Despite the promising findings from short-term intervention trials, the long-term effect of habitual fruit and vegetable intake on blood pressure (BP) remains uncertain. We therefore assessed the prospective association between baseline intake of fruits and vegetables and the risk of hypertension in a large cohort of middle-aged and older women.
We conducted analyses among 28,082 US female health professionals aged ≥39 years, free of cardiovascular disease, cancer, and hypertension at baseline. Baseline intake of fruits and vegetables was assessed using semi-quantitative food frequency questionnaires. Incident hypertension was identified from annual follow-up questionnaires.
During 12.9 years of follow-up, 13,633 women developed incident hypertension. After basic adjustment including age, race, and total energy intake, the hazard ratio and 95% CI of hypertension was 0.97 (0.89-1.05), 0.93 (0.85-1.01), 0.89 (0.82-0.97), and 0.86 (0.78-0.94) comparing women who consumed 2-<4, 4-<6, 6-<8, and ≥8 servings/day of total fruits and vegetables with those consuming <2 servings/day. These associations did not change after additionally adjusting for lifestyle factors but were attenuated after further adjustment for other dietary factors. When fruits and vegetables were analyzed separately, higher intake of all fruits but not all vegetables remained significantly associated with reduced risk of hypertension after adjustment for lifestyle and dietary factors. Adding body mass index to the models eliminated all associations.
Higher intake of fruits and vegetables, as part of a healthy dietary pattern, may only contribute a modest beneficial effect to hypertension prevention, possibly through improvement in body weight regulation.
fruits; vegetables; diet; hypertension; prospective; women
Background and aims
Hypertension is a major public health problem. While many dietary factors affect the risk of developing hypertension, limited data are available on the association between consumption of breakfast cereal and incident hypertension. We examined the association between breakfast cereal consumption and the risk of hypertension.
We prospectively analyzed data from 13,368 male participants of the Physicians’ Health Study I. Consumption of breakfast cereals was estimated using an abbreviated food frequency questionnaire and incident hypertension was ascertained through yearly follow-up questionnaires.
The average age of study participants was 52.4 ±8.9 years (range 39.7-85.9) during the initial assessment of cereal intake (1981-1983). During a mean follow up of 16.3 years, 7,267 cases of hypertension occurred. The crude incidence rates of hypertension were 36.7, 34.0, 31.7, and 29.6 cases/1,000 person-years for people reporting breakfast cereal intake of 0, ≤ 1, 2-6, and ≥ 7 servings/week, respectively. In a Cox regression model adjusting for age, smoking, body mass index, alcohol consumption, fruit and vegetable consumption, physical activity, and history of diabetes mellitus, hazard ratios (95% CI) for hypertension were 1.0 (reference), 0.93 (0.88-0.99), 0.88 (0.83-0.94), and 0.81 (0.75-0.86) from the lowest to the highest category of cereal consumption, respectively (p for trend <0.0001). This association was strongest for whole grain cereals and was observed in lean as well as overweight or obese participants.
The results of this longitudinal cohort study suggest that whole grain breakfast cereal consumption confers a lower risk of hypertension in middle-aged adult males
cereals; hypertension; epidemiology
In studies enrolling stroke patients, higher levels of pre-stroke physical activity are associated with better functional outcomes. However, prospective studies evaluating this association are sparse. Using a cohort of initially healthy men, we aimed to prospectively assess the association between physical activity and functional outcomes from cerebral vascular events.
Prospective cohort study among 21,794 men enrolled in the Physician's Health Study who provided information on physical activity at baseline and who did not have a history of stroke or transient ischemic attack (TIA). Baseline levels of physical activity were categorized as: vigorous exercise <1, 1, 2–4 and ≥5 times/week. Possible functional outcomes included TIA and stroke with mRS score of 0–1, 2–3 or 5–6. Multinomial logistic regression was used to determine the association between physical activity and functional outcomes from cerebral vascular events.
After a mean of 20.2 years of follow-up, 761 TIAs, 1146 ischemic strokes, 221 hemorrhagic strokes and 11 strokes of unknown type occurred. Compared with men who did not experience a stroke or TIA and who exercise vigorously <1 time/week, men who exercise vigorously ≥5 times/week had adjusted relative risk (95% CIs) of 0.67 (0.53–0.86) for TIA, 0.84 (0.61–1.14) for stroke with mRS 0–1, 0.85 (0.67–1.08) for mRS 2–3, and 1.12 (0.78–1.60) for mRS 5–6 after total stroke. Other levels of physical activity did not have a significant impact on the risk of our outcomes.
Physical activity prior to TIA or stroke does not appear to influence functional outcomes after cerebral vascular events.
Increased levels of serum immunoglobulin E (IgE) because of allergies have been inversely associated with risk of glioma in observational studies. Despite consistency across studies examining history of allergies and glioma, questions remain as to whether those are causal associations. An inverse association between serum IgE and risk of glioma was reported in a large case–control study, but reverse causality and treatment effects remain potential explanations for those findings.
We combined data from four prospective cohort studies and used a nested case–control design to examine the association between allergy and glioma. We included glioma case subjects who were confirmed from medical or pathology records or from death certificates, and with prediagnostic blood available. We matched three control subjects per case subject, and the final numbers for analyses were 169 case subjects and 520 control subjects. Total IgE, food allergen–specific IgE, and respiratory allergen–specific IgE levels were measured using a highly sensitive fluorescent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression analysis. Stratified analyses were conducted by age and birth cohorts.
Borderline elevated total IgE levels (25–100 kU/L) showed a statistically significant inverse association with glioma (OR = 0.63, 95% CI = 0.42 to 0.93), but no association was noted between elevated IgE (>100 kU/L) and glioma (OR = 0.98, 95% CI = 0.61 to 1.56) compared with clinically normal IgE levels (<25 kU/L). The association between glioma and total IgE was consistent for both men and women. Non-statistically significant inverse associations were noted for elevated IgE levels among individuals born before year 1930 (OR = 0.67, 95% CI = 0.34 to 1.34) and when restricting analyses to highly fatal (deceased within 2 years of diagnosis) glioma case subjects (OR = 0.64, 95% CI = 0.34 to 1.19) compared with individuals with clinically normal IgE levels. No associations were observed for either food allergen–specific or respiratory allergen–specific IgE levels.
Overall, our prospective findings are consistent with recent retrospective studies and support an association between total IgE levels and glioma. However, this association requires further elucidation.
The threat of prostate cancer (PC) and the significant and often negative impact of its treatment underscore the importance of prevention. High-grade prostatic intraepithelial neoplasia (HGPIN) has been identified as a potential premalignant lesion marking an increased risk of PC, and substantial evidence suggests that men with HGPIN are in need of PC prevention. In vitro, in vivo, epidemiologic, and clinical trial evidence that selenium supplementation protects against PC motivated the study we report here: A double-blind, randomized, placebo-controlled trial of selenium 200 (mcg/day) as selenomethionine in men with HGPIN. The primary endpoint was progression of HGPIN to PC over a three-year period. This NCI Intergroup trial was coordinated by the Southwest Oncology Group (SWOG). Of 619 enrolled patients, 423 randomized men with HGPIN (212, selenium; 211, placebo) were eligible (by central pathology review) and included in the primary analysis. Three-year cancer rates were 36.6% (placebo) versus 35.6% (selenium; P = 0.73, adjusted). The majority of patients who developed cancer on trial (70.8%, selenium, and 75.5%, placebo) had a Gleason score of ≤ 6; there were no differences in Gleason scores between the two arms. Subset analyses included the finding of a nonsignificantly reduced PC risk (relative risk = 0.82; 95% confidence interval, 0.40–1.69) in selenium versus placebo patients in the lowest quartile of baseline plasma selenium level (< 106 ng/ml). Overall, and in all other subsets defined by baseline blood selenium levels, selenium supplementation had no effect on PC risk. The 36% PC rate in men with HGPIN indicates the association of this lesion with an elevated PC risk. Future study in this setting should focus on selenium-deficient populations and selenium pharmacogenetics.
Chemoprevention; selenium; prostate cancer; intraepithelial neoplasia; prevention; clinical trials
To evaluate the association between restless legs syndrome (RLS) and all-cause mortality.
Four prospective cohort studies.
The Dortmund Health Study (DHS) and the Study of Health in Pomerania (SHIP) from Germany. The Women's Health Study (WHS) and the Physicians’ Health Study (PHS) from the USA.
In DHS: a random sample (n=1 299) from the population of Dortmund; in SHIP: a sample (n=4 291) from residents living in West Pomerania were drawn by multistage random sampling design; in WHS: female healthcare professionals (n=31 370); in PHS: male physicians (n=22 926)
Main outcome measures
The prevalence of RLS ranged between 7.4% and 11.9% at baseline. During follow-up (ranging between 6 and 11 years) RLS was not associated with increased risk of all-cause mortality in any of the four cohorts. The multivariable-adjusted HRs (95% CI) for all-cause mortality ranged from 0.21 (0.03 to 1.53) to 1.07 (0.93 to 1.23) across the four studies. The HRs for all-cause mortality did not differ according to gender.
In these four independently conducted large prospective cohort studies from Germany and the USA, RLS did not increase the risk of all-cause mortality. These findings do not support the hypothesis that RLS is a risk factor for mortality of any cause.
restless legs sydrome; prospective cohort study; mortality
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.
Bromocriptine-QR (a quick-release formulation of bromocriptine mesylate), a dopamine D2 receptor agonist, is a US Food and Drug Administrration–approved treatment for type 2 diabetes mellitus (T2DM). A 3070-subject randomized trial demonstrated a significant, 40% reduction in relative risk among bromocriptine-QR-treated subjects in a prespecified composite cardiovascular (CV) end point that included ischemic-related (myocardial infarction and stroke) and nonischemic-related (hospitalization for unstable angina, congestive heart failure [CHF], or revascularization surgery) end points, but did not include cardiovascular death as a component of this composite. The present investigation was undertaken to more critically evaluate the impact of bromocriptine-QR on cardiovascular outcomes in this study subject population by (1) including CV death in the above-described original composite analysis and then stratifying this new analysis on the basis of multiple demographic subgroups and (2) analyzing the influence of this intervention on only the “hard” CV end points of myocardial infarction, stroke, and CV death (major adverse cardiovascular events [MACEs]).
Methods and Results
Three thousand seventy T2DM subjects on stable doses of ≤2 antidiabetes medications (including insulin) with HbA1c ≤10.0 (average baseline HbA1c=7.0) were randomized 2:1 to bromocriptine-QR (1.6 to 4.8 mg/day) or placebo for a 52-week treatment period. Subjects with heart failure (New York Heart Classes I and II) and precedent myocardial infarction or revascularization surgery were allowed to participate in the trial. Study outcomes included time to first event for each of the 2 CV composite end points described above. The relative risk comparing bromocriptine-QR with the control for the cardiovascular outcomes was estimated as a hazard ratio with 95% confidence interval on the basis of Cox proportional hazards regression. The statistical significance of any between-group difference in the cumulative percentage of CV events over time (derived from a Kaplan–Meier curve) was determined by a log-rank test on the intention-to-treat population. Study subjects were in reasonable metabolic control, with an average baseline HbA1c of 7.0±1.1, blood pressure of 128/76±14/9, and total and LDL cholesterol of 179±42 and 98±32, respectively, with 88%, 77%, and 69% of subjects being treated with antidiabetic, antihypertensive, and antihyperlipidemic agents, respectively. Ninety-one percent of the expected person-year outcome ascertainment was obtained in this study. Respecting the CV-inclusive composite cardiovascular end point, there were 39 events (1.9%) among 2054 bromocriptine-QR-treated subjects versus 33 events (3.2%) among 1016 placebo subjects, yielding a significant, 39% reduction in relative risk in this end point with bromocriptine-QR exposure (P=0.0346; log-rank test) that was not influenced by age, sex, race, body mass index, duration of diabetes, or preexisting cardiovascular disease. In addition, regarding the MACE end point, there were 14 events (0.7%) among 2054 bromocriptine-QR-treated subjects and 15 events (1.5%) among 1016 placebo-treated subjects, yielding a significant, 52% reduction in relative risk in this end point with bromocriptine-QR exposure (P<0.05; log-rank test).
These findings reaffirm and extend the original observation of relative risk reduction in cardiovascular adverse events among type 2 diabetes subjects treated with bromocriptine-QR and suggest that further investigation into this impact of bromocriptine-QR is warranted.
Clinical Trial Registration
URL: http://clinicaltrials.gov. Unique Identifier: NCT00377676
bromocriptine; circadian rhythm; Cycloset; diabetes mellitus type 2; infarction
While cross-sectional studies have identified lifestyle factors associated with high-density lipoprotein cholesterol (HDL-C), no studies have examined the association between changes in lifestyle factors and long-term changes in HDL-C.
We examined the association between changes in lifestyle factors and changes in HDL-C over a 14 year period in a cohort of 4,168 U.S. male physicians followed between 1982 and 1997 and with HDL-C measured at both time points. Using linear regression, we examined the association between HDL-C change and categorized changes in alcohol consumption, physical activity, body mass index (BMI), and smoking, adjusting for age, baseline HDL-C, and other covariates.
Stable BMI of <25 kg/m2 or BMI reduction from ≥25 kg/m2 to <25 kg/m2 were associated with increases in HDL-C of 3.1 to 4.7 mg/dL over 14 years. Alcohol consumption of ≥1 drink daily or increase in alcohol consumption from <1 to ≥1 drink daily were associated with increases in HDL-C of 2.4 to 3.3 mg/dL over 14 years. Adopting a sedentary lifestyle was associated with decreases in 14-year decreases in HDL-C.
These findings suggest that reductions in BMI and increases in alcohol consumption are associated with 14-year increases in HDL-C, while decreases physical activity are associated with 14-year decreases in HDL-C.
The oxidant/antioxidant balance in lung tissue is hypothesised to contribute to chronic obstructive pulmonary disease (COPD) risk. Observational studies consistently report higher antioxidant status associated with lower COPD risk, but few randomised studies have been reported.
A post-hoc analysis of 38,597 women without chronic lung disease at baseline was conducted in the Women’s Health Study (WHS) to test the effect of vitamin E on risk of incident chronic lung disease. The WHS was a randomised, double-blind, placebo-controlled, factorial trial of vitamin E (600 IU every other day) and aspirin (100 mg every other day) in female health professionals aged ≥45. Using Cox proportional hazards models, the effect of randomised vitamin E assignment on self-reported, physician-diagnosed chronic lung disease was evaluated.
During 10 years of follow-up (376,710 person-years), 760 first occurrences of chronic lung disease were reported in the vitamin E arm compared to 846 in the placebo arm (Hazard Ratio [HR] 0.90; 95% confidence interval [CI] 0.81–0.99; p=0.029). This 10% reduction in the risk of incident chronic lung disease was not modified by cigarette smoking, age, randomised aspirin assignment, multivitamin use, or dietary vitamin E intake (minimum P for interaction = 0.19). Current cigarette smoking was a strong predictor of chronic lung disease risk (HR 4.17; 95% CI 3.70–4.70; versus never smokers).
In this large, randomised trial, assignment to 600 IU of vitamin E led to a 10% reduction in the risk of chronic lung disease in women.
pulmonary disease; chronic obstructive; antioxidants; tocopherols; intervention studies; randomised controlled trial
To evaluate the association between restless legs syndrome (RLS) and incident cardiovascular disease (CVD).
Prospective cohort study.
Women's Health Study (WHS) and Physicians' Health Study (PHS), USA.
29 756 female health professionals aged ≥45 years and 19 182 male physicians aged ≥40 years at baseline.
Main outcome measures
Main outcome was incidence of major CVD; secondary outcomes were first incidence of myocardial infarction, stroke, death due to CVD or coronary revascularisation.
3487 (11.7%) women and 1373 (7.2%) men met International Restless Legs Study Group criteria for RLS. In the WHS 450 major CVD events occurred and 1064 major CVD events were confirmed in the PHS. In both cohorts, RLS was not associated with increased risk of major CVD, stroke, myocardial infarction, CVD death or coronary revascularisation. After adjustment for major vascular risk factors, the HRs (95% CI) for major CVD were 1.15 (0.88 to 1.50) in women and 1.01 (0.81 to 1.25) in men. Highest multivariable-adjusted HRs were 1.29 (0.91 to 1.82) for total stroke in women and 1.22 (0.87 to 1.70) for CVD death in men. Excluding participants with comorbidities potentially leading to RLS did not substantially change the effect estimates.
In these large prospective studies of female and male health professionals, RLS was not associated with an increased risk of any incident CVD event. The data do not support the hypothesis that RLS is a marker of increased risk of vascular disease.
The aim of this study is to evaluate the association between RLS and incident cardiovascular events in two large prospective cohort studies.
The results of our two large prospective cohorts do not suggest that either women or men suffering from RLS are at increased risk for any vascular disease event.
RLS should not be considered a marker for increased CVD risk.
Strengths and limitations of this study
Strengths of this study include the large number of participants and outcome events, the prospective study design, the standardised assessment of RLS according to the four minimal diagnostic criteria and confirmation of CVD cases by medical record review.
The following limitations should be considered: the information on RLS was self-reported and misclassification of cases is possible. No information on frequency, severity and duration of RLS symptoms was available and both cohorts consist of white health professionals, which may limit the generalisability of the results to other populations.
Large prospective cohort studies are critical for identifying etiologic factors for disease, but they require substantial long-term research investment. Such studies can be conducted as multisite consortia of academic medical centers, combinations of smaller ongoing studies, or a single large site such as a dominant regional health-care provider. Still another strategy relies upon centralized conduct of most or all aspects, recruiting through multiple temporary assessment centers. This is the approach used by a large-scale national resource in the United Kingdom known as the “UK Biobank,” which completed recruitment/examination of 503,000 participants between 2007 and 2010 within budget and ahead of schedule. A key lesson from UK Biobank and similar studies is that large studies are not simply small studies made large but, rather, require fundamentally different approaches in which “process” expertise is as important as scientific rigor. Embedding recruitment in a structure that facilitates outcome determination, utilizing comprehensive and flexible information technology, automating biospecimen processing, ensuring broad consent, and establishing essentially autonomous leadership with appropriate oversight are all critical to success. Whether and how these approaches may be transportable to the United States remain to be explored, but their success in studies such as UK Biobank makes a compelling case for such explorations to begin.
cohort studies; epidemiology; prospective studies
The relations between chronic kidney disease (CKD) and incident heart failure remain unclear.
Methods and Results
We related CKD to incident nonfatal heart failure and cardiovascular (CVD) death (as separate and combined endpoints) in 10,181 male participants (mean age, 67years). Kidney function was assessed by estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease equation in clinically relevant categories of <60 and ≥60 ml/min/1.73 m2 (referent); and <45, 45 to 60, 60 to 90 and ≥90 ml/min/1.73 m2 (referent). During follow up (mean 10.1years; range 0.03-12.2), 439 developed heart failure and 832 had CVD death/heart failure. In multivariable models, men with eGFR <60ml/min/1.73 m2 had a 2-fold risk of heart failure (95% confidence interval [CI], 1.62-2.56, p<0.0001) compared to referent category. The hazard ratio [HR] (with corresponding 95% CI) for development of heart failure according to eGFR categories of 60-90, 45-60, and <45ml/min/1.73m2 compared to referent category were 1.24 (0.98-1.56), 2.58 (1.91-3.49) and 1.52 (0.92-2.76) respectively. In the analyses restricted to subgroup of non-diabetics and normotensive individuals at baseline (n=7545), men with eGFR <60 ml/min/1.73 m2 had 2.2-fold risk of heart failure (95% CI 1.66-2.95), compared to men with eGFR≥60 ml/min/1.73 m2. Additionally, risk of heart failure or CVD death was >2.5-fold higher among individuals with eGFR 45-60 and <45 ml/min/1.73 m2, compared to referent category.
Moderate level of CKD, even in absence of diabetes and hypertension at baseline, is associated with a higher risk of developing heart failure and CVD death/heart failure in men.
Heart Failure; Congestive; Epidemiology; Renal disease
Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease.
330 SNPs in 52 genes were studied in relation to plasma homocysteine and global genomic DNA methylation. SNPs were selected based on functional effects and gene coverage, and assays were completed on the Illumina Goldengate platform. Age-, smoking-, and nutrient-adjusted genotype--phenotype associations were estimated in regression models.
Using a nominal P ≤ 0.005 threshold for statistical significance, 20 SNPs were associated with plasma homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes remained associated with plasma homocysteine. Gene by vitamin B-6 interactions were identified for both Alu and LINE-1 methylation, and epistatic interactions with the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Pleiotropy involving the MTHFD1L and SARDH genes for both plasma homocysteine and Alu methylation phenotypes was identified.
No single gene was associated with all three phenotypes, and the set of the most statistically significant SNPs predictive of homocysteine or Alu or LINE-1 methylation was unique to each phenotype. Genetic variation in folate-mediated one-carbon metabolism, other than the well-known effects of the MTHFR c.665C>T (known as c.677 C>T, rs1801133, p.Ala222Val), is predictive of cardiovascular disease biomarkers.
Background and Aims
While nut consumption has been shown to lower the risk of hypertension and coronary disease, it is not known whether nut consumption is associated with the risk of stroke. We sought to examine whether nut consumption is associated with total and subtypes of stroke.
Prospective cohort of 21,078 participants from the Physicians’ Health Study (1982–2008) who were free of stroke at baseline. Nut consumption was assessed using a simple 19-item food questionnaire and stroke cases were confirmed after reviewing medical records. We used Cox proportional hazards regression to estimate relative risks of total, ischemic, and hemorrhagic stroke according to consumption of any nuts.
During a mean follow up of 21.1 years, 1,424 incident cases of stroke occurred (219 hemorrhagic, 1,189 ischemic, and 16 of undetermined cause). There was no statistically significant association between nut consumption and total or ischemic stroke. In contrast, there was a suggestive non-linear relation between nut intake and hemorrhagic stroke: compared to subjects who did not consume nuts, multivariable adjusted hazard ratios (95% CI) for hemorrhagic stroke for subjects consuming nuts < 1, 1, 2–4, 5–6, and ≥ 7 times/week were 1.13 (0.78–1.62), 1.05 (0.70–1.58), 0.49 (0.27–0.89), 1.50 (0.79–2.84), and 1.84 (0.95–3.57), respectively (p for quadratic trend 0.12).
Our data showed no association between nuts and ischemic stroke and suggested a J-shaped relation between nut consumption and hemorrhagic stroke. Replication of our findings in the general population is warranted.
Diet; stroke; epidemiology; nuts; nutrition
Dietary intake of various fats may have different effects on blood pressure. We conducted a prospective cohort study to examine the association between intake of subtype and individual fatty acids (FAs) and the risk of developing hypertension among 28,100 US women aged ≥39 years and free of cardiovascular disease and cancer. Baseline intake of FAs was assessed using semiquantitative food frequency questionnaires. Incident hypertension was identified from annual follow-up questionnaires based on self-reported physician diagnosis, medication use, and blood pressure levels. A total of 13,633 women developed incident hypertension during 12.9 years of follow-up. After adjusting for demographic, lifestyle, and other dietary factors, intake of saturated FAs (SFAs), monounsaturated FAs (MUFAs), trans-unsaturated FAs (trans FAs) was positively associated with the risk of hypertension. The multivariable relative risks (RRs) and 95% confidence intervals (CIs) of hypertension in the highest compared to the lowest quintile of intake were 1.12 (1.05–1.20) for SFAs, 1.11 (1.04–1.18) for MUFAs, and 1.15 (1.08–1.22) for trans FAs. After additional adjustment for body mass index and history of diabetes and hypercholesterolemia, these associations were attenuated and remained statistically significant only for trans FAs (RR in the highest quintile: 1.08, 95% CI: 1.01–1.15). Intake of polyunsaturated FAs (PUFAs), including ω3 and ω6 PUFAs, was not significantly associated with the risk of hypertension. In conclusion, higher intake of SFAs, MUFAs, and trans FAs was each associated with increased risk of hypertension among middle-aged and older women, whereas only association for trans FAs remained statistically significant after adjustment for obesity-related factors.
diet; fatty acids; hypertension; epidemiology; women
Most cardiovascular disease (CVD) occurs after age 65. The additive benefits of aggressive risk factor management with advancing age are not well established.
Evaluate the relationship between control of 4 modifiable risk factors [smoking, non-high density lipoprotein cholesterol (non-HDL-C), blood pressure, and aspirin use] and CVD risk in a primary prevention population of older men.
Physicians’ Health Study participants who in 1997 were ≥65 years and had a blood sample. Cox proportional hazard models were adjusted for age and competing causes of death.
U.S. male physicians from epidemiologic follow-up of a randomized trial of aspirin and beta-carotene.
4182 men aged ≥65 years free of CVD and diabetes.
Main outcome measure
First of any CVD event, defined as cardiovascular death, non-fatal myocardial infarction, angina, coronary revascularization, non-fatal stroke, transient ischemic attack, carotid artery surgery, and other peripheral vascular disease surgery.
Mean follow-up was 9.3 years, mean age was 73 years, and 96% were nonsmokers. Compared to when 4 of 4 risk factors were controlled (6.0% of participants), control of 0 of 4 risk factors almost quadrupled CVD risk (0.4% of participants; event rate 41.2%; HR 3.83, 95% CI 1.72–8.55); control of 1 of 4 risk factors more than double the risk (14.2% of participants; HR 2.53, 95% CI 1.80–3.57); control of 2 of 4 risk factors almost doubled risk (43.8% of participants; HR 1.94, 95% CI 1.41–2.69), and those with control of 3 of 4 risk factors also were at increased risk (35.6% of participants; HR 1.80, 95% CI 1.30–2.50). Control of each additional risk factor was associated with greater cardiovascular protection (p for trend p=0.002). Depending on the number of risk factors controlled, the number-needed to control to prevent one CVD event ranged from 5 to 22.
Control of 4 treatable risk factors (nonsmoking, control of non-HDL-C and blood pressure, and aspirin use) were associated with substantial protection against incident cardiovascular events in older men even after adjustment for competing causes of mortality.
Although basic research has implicated abnormal glucose metabolism in the pathogenesis of hypertension, epidemiologic studies are limited.
We assessed whether baseline hemoglobin A1c was prospectively associated with hypertension in the Women’s Health Study. We analyzed 19,858 women initially free of hypertension, diabetes, and cardiovascular disease with baseline blood samples. We considered quintiles and clinical cutpoints of hemoglobin A1c for the risk of hypertension, defined as either a new physician diagnosis, the initiation of antihypertensive treatment, or systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mmHg.
During a median follow-up of 11.6 years, 9408 (47.5%) women developed hypertension. In models adjusted for traditional cardiovascular risk factors, the hazard ratios (HRs) from the lowest (<4.8 %, referent) to the highest (≥ 5.2%) quintile of hemoglobin A1c were 1.0 (referent), 0.99, 1.06, 1.08, and 1.21 (p, linear trend <.0001). However, additional adjustment for body mass index eliminated the relation (extreme quintile comparison HR 1.04; p, linear trend 0.10). For clinical cutpoints, a similar pattern emerged although a positive association between hemoglobin A1c and hypertension remained in the highest category.
Hemoglobin A1c in women without diabetes was associated with an increased risk of hypertension in models controlling for the majority of traditional hypertension and coronary risk factors, but this relation was no longer significant after adjustment for body mass index. These findings underscore the need for additional studies to delineate the important inter-relationships between glycemia and adiposity with the risk of hypertension in other study populations.
epidemiology; diabetes; body mass index
The authors performed a matched case-control study (1982–2007) nested in a prospective cohort of 22,071 US men to determine the prevalence of chronic diseases of aging in those with newly diagnosed cancer. They matched one control by age to each of 5,622 men who developed cancer over the 25 years of follow-up, as of the date of cancer diagnosis. A modified Charlson score was calculated that reflected comorbidities prior to the matching date, and the authors used conditional logistic regression to determine the odds ratios of various diseases. No substantial differences were found between the scores of cases and controls overall, by cancer subtype, or by age at diagnosis. Overall, men who developed cancer were less likely to have had hypercholesterolemia (odds ratio (OR) = 0.79, 95% confidence interval (CI): 0.72, 0.87) or coronary artery disease (OR = 0.85, 95% CI: 0.77, 0.96). Compared with controls, men with cancers for which there is routine screening had fewer diseases, whereas those with smoking-related cancers had more. Prostate cancer was inversely associated with both coronary artery disease (OR = 0.72, 95% CI: 0.62, 0.84) and diabetes (OR = 0.72, 95% CI: 0.58, 0.89). Overall, men who developed cancer had no more comorbidity or frequent history of chronic disease than their age-matched controls.
aging; case-control studies; geriatrics; neoplasms; risk
Quick-release bromocriptine (bromocriptine-QR), a D2 dopamine receptor agonist, is indicated as a treatment for type 2 diabetes. The Cycloset Safety Trial, a 52-week, randomized, double-blind, multicenter trial, evaluated the overall safety and cardiovascular safety of this novel therapy for type 2 diabetes.
RESEARCH DESIGN AND METHODS
A total of 3,095 patients with type 2 diabetes were randomized 2:1 to bromocriptine-QR or placebo in conjunction with the patient's usual diabetes therapy (diet controlled only or up to two antidiabetes medications, including insulin). The all-cause–safety end point was the occurrence of any serious adverse event (SAE), with a hazard ratio (HR) noninferiority margin of 1.5. In a prespecified analysis, the frequency of cardiovascular disease (CVD) events defined as a composite of myocardial infarction, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure was evaluated using modified intent-to-treat analysis (clinicaltrials.gov, NCT00377676).
In the bromocriptine-QR group, 176 (8.6%) people reported SAEs compared with 98 (9.6%) in the placebo group (HR 1.02 [96% one-sided CI 1.27]). Fewer people reported a CVD end point in the bromocriptine-QR group versus the placebo group (37 [1.8%] vs. 32 [3.2%], respecively) (HR 0.60 [95% two-sided CI 0.35–0.96]). Nausea was the most commonly reported adverse event in the bromocriptine-QR group.
The frequency of SAEs was comparable between the treatment arms. Compared with patients in the placebo arm, fewer patients taking bromocriptine-QR experienced a cardiovascular end point.
Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes.
Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60–92 years (mean = 71.3 years), in the Physicians’ Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5–4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline.
Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was −0.62 (−1.15, −0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03).
Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.
Insulin; C-Peptide; Cognitive decline; Dementia; Diabetes
Systemic inflammation and endothelial activation are implicated in the development of hypertension. However, epidemiologic studies have yet to compare multiple corresponding biomarkers in relation to risk of hypertension, particularly in multiethnic populations.
We identified 800 cases of incident hypertension and 800 matched controls with equal numbers of White and Black women in a nested case-control study within the Women’s Health Initiative Observational Study. We measured markers of inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], interleukin-1β [IL-1β], tumor necrosis factor receptor 2 [TNF-r2]) and endothelial activation (soluble intercellular adhesion molecule-1 [sICAM-1]) in baseline blood samples.
Before adjustment for measures of adiposity, higher hsCRP and IL-6 were associated with increased risk of hypertension in both White and Black women, higher TNF-r2 was associated with increased risk of hypertension only in Black women, and IL-1β and sICAM-1 were unassociated with risk of hypertension. All the positive associations were attenuated after adjustment for body mass index. The resulting multivariable-adjusted relative risks (95% CI) of hypertension comparing the highest versus lowest quartile were 1.52 (0.94–2.48) and 1.23 (0.76–1.97) for hsCRP and IL-6 in White women, and 1.30 (0.81–2.07), 1.58 (0.96–2.59), and 1.49 (0.94–2.36) for hsCRP, IL-6, and TNF-r2 in Black women. The results after adjustment for waist circumference were similar.
After adjustment for measures of adiposity, there was no significant association of hsCRP, IL-6, IL-1β, TNF-r2, and sICAM-1 with incident hypertension in either White or Black women. The interrelationships between inflammation and adiposity in development of hypertension need further investigation.
inflammation; endothelium-derived factors; hypertension; women; epidemiology
Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline, among healthy, community-dwelling older men without diabetes.
Fasting plasma insulin and c-peptide (insulin secretion) levels were measured in 1,353 non-diabetic men, aged 60–92 years (mean=71.3), in the Physicians’ Health Study II who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range=1.5–4.0) using telephone-based tests (general cognition, verbal memory, and category fluency). Primary outcomes were the Telephone interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging four verbal tests). Multivariable linear regression models were used to estimate relations of insulin and c-peptide to cognitive decline.
Higher fasting insulin was associated with worse decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency: e.g., the multivariable-adjusted mean difference (95% CI) in decline for men with the highest vs. lowest insulin levels was −0.62 (−1.15, −0.09) points on the TICS (p-trend=0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was worse decline across all tests with increasing c-peptide, but findings were statistically significant only for global score (p-trend=0.03).
Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.
insulin; c-peptide; cognitive decline; dementia; diabetes
Objective To evaluate the relation between Parkinson’s disease and prior use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large cohort of men.
Design Case-control analysis nested in the Physicians’ Health Study.
Participants 22 007 male physicians aged 40–84 years without indications for or contraindications to regular NSAID use and free of Parkinson’s disease at baseline. Cases and controls were matched by age alone or by age and scores for confounders (comorbidity and indicators of NSAID use). Up to five controls were matched to each of 616 cases by age and 565 cases by age and confounder scores.
Setting United States.
Main outcome measures Odds of having been exposed to prior non-aspirin NSAID or aspirin use by participants with Parkinson’s disease and by their controls in each case-control set.
Results Participants who had ever used non-aspirin NSAIDs had an increased risk of Parkinson’s disease (odds ratio 1.28 (95% CI 1.05 to 1.56) in the age matched group but not in the group also matched on confounder scores (odds ratio 1.17 (0.94 to 1.46)). There was an increased risk of Parkinson’s disease in men who had 1–2 years of regular non-aspirin NSAID use (odds ratio 1.35 (1.07 to 1.70)), a finding that remained significant after matching for confounder scores as well (odds ratio 1.35 (1.05 to 1.75)). In contrast, the significant association of use of non-aspirin NSAIDs for ≥5 years (odds ratio 1.48 (1.05 to 2.09)) in the age matched group was entirely attenuated in the group also matched on confounder scores (1.03 (0.70 to 1.53)). There was also a suggestion that men who regularly used aspirin had an increased risk of Parkinson’s disease. Positive associations between non-aspirin NSAID or aspirin and risk of Parkinson’s disease tended to disappear when analyses were limited to drug use ≥5 years before the disease diagnosis.
Conclusions This case-control study did not find evidence that NSAID use reduces Parkinson’s disease risk. The positive associations observed between NSAID use and Parkinson’s disease might have been due to confounding by indication as the use was clustered in the few years before disease diagnosis.