Folic acid, vitamin B6, and vitamin B12 act in concert in the one-carbon metabolism and may protect against colorectal neoplasia. We examined the effect of combined B-vitamin treatment on the occurrence of colorectal adenoma.
The Women’s Antioxidant and Folic Acid Cardiovascular Study was a randomized, double-blind, placebo-controlled trial of 5442 female health professionals at high risk for cardiovascular disease from April 1998 through July 2005. Participants were randomly assigned to receive a combination pill of folic acid (2.5mg), vitamin B6 (50mg), and vitamin B12 (1mg) or placebo. This study included 1470 participants who were followed up for as long as 9.2 years and underwent an endoscopy at any point during follow-up. We estimated relative risks using a generalized linear model with a natural logarithm link function and Poisson distributed errors. All statistical tests were two-sided.
The risk of colorectal adenoma was similar among participants receiving treatment (24.3%, 180 of 741 participants) vs placebo (24.0%, 175 of 729 participants) (multivariable adjusted relative risk = 1.00, 95% confidence interval = 0.83 to 1.20). Treatment was not associated with the risk of adenoma when data were analyzed by subsite, size, stage, and the number of adenomas. There was no statistically significant effect modification by alcohol intake, history of cancer or adenoma, or baseline plasma levels or intakes of folate, vitamin B6, or vitamin B12.
Our results indicate no statistically significant effect of combined folic acid, vitamin B6, and vitamin B12 treatment on colorectal adenoma among women at high risk for cardiovascular disease.
Although studies have shown health benefits for moderate-intensity physical activity, there is limited evidence to support beneficial effects for high amounts of vigorous activity among middle-aged and older men. The objective of this study was to examine the relationship between vigorous-intensity physical activity, compared to moderate-intensity activity, and risk of major chronic disease in men.
We prospectively examined the associations between vigorous- and moderate-intensity physical activity and risk of major chronic disease among 44,551 men aged 40–75 years in 1986. Leisure-time physical activity was assessed biennially by questionnaire. During 22 years of follow-up, we documented 14,162 incident cases of major chronic disease, including 4769 cardiovascular events, 6449 cancer events, and 2944 deaths from other causes.
The hazard ratio (HR) of major chronic disease comparing ≥ 21 to 0 MET-hours/week of exercise was 0.86 (95% CI: 0.81, 0.91) for vigorous-intensity activity and 0.85 (95% CI: 0.80, 0.90) for moderate activity. For CVD, the corresponding HR were 0.78 (95% CI: 0.70, 0.86) and 0.80 (95% CI: 0.72, 0.88), respectively. When examined separately, running, tennis, and brisk walking were inversely associated with CVD risk. Furthermore, more vigorous activity was associated with lower disease risk; the HR comparing >70 to 0 MET-hours/week of vigorous-intensity exercise was 0.79 (95% CI: 0.68, 0.92; P <0.0001 for trend) for major chronic disease and 0.73 (95% CI: 0.56, 0.96; P <0.0001 for trend) for CVD.
Vigorous- and moderate-intensity physical activity were associated with lower risk of major chronic disease and cardiovascular disease. Increasing amounts of vigorous activity remained inversely associated with disease risk, even among men in the highest categories of exercise.
exercise; epidemiology; cardiovascular disease; cancer; risk factors
Adiponectin may have a protective role in the development of obesity-related metabolic and vascular disorders including hypertension. We conducted a prospective, nested case-control study to investigate the relationship between baseline plasma adiponectin, measures of adiposity, and subsequent risk of hypertension.
We selected 400 White and 400 Black postmenopausal women, aged <70 years, who have developed incident hypertension during 5.9-year follow-up and an equal number of age and race matched controls in the Women's Health Initiative Observational Study. We measured plasma concentrations of total adiponectin in their baseline bloods.
In crude matched models, plasma adiponectin was inversely associated with risk of hypertension among both White and Black women. The association appeared to be non-linear in White women but dose-related in Black women. Adjustment for lifestyle factors, measures of obesity, and obesity-related clinical factors attenuated these associations. The multivariable relative risks (95% confidence interval) of hypertension across increasing quartiles of plasma adiponectin were 1.00, 0.98 (0.66-1.46), 0.63 (0.41-0.97), and 0.92 (0.60-1.42) in White women (p, trend: 0.38) and 1.00, 0.96 (0.64-1.46), 0.83 (0.53-1.29), and 0.58 (0.36-0.94) in Black women (p, trend: 0.02). Further adjustment for inflammatory markers and endothelial markers eliminated the association in White, but not Black, women.
In this prospective, nested case-control study, we found an inverse association between plasma adiponectin and risk of hypertension in White and Black postmenopausal women. The reduced risk of hypertension was limited to intermediate levels of adiponectin in White women while was graded across quartiles of adiponectin in Black women.
adiponectin; hypertension; epidemiology; prospective study; postmenopausal women
Risk reclassification methods have become popular in the medical literature as a means of comparing risk prediction models. In this issue of the Journal, Pencina et al. (Am J Epidemiol. 2012;176(6):492–494) present further results for continuous measures of model discrimination and describe their characteristics in nested models with normally distributed variables. Measures include the change in the area under the receiver operating characteristic curve, the integrated discrimination improvement, and the continuous net reclassification improvement. Although theoretically interesting, these continuous measures may not be the most appropriate to assess clinical utility. The continuous net reclassification improvement, in particular, is a measure of effect rather than model improvement and can sometimes exhibit erratic behavior, as illustrated in 2 examples. Caution is needed before using this as a measure of improvement. Further, the test of the continuous net reclassification improvement and that for the integrated discrimination improvement are similar to the likelihood ratio test in nested models and may be overinterpreted. Reclassification in risk strata, while requiring thresholds, may be more relevant clinically with its ability to examine potential changes in treatment decisions.
calibration; discrimination; model fit; risk prediction
Sex steroid hormones have been postulated to involve in blood pressure (BP) regulation. We examine the association of endogenous sex hormone levels with longitudinal change of BP and risk of developing hypertension in initially normotensive postmenopausal women.
We conducted prospective analysis among 619 postmenopausal women free of hypertension at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Change of BP and development of incident hypertension were assessed during a mean of 4.8 years follow-up.
After adjusting for age, race/ethnicity, and lifestyle factors, baseline serum estradiol (E2), total and bioavailable testosterone (T), dehydroepiandrosterone (DHEA) were each positively and sex- hormone binding globulin (SHBG) was inversely associated with risk of hypertension. Additional adjustment for body mass index eliminated the associations for E2 and T but only attenuated the associations for DHEA and SHBG. The corresponding multivariable hazard ratios (95% CIs) in the highest quartile were 1.28 (0.83–1.97) for E2, 1.38 (0.89–2.14) for total T, 1.42 (0.90–2.23) for bioavailable T, 1.54 (1.02–2.31) for DHEA, and 0.48 (0.30–0.76) for SHBG. Adjustment for fasting glucose, insulin, and C-reactive protein further attenuated the association for DHEA but not SHBG. Associations of sex hormones with longitudinal BP change were similar.
In postmenopausal women, higher endogenous E2, T, and DHEA and lower SHBG were associated with higher incidence of hypertension and greater longitudinal rise in BP. The associations for E2, T, and DHEA were mostly explained by adiposity, while the association for SHBG was independent of measures of adiposity, insulin resistance, and systemic inflammation.
sex steroid hormones; hypertension; blood pressure; postmenopausal women; prospective study; epidemiology
Findings regarding the association of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass with incident cardiovascular disease (CVD) have been inconsistent, and their role in risk prediction is uncertain.
A case-cohort sample from the Women’s Health Initiative Observational Study (WHI-OS) comprised 1,821 CVD cases and a subcohort of 1,992. Cox regression models with inverse sampling weights assessed the association of Lp-PLA2 mass and activity with CVD (myocardial infarction [MI], stroke, and CVD mortality).
Subcohort means were 184.3 mmol/min/mL for Lp-PLA2 activity and 499.2 ng/mL for Lp-PLA2 mass, with 99% having mass above 200 ng/mL, the clinically recommended cut-point. Both activity and mass were positively associated with incident CVD in age- and race/ethnicity-adjusted analyses. Following adjustment by CVD risk factors, the association with activity became null (hazard ratio [HR] = 1.02 for top vs. bottom quartile, 95% confidence interval [CI] = 0.79-1.33, p-trend=0.65), but the association with mass remained (HR = 1.84, 95% CI = 1.45-2.34, p-trend <0.0001). In contrast to blood pressure, HDL, and hsCRP, reclassification statistics for Lp-PLA2 mass did not suggest improvement for overall CVD after full adjustment.
In the WHI-OS Lp-PLA2 mass, but not activity, was independently associated with CVD. However, model fit did not significantly improve with Lp-PLA2, and assay calibration remains a clinical concern.
To relate dietary fat types to cognitive change in healthy community-based elders.
Among 6,183 older participants in the Women’s Health Study, we related intake of major fatty acids (FAs) (saturated [SFA], mono-unsaturated [MUFA], total poly-unsaturated [PUFA], trans-unsaturated) to late-life cognitive trajectory. Serial cognitive testing, conducted over 4 years, began 5 years post-dietary assessment. Primary outcomes were global cognition (averaging tests of general cognition, verbal memory and semantic fluency) and verbal memory (averaging tests of recall). We used analyses of response profiles and logistic regression to estimate multivariable-adjusted differences in cognitive trajectory and risk of worst cognitive change (worst 10%) by fat intake.
Higher SFA intake was associated with worse global cognitive (p-linear-trend=0.008) and verbal memory (p-linear-trend=0.01) trajectories. There was a higher risk of worst cognitive change, comparing highest vs. lowest SFA quintiles: the multivariable-adjusted odds ratio (OR) (95% confidence interval, CI) was 1.64 (1.04,2.58) for global cognition and 1.65 (1.04,2.61) for verbal memory. By contrast, higher MUFA intake was related to better global cognitive (p-linear-trend<0.001) and verbal memory (p-linear-trend=0.009) trajectories, and lower OR (95% CI) of worst cognitive change in global cognition (0.52 [0.31,0.88]) and verbal memory (0.56 [0.34,0.94]). Total fat, PUFA, and trans fat intakes were not associated with cognitive trajectory.
Higher SFA intake was associated with worse global cognitive and verbal memory trajectories, while higher MUFA intake was related to better trajectories. Thus, different consumption levels of the major specific fat types, rather than total fat intake itself, appeared to influence cognitive aging.
Randomized evidence for aspirin in the primary prevention of cardiovascular disease (CVD) among women is limited and suggests at most a modest effect for total CVD. Lack of compliance, however, can null-bias estimated effects. We used marginal structural models (MSMs) to estimate the etiologic effect of continuous aspirin use on CVD events among 39,876 apparently healthy female health professionals aged 45 years and older in the Women’s Health Study, a randomized trial of 100 mg aspirin every other day versus placebo. As-treated analyses and MSMs controlled for time-varying determinants of aspirin use and CVD. Predictors of aspirin use differed by randomized group and prior use and included medical history, CVD risk factors, and intermediate CVD events. Previously reported intent-to-treat analyses found small non-significant effects of aspirin on total CVD (hazard ratio (HR) =0.91, 95% confidence interval (CI) =0.81–1.03) and CVD mortality (HR=0.95, 95% CI=0.74–1.22). As-treated analyses were similar for total CVD with a slight reduction in CVD mortality (HR=0.88, 95%CI=0.67–1.16). MSMs, which adjusted for non-compliance, were similar for total CVD (HR=0.93; 95% CI: 0.81, 1.07) but suggested lower CVD mortality with aspirin use (HR = 0.76; 95% CI: 0.54, 1.08). Adjusting for non-compliance had little impact on the estimated effect of aspirin on total CVD, but strengthened the effect on CVD mortality. These results support a limited effect of low-dose aspirin on total CVD in women, but potential benefit for CVD mortality.
Aspirin; cardiovascular disease; marginal structural model; myocardial infarction; stroke
Framingham-based and Reynolds risk scores for cardiovascular disease (CVD) prediction have not been directly compared in an independent validation cohort.
Methods and Results
We selected a case-cohort sample of the multi-ethnic Women’s Health Initiative Observational Cohort, comprising 1722 cases of major CVD (752 MIs, 754 ischemic strokes, and 216 other CVD deaths) and a random subcohort of 1994 women without prior CVD. We estimated risk using the ATP-III score, the Reynolds risk score, and the Framingham CVD model, reweighting to reflect cohort frequencies. Predicted 10-year risk varied widely between models, with 10% or higher risk in 6%, 10%, and 41% of women using the ATP-III, Reynolds, and Framingham CVD models, respectively. Calibration was adequate for the Reynolds model, but the ATP-III and Framingham CVD models over-estimated risk for CHD and major CVD, respectively. After recalibration, the Reynolds model demonstrated improved discrimination over the ATP-III model through a higher c-statistic (0.765 vs. 0.757, p=0.03), positive net reclassification improvement (NRI) (4.9%, p=0.02) and positive integrated discrimination improvement (IDI) (4.1%, p<0.0001) overall, excluding diabetics (NRI=4.2%, p=0.01), and in white (NRI=4.3%, p=0.04) and black (NRI=11.4, p=0.13) women. The Reynolds (NRI=12.9, p<0.0001) and ATP-III (NRI=5.9%, p=0.0001) models demonstrated better discrimination than the Framingham CVD model.
The Reynolds Risk Score was better calibrated than the Framingham-based models in this large external validation cohort. The Reynolds score also showed improved discrimination overall and in black and white women. Large differences in risk estimates exist between models, with clinical implications for statin therapy.
cardiovascular disease risk factors; models; prediction; risk score; statins
Atrial fibrillation (AF) is associated with adverse outcome. Whether recently discovered genetic risk markers improve AF risk prediction is unknown.
Methods and results
We derived and validated a novel AF risk prediction model from 32 possible predictors in the Women's Health Study (WHS), a cohort of 20 822 women without cardiovascular disease (CVD) at baseline followed prospectively for incident AF (median: 14.5 years). We then created a genetic risk score (GRS) comprised of 12 risk alleles in nine loci and assessed model performance in the validation cohort with and without the GRS. The newly derived WHS AF risk algorithm included terms for age, weight, height, systolic blood pressure, alcohol use, and smoking (current and past). In the validation cohort, this model was well calibrated with good discrimination [C-index (95% CI) = 0.718 (0.684–0.753)] and improved all reclassification indices when compared with age alone. The addition of the genetic score to the WHS AF risk algorithm model improved the C-index [0.741 (0.709–0.774); P = 0.001], the category-less net reclassification [0.490 (0.301–0.670); P < 0.0001], and the integrated discrimination improvement [0.00526 (0.0033–0.0076); P < 0.0001]. However, there was no improvement in net reclassification into 10-year risk categories of <1, 1–5, and 5+% [0.041 (−0.044–0.12); P = 0.33].
Among women without CVD, a simple risk prediction model utilizing readily available risk markers identified women at higher risk for AF. The addition of genetic information resulted in modest improvements in predictive accuracy that did not translate into improved reclassification into discrete AF risk categories.
Women; Atrial fibrillation; Genetics; Risk prediction; Epidemiology
The performance of prediction models can be assessed using a variety of different methods and metrics. Traditional measures for binary and survival outcomes include the Brier score to indicate overall model performance, the concordance (or c) statistic for discriminative ability (or area under the receiver operating characteristic (ROC) curve), and goodness-of-fit statistics for calibration.
Several new measures have recently been proposed that can be seen as refinements of discrimination measures, including variants of the c statistic for survival, reclassification tables, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Moreover, decision–analytic measures have been proposed, including decision curves to plot the net benefit achieved by making decisions based on model predictions.
We aimed to define the role of these relatively novel approaches in the evaluation of the performance of prediction models. For illustration we present a case study of predicting the presence of residual tumor versus benign tissue in patients with testicular cancer (n=544 for model development, n=273 for external validation).
We suggest that reporting discrimination and calibration will always be important for a prediction model. Decision-analytic measures should be reported if the predictive model is to be used for making clinical decisions. Other measures of performance may be warranted in specific applications, such as reclassification metrics to gain insight into the value of adding a novel predictor to an established model.
Few prospective studies have explored the association between renal function and risk of incident atrial fibrillation (AF) in apparently healthy populations. A total of 24,746 women participating in the Women’s Health Study who were free of cardiovascular disease (CVD), AF and provided a blood sample at baseline were prospectively followed for incident AF from 1993 to 2010. AF events were confirmed by medical chart review. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine using the Chronic Kidney Disease – Epidemiology equation. Cox models were used to estimate hazard ratios (HR) and 95% CI for incident AF across eGFR categories controlling for AF risk factors. During 15.4 years (median) of follow-up, 786 incident AF events occurred. The multivariable-adjusted HR for incident AF across eGFR categories (<60, 60–74.9, 75–89, and ≥ 90 ml/min/1.73 m2) were:1.36 (1.00–1.84), 0.90 (0.71–1.14), 0.99 (0.84–1.18) and 1.00, respectively, without evidence of a linear association (P for trend, 0.48). Similarly, there was no significant curvilinear association (P quadratic, 0.10) in multivariable analysis across categories. As compared to women with an eGFR ≥ 60 ml/min/1.73 m2, the 1008 women with an eGFR < 60 ml/min/1.73 m2 had a multivariable adjusted HR for AF of 1.39 (1.04–1.86, p value 0.03). In conclusion, no significant linear or curvilinear relationship was observed between incident AF and less severe impairment of renal function in this large prospective cohort of women. However, a significant elevation in AF risk was observed at a threshold eGFR of < 60 ml/min/1.73 m2.
atrial fibrillation; renal function
Data from laboratory studies, observational research, and/or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease (CVD), but primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a large randomized, double-blind, placebo-controlled, 2×2 factorial trial of vitamin D (in the form of vitamin D3 [cholecalciferol], 2000 IU/day) and marine omega-3 fatty acid (Omacor® fish oil, eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], 1 g/day) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥50 and women aged ≥55. The mean treatment period will be 5 years. Baseline blood samples will be collected in at least 16,000 participants, with follow-up blood collection in about 6000 participants. Yearly follow-up questionnaires will assess treatment compliance (plasma biomarker measures will also assess compliance in a random sample of participants), use of non-study drugs or supplements, occurence of endpoints, and cancer and vascular risk factors. Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment, and deaths will be ascertained through national registries and other sources. Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance; hypertension; cognitive decline; depression; osteoporosis and fracture; physical disability and falls; asthma and other respiratory diseases; infections; rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and other autoimmune disorders.
Cancer; cardiovascular disease; cholecalciferol; primary prevention; omega-3 fatty acids; vitamin D; randomized controlled trial
To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics.
Methods and results
Randomized controlled trial data from the Women's Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50.
Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.
Trial registration information: Clinicaltrials.gov identifier number: NCT00000479.
Aspirin; Primary prevention; Treatment effect prediction; Net benefit
Adiponectin is linked to reduced diabetes risk and may be anti-atherogenic, yet clinical data show no consistent relationship with incident cardiovascular events, especially among women. To our knowledge, no prior prospective studies have evaluated adiponectin, including high-molecular-weight (HMW) adiponectin, and incident peripheral artery disease (PAD).
Methods & Results
We evaluated the relationship of total, HMW and the HMW-to-total adiponectin ratio with incident symptomatic PAD in a prospective, nested case-control study conducted within the Women’s Health Study (n=110 cases, n=230 controls, frequency matched in strata defined by five-year age categories, smoking, fasting status and follow-up time; median cohort follow-up=13.2 yrs). Baseline median levels of HMW and total adiponectin were significantly lower in women developing PAD than those remaining event-free(HMW: 3.3 vs. 3.8 μg/mL, P=0.0005; total: 5.6 vs. 7.4 μg/mL, P<0.0001). The ratio did not differ significantly between groups. Age-adjusted PAD odds ratios (95% CI) across tertiles were 1.0, 0.66 (0.39–1.13) and 0.40 (0.22–0.74)for HMW and 1.0, 0.74 (0.43–1.25) and 0.35 (0.18–0.65) for total adiponectin (P-trend=0.004 and 0.001, respectively). Results were similar after adjustment for traditional cardiovascular risk factors, use of post-menopausal hormone therapy, high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, leptin, hemoglobin A1c and fasting insulin [adjusted OR and 95% CI for HMW: 1.0, 0.62 (0.29–1.34), 0.30 (0.12–0.74); total: 1.0, 0.46 (0.22–1.00), 0.30 (0.12–0.76 );Ptrend=0.01 for both].
Total and HMW adiponectin are inversely associated with incident PAD among initially healthy women. These prospective data support a protective role for this adipokine in peripheral atherosclerosis development.
adiponectin; biomarker; epidemiology; peripheral artery disease; women
It is unclear whether models which include hemoglobin A1c (HbA1c) levels only for diabetic patients improve ability to predict cardiovascular disease (CVD) risk when compared to the currently recommended classification of diabetes as a cardiovascular risk equivalent.
24,674 women (including 685 diabetic participants at baseline) and 11,280 men (including 563 diabetic participants at baseline) were followed prospectively for CVD. 125 CVD events occurred in diabetic women (666 in non-diabetic women) and 170 events occurred in diabetic men (1382 in non-diabetic men). Models for CVD risk were generated separately for men and women using the traditional CVD risk factors with the addition of a term for HbA1c levels only for diabetic individuals. In diabetic participants, the resulting predicted risks were compared to classification of diabetes as a cardiovascular risk equivalent (10-year CVD-risk of at least 20%).
In women, the models including HbA1c levels in diabetic participants improved the c-statistic by 0.177 (p <0.001) over the risk equivalence model and showed improved reclassification (NRI of 26.7%, p = 0.001). In men, the improvements were more modest but still statistically significant (c-statistic change of 0.039, p=0.015; NRI of 9.2%, p= 0.042). Including HbA1c levels also improved prediction over a dichotomous term for diabetes in women (NRI of 11.8%, p = 0.033) but not in men.
In both women and men with baseline diabetes, we observed significant improvements in predictive ability of CVD risk using models incorporating HbA1c levels compared to classification of diabetes as a cardiovascular risk equivalent.
High homocysteine levels may be neurotoxic and contribute to cognitive decline in older persons.
Examine the effect of supplementation with folic acid, vitamin B12 and vitamin B6 on cognitive change among women with cardiovascular disease (CVD) or CVD risk factors.
The Women's Antioxidant and Folic Acid Cardiovascular Study is a randomized, placebo-controlled trial to test a combination of B vitamins (folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg, daily) for secondary prevention of CVD. Randomization took place among 5,442 female health professionals, 40+ years, with CVD or at least three coronary risk factors in 1998 (after folic acid fortification began in the US). Shortly after randomization (mean=1.2 years), a cognitive function substudy was initiated among 2009 participants aged 65+ years. Telephone cognitive function testing was administered up to four times over 5.4 years with 5 tests of general cognition, verbal memory and category fluency. Repeated measures analyses were conducted. The primary outcome was a global composite score averaging all tests.
Mean cognitive change from baseline did not differ between the B vitamin and placebo groups (difference in change in global score= 0.03, 95% CI −0.03, 0.08; p=0.30). However, supplementation appeared to confer benefits in preserving cognition among women with low baseline dietary intake of B vitamins.
Combined B vitamin supplementation did not delay cognitive decline among women with CVD or CVD risk factors. Possible cognitive benefits of supplementation among women with low dietary intake of B vitamins warrant further study.
The effects of physical activity on risk of myocardial infarction (MI) are well documented and may include beneficial changes in blood lipids, inflammatory markers, and insulin sensitivity. The degree to which these and other traditional and nontraditional cardiovascular biomarkers mediate the inverse association between physical activity and risk of MI in men remains unclear.
We conducted a nested case-control study among 18,225 men in the Health Professionals Follow-up Study followed from 1994 to 2004. A total of 412 men with incident MI were matched 1:2 with control participants on age and smoking status using risk-set sampling. From detailed responses to a modified Paffenbarger physical activity questionnaire, we determined the association between average hours of vigorous-intensity activity (activities requiring METs ≥ 6) and MI risk.
For a 3-hour per week increase in vigorous-intensity activity, the multivariate relative risk (RR) of MI was 0.78 (95% CI 0.61, 0.98). In models including pre-existing CVD-related conditions, further adjustment for HDL-C, vitamin D, apolipoprotein B, and hemoglobin A1c attenuated the RR by 70% (95% CI 12%, 127%) to a RR of 0.93 (95% CI 0.72, 1.19).
Participating in three hours per week of vigorous-intensity activity is associated with a 22% lower risk of MI among men. This inverse association can be partially explained by beneficial effects of physical activity on HDL-C, vitamin D, apolipoprotein B, and hemoglobin A1c. While the inverse association attributable to these biomarkers is substantial, future research should explore benefits of exercise beyond these biomarkers of risk.
exercise; men; epidemiology; coronary heart disease; risk factors
Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations.
We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who later developed colorectal cancer from the Women's Health Initiative Observational Cohort. As the distribution of HGF levels was highly skewed, we transformed HGF concentrations for all women into a log-, ranked-, or normal score-scale value. Multiple linear regression with adjustment for age was used to evaluate the associations.
We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and HGF levels in ranked and normal score scales (corrected p values ≤0.02), although the association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.16). The associations remained unchanged after additional adjustment for hormone therapy use and estradiol levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D′≥97%, r2≥56%), constituted a block with 2 common haplotypes accounting for 82% frequency. The most common haplotype, TCCCA, was associated with lower ranked- or normal score-transformed HGF levels (corrected p values ≤0.001), whereas the second most common haplotype, CTTCA, was associated with higher ranked- or normal score-transformed HGF levels (corrected p values ≤0.02).
Our findings of a potential association between the CYP19A1 variants and circulating HGF levels warrant confirmation in studies with larger sample size.
Concerns have been raised about the use of traditional measures of model fit in evaluating risk prediction models for clinical use, and reclassification tables have been suggested as an alternative means of assessing the clinical utility of a model. Several measures based on the table have been proposed, including the reclassification calibration (RC) statistic, the net reclassification improvement (NRI), and the integrated discrimination improvement (IDI), but the performance of these in practical settings has not been fully examined. We used simulations to estimate the type I error and power for these statistics in a number of scenarios, as well as the impact of the number and type of categories, when adding a new marker to an established or reference model. The type I error was found to be reasonable in most settings, and power was highest for the IDI, which was similar to the test of association. The relative power of the RC statistic, a test of calibration, and the NRI, a test of discrimination, varied depending on the model assumptions. These tools provide unique but complementary information.
Calibration; Discrimination; Model accuracy; Prediction; Reclassification
Very low levels of cardiac troponin T associate with increased risk of cardiovascular death in patients with stable chronic coronary disease. Whether high-sensitivity cardiac troponin T (hsTnT) levels associate with adverse cardiovascular outcomes in individuals without cardiovascular disease (CVD) has not been well studied.
Methods and Results
Utilizing two complementary study designs, we evaluated the relationship between baseline cardiac troponin and incident CVD events among diabetic and non-diabetic participants in the Women’s Health Study (median follow-up 12.3 years). All diabetic women with blood specimens were included in a cohort study (n=512 diabetic women, n=65 events) and non-diabetic women were sampled for inclusion in a case-cohort analysis (n=564 comprising the subcohort, n=479 events). HsTnT was detectable (≥0.003 μg/L) in 45.5% of diabetic women and 30.3% of non-diabetic women (P<0.0001). In models adjusted for traditional risk factors and hemoglobin A1c, detectable hsTnT was associated with subsequent CVD (myocardial infarction, stroke, cardiovascular death) in diabetic women (adjusted HR 1.79, 95% CI 1.04-3.07, P=0.036), but not non-diabetic women (adjusted HR 1.13, 95% CI 0.82-1.55, P=0.46). Further adjustment for NT-proBNP and estimated renal function did not substantially alter this relationship among diabetic women (HR 1.76, 95% CI 1.00-3.08, P=0.0499), which appeared to be driven by a threefold increase in CVD death that was not observed in non-diabetic women.
Very low but detectable levels of cardiac troponin T associate with total CVD and CVD death in women with diabetes. Among healthy non-diabetic women, detectable compared to undetectable troponin was not associated with CVD events.
Primary prevention; cardiovascular disease risk factors; troponin; diabetes mellitus type 2; women
Homozygosity for a common non-synonymous single nucleotide polymorphism (Gln27Glu) in the beta-2 adrenergic receptor gene (ADRB2) has been inconsistently associated with sudden cardiac death (SCD) in individual studies of small sample size.
To examine the association between the Gln27Glu polymorphism and SCD in a large combined sample of SCD cases.
Nested case-control analysis among individuals of Caucasian ancestry enrolled in six prospective cohort studies. Genotypes for the Gln27Glu variant were determined for 492 cases of SCD and 1388 controls matched on age, sex, cohort, follow-up time, and history of cardiovascular disease (CVD) and at the time of the blood draw. Individual studies were combined with conditional logistic regression with fixed effects meta-analysis assuming a recessive model.
Homozygosity for the Gln27 allele conferred a non-significant elevation of the age-adjusted odds ratio (OR=1.22; 95% CI, 0.98-1.53; P=0.08) for SCD, which became marginally significant after controlling for multiple cardiac risk factors (OR=1.30, 95% CI: 1.01-1.67; P=0.046). In secondary analyses using controls additionally matched for the development of nonfatal CVD after the blood draw, results were attenuated (OR=1.19, 95%CI: 0.92-1.52; P=0.19). When the results of the primary analysis were combined in meta-analysis with published reports, a significant association between ADRB2 genotype and SCD emerged (OR=1.35, 95% CI: 1.15-1.60; P=0.0003).
These data from a large prospective case-control series, when combined with published studies, provide further evidence for an association between ADRB2 genotype and SCD. The mechanism is unknown, but appears to be partly mediated by development of CVD.
Sudden Cardiac Death; Genetic Epidemiology; Sympathetic Nervous System; Beta-2 Adrenergic Receptor
This study sought to determine the relation between and discriminative capability of Lipoprotein-associated phospholipase A2 (Lp-PLA2) and coronary heart disease (CHD) in a large population of disease-free women.
Among participants of the Nurses’ Health Study who provided a blood sample, there were 421 cases of incident myocardial infarction (MI) during 14 years of follow-up. Controls were matched to cases 2:1 using risk-set sampling based on age, smoking, and blood draw date.
Conditioning on the matching factors, Lp-PLA2 activity was significantly associated with MI (RR=2.86 for extreme quartiles; 95% Confidence Interval (CI): 1.98, 4.12). After adjustment for lipid, inflammatory, and clinical risk factors, the relative risk remained statistically significant was assessed by (RR=1.75; 95%CI: 1.09, 2.84). The discriminative capability of Lp-PLA2 comparing area under the receiver operating characteristic curves (AUROC) for models with and without Lp-PLA2, and by calculating the net reclassification improvement index (NRI). Adding Lp-PLA2 activity to a multivariable-adjusted model increased the AUROC from 0.720 to 0.733, and significantly improved the NRI (p = 0.004).
Levels of Lp-PLA2 activity were significantly associated with incident CHD among women. In addition, Lp- PLA2 activity added significantly to CHD risk discrimination.