Artificially Sweetened Beverage Consumption Is Positively Associated with Newly Diagnosed Diabetes in Normal-Weight but Not in Overweight or Obese Brazilian Adults.

BACKGROUND: Recent animal studies suggest that artificially sweetened beverage (ASB) consumption increases diabetes risk. OBJECTIVE: We examined the relation of ASB intake with newly diagnosed diabetes and measures of glucose homeostasis in a large Brazilian cohort of adults. METHODS: We used cross-sectional data from 12,884 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). ASB use was assessed by questionnaire and newly diagnosed diabetes by a 2-h 75-g oral glucose tolerance test and/or glycated hemoglobin. Logistic and linear regression analyses were performed to examine the association of ASB consumption with diabetes and continuous measures of glucose homeostasis, respectively. RESULTS: Although ASB consumption was not associated with diabetes in logistic regression analyses after adjustment for body mass index (BMI; in kg/m(2)) overall, the association varied across BMI categories (P-interaction = 0.04). Among those with a BMI <25, we found a 15% increase in the adjusted odds of diabetes for each increase in the frequency of ASB consumption per day (P = 0.001); compared with nonusers, ASB users presented monotonic increases in the adjusted ORs (95% CIs) of diabetes with increased frequency of consumption: 1.03 (0.60, 1.77), 1.43 (0.93, 2.20), 1.62 (1.08, 2.44), and 2.51 (1.40, 4.50) for infrequent, 1-2, 3-4, and >4 times/d, respectively. In linear regression analyses, among normal-weight individuals, greater ASB consumption was also associated with increased fasting glucose concentrations (P = 0.01) and poorer ß-cell function (P = 0.009). No such associations were seen for those with BMI ≥25. In fact, in overweight or obese participants, greater ASB consumption was significantly associated with improved indexes of insulin resistance and 2-h postload glucose. CONCLUSIONS: Normal-weight, but not excess-weight, individuals with greater ASB consumption presented diabetes more frequently and had higher fasting glucose and poorer ß-cell function.

Influence of single nucleotide polymorphisms in factor VIII and von Willebrand factor genes on plasma factor VIII activity: the ARIC Study.

Factor VIII (FVIII) functions as a cofactor for factor IXa in the contact coagulation pathway and circulates in a protective complex with von Willebrand factor (VWF). Plasma FVIII activity is strongly influenced by environmental and genetic factors through VWF-dependent and -independent mechanisms. Single nucleotide polymorphisms (SNPs) of the coding and promoter sequence in the FVIII gene have been extensively studied for effects on FVIII synthesis, secretion, and activity, but impacts of non-disease-causing intronic SNPs remain largely unknown. We analyzed FVIII SNPs and FVIII activity in 10,434 healthy Americans of European (EA) or African (AA) descent in the Atherosclerosis Risk in Communities (ARIC) study. Among covariates, age, race, diabetes, and ABO contributed 2.2%, 3.5%, 4%, and 10.7% to FVIII intersubject variation, respectively. Four intronic FVIII SNPs associated with FVIII activity and 8 with FVIII-VWF ratio in a sex- and race-dependent manner. The FVIII haplotypes AT and GCTTTT also associated with FVIII activity. Seven VWF SNPs were associated with FVIII activity in EA subjects, but no FVIII SNPs were associated with VWF Ag. These data demonstrate that intronic SNPs could directly or indirectly influence intersubject variation of FVIII activity. Further investigation may reveal novel mechanisms of regulating FVIII expression and activity.

Twenty-two-year trends in incidence of myocardial infarction, coronary heart disease mortality, and case fatality in 4 US communities, 1987-2008.

BACKGROUND: Knowledge of trends in the incidence of and survival after myocardial infarction (MI) in a community setting is important to understanding trends in coronary heart disease (CHD) mortality rates. METHODS AND RESULTS: We estimated race- and gender-specific trends in the incidence of hospitalized MI, case fatality, and CHD mortality from community-wide surveillance and validation of hospital discharges and of in- and out-of-hospital deaths among 35- to 74-year-old residents of 4 communities in the Atherosclerosis Risk in Communities (ARIC) Study. Biomarker adjustment accounted for change from reliance on cardiac enzymes to widespread use of troponin measurements over time. During 1987-2008, a total of 30 985 fatal or nonfatal hospitalized acute MI events occurred. Rates of CHD death among persons without a history of MI fell an average 4.7%/y among men and 4.3%/y among women. Rates of both in- and out-of-hospital CHD death declined significantly throughout the period. Age- and biomarker-adjusted average annual rate of incident MI decreased 4.3% among white men, 3.8% among white women, 3.4% among black women, and 1.5% among black men. Declines in CHD mortality and MI incidence were greater in the second decade (1997-2008). Failure to account for biomarker shift would have masked declines in incidence, particularly among blacks. Age-adjusted 28-day case fatality after hospitalized MI declined 3.5%/y among white men, 3.6%/y among black men, 3.0%/y among white women, and 2.6%/y among black women. CONCLUSIONS: Although these findings from 4 communities may not be directly generalizable to blacks and whites in the entire United States, we observed significant declines in MI incidence, primarily as a result of downward trends in rates between 1997 and 2008.

Troponin T and N-terminal pro-B-type natriuretic peptide: a biomarker approach to predict heart failure risk--the atherosclerosis risk in communities study.

BACKGROUND: Among the various cardiovascular diseases, heart failure (HF) is projected to have the largest increases in incidence over the coming decades; therefore, improving HF prediction is of significant value. We evaluated whether cardiac troponin T (cTnT) measured with a high-sensitivity assay and N-terminal pro-B-type natriuretic peptide (NT-proBNP), biomarkers strongly associated with incident HF, improve HF risk prediction in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: Using sex-specific models, we added cTnT and NT-proBNP to age and race ("laboratory report" model) and to the ARIC HF model (includes age, race, systolic blood pressure, antihypertensive medication use, current/former smoking, diabetes, body mass index, prevalent coronary heart disease, and heart rate) in 9868 participants without prevalent HF; area under the receiver operating characteristic curve (AUC), integrated discrimination improvement, net reclassification improvement (NRI), and model fit were described. RESULTS: Over a mean follow-up of 10.4 years, 970 participants developed incident HF. Adding cTnT and NT-proBNP to the ARIC HF model significantly improved all statistical parameters (AUCs increased by 0.040 and 0.057; the continuous NRIs were 50.7% and 54.7% in women and men, respectively). Interestingly, the simpler laboratory report model was statistically no different than the ARIC HF model. CONCLUSIONS: cTnT and NT-proBNP have significant value in HF risk prediction. A simple sex-specific model that includes age, race, cTnT, and NT-proBNP (which can be incorporated in a laboratory report) provides a good model, whereas adding cTnT and NT-proBNP to clinical characteristics results in an excellent HF prediction model.

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort.

von Willebrand factor (VWF) is an essential component of hemostasis and has been implicated in thrombosis. Multimer size and the amount of circulating VWF are known to impact hemostatic function. We associated 78 VWF single nucleotide polymorphisms (SNPs) and haplotypes constructed from those SNPs with VWF antigen level in 7856 subjects of European descent. Among the nongenomic factors, age and body mass index contributed 4.8% and 1.6% of VWF variation, respectively. The SNP rs514659 (tags O blood type) contributed 15.4% of the variance. Among the VWF SNPs, we identified 18 SNPs that are associated with levels of VWF. The correlative SNPs are either intronic (89%) or silent exonic (11%). Although SNPs examined are distributed throughout the entire VWF gene without apparent cluster, all the positive SNPs are located in a 50-kb region. Exons in this region encode for VWF D2, D', and D3 domains that are known to regulate VWF multimerization and storage. Mutations in the D3 domain are also associated with von Willebrand disease. Fifteen of these 18 correlative SNPs are in 2 distinct haplotype blocks. In summary, we identified a cluster of intronic VWF SNPs that associate with plasma levels of VWF, individually or additively, in a large cohort of healthy subjects.

Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.

BACKGROUND: We evaluated whether cardiac troponin T (cTnT) measured with a new highly sensitive assay was associated with incident coronary heart disease (CHD), mortality, and hospitalization for heart failure (HF) in a general population of participants in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS AND RESULTS: Associations between increasing cTnT levels and CHD, mortality, and HF hospitalization were evaluated with Cox proportional hazards models adjusted for traditional CHD risk factors, kidney function, high-sensitivity C-reactive protein, and N-terminal pro-B-type natriuretic peptide in 9698 participants aged 54 to 74 years who at baseline were free from CHD and stroke (and HF in the HF analysis). Measurable cTnT levels (≥0.003 µg/L) were detected in 66.5% of individuals. In fully adjusted models, compared with participants with undetectable levels, those with cTnT levels in the highest category (≥0.014 µg/L; 7.4% of the ARIC population) had significantly increased risk for CHD (hazard ratio=2.29; 95% confidence interval, 1.81 to 2.89), fatal CHD (hazard ratio=7.59; 95% confidence interval, 3.78 to 15.25), total mortality (hazard ratio=3.96; 95% confidence interval, 3.21 to 4.88), and HF (hazard ratio=5.95; 95% confidence interval, 4.47 to 7.92). Even minimally elevated cTnT (≥0.003 µg/L) was associated with increased risk for mortality and HF (P<0.05). Adding cTnT to traditional risk factors improved risk prediction parameters; the improvements were similar to those with N-terminal pro-B-type natriuretic peptide and better than those with the addition of high-sensitivity C-reactive protein. CONCLUSIONS: cTnT detectable with a highly sensitive assay was associated with incident CHD, mortality, and HF in individuals from a general population without known CHD/stroke.

Relationship between circulating levels of RANTES (regulated on activation, normal T-cell expressed, and secreted) and carotid plaque characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study.

AIMS: To assess the relationship between regulated on activation, normal T-cell expressed and secreted (RANTES) and carotid atherosclerotic plaque burden and plaque characteristics. METHODS AND RESULTS: Gadolinium-enhanced magnetic resonance imaging (MRI) of the carotid artery was performed in 1901 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Wall thickness and volume, lipid-core volume, and fibrous cap thickness (by MRI) and plasma RANTES levels (by ELISA) were measured. Regression analysis was performed to study the associations between MRI variables and RANTES. Among 1769 inclusive participants, multivariable regression analysis revealed that total wall volume [beta-coefficient (ß) = 0.09, P = 0.008], maximum wall thickness (ß = 0.08, P = 0.01), vessel wall area (ß = 0.07, P = 0.02), mean minimum fibrous cap thickness (ß = 0.11, P = 0.03), and high-sensitivity C-reactive protein (ß = 0.09, P = 0.01) were positively associated with RANTES. Total lipid-core volume showed positive association in unadjusted models (ß = 0.18, P = 0.02), but not in fully adjusted models (ß = 0.13, P = 0.09). RANTES levels were highest in Caucasian females followed by Caucasian males, African-American females, and African-American males (P < 0.0001). Statin use attenuated the relationship between RANTES and measures of plaque burden. CONCLUSION: Positive associations between RANTES and carotid wall thickness and lipid-core volume (in univariate analysis) suggest that higher RANTES levels may be associated with extent of carotid atherosclerosis and high-risk plaques. Associations between fibrous cap thickness and RANTES likely reflect the lower reliability estimate for fibrous cap measurements compared with wall volume or lipid-core volume measurements. Statin use may modify the association between RANTES and carotid atherosclerosis. Furthermore, RANTES levels vary by race.

Carotid artery wall thickness and risk of stroke subtypes: the atherosclerosis risk in communities study.

BACKGROUND AND PURPOSE: Understanding associations of carotid atherosclerosis with stroke subtypes may contribute to more effective prevention of stroke. METHODS: Between 1987 and 1989, 13 560 men and women aged 45 to 64 years and free of clinical stroke took part in the first examination of the Atherosclerosis Risk in Communities (ARIC) study. Incident strokes were ascertained by hospital surveillance. RESULTS: During an average follow-up of 15.7 years, 82 incident hemorrhagic and 621 incident ischemic strokes (131 lacunar, 358 nonlacunar, and 132 cardioembolic strokes) occurred. The incidence rates of hemorrhagic and ischemic strokes were greater across higher carotid intima-media thickness levels. Although this positive association was observed for all stroke subtypes, the age-, gender-, and race-adjusted risk ratios were higher for cardioembolic and nonlacunar strokes than for hemorrhagic and lacunar strokes. Compared with participants in the lowest quintile (<0.61 mm), the adjusted risk ratios for those in the highest quintile (≥0.85 mm) of intima-media thickness were 2.55 (95% CI, 1.09-5.94) for hemorrhagic, 2.89 (95% CI, 1.50-5.54) for lacunar, 3.61 (95% CI, 2.33-5.99) for nonlacunar, and 6.12 (95% CI, 2.71-13.9) for cardioembolic stroke. The risk ratios were attenuated by additional adjustment for covariates but remained statistically significant for nonlacunar and cardioembolic strokes (P for trend <0.001, respectively). The association between carotid intima-media thickness and lacunar stroke was somewhat stronger in blacks than in whites (P for interaction=0.07). CONCLUSIONS: Carotid atherosclerosis was associated with increased risk of all stroke subtypes, but the association of carotid atherosclerosis with stroke may vary by subtypes.

Several methods to assess improvement in risk prediction models: extension to survival analysis.

Risk prediction models have been widely applied for the prediction of long-term incidence of disease. Several parameters have been identified and estimators developed to quantify the predictive ability of models and to compare new models with traditional models. These estimators have not generally accounted for censoring in the survival data normally available for fitting the models. This paper remedies that problem. The primary parameters considered are net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We have previously similarly considered a primary measure of concordance, area under the ROC curve (AUC), also called the c-statistic. We also include here consideration of population attributable risk (PAR) and ratio of predicted risk in the top quintile of risk to that in the bottom quintile. We evaluated estimators of these various parameters both with simulation studies and also as applied to a prospective study of coronary heart disease (CHD). Our simulation studies showed that in general our estimators had little bias, and less bias and smaller variances than the traditional estimators. We have applied our methods to assessing improvement in risk prediction for each traditional CHD risk factor compared to a model without that factor. These traditional risk factors are considered valuable, yet when adding any of them to a risk prediction model that has omitted the one factor, the improvement is generally small for any of the parameters. This experience should prepare us to not expect large values of the risk prediction improvement evaluation parameters for any new risk factor to be discovered.

Association of circulating matrix metalloproteinases with carotid artery characteristics: the Atherosclerosis Risk in Communities Carotid MRI Study.

OBJECTIVE: To examine the relationship of plasma levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase 1 (TIMP-1) with carotid artery characteristics measured by MRI in a cross-sectional investigation among Atherosclerosis Risk in Communities Carotid MRI Study participants. METHODS AND RESULTS: A stratified random sample was recruited based on intima-media thickness from a previous ultrasonographic examination. A high-resolution gadolinium-enhanced MRI examination of the carotid artery was performed from 2004 to 2005 on 1901 Atherosclerosis Risk in Communities cohort participants. Multiple carotid wall characteristics, including wall thickness, lumen area, calcium area, lipid core, and fibrous cap measures, were evaluated for associations with plasma MMPs 1, 2, 3, 7, 8, and 9 and TIMP-1. Plasma MMPs 1, 3, and 7 were significantly higher among participants in the high intima-media thickness group compared with those in the low intima-media thickness group. The normalized wall index was independently associated with MMPs 3 and 7 and TIMP-1. MMP-7 was positively associated with carotid calcification. The mean fibrous cap thickness was significantly higher in individuals with elevated TIMP-1 levels. In addition, TIMP-1 was positively associated with measures of lipid core. CONCLUSION: Circulating levels of specific MMPs and TIMP-1 were associated with carotid wall remodeling and structural changes related to plaque burden in elderly participants.

The contribution of major risk factors and job strain to occupational class differences in coronary heart disease incidence: the MONICA Brianza and PAMELA population-based cohorts.

OBJECTIVES: We investigated the contribution of major coronary heart disease (CHD) risk factors and job strain to occupational class differences in CHD incidence in a pooled-cohort prospective study in northern Italy. METHODS: 2964 men aged 25-74 from four northern Italian population-based cohorts were investigated at baseline and followed for first fatal or non-fatal CHD event (171 events). Standardised procedures were used for baseline risk factor measurements, follow-up and validation of CHD events. Four occupational classes were derived from the Erikson-Goldthorpe-Portocarero social class scheme: higher and lower professionals and administrators, non-manual workers, skilled and unskilled manual workers, and the self-employed. HRs were estimated with Cox models. RESULTS: Among CHD-free subjects, with non-manual workers as the reference group, age-adjusted excess risks were found for professionals and administrators (+84%, p=0.02), the self-employed (+72%, p=0.04) and manual workers (+63%, p=0.04). The relationship was consistent across different CHD diagnostic categories. Adjusting for major risk factors only slightly reduced the reported excess risks. In a sub-sample of currently employed subjects, adjusting for major risk factors, sport physical activity and job strain reduced the excess risk for manual workers (relative change = -71.4%) but did not substantially modify the excess risks of professionals and administrators and the self-employed. CONCLUSIONS: In our study, we found higher CHD incidence rates for manual workers, professionals and administrators, and the self-employed, compared to non-manual workers. When the entire spectrum of job categories is considered, the job strain model helped explain the CHD excess risk for manual workers but not for other occupational classes.

Gender differences in the association between education and the incidence of cardiovascular events in Northern Italy.

BACKGROUND: The educational differences in the incidence of major cardiovascular events are under-studied in Southern Europe and among women. METHODS: The study sample includes n = 5084 participants to 4 population-based Northern Italian cohorts, aged 35-74 at baseline and with no previous cardiovascular events. The follow-up to ascertain the first onset of coronary heart disease (CHD) or ischaemic stroke ended in 2002. At baseline, major cardiovascular risk factors were investigated adopting the standardized MONICA procedures. Two educational classes were obtained from years of schooling. Age- and risk factors-adjusted hazard ratios of first CHD or ischaemic stroke were estimated through sex-specific separate Cox models (high education as reference). RESULTS: Median follow-up time was 12 years. Event rates were 6.38 (CHD) and 2.12 (ischaemic stroke) per 1000 person-years in men; and 1.59 and 0.94 in women. In men, low education was associated with higher mean Body Mass Index and prevalence of diabetes and cigarette smokers; but also with higher HDL cholesterol and a more favourable alcohol intake pattern. Less-educated women had higher mean systolic blood pressure, Body Mass Index and HDL cholesterol and were more likely to have diabetes. Men and women in the low educational class had a 2-fold increase in ischaemic stroke and CHD incidence, respectively, after controlling for major risk factors. Education was not associated with CHD incidence in men. Higher ischaemic stroke rates were observed among more educated women. CONCLUSION: In this northern Italian population, the association between education and cardiovascular risk seems to vary by gender.

Remodeling of carotid arteries detected with MR imaging: atherosclerosis risk in communities carotid MRI study.

PURPOSE: To determine the extent of thickening of the carotid arterial walls that may be accommodated by outward remodeling. MATERIALS AND METHODS: Institutional review board approval was obtained at each participating site, and informed consent was obtained from each participant. All study sites conducted this study in compliance with HIPAA requirements. A total of 2066 participants (age range, 60-85 years) from the Atherosclerosis Risk in Communities (ARIC) study were enrolled in the ARIC Carotid MRI Study. Maximum wall thickness and luminal area were measured with gadolinium-enhanced magnetic resonance (MR) imaging in both common carotid arteries (CCAs) and in one internal carotid artery (ICA) 2 mm above the flow divider. Complete data were available for 1064 ICAs and 3348 CCAs. The association of maximum wall thickness with lumen area was evaluated with linear regression, and adjustments were made for participant age, sex, race, height, and height squared. RESULTS: In the ICA, lumen area was relatively constant across patients with a wall thickness of 1.38 mm or less. In patients with a wall thickness of more than 1.38 mm, however, lumen area decreased linearly as wall thickness increased. Wall area represented a median of 61.9% of the area circumscribed by the vessel at a maximum wall thickness of 1.50 mm +/- 0.05 (standard deviation) and 75.4% at a maximum wall thickness of 4.0 mm +/- 0.10. In the CCA, lumen area was preserved across wall thicknesses less than 2.06 mm, representing 99% of vessels. CONCLUSION: Atherosclerotic thickening in the ICA appears to be accommodated for vessels with a maximum wall thickness of less than 1.5 mm. Beyond this threshold, greater thickness is associated with a smaller lumen. The CCA appears to accommodate a wall thickness of less than 2.0 mm. These estimates indicate that the carotid arteries are able to compensate for a greater degree of thickening than are the coronary arteries.

Relationship between non-specific prescription pill adherence and ischemic stroke outcomes.

BACKGROUND: Adherence to non-specific prescription therapy may be associated with clinical outcomes beyond a given treatment effect. We assessed the association of blinded randomized pill prescription adherence with vascular outcomes after ischemic stroke. METHODS: We analyzed the Vitamin Intervention for Stroke Prevention (VISP) study database. VISP was a double-blind randomized trial, designed to determine whether high doses of vitamins (vs. low doses) would reduce recurrent stroke risk in 3,680 participants over a 2-year period. We examined the independent association of adherence with a composite endpoint (stroke, myocardial infarction, death). RESULTS: Among 3,357 (91%) subjects with complete data, women, non-White persons, current smokers, those not on statins and those without a history of coronary artery bypass surgery were significantly less likely to be optimally adherent. Over the trial, persons who adhered well to treatment were less likely to experience the combined outcome than those who adhered poorly (13.4 vs. 20.6%, p < 0.0001). After multivariable analysis using various adherence measures, there were no significant differences between >or=80% vs. <80% adherence, but compared to <65% adherence, pill adherence levels of >or=90 to <99% (HR 0.56, 95% CI = 0.34-0.91; p = 0.02) and >or=99% (HR 0.46, 95% CI = 0.29-0.73; p = 0.001) were associated with lower occurrence of the combined outcome at 18 months. CONCLUSIONS: Long-term excellent adherence to non-specific pill prescription among ischemic stroke patients is independently associated with lower vascular risk, and is likely a marker of overall healthy behavior that may be helpful in targeting stroke patients with unhealthy practices.

Military combat and burden of subclinical atherosclerosis in middle aged men: the ARIC study.

BACKGROUND: Studies of the cardiovascular consequences of combat stress are few and inconclusive. OBJECTIVE: The association between combat exposure and subclinical atherosclerosis at Atherosclerosis Risk in Communities (ARIC) Study visits 1 (1987-1989) and 2 (1990-1992) was assessed among 5347 men from four U.S. communities. METHODS: Measured an average of 36 years after military entry, carotid intima-media thickness (CIMT) and carotid plaque among non-combat veterans (n=2127) were compared with non-veterans (n=2042) and veterans reporting combat experience (n=1178). RESULTS: Compared to non-combat veterans, non-veterans (risk difference (RD): 10.61; 95% confidence interval (CI): 0.81, 20.41) and combat veterans (RD: 12.79; 95% CI: 0.72, 24.86) had higher age-adjusted mean CIMT. Differences remained for combat veterans after adjustment for race, father's education and age at service entry but not years of service and for non-veterans after adjustment for race but not father's education. No differences in carotid plaque were noted. CONCLUSION: Results do not suggest that combat has a long-term detrimental effect on subclinical atherosclerosis among men.

Using the whole cohort in the analysis of case-cohort data.

Case-cohort data analyses often ignore valuable information on cohort members not sampled as cases or controls. The Atherosclerosis Risk in Communities (ARIC) study investigators, for example, typically report data for just the 10%-15% of subjects sampled for substudies of their cohort of 15,972 participants. Remaining subjects contribute to stratified sampling weights only. Analysis methods implemented in the freely available R statistical system (http://cran.r-project.org/) make better use of the data through adjustment of the sampling weights via calibration or estimation. By reanalyzing data from an ARIC study of coronary heart disease and simulations based on data from the National Wilms Tumor Study, the authors demonstrate that such adjustment can dramatically improve the precision of hazard ratios estimated for baseline covariates known for all subjects. Adjustment can also improve precision for partially missing covariates, those known for substudy participants only, when their values may be imputed with reasonable accuracy for the remaining cohort members. Links are provided to software, data sets, and tutorials showing in detail the steps needed to carry out the adjusted analyses. Epidemiologists are encouraged to consider use of these methods to enhance the accuracy of results reported from case-cohort analyses.

Serum and dietary magnesium and risk of ischemic stroke: the Atherosclerosis Risk in Communities Study.

The authors sought to examine the relation between serum or dietary magnesium and the incidence of ischemic stroke among blacks and whites. Between 1987 and 1989, 14,221 men and women aged 45-64 years took part in the first examination of the Atherosclerosis Risk in Communities Study cohort. The incidence of stroke was ascertained from hospital records. Higher serum magnesium levels were associated with lower prevalence of hypertension and diabetes mellitus at baseline. During the 15-year follow-up, 577 ischemic strokes occurred. Serum magnesium was inversely associated with ischemic stroke incidence. The age-, sex-, and race-adjusted rate ratios of ischemic stroke for those with serum magnesium levels of or=1.8 mEq/L were 1.0, 0.78 (95% confidence interval (CI): 0.62, 0.96), 0.70 (95% CI: 0.56, 0.88), and 0.75 (95% CI: 0.59, 0.95) (P(trend) = 0.005). After adjustment for hypertension and diabetes, the rate ratios were attenuated to nonsignificant levels. Dietary magnesium intake was marginally inversely associated with the incidence of ischemic stroke (P(trend) = 0.09). Low serum magnesium levels could be associated with increased risk of ischemic stroke, in part, via effects on hypertension and diabetes.

Repeatability and measurement error in the assessment of choline and betaine dietary intake: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: The repeatability of a risk factor measurement affects the ability to accurately ascertain its association with a specific outcome. Choline is involved in methylation of homocysteine, a putative risk factor for cardiovascular disease, to methionine through a betaine-dependent pathway (one-carbon metabolism). It is unknown whether dietary intake of choline meets the recommended Adequate Intake (AI) proposed for choline (550 mg/day for men and 425 mg/day for women). The Estimated Average Requirement (EAR) remains to be established in population settings. Our objectives were to ascertain the reliability of choline and related nutrients (folate and methionine) intakes assessed with a brief food frequency questionnaire (FFQ) and to estimate dietary intake of choline and betaine in a bi-ethnic population. METHODS: We estimated the FFQ dietary instrument reliability for the Atherosclerosis Risk in Communities (ARIC) study and the measurement error for choline and related nutrients from a stratified random sample of the ARIC study participants at the second visit, 1990-92 (N = 1,004). In ARIC, a population-based cohort of 15,792 men and women aged 45-64 years (1987-89) recruited at four locales in the U.S., diet was assessed in 15,706 baseline study participants using a version of the Willett 61-item FFQ, expanded to include some ethnic foods. Intraindividual variability for choline, folate and methionine were estimated using mixed models regression. RESULTS: Measurement error was substantial for the nutrients considered. The reliability coefficients were 0.50 for choline (0.50 for choline plus betaine), 0.53 for folate, 0.48 for methionine and 0.43 for total energy intake. In the ARIC population, the median and the 75th percentile of dietary choline intake were 284 mg/day and 367 mg/day, respectively. 94% of men and 89% of women had an intake of choline below that proposed as AI. African Americans had a lower dietary intake of choline in both genders. CONCLUSION: The three-year reliability of reported dietary intake was similar for choline and related nutrients, in the range as that published in the literature for other micronutrients. Using a brief FFQ to estimate intake, the majority of individuals in the ARIC cohort had an intake of choline below the values proposed as AI.

Heart failure incidence and survival (from the Atherosclerosis Risk in Communities study).

Heart failure (HF) is increasing in prevalence in the United States. Little data exists on race and gender differences in HF incidence rates and case fatality. The Atherosclerosis Risk in Communities (ARIC) cohort is a population-based study from 4 United States communities (1987 to 2002). Prevalent HF cases (n = 750) were identified by self-report and were excluded. Incident HF was defined by the International Classification of Diseases codes for HF (428.0 to 428.9, I50) from a hospitalization (n = 1,206) or death certificate (n = 76). There were 1,282 incident HF cases over 198,417 person-years. The age-adjusted incidence rate (per 1,000 person-years) for Caucasian women, 3.4, was significantly less compared with all other groups (Caucasian men, 6.0; African-American women, 8.1; African-American men, 9.1). Age-adjusted HF incidence rates were greater for African-Americans than Caucasians, but adjustment for confounders attenuated the difference. The adjusted African-American-to-Caucasian hazard ratio was 0.86 (95% confidence interval, 0.70 to 1.06) for men, and similarly, 0.93 (95% confidence interval, 0.46 to 1.90) for women during the second half of follow-up. The hazard ratio for women during the first half of follow-up was 1.79 (95% confidence interval, 1.25 to 2.55). Thirty-day, 1-year, and 5-year case fatalities following hospitalization for HF were 10.4%, 22%, and 42.3%, respectively. African-Americans had a greater 5-year case fatality compared with Caucasians (p <0.05). In conclusion, heart failure incidence rates in African-American women were more similar to those of men than of Caucasian women. The greater HF incidence in African-Americans than in Caucasians is largely explained by African-Americans' greater levels of atherosclerotic risk factors.

Risk prediction of coronary heart disease based on retinal vascular caliber (from the Atherosclerosis Risk In Communities [ARIC] Study).

Recent studies showed that such retinal vascular signs as quantitative retinal vascular caliber were associated with increased risk of incident coronary heart disease (CHD), but whether these retinal vascular signs add to the prediction of CHD over and above traditional CHD risk factors was not addressed. Whether these signs add to the prediction of CHD over and above the Framingham risk score in people (n = 9,155) without diabetes selected from the ARIC Study was investigated. Incident CHD was ascertained using standardized methods, and retinal vascular caliber and other retinal signs were measured from retinal photographs. After a mean of 8.8 years of follow-up, there were 700 incident CHD events. Women with wider retinal venular caliber (hazard ratio 1.27/1-SD increase, 95% confidence interval 1.08 to 1.50) and narrower retinal arteriolar caliber (hazard ratio 1.31/1-SD decrease, 95% confidence interval 1.10 to 1.56) had a higher risk of incident CHD after adjusting for Framingham risk score variables. Area under the receiver operator characteristic curve increased from 0.695 to 0.706 (1.7% increase) with the addition of retinal vascular caliber to the Framingham risk model. Risk prediction models with and without retinal vascular caliber both fitted the data and were well calibrated for women. In men, retinal vascular caliber was not associated with CHD risk after adjustment. Other retinal vascular signs were not associated with 10-year incident CHD in men or women. In conclusion, although retinal vascular caliber independently predicted CHD risk in women, the incremental predictive ability over that of the Framingham model was modest and unlikely to translate meaningfully into clinical practice.