-density lipoprotein cholesterol and triglyceride levels (mmol/L), and fasting glucose

Age-Related Macular Degeneration and Risk for Stroke

Context The evidence linking age-related macular degeneration (AMD) to stroke is only from cross-sectional studies. Contribution A total of 10405 participants in a community-based cohort study had retinal photographs in 19931995 and monitoring for incident stroke through 2002. In the 498 participants with early AMD, the incidence of stroke was higher than in those without early AMD: After adjustment for stroke risk factors, the risk ratio was 1.87 (95% CI, 1.21 to 2.88). Cautions Stroke and AMD were relatively infrequent in this middle-aged cohort. Only 1 retinal photograph was taken, through nondilated pupils. Implications This cohort study increases the likelihood that early AMD is a risk factor for stroke. The Editors Age-related macular degeneration (AMD) and stroke affect significant numbers of individuals older than 40 years of age in the United States (1, 2). Research shows that AMD is the most common cause of blindness (1), whereas stroke is a leading cause of death, hospitalization, and severe neurologic disability (2). Both conditions are associated with poorer quality of life and increased socioeconomic burden. Some investigators have suggested that AMD and stroke share common pathogenic mechanisms and risk factors (3). Epidemiologic studies show that individuals with cardiovascular risk factors, such as hypertension and cigarette smoking, are more likely to have AMD (48). Carotid artery disease, a well-established risk factor for stroke (9), has also been associated with AMD (10). Furthermore, emerging research suggests that inflammatory processes and the genes that code for some of these processes may be linked with both stroke and AMD (1115). Few studies, however, have directly examined the relationship between AMD and stroke (6, 1619), and none have been able to demonstrate a consistent association. After adjustment for age, sex, ethnicity, and dietary intake, a cross-sectional analysis of the Cardiovascular Health Study showed that early signs of AMD were associated with evidence of subclinical lesions in cerebral white matter on magnetic resonance imaging (odds ratio, 1.50 [95% CI, 1.05 to 2.16]) but not with prevalent clinical stroke (18). There are no prospective data on whether individuals with AMD are at higher risk for stroke. The purpose of this study is to describe the relationship between AMD and incident clinical stroke in a large, population-based cohort of men and women. Methods Study Sample The Atherosclerosis Risk in Communities study was a population-based cohort study that included 15792 women and men between 45 and 64 years of age at recruitment in 1987 through 1989 (20). The participants were selected by probability sampling from 4 U.S. communities: suburbs of Minneapolis, Minnesota; Washington County, Maryland; Jackson, Mississippi; and Forsyth County, North Carolina. The Jackson sample included African-American participants only; in the other study sites, samples were representative of the populations in these communities (mostly white in Minnesota and Maryland, and about 15% African American in North Carolina). Of 15792 participants at baseline who returned for follow-up at 3-year intervals, 14346 (93% of survivors) had a second examination between 1990 and 1992, and 12887 (86% of survivors) had a third examination between 1993 and 1995. Differences between participants and nonparticipants at the baseline examination have been presented elsewhere (21). Our study cohort consisted of persons who returned for a third examination between 1993 and 1995, when retinal photography was performed (19). Characteristics of the cohort with and without gradable retinal photographs have been previously reported (19). Individuals without gradable photographs were older and more likely to be African American and to have hypertension and diabetes, but sex and smoking status did not differ from those of participants with gradable photographs (19). Of 12887 participants who returned for the examination, we excluded 38 who were not African American or white because of small numbers in other racial groups. We also excluded 42 African-American participants in Minnesota and Maryland to create the following 5 categories of ethnicity and site: white patients in Minnesota and Maryland, African-American patients in Mississippi, white patients in North Carolina, and African-American patients in North Carolina. Other reasons for exclusion were absence of retinal photographs (n= 271) and retinal photographs that were ungradable or showed confounding retinal lesions (such as those associated with advanced hypertension or diabetic retinopathy) (n= 929), prevalent stroke (n= 270), or prevalent coronary heart disease (n= 932). The remaining 10405 persons provided data for the current analysis. Institutional review boards at each site approved the study. All participants provided informed consent, and the study was conducted in accordance with the Declaration of Helsinki. Retinal Photography Procedures and Grading Details of the retinal photography procedures and assessment of AMD have been previously reported (19). After the patient was given 5 minutes to adapt to the darkness, a technician took a 45-degree nonmydriatic retinal photograph that was centered on the region of the optic disc and the macula of 1 randomly selected eye. Investigators at the University of WisconsinMadison, who were masked to the participants identity, graded the photographs for AMD (19) and retinal arteriolar signs (22). We evaluated AMD by using a simplified version of the Wisconsin age-related maculopathy grading system (23), as previously described (19). For grading, a grid consisting of 4 radial lines and 2 circles concentric with the center of the macula was superimposed over the photograph. The outermost circle of the grading grid corresponded to 3450 m in the fundus of an average eye. We examined the macular area circumscribed by this circle for the presence of soft drusen, retinal pigment epithelial depigmentation, increased retinal pigment, pure geographic atrophy, and signs of exudative macular degeneration (subretinal hemorrhage, subretinal fibrous scar, retinal pigment epithelial detachment, and serous detachment of the sensory retina). Soft drusen were defined as those with a diameter larger than 63 m. Epithelial depigmentation of retinal pigment and AMD-associated increases in retinal pigment (the presence of granules or clumps of gray or black pigment in or beneath the retina) were defined as present, absent, or questionable. Any pigmentary abnormality was defined as either depigmentation or increased pigmentation. Early-stage AMD was defined as the presence of soft drusen alone, retinal pigment epithelial depigmentation alone, or a combination of soft drusen with increased retinal pigment or epithelial depigmentation of retinal pigment in the absence of late-stage AMD (19). Late-stage disease was defined as the presence of exudative AMD or pure geographic atrophy (19). Any AMD was defined as either early- or late-stage AMD. Retinal photographs were also evaluated for the presence of retinal arteriolar abnormalities, including arteriovenous nicking and focal arteriolar narrowing, according to standardized methods (22). Quality control procedures, based on repeated assessment of photographs for 520 participants, showed weighted values of 0.67 to 0.81 for intragrader comparisons and 0.55 to 0.92 for intergrader comparisons (19). Incident Stroke Standardized ascertainment and classification of incident stroke events were conducted in the study cohort (24). Information concerning events was obtained during annual follow-up telephone interviews, by reviewing local hospital discharge lists, and by checking death certificates. A hospitalization was considered eligible for possible validation as a stroke if it contained a discharge diagnosis code of cerebrovascular disease (International Classification of Diseases, Ninth Revision [ICD-9], codes 430 to 438, and International Classification of Diseases, Tenth Revision [ICD-10], codes I11 to I52). Out-of-hospital deaths coded as fatal strokes in the death certificate were also identified but were not validated; therefore, these instances were excluded from the case definition. When a potential stroke was identified, hospital records were sent for abstraction by a trained nurse. A computer algorithm and an expert physician reviewer independently classified each eligible case by using criteria adapted from the National Survey of Stroke; these criteria included autopsy evidence, results of neuroimaging and other diagnostic procedures, and information on combinations of symptom type, duration, and severity (24). Differences in diagnosis were adjudicated by another physician reviewer. Details on quality assurance are presented elsewhere (24). Incident stroke was defined to include new stroke events occurring between the time of retinal photography (1993 to 1995) and 31 December 2002. These events were further classified into subcategories of ischemic stroke (thrombotic or embolic brain infarction), hemorrhagic stroke (intracerebral hemorrhage), and subarachnoid hemorrhage, as described elsewhere (24). Definition of Other Variables Participants underwent standardized evaluations of vascular risk factors at each examination (25). Blood pressure was measured 3 times with a random-zero sphygmomanometer; the mean of the last 2 measurements was used for analyses. Examiner-administered questionnaires were used to collect patient data regarding educational level, cigarette smoking status, alcohol consumption, hypertension and diabetes history, and use of antihypertensive and antidiabetic medications. Hypertension was defined as systolic blood pressure 140 mm Hg or higher, diastolic blood pressure 90 mm Hg or higher, or use of antihypertensive medication during the previous 2 weeks. Diabetes mellitus was defined as a fasting plasma glucose level 7.0 mmol/L (126 mg/dL) or higher, a nonfastin

Leptin and incident type 2 diabetes: risk or protection?

Aims/hypothesisThe aim of this study was to investigate the association of leptin levels with incident diabetes in middle-aged adults, taking into account factors purportedly related to leptin resistance.Subjects and methodsWe conducted a case–cohort study (570 incident diabetes cases and 530 non-cases) representing the 9-year experience of 10,275 participants of the Atherosclerosis Risk in Communities Study. Plasma leptin was measured by direct sandwich ELISA.ResultsIn proportional hazards models adjusting for age, study centre, ethnicity and sex, high leptin levels (defined by sex-specific cut-off points) predicted an increased risk of diabetes, with a hazard ratio (HR) comparing the upper with the lower quartile of 3.9 (95% CI 2.6–5.6). However, after further adjusting additionally for obesity indices, fasting insulin, inflammation score, hypertension, triglycerides and adiponectin, high leptin predicted a lower diabetes risk (HR=0.40, 95% CI 0.23–0.67). Additional inclusion of fasting glucose attenuated this protective association (HR=0.59, 95% CI 0.32–1.08, p<0.03 for linear trend across quartiles). In similar models, protective associations were generally seen across subgroups of sex, race, nutritional status and smoking, though not among those with lower inflammation scores or impaired fasting glucose (interaction p=0.03 for both).Conclusions/interpretationHigh leptin levels, probably reflecting leptin resistance, predict an increased risk of diabetes. Adjusting for factors purportedly related to leptin resistance unveils a protective association, independent of adiponectin and consistent with some of leptin’s described protective effects against diabetes.

Cross sectional study of the relation between sibling number and asthma, hay fever, and eczema

OBJECTIVES To document the relation between sibling number and atopic disease, and to assess the contribution of possible confounding factors to the protective effect of siblings in relation to asthma and hay fever. DESIGN AND SUBJECTS Cross sectional survey by parental questionnaire in Tasmania, Australia, on 6378 children (92% of those eligible) who reached 7 years of age during 1995. METHODS Exercise challenge lung function testing was conducted on 428 children. Analyses reported were conducted on singleton births only (n = 6158). RESULTS The prevalences of a history of asthma ever, hay fever, and eczema were 27%, 19%, and 22%, respectively. Asthma and hay fever, but not eczema, were inversely related to sibling number, with evidence of a dose–response trend. The mean age at onset for asthma or wheezy breathing decreased as the number of siblings increased. The inverse association between sibling number and asthma or hay fever persisted after adjustment for several confounders, such as parental smoking or breast feeding, but did not persist after adjustment for household size in 1995. CONCLUSIONS The protective effect of high sibling number could not be separated from household size at age 7, and it appears to be operating after birth and influences the age at onset of asthma symptoms. Further work to increase knowledge of how the protective effect of the presence of siblings works might have important implications for the understanding of the pathogenesis of asthma.

Exercise-induced bronchial hyperresponsiveness and parental ISAAC questionnaire responses.

The predictive value of parental questionnaire responses for exercise-induced bronchoconstriction in childhood asthma has not been fully clarified. The aim of this study was to compare exercise-induced bronchial hyperresponsiveness in 7 year old children with parental responses to core questions in the International Study of Asthma and Allergies in Childhood (ISAAC) study. A cross-sectional study was conducted on 191 (91% of eligible) children from seven randomly selected schools in Southern Tasmania. Study measurements included a parental questionnaire and exercise challenge testing, using a recently validated 6 min free-running protocol. The response to exercise was assessed using forced expiratory volume in one second (FEV1) measurement. The median percentage fall in FEV1 was significantly higher in children whose parents responded positively to ISAAC questions on a history of wheeze (p = 0.0031) or asthma (p = 0.0005), recent wheeze (p = 0.0005), sleep disturbance due to wheeze (p = 0.0005), or exercise-induced wheeze (p = 0.0015). Receiver operating characteristic (ROC) curve analysis showed exercise-induced bronchial hyperresponsiveness to be a good indicator of current asthma status. Using a 12% or greater fall in FEV1 postexercise as a positive test response, the exercise challenge had sensitivity and specificity estimates for current asthma and exercise-induced wheeze of (0.58 and 0.77) and (0.60 and 0.77), respectively. In conclusion, the respiratory response to exercise was consistent with parental responses to the ISAAC questionnaire in a population-based sample of 7 year old children. These findings will assist interpretation of large ISAAC studies in terms of asthma prevalence.

Association between use of a quilt and sudden infant death syndrome : case-control study

The relation between an infants sleeping environment and development of the sudden infant death syndrome depends on the infants sleep position.1 We report how the association between the use of a quilt and the syndrome depends on sleep position. Between 1 October 1988 and 31 December 1995 in Tasmania 107 infants <1 year old died of the sudden infant death syndrome. Of the families affected, 100 (93%) participated in this study and were compared directly with 196 age matched controls. Methods are described elsewhere.1 A quilt is a coverlet made by stitching two thicknesses of fabric together with a filling (usually synthetic) enclosed between the layers. Conditional multiple logistic regression2 was used to evaluate interaction effects; egret 0.26.6 software (Cytel Software, Cambridge, MA, USA) provided matched odds ratios with logit-based 95% confidence intervals. An adverse effect of quilt use was evident in infants who did not sleep prone but not in infants who slept prone (1). This interaction was not altered by adjustment for sleeping on sheepskin; the interaction between sleeping on sheepskin and sleeping prone; mattress liner; mattress type; use of a quilt under the infant; use of a pillow; infant illness; heating …

Cost and Cost-effectiveness of the COMBINE Study in Alcohol-Dependent Patients

CONTEXT The COMBINE (Combined Pharmacotherapies and Behavioral Intervention) clinical trial recently evaluated the efficacy of medications, behavioral therapies, and their combinations for the outpatient treatment of alcohol dependence. The costs and cost-effectiveness of these combinations are unknown and of interest to clinicians and policy makers. OBJECTIVE To evaluate the costs and cost-effectiveness of the COMBINE Study interventions after 16 weeks of treatment. DESIGN A prospective cost and cost-effectiveness study of a randomized controlled clinical trial. SETTING Eleven US clinical sites. PARTICIPANTS One thousand three hundred eighty-three patients having a diagnosis of primary alcohol dependence. INTERVENTIONS The study included 9 treatment groups; 4 groups received medical management for 16 weeks with naltrexone, 100 mg/d, acamprosate, 3 g/d, or both, and/or placebo; 4 groups received the same therapy as mentioned earlier with combined behavioral intervention; and 1 group received combined behavioral intervention only. MAIN OUTCOMES MEASURES Incremental cost per percentage point increase in percentage of days abstinent, incremental cost per patient of avoiding heavy drinking, and incremental cost per patient of achieving a good clinical outcome. RESULTS On the basis of the mean values of cost and effectiveness, 3 interventions are cost-effective options relative to the other interventions for all 3 outcomes: medical management (MM) with placebo (

Modeling Partly Conditional Means with Longitudinal Data

409 per patient), MM plus naltrexone therapy (

Determinants of dust mite allergen concentrations in infant bedrooms in Tasmania.

671 per patient), and MM plus combined naltrexone and acamprosate therapy (

Is this finding relevant? Generalisation and epidemiology

1003 per patient). CONCLUSIONS To our knowledge, this is only the second prospective cost-effectiveness study with a randomized controlled clinical trial design that has been performed for the treatment of alcohol dependence. Focusing only on effectiveness, MM-naltrexone-acamprosate therapy is not significantly better than MM-naltrexone therapy. However, considering cost and cost-effectiveness, MM-naltrexone-acamprosate therapy may be a better choice, depending on whether the cost of the incremental increase in effectiveness is justified by the decision maker.