Vitamin intervention for stroke prevention trial: An efficacy analysis

Background and Purpose - The Vitamin Intervention for Stroke Prevention trial (VISP) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke. Reasons for lack of efficacy may have included folate fortification of grain products, inclusion of the recommended daily intake for B12 in the low-dose arm, treatment with parenteral B12 in patients with low B12 levels in both study arms, a dose of B12 too low for patients with malabsorption, supplementation with nonstudy vitamins, and failure of patients with significant renal impairment to respond to vitamin therapy. We conducted an efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence developed since VISP was initiated. The criteria for this subgroup were defined before any data analysis. Methods - For this analysis, we excluded patients with low and very high B12 levels at baseline (\u3c250 and \u3e637 pmol/L, representing the 25th and 95th percentiles), to exclude those likely to have B12 malabsorption or to be taking B12 supplements outside the study and patients with significant renal impairment (glomerular filtration rate \u3c46.18; the 10th percentile). Results - This subgroup represents 2155 patients (37% female), with a mean age of 66±10.7 years. For the combined end point of ischemic stroke, coronary disease, or death, there was a 21% reduction in the risk of events in the high-dose group compared with the low-dose group (unadjusted P=0.049; adjusted for age, sex, blood pressure, smoking, and B12 level P=0.056). In Kaplan-Meier survival analysis comparing 4 groups, patients with a baseline B12 level at the median or higher randomized to high-dose vitamin had the best overall outcome, and those with B12 less than the median assigned to low-dose vitamin had the worst (P=0.02 for combined stroke, death, and coronary events; P=0.03 for stroke and coronary events). Conclusions - In the era of folate fortification, B12 plays a key role in vitamin therapy for total homocysteine. Higher doses of B12, and other treatments to lower total homocysteine may be needed for some patients. © 2005 American Heart Association, Inc

Marginal additive hazards model for case-cohort studies with multiple disease outcomes: an application to the Atherosclerosis Risk in Communities (ARIC) study

In the case-cohort studies conducted within the Atherosclerosis Risk in Communities (ARIC) study, it is of interest to assess and compare the effect of high-sensitivity C-reactive protein (hs-CRP) on the increased risks of incident coronary heart disease and incident ischemic stroke. Empirical cumulative hazards functions for different levels of hs-CRP reveal an additive structure for the risks for each disease outcome. Additionally, we are interested in estimating the difference in the risk for the different hs-CRP groups. Motivated by this, we consider fitting marginal additive hazards regression models for case-cohort studies with multiple disease outcomes. We consider a weighted estimating equations approach for the estimation of model parameters. The asymptotic properties of the proposed estimators are derived and their finite-sample properties are assessed via simulation studies. The proposed method is applied to analyze the ARIC Study

Absolute and Attributable Risks of Heart Failure Incidence in Relation to Optimal Risk Factors

Epidemiologic studies have shown that a large proportion of coronary heart disease and stroke events are explained by borderline or elevated risk factors, and that adults with optimal risk factors greatly avoid these events. The degree to which this applies to heart failure incidence is not well documented

Identification of Heart Failure Events in Medicare Claims: The Atherosclerosis Risk in Communities (ARIC) Study

We examined the accuracy of CMS Medicare HF diagnostic codes in the identification of acute decompensated and chronic stable HF (ADHF and CSHF)

MMP2 genetic variation is associated with measures of fibrous cap thickness: The Atherosclerosis Risk in Communities Carotid MRI Study

Objective- Genetic variation in matrix metalloproteinase (MMP) promoter regions alters the transcriptional activity of MMPs and has been consistently associated with CHD, presumably through plaque degradation and remodeling. We examined the association of MMP promoter variation with multiple plaque characteristics measured by gadolinium-enhanced MRI among 1,700 participants in the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study. Methods—For the analyses presented here, 1,700 participants of the biracial ARIC Carotid MRI Study (~1,000 participants with thick carotid artery walls and ~700 randomly sampled participants) were evaluated for associations of MMP genetic variation with multiple plaque characteristics, including carotid artery wall thickness, lipid core and fibrous cap measures. MRI studies were performed on a 1.5T scanner equipped with a bilateral 4-element phased array carotid coil. Results—Fifty-one percent of the participants were female, 77% white, 23% African American, and the mean age was 70 years. MMP2 C-1306T variant genotypes (CT+TT) were significantly associated with higher cap thickness measures, but not with wall thickness or lipid core measures. Individuals with the CC genotype had approximately 0.1 mm thinner cap thickness compared to those carrying a T allele (p=0.02). Conclusion—Genetic variation within the MMP2 promoter region was associated with cap thickness and therefore may influence the role of MMP2 in plaque vulnerability

Obesity and Vital Exhaustion: Analysis of the Atherosclerosis Risk in the Communities Study

This study aimed to determine whether vital exhaustion (VE) was associated with BMI cross-sectionally and after 3 and 6 years of follow-up. Extant data from the Atherosclerosis Risk in Communities (ARIC) study were used to examine the relationship between VE and BMI among 13,727 white and African-American adults cross-sectionally (baseline) and longitudinally (3 and 6 years later). We used adjusted and nonadjusted general linear regression models. Associations with excess weight gain (≥5.0%) were also examined using logistic regression. Results showed that BMI was significantly higher among both white and African-American men and women in the highest VE quartile compared to those with no VE. Similarly, high VE at baseline was associated with higher BMI 3 and 6 years later, although VE was not able to predict future BMI after adjusting for baseline BMI. Baseline VE predicted future excess weight gain in white men and women, but not in African Americans. These results suggest that reducing VE levels may play an important role in reducing the prevalence of obesity. High VE was associated with higher current BMI (all races) and excess weight gain (whites only). Although high VE predicted future weight gain without baseline BMI adjustment, the magnitude of change in BMI over time was similar among those with low and high VE; suggesting that any relationship between VE and BMI was already established at baseline. Assessment of VE and BMI over time would help to elucidate uncertainties between the temporal nature of the relationship between them

Validity and reproducibility of retinal arteriole and venule diameter measurements : ELSA-Brasil study : a cross-sectional study

BACKGROUND: Investigation of alterations to retinal microvasculature may contribute towards understanding the role of such changes in the pathophysiology of several chronic non-communicable diseases. The objective here was to evaluate the validity and reproducibility of retinal arteriole and venule diameter measurements made by Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) graders. DESIGN AND SETTING: Cross-sectional study at six teaching and research institutions. METHODS: To evaluate validity, each of 25 retinal images from the University of Wisconsin (gold standard) was measured by five ELSA-Brasil graders. To evaluate reproducibility, 105 images across the spectrum of vessel diameters were selected from 12,257 retinal images that had been obtained between 2010 and 2012, and each image was reexamined by the same grader and by an independent grader. All measurements were made using the Interactive Vessel Analysis (IVAN) software. Bland-Altman plots, paired t tests and intraclass correlation coefficients (ICCs) were analyzed. RESULTS: Mean differences between ELSA-Brasil and gold-standard readings were 0.16 μm (95% CI -0.17‑0.50; P = 0.31) for central retinal artery equivalent (CRAE), -0.21 μm (95% CI -0.56-0.14; P = 0.22) for central retinal vein equivalent (CRVE) and 0.0005 (95% CI -0.008-0.009; P = 0.55) for arteriole/venule ratio (AVR). Intragrader ICCs were 0.77 (95% CI 0.67-0.86) for CRAE, 0.90 (95% CI 0.780.96) for CRVE and 0.70 (0.55‑0.83) for AVR. Intergrader ICCs were 0.75 (95% CI 0.64-0.85) for CRAE, 0.90 (95% CI 0.79-0.96) for CRVE and 0.68 (95% CI 0.55‑0.82) for AVR. CONCLUSIONS: Retinal microvascular diameter measurements are valid and present moderate to high intra and intergrader reproducibility in ELSA-Brasil

Effect of Correcting for Long-Term Variation in Major Coronary Heart Disease Risk Factors: Relative Hazard Estimation and Risk Prediction in the Atherosclerosis Risk in Communities Study

To examine the effect of correcting coronary heart disease (CHD) risk factors for long-term within-person variation on CHD risk

Assessment of pre- and post-methionine load homocysteine for prediction of recurrent stroke and coronary artery disease in the Vitamin Intervention for Stroke Prevention Trial

Methionine (Met) loading increases total plasma homocysteine (tHcy) and assesses homocysteine metabolism. We tested the hypothesis that pre- or post-Met tHcy will predict recurrent stroke or coronary artery disease (CAD) in a subgroup analysis of the Vitamin Intervention for Stroke Prevention (VISP) trial. VISP subjects with non-disabling stroke underwent measurement of tHcy at baseline (fasting pre- and post-Met load) and were randomized to high/low-dose B-vitamin therapy for prevention of recurrent stroke or CAD. In the sample cohort of 2,124 subjects, mean ± SD tHcy levels in µmol/L were: pre-Met 13.2 ± 4.3, post-Met 30.4 ± 9.76, and pre/post-Met Δ 17.1 ± 8.3. The hazard ratio (HR) for recurrent stroke was 1.16 (p=0.026) for 1 SD higher pre-Met tHcy and 1.15 (p=0.054) for 1 SD higher post-Met tHcy. For CAD, the HR for 1 SD higher pre-Met tHcy was 1.27 (p=0.001) and was 1.00 (p=0.99) for post-Met tHcy. In survival analyses using pre- or post-Met as covariates, the coefficient of pre/post-Met Δ was not significant for stroke and was only marginally significant for CAD (p<0.08), but was negative. We conclude that fasting, pre-Met tHcy is as effective as post-Met tHcy or pre/post-Met Δ in predicting the risk for stroke and CAD

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