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Background: The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a recently completed randomized, double-blind, placebo-controlled, 2x2 factorial trial of a multivitamin and cocoa extract supplement (containing 500 mg/d flavanols) in 21,442 older adults. In view of favorable effects of multivitamins on cognition and promising signals for cardiovascular risk reduction with cocoa extract, we conducted a pilot study to explore whether these interventions affected gut microbial composition and function. Methods: We conducted deep shotgun metagenomic sequencing in 30 COSMOS participants using fecal samples collected at baseline and year 2. We performed taxonomic profiling using MetaPhlAn2 and functional profiling using HUMAnN2. After proper quality filtering, we analyzed effects of both interventions on 2-year changes in microbial features, adjusting for age, sex, and body mass index. Results: Cocoa extract supplementation significantly altered the overall gut microbial taxonomic compositions from baseline to year 2, and explained 5.5% of the variance in the 2-year changes in relative abundance of all microbial species ( P =0.008). We further found that randomized cocoa extract supplementation altered the relative abundance of a few microbial species, including those previously linked to anti-inflammatory and cardiometabolic benefits (e.g., Akkermansia muciniphila , nominal P de novo biosynthesis, FDR=0.03, and 28 other pathways with nominal P P Summary: Our pilot study suggests that cocoa extract and multivitamin supplementation in COSMOS may alter the gut microbiome and influence pathways relevant to health, emphasizing the need for larger studies that allow for more detailed investigations.

Introduction: Chocolate intake has shown potential cardiometabolic health benefits in recent studies. We recently reported an association between chocolate intake and longer telomere length. Epigenetic age acceleration, an emerging marker of biological aging, predicts cardiovascular morbidity and mortality. But the relationship between chocolate intake and epigenetic aging has not been investigated. Hypothesis: We examined the association between chocolate intake and epigenetic aging among African Americans. Methods: A genome-wide methylation scan was performed among 50 overweight and obese African Americans using the Illumina Human Methylation 850K Bead Chip on peripheral blood mononuclear cell DNA. DNA methylation ages were calculated according to the Horvath and the Hannum clocks. Methylation-based age acceleration (ΔAge) was extracted from a linear regression of DNA methylation age on chronological age. Chocolate intake frequency over the past year was obtained by questionnaire, along with other major cardiovascular risk factors. Results: Fifty participants (aged 26.1 ± 9.3 years, 16% male) were included in the study. Fifteen (30%), 20 (40%), and 15 (30%) participants consumed less than 1 serving/month, 1-3 servings/month, and ≥1 serving/week of chocolate, respectively. Chocolate intake of ≥1 serving/week was associated with decreased Δage in both Horvath clock (β= -3.31, p-value = 0.046) and Hannum clock (β= -3.59, p-value = 0.096) after adjustment of age, sex, body mass index, 25(OH)D and CD4%. Conclusions: Chocolate intake may be associated with decreased epigenetic aging, with randomized controlled trials needed to establish any beneficial effects of chocolate intake on epigenetic aging processes.

Background: Given the increased prevalence of cancer survivors in the United States, it is imperative to define risk factors for potential reductions in total and cause-specific mortality. Physical activity (PA) represents a promising target for intervention. Design: We prospectively evaluated PA from questionnaires before and after cancer diagnosis with total and cause-specific mortality among 13,297 subjects diagnosed with invasive cancer combined from the Physicians’ Health Study (PHS) (n=6328), Physicians’ Health Study II (PHS II) (n=912), and Women's Health Study (WHS) (n=6057). WHS and PHS participants were free of baseline cancer; PHS II participants reported no active cancer at baseline. We ascertained PA before and after an incident cancer diagnosis based on reports on repeated follow-up questionnaires. Death was ascertained by medical records and death certificates. Cox regression estimated combined hazard ratios (HRs) of mortality by PA adjusted for age, randomized treatments, BMI, and other lifestyle/demographic factors. We evaluated the interaction between PA before and after cancer diagnosis by comparing PA ≤1 versus ≥2 times/wk. Results: The mean follow-up after cancer diagnosis was 8.0, 7.5, and 5.2 y for WHS, PHS, and PHS II, respectively, during which there were 5623 deaths (WHS, 2164; PHS, 3269; PHS II; 190). Higher PA before cancer diagnosis was associated with significantly lower mortality. Compared with PA ≤ once/wk, the HRs (95% CIs) associated with PA 2-4 and >4 times/wk were 0.87 (0.82-0.93) and 0.88 (0.82-0.94) for total mortality; 0.77 (0.63-0.95) and 0.79 (0.62-0.997) for CVD mortality, and 0.90 (0.83-0.98) and 0.90 (0.83-0.98) for cancer mortality. Higher PA after cancer diagnosis was associated with significantly lower total and cancer mortality and non-significantly lower CVD mortality, with HRs (95% CIs) of 0.65 (0.58-0.72) and 0.66 (0.59-0.73) for total mortality; 0.78 (0.59-1.03) and 0.82 (0.61-1.10) for CVD mortality, and 0.66 (0.57-0.77) and 0.64 (0.55-0.74) for cancer mortality. There was a significant interaction of PA before and after cancer diagnosis for total (p int =0.02) and cancer (p int =0.007) mortality, but not CVD mortality (p int =0.38). Conclusions: Greater PA both before and after cancer diagnosis were significantly associated with lower total and cancer mortality. Higher PA before cancer diagnosis was also associated with lower CVD mortality. PA may be an important target for lower mortality after cancer diagnosis.

Background: Large-scale trials have not supported a role of vitamin E supplementation in reducing the risk of cardiovascular disease (CVD). We investigated whether baseline diet quality and vitamin E intake modified the effect of randomized vitamin E supplementation on the risk of CVD in the Physicians’ Health Study II (PHS II). Methods: The PHS II was a randomized, double-blind, placebo-controlled trial testing 400 IU synthetic α-tocopherol on alternate days. 14,641 men aged ≥50 years were included. 13,316 men (91%) completed a 116-item food frequency questionnaire and were included in our intention-to-treat analysis. We examined effect modification by baseline diet quality as assessed by dietary patterns (tertiles of the Alternate Healthy Eating Index [AHEI] and Alternate Mediterranean Diet [AMED]), and by dietary and supplemental vitamin E intake. Results: During a mean 8.0 years of follow-up, baseline diet quality or vitamin E intake did not modify the effect of vitamin E use on the primary endpoint of major CVD events ( Table ). However, AHEI modified the effect of randomized vitamin E use on the secondary endpoint of MI (P, interaction=0.02), with a statistically significant 39% lower risk among men in the lowest tertile of the AHEI. A similar and statistically significant 37% lower risk of MI was observed in the lowest category of the AMED (P, interaction=0.08). There was no evidence that diet quality modified the effect of vitamin E use on risks of stroke or CVD mortality, and baseline dietary and supplemental vitamin E intake did not modify the effects on any outcome. Conclusion: Diet quality did not modify the effect of vitamin E supplementation on most CVD outcomes but did modify its effect on MI. Given concerns about multiple comparisons and the need for replication, our findings should be interpreted with caution.

Background: Abdominal aortic aneurysm (AAA) is an increasingly recognized cause of morbidity and mortality in the aging US population. While moderate alcohol consumption has been shown to be associated with a lower risk of atherosclerotic macrovascular disease, its relationship with AAA remains inconsistent in previous studies. We therefore sought to elucidate the relationship between alcohol consumption and risk of AAA in a prospective cohort of middle-aged and older men. Methods: Our study included 21,842 male physicians (mean age: 53.7 years) in the Physicians’ Health Study I who reported no history of AAA at baseline. Self-reported information on alcohol consumption and known AAA risk factors including body mass index (BMI), smoking and exercise was obtained on baseline questionnaires. Incidence of clinically diagnosed AAA was assessed via self-reported information on annual questionnaires and validated successfully in a subsample. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of AAA in each category of alcohol intake. Cubic spline regression was used to assess non-linear trend. Results: During an average follow-up of 23.0 years, 655 cases of newly diagnosed AAA were reported. Compared with men reporting less than one alcoholic drink (combined beer, wine, and liquor) per month, the HR [95% CI] of incident AAA after adjustment for age, BMI, smoking, and exercise was 0.69 [0.50 - 0.95] with one to three drinks per month, 0.80 [0.60 - 1.08] with one drink per week, 0.75 [0.58 - 0.97] with two to four drinks per week, 0.67 [0.49 - 0.90] with five to six drinks per week, 0.77 [0.61 - 0.99] with one drink per day, and 0.73 [0.47 - 1.13] with two or more drinks per day (P, non-linear trend=0.17). Conclusions: In this large cohort of middle-aged and older male physicians, light-to-moderate alcohol consumption was associated with a lower risk of clinically diagnosed AAA.

Background: High intake of polyphenols has been linked to a lower risk of cardiovascular disease (CVD). Berries are high in polyphenols, including anthocyanins, along with other key nutrients. However, few studies have investigated the association between longitudinal changes in berry intake and long-term risk of CVD. The aim of this study was to investigate whether longitudinal changes in berry intake are associated with the risk of major CVD endpoints. Methods: Longitudinal changes in berry intake (sum of blueberries and strawberries) were assessed from two 131-item food-frequency questionnaires (FFQ) completed in 1992-1995 (FFQ1) and 2004 (FFQ2) among 29,598 middle-aged and older women free of CVD from the Women’s Health Study. Women also provided self-reports of a wide range of lifestyle, clinical and dietary factors at both timepoints. For each FFQ, women were categorized into two categories of total berry, blueberry, and strawberry intake: never/rarely and ≥1 time/month. Women were then categorized as having consistent low intake (never/rarely), consistent any intake (≥1 time/month), any increase in intake, and any decrease in intake between FFQ assessments. We used Cox proportional hazards models to calculate age and multivariable-adjusted hazard ratios (HRs) (95% confidence intervals (CI)). We included age, randomization assignments, smoking status, body mass index, physical activity, hormone replacement therapy, family history of myocardial infarction (MI), hypercholesterolemia, hypertension, diabetes, fruit and vegetable intake, saturated fatty acid intake, and omega-3 intake as covariates at the FFQ2 assessment. Results: During a mean follow-up of 9.9 years, we identified 851 cases of incident major CVD (MI, stroke, and CVD death). The intakes of total berries at FFQ1 were 23% (never/rarely) and 77% (≥1 time/month). Corresponding intakes at FFQ2 were 15% and 85%, respectively. In multivariable-adjusted models, consistently having any berry intake (HR: 1.00 (0.78-1.28)), any increase (HR: 0.89 (0.66-1.19)), or any decrease (HR: 0.84 (0.60-1.18)) in total berry intake over 10 years were not significantly associated with the risk of major CVD compared to women with consistently having no intake. A similar lack of association was observed for changes in strawberry intake. Increasing blueberry intake was associated with a lower risk of major CVD (HR: 0.83 (0.69-0.99)), whereas consistently having any blueberry intake (HR: 1.09 (0.91-1.29)) and any decrease in blueberry intake (HR: 0.97 (0.75-1.27)) were not associated with CVD. Conclusions: The results from this prospective study of middle-aged and older women initially free of CVD suggest that increasing blueberry intake over time may lower the risk of subsequent CVD.

Background: Blood pressure (BP) is an established risk factor for several chronic diseases. Clinical measurement of BP is the preferable method to assess BP, but may not be feasible in large-scale epidemiologic studies. Self-reported BP has been widely collected as an alternative. It has not been well-studied whether self-reported BP is comparable to measured BP, particularly in the general population. Method: We conducted a cross-sectional analysis in a large, mail-based randomized controlled trial - VITamin D and OmegA-3 TriaL (VITAL) - to compare BP levels assessed using different methods. Participants of VITAL were women aged ≥55 years and men aged ≥50 years, free of cardiovascular disease and cancer. Among a total of 21,025 VITAL participants who reported BP in multiple categories on the baseline questionnaire, 1,955 also had seated BP measured at baseline clinic-based or home-based visits, and 269 also completed assessment of 24 hour ambulatory BP (24-hr ABP) monitoring. We included 264 VITAL participants who had all three BP measures in analysis, converted the self-reported BP levels to ordinal variable by using the median of each category, and examined the associations between the different BP measurements with estimation of correlation and linear regression. Results: The 264 VITAL participants were on average aged 63.8 years, 59% women, 23.5% African-Americans, 54.9% with post-college education, and 6.4% with a history of hypertension. The mean (SD) of self-reported BP, seated BP, and 24-hr ABP were 120.1 (9.1), 120.2 (12.5), and 128.2 (11.3) mmHg for systolic BP (SBP) and 73.0 (6.3), 72.3 (9.8), and 76.9 (7.9) mmHg for diastolic BP (DBP), respectively. Spearman correlation coefficients (Spearman r) between BP measured using three different methods ranged from 0.37 (self-reported vs. seated) to 0.49 (seated vs. 24-hr ambulatory) for SBP and from 0.30 (seated vs. 24-hr ambulatory) to 0.34 (self-reported vs. seated) for DBP (all P Conclusion: In this large, mail-based study of older men and women from general US population, self-reported BP correlates reasonably well with both seated BP and 24-hr ABP. Self-reported BP can be used to estimate measured BP in large-scale epidemiologic studies.

Background: Many in the US population take a multivitamin supplement to improve or maintain health however, evidence for long-term health benefits remains scarce. The Physicians’ Health Study II (PHS II) is the only randomized trial investigating the effect from a common multivitamin in men, for which no effect was seen on cardiovascular disease (CVD). An important consideration is the modifying role of baseline nutritional status, as a multivitamin may be more or less efficacious to those with extreme nutritional intake. Hypothesis: Baseline nutritional status modifies the effect of a multivitamin on the risk of CVD. Methods: The PHS II is a randomized, double-blind, placebo-controlled trial evaluating the effects of a multivitamin (Centrum Silver or placebo daily) including 14,641 men aged ≥50 years. Baseline diet was assessed through a 116-item food frequency questionnaire among 13,316 men (91%). We tested the interaction between the randomized multivitamin and tertiles of each dietary factor (Alternate Healthy Eating Index, Alternate Mediterranean Diet score, vitamin B6, B12, folate, vitamin C, calcium, and magnesium) as well as the trend in HRs across tertiles. Results: During an average 11.2 years of follow-up, there were 1487 cases of CVD, 586 cases of myocardial infarction (MI), 559 cases of total stroke, 626 CVD death, and 2086 total deaths. There was no consistent evidence for effect modification by dietary factors. Vitamin B6 modified the effect of multivitamin use on MI (P, interaction=0.01) with an increased risk among men in lowest tertile and decreased risk in highest tertile. The effect on CVD death was modified by vitamin B12 intake with a nonsignificant decreased risk only among men in the lowest tertile, with similar effects noted for total mortality (P, interaction=0.04). Conclusion: For the majority of dietary factors, there was no evidence that the effect of multivitamin use on major CVD and associated endpoints is modified by individual baseline dietary factors in middle-aged and older male physicians.

Background: Experimental studies suggest that vitamin D may potentially prevent the development of hypertension through down-regulation of the renin-angiotensin system. However, evidence from epidemiologic studies remains limited. Objective: In parallel nested case-control studies of women from the Women’s Health Study (WHS) and men from the Physicians’ Health Study (PHS) with >10 years follow-up, we examined the prospective associations between the circulating biomarkers of vitamin D status with risk of hypertension, as well as the inter-relation between vitamin D biomarkers and renin production. Methods: In each cohort, 500 incident hypertension cases and 500 controls were randomly selected from participants who were free of cardiovascular disease, cancer, and hypertension and provided bloods at baseline. Hypertension cases were identified based on self-reported blood pressure, physician’s diagnosis, or medication use. Controls were matched to cases on gender, age, race, follow-up time, and month of blood draw. Baseline plasma 25(OH)-vitamin D, parathyroid hormone (PTH), and total renin (pro-renin plus active renin) concentrations were measured. Analyses were first performed in each cohort separately and, given the similar results, finally combined for both cohorts. Results: Baseline concentrations of 25(OH)-vitamin D (mean of 26.6 vs. 27.0 ng/mL) and PTH (32.6 vs. 32.2 pg/mL) were similar in hypertension cases and controls. In the crude matched model, the risk of hypertension did not change with 25(OH)-vitamin D or PTH concentrations. Additional adjustment for other known hypertension-related risk factors minimally affected the associations. After adjusting for baseline smoking, alcohol use, exercise, menopausal status and hormone therapy use among women, body mass index, and history of diabetes and hypercholesterolemia, the relative risks of incident hypertension across increasing quintiles of 25(OH)-vitamin D were 1.00, 1.42 (95% CI: 0.94-2.16), 0.94 (95% CI: 0.60-1.48), 0.99 (95% CI: 0.61-1.61), and 1.03 (95% CI: 0.63-1.69) (p, trend, 0.48), and across increasing quintiles of PTH were 1.00, 1.26 (95% CI: 0.83-1.92), 0.91 (95% CI: 0.60-1.40), 1.10 (95% CI: 0.70-1.71), 0.92 (95% CI: 0.59-1.44) (p, trend, 0.50). These associations were similar in men and women. Among controls, plasma 25(OH)-vitamin D was inversely correlated with PTH (Pearson r: -0.24, p Conclusions: In prospective cohorts of men and women, we found no association between either baseline plasma 25(OH)-vitamin D or PTH with the risk of hypertension, or between either 25(OH)-vitamin D or PTH with total renin concentration. More research is needed to further elucidate the specific effect of vitamin D in the development of hypertension.

Background— Elevated body mass index (BMI; weight in kilograms divided by height in meters squared) in the obese range (≥30 kg/m 2 ) is associated with an excess risk of heart failure (HF). However, the impact of overweight or preobese (BMI, 25 to 29.9 kg/m 2 ) status and physical activity on HF risk is unclear. Methods and Results— In a prospective cohort of 21 094 men (mean age, 53 years) without known coronary heart disease at baseline in the Physicians’ Health Study, we examined the individual and combined effects of BMI and vigorous physical activity (exercise to the point of breaking a sweat) on HF incidence from 1982 to 2007. We evaluated BMI as both a continuous (per 1-kg/m 2 increment) and a categorical (lean, 2 ; overweight, 25 to 29.9 kg/m 2 ; and obese, ≥30 kg/m 2 ) variable; we evaluated vigorous physical activity primarily as a dichotomous variable (inactive [rarely/never] versus active [≥1 to 3 times a month]). During follow-up (mean, 20.5 years), 1109 participants developed new-onset HF. In multivariable analyses, every 1-kg/m 2 increase in BMI was associated with an 11% (95% confidence interval [CI], 9 to 13) increase in HF risk. Compared with lean participants, overweight participants had a 49% (95% CI, 32 to 69) and obese participants had a 180% (95% CI, 124 to 250) increase in HF risk. Vigorous physical activity conferred an 18% (95% CI, 4 to 30) decrease in HF risk. No interaction was found between BMI and vigorous physical activity and HF risk ( P =0.96). Lean active men had the lowest and obese inactive men had the highest risk of HF. Compared with lean active men, the hazard ratios were 1.19 (95% CI, 0.94 to 1.51), 1.49 (95% CI, 1.30 to 1.71), 1.78 (95% CI, 1.43 to 2.23), 2.68 (95% CI, 2.08 to 3.45), and 3.93 (95% CI, 2.60 to 5.96) in lean inactive, overweight active, overweight inactive, obese active, and obese inactive men, respectively. Conclusions— In this cohort of men, elevated BMI, even in the preobese range, was associated with an increased risk of HF, and vigorous physical activity was associated with a decreased risk. Public health measures to curtail excess weight, to maintain optimal weight, and to promote physical activity may limit the scourge of HF.

Background: Although multivitamins are widely used by US adults, few prospective studies have investigated their association with the long- and short-term risk of cardiovascular disease (CVD). The aim of this study was to investigate how multivitamin use is associated with the risk of CVD in initially healthy men free of CVD at baseline. Methods: We studied 21,981 male physicians aged ≥40y from the Physicians Health Study I cohort who were free of CVD and cancer at baseline starting in 1982. All men provided a wide range of self-reported lifestyle and clinical factors plus intake of selected food and dietary supplements. Men were categorized at baseline as (1) no current use and (2) current use of multivitamins. Men were followed from baseline to the end of PHS I follow-up. Cox proportional hazards models were used to calculate multivariable-adjusted rate ratios (RR) (95% confidence intervals (CI)). Results: During an average of 13.7 y (total of 301,480 person-years) of follow-up, there were 1,269 incident cases of major CVD (defined as nonfatal myocardial infarction (MI), nonfatal stroke, and CVD death). In multivariable analyses, there were no statistically significant RRs (95% CIs) observed when comparing current multivitamin use versus no use for the risk of major CVD events (0.97 (0.79-1.04)), MI (0.94 (0.76-1.16), stroke (0.97 (0.77-1.23), or CVD death (1.02 (0.83-1.14)) but an inverse association was observed for cardiac revascularization (0.87 (0.75-1.00)). Conclusion: In this long-term prospective study among initially healthy men, baseline multivitamin use was not associated with the long-term risk of major CVD events.

Background: Vitamin D is involved in the regulation of blood pressure (BP) through multiple mechanisms. Genetic variation may influence the effect of vitamin D on BP, but data from epidemiologic studies remain limited. Methods: We conducted a comprehensive genetic association study to investigate the variants in an expanded vitamin D metabolism and signaling pathway in relation to BP. Analyses were conducted in the Women’s Genome Health Study (WGHS) with genome-wide genotype data among 23,294 women of European ancestry and in the International Consortium of Blood Pressure (ICBP) with published genome-wide meta-analysis results from 69,395 men and women of European ancestry. Results: Analyses were conducted in three stages. First, among 5 candidate single-nucleotide polymorphisms (SNPs) in the vitamin D related genes that were previously found associated with BP, none was associated with systolic (SBP) or diastolic BP (DBP) in the WGHS or ICBP. Second, in an expanded set of 61 SNPs involved in vitamin D metabolism and signaling pathway, rs1507023 (in RBFOX1 ) and rs2296241 (in CYP24A1 ) showed nominally significant associations with SBP, DBP, mean arterial pressure (MAP), or pulse pressure (PP) in the WGHS, but the associations were no longer significant after correction for multiple hypothesis testing. Similarly, nominally significant associations found in the ICBP were also not significant after multiple testing corrections. Third , among 24 candidate genes across the vitamin D pathway, associations with BP traits that meet gene-wide significance level (gene-based empirical pNCOA3 (rs2235734), RXRA (rs875444), DHCR7 (rs1790370), VDR (rs2544037), and NCOR2 (rs1243733 and rs1147289). Similar gene-wide significant associations (gene-based pNCOR1 , TP53BP1 and TYRP1 . After further correction for number of genes in the pathway, however, only the association of TYRP1 with SBP in the ICBP reached significance threshold. Further, the WGHS observed associations were not replicated in the ICBP, and vice versa. Conclusions: Our study in large samples of Caucasian population did not replicate several previously observed associations of candidate SNPs in the vitamin D pathway with BP. However, we found suggestive evidence for associations of other vitamin D pathway gene variants with BP traits. Future studies are needed to replicate our findings.

Background: Laboratory studies suggest that ω3 and ω6 polyunsaturated fatty acids (PUFA) may have divergent effects on the development of obesity. Epidemiologic studies comparing the associations for ω3 and ω6 PUFA are limited. Objective: We prospectively examined whether the baseline proportions of ω3 and ω6 PUFAs on erythrocyte membranes were associated with the risk of becoming overweight and changes in body weight in the Women’s Health Study (WHS). Methods: We identified WHS participants in a previous nested case-control study of hypertension who reported a body mass index (BMI) 2 at baseline. Baseline fatty acid (FA) composition of erythrocyte membranes was measured as biomarkers of dietary FA intake using gas chromatography. Women who subsequently reported a BMI ≥25 kg/m 2 during follow-up were defined as becoming overweight. Body weight change was calculated as the difference in reported body weight from baseline to annual follow-up questionnaires. Results: Among 534 women with baseline BMI 2 , 186 became overweight during an average of 10 years of follow-up. After initial adjustment for age, race, randomized treatment, the hazard ratios (HR) and 95% confidence interval (95% CI) for becoming overweight across increasing quartiles of erythrocyte PUFA were 1.00, 0.77 (0.49-1.21), 1.12 (0.75-1.67), and 1.19 (0.79-1.77) for cis ω6 PUFA (p, trend: 0.31), 1.00, 0.90 (0.61-1.31), 0.76 (0.51-1.13), 0.71 (0.45-1.10) for cis ω3 PUFA (p, trend: 0.09), and 1.00, 1.37 (0.84-2.22), 1.57 (1.01-2.43), and 1.58 (1.01-2.46) for ω6 to ω3 PUFA ratio (p, trend: 0.046). Additional adjustment for lifestyle and dietary factors did not substantially attenuate these associations, with HR (95% CI) of 1.00, 1.26 (0.76-2.08), 1.44 (0.91-2.28), and 1.56 (0.97-2.51) across increasing quartiles of ω6 to ω3 PUFA ratio (p, trend: 0.064). Analysis of longitudinal change in body weight showed similar associations. After multivariable adjustment, the mean±standard error of weight gain over an average of 10 years of follow-up across increasing quartiles of erythrocyte PUFA were 2.34±0.49, 1.92±0.53, 2.86±0.54, and 3.10±0.53 kg for cis ω6 PUFA (p, trend: 0.04), 2.97±0.52, 2.60±0.53, 2.74±0.53, 2.16±0.51 kg for cis ω3 PUFA (p, trend: 0.095), and 2.13±0.51, 2.65±0.54, 2.77±0.53, 2.98±0.52 kg for ω6 to ω3 PUFA ratio (p, trend: 0.05). trans PUFA 18:2 was not associated with the risk of becoming overweight or longitudinal weight gain. Analyses of joint categories of ω3 and ω6 PUFA did not show significant interaction . Conclusion: In this prospective study, we found suggestive evidence that the proportion of cis ω6 PUFA on erythrocyte membrane was positively associated, and cis ω3 PUFA inversely associated, with the risk of becoming overweight and weight gain in initially normal-weight women.

Background: Dairy products have been positively associated with weight loss and inversely associated with weight gain. However, limited number of studies has investigated the role of dairy consumption in the prevention of becoming overweight or obese. The aim of this study was to prospectively investigate how consumption of dairy products was associated with the risk of becoming overweight or obese among initially normal-weight women. Methods: We studied 19,180 women aged ≥45y from the Women’s Health Study free of cardiovascular disease (CVD), cancer, and diabetes with an initial body mass index (BMI) of 18.5-2 . Dairy intake was assessed through a 131-item food-frequency questionnaire. Total dairy intake was defined as the sum of servings per day of low-fat dairy products (skim/low-fat milk, sherbet, yogurt, and cottage/ricotta cheese) and high-fat dairy products (whole milk, cream, sour cream, ice cream, cream cheese, other cheese, and butter). Women self-reported body weight along with obesity-related risk factors on baseline and annual follow-up questionnaires. In multivariable-adjusted analyses, we included the following covariates: baseline age, randomization treatment, BMI, smoking status, vigorous exercise, postmenopausal status, postmenopausal hormone use, history of hypercholesterolemia, history of hypertension, multivitamin use, alcohol intake, total energy intake, and fruit and vegetable intake. Results: During a mean follow-up of 11.2y (216,979 person-years), 8,582 women became overweight or obese (BMI ≥25 kg/m 2 ). The multivariable-adjusted mean changes in body weight (95% confidence interval (CI)) during the follow-up were 3.9 (3.5-4.3), 3.9 (3.5-4.2), 3.8 (3.5-4.2), 3.7 (3.4-4.1), and 3.4 (3.0-3.7) lbs in quintiles 1-5 of total dairy consumption (P-trend: 0.01), respectively. In multivariable-adjusted analyses (Table 1) , women in the highest versus lowest quintile of had a rate ratio (RR) of 0.91 (0.84-0.98, P-trend: 0.16) of becoming overweight or obese. No associations were observed in highest quintiles of low-fat dairy and high-fat dairy intakes. Conclusion: Greater consumption of dairy products may be inversely ssociated with risk of becoming overweight or obese in women.

Objectives: Short-term metabolic studies have shown that caffeine improves insulin-sensitivity. However, epidemiological studies evaluating the relationship of caffeine intake with risk of type 2 diabetes (DM) have shown inconsistent results. We examined whether caffeine intake is associated with the risk of DM in the Physicians’ Health Study and supplemented the results with a meta-analysis. Methods: We prospectively analyzed data on 18,432 PHS participants that were free of DM at baseline (1997-2001). Caffeine intake was assessed using a food-frequency questionnaire. Incident DM was ascertained via annual follow-up questionnaires and validated in a subsample by review of medical records. We used Cox proportional hazards models to estimate the HR and 95% CI of DM. Meta-analysis was conducted through a systematic literature search using PubMed and EMBASE. A random-effect model was used and between-studies heterogeneity was estimated with I 2 . Results: In the PHS, mean age at baseline was 66.4 ± 9.3 years, and 1,137 men (6.2%) developed DM during mean follow up of 9.2 years. In a multivariable model adjusted for conventional risk factors of DM, HRs (95% CI) for DM were 1.0 (ref), 1.08 (0.90-1.29), 1.03 (0.85-1.24), 0.98 (0.81-1.18), and 0.86 (0.70-1.04) across consecutive quintiles of caffeine intake (p for linear trend= 0.69). Meta-analysis included 6 studies consisted of 7 separate cohorts comprising 275,971 individuals and 10,048 cases of incident DM. The pooled odds ratio (95% CI) for DM was 0.79 (0.68-0.93) when the highest caffeine intake was compared to the lowest group in random effects model (I 2 =75%). Conclusion: While only the highest category of caffeine intake was associated with a modest and non-significant association with DM in the PHS, results from the meta-analysis were consistent with a lower risk of DM.

Background Few studies have examined the effects of paternal and maternal history of myocardial infarction (MI), including age at MI, on cardiovascular disease (CVD) risk, particularly among women. Methods and Results We prospectively studied 22 071 men from the Physicians’ Health Study and 39 876 women from the Women’s Health Study with data on parental history and age at MI. Among men, 2654 CVD cases developed over 13.0 years; among women, 563 CVD cases occurred over 6.2 years. Compared with men with no parental history, only maternal, only paternal, and both maternal and paternal history of MI conferred relative risks (RRs) of CVD of 1.71, 1.40, and 1.85; among women, the respective RRs were 1.46, 1.15, and 2.05. For men, maternal age at MI of Conclusions An early history of parental MI (

Background —Physical activity is associated with a decreased risk of coronary heart disease (CHD). However, it is unclear whether the duration of exercise episodes is important: Are accumulated shorter sessions as predictive of decreased risk as longer sessions if the same amount of energy is expended? Methods and Results —In the Harvard Alumni Health Study, we prospectively followed 7307 Harvard University alumni (mean age 66.1 years) from 1988 through 1993. At baseline, men reported their walking, stair climbing, and participation in sports or recreational activities. For each of the latter activities, they also reported the frequency and average duration per episode. During follow-up, 482 men developed CHD. In age-adjusted analysis, a longer duration of exercise episodes predicted lower CHD risk ( P trend=0.04). However, after total energy expended on physical activity and potential confounders was accounted for, duration no longer had an independent effect on CHD risk ( P trend=0.25); that is, longer sessions of exercise did not have a different effect on risk compared with shorter sessions, as long as the total energy expended was similar. In contrast, higher levels of total energy expenditure significantly predicted decreased CHD risk in both age-adjusted ( P trend=0.009) and multivariate ( P trend=0.046) analyses. Conclusions —These data clearly indicate that physical activity is associated with decreased CHD risk. Furthermore, they lend some support to recent recommendations that allow for the accumulation of shorter sessions of physical activity, as opposed to requiring 1 longer, continuous session of exercise. This may provide some impetus for those sedentary to become more active.

Background —It is unclear whether, given a current blood pressure level, the previous 2-year change in blood pressure adds important predictive information for cardiovascular disease (CVD). Methods and Results —We conducted a prospective cohort study of 11 150 middle-aged and older men reporting blood pressure in the Physicians’ Health Study. These men had no history of CVD or antihypertensive medication use through the time of the 2-year follow-up questionnaire; after this time, follow-up for the current study began. A total of 905 incident cases of CVD (705 cases of coronary heart disease and 200 cases of stroke) occurred during a median follow-up of 10.8 years. After controlling for current blood pressure and other coronary risk factors, we found that previous 2-year changes in systolic blood pressure were not associated with the risk of CVD. A similar lack of association was found for individual end points of coronary heart disease and stroke. However, previous 2-year changes in diastolic blood pressure (DBP) may be inversely associated with the risk of CVD (linear trend, P =0.049) independent of coronary risk factors and current DBP. In subgroup analyses, previous 2-year blood pressure changes only added information in leaner men (body mass index 2 ). Conclusions —In this normotensive population of men, the prior 2-year change in DBP, but not systolic blood pressure, may add information to current levels in relation to the risk of CVD. Clinicians may need to consider the previous pattern of DBP change when considering the risk associated with the current DBP level. These data require confirmation in other studies in which blood pressure is measured.

BACKGROUND: Few studies have examined prospectively the relationship between baseline high-density lipoprotein (HDL) cholesterol and longevity. OBJECTIVES: We sought to examine whether higher HDL levels were associated with lower risk of all-cause, cardiovascular (CVD), and non-CVD mortality prior to age 90 in the Physicians’ Health Study (PHS). METHODS: We considered a baseline cohort of 1351 PHS participants who provided bloods between 1997 and 2001 and were old enough to reach age 90 by March 4, 2009. Included subjects had complete baseline data on HDL and total cholesterol; lifestyle factors including smoking, exercise, alcohol consumption, and BMI; and comorbidities including hypertension, diabetes mellitus, congestive heart failure, cancer, and stroke. We used Cox proportional hazards to determine the HRs and 95% CIs for all-cause, CVD, and non-CVD mortality prior to age 90, adjusting for baseline age, co-morbidities, and non-HDL cholesterol. RESULTS: At baseline, the cohort had a mean (SD) age of 81.9 (2.9) years and a mean (SD) HDL cholesterol of 44.8(16.5) mg/dL. After a mean follow-up of 6.8 years (maximum 12.3 years), 501 (37.1%) of men died prior to age 90. In multi-variable adjusted analyses, men in the highest HDL-C quartile (≥54.1 mg/dL) had a 28% lower risk (HR 0.72, 95% CI 0.55-0.95) of all-cause mortality prior to age 90 compared to men in the lowest HDL-C quartile ( CONCLUSION: In a cohort of older male physicians with long-term follow-up, baseline HDL cholesterol was inversely associated with the risk of dying prior to age 90, largely explained by an inverse association between HDL and CVD mortality.

The 2008 US federal guidelines require a minimum of 150 minutes/week of moderate-intensity, or 75 minutes/week of vigorous-intensity physical activity, or an equivalent combination of the two, for health benefits. Thus, they assume a 2:1 equivalence between the two intensities of activity; i.e., 2 minutes of moderate-intensity activity is equivalent to 1 minute of vigorous-intensity activity. However, no studies have specifically examined whether this assumption is correct. Purpose: To examine the effect of replacing 150 minutes/week of moderate-intensity with 75 minutes/week of vigorous-intensity physical activity on all-cause and cardiovascular disease (CVD) mortality. Methods: 8,859 men (mean age, 66.4 yr) from the Harvard Alumni Health Study, free from CVD and cancer, were followed from 1988 to 2008. At baseline (1988) and in 1993, men reported physical activity (blocks walked, stairs climbed, and a listing of sports/recreational activities and participation time). Time spent per week in sports/recreational activities of moderate-intensity (3 to Results: During follow-up, 4,064 men died, including 1,192 from CVD. In multivariate analyses, controlling for the total physical activity, age, smoking, intakes of alcohol, vegetable, fruit, and saturated fat, and total caloric intake, replacing 150 minutes/week of moderate-intensity with 75 minutes/week of vigorous-intensity physical activity was associated with an additional 2% reduction in all-cause mortality (Hazard Ratio (95% confidence interval) = 0.98 (0.96, 1.00); p = 0.05), and an additional 5% reduction in CVD mortality (0.95 (0.92, 0.99); p = 0.02). Conclusions: The assumption that 2 minutes of moderate-intensity activity is equivalent to 1 minute of vigorous-intensity activity under current federal guidelines is not strictly correct. Vigorous-intensity physical activity is associated with additional risk reduction for CVD mortality compared to moderate-intensity physical activity. Although there is an added, statistically significant benefit of vigorous-intensity over moderate-intensity physical activity, the magnitude of benefit is small.

Such a change would make the title imprecise becausethe information on all of the 3 variables—value of body mass index,frequency of vigorous physical activity, and diagnosis of heartfailure (HF)—mentioned in the title was based on self-reports byphysician participants. Furthermore, it may be inaccurate to assumethat participants who rarely or never vigorously exercised werephysically inactive because nonvigorous (light or moderate intensity)physical activity was not ascertained at baseline. Therefore, webelieve that the title of our article is appropriate as is.Our statement that “any vigorous physical activity is an indicatorof healthier lifestyle in men at risk of developing HF” should beinterpreted in the milieu of a reduction in the risk of HF even amongparticipants who reported exercising vigorously enough to work upa sweat at a frequency as low as 1 to 3 times a month (multivariable22% reduced risk of HF compared with rarely or never group; Table2).

Background— Current recommendations prescribe at least moderate-intensity physical activity, requiring ≥3 METs (metabolic equivalents) for ≥30 minutes almost daily, generating ≈1000 kcal/wk. Defining intensity using an absolute scale in METs may be limited because it neglects variations in physical fitness: an activity requiring a particular MET value commands greater physical effort among less fit than more fit persons. It is unknown whether moderate-intensity exercise, relative to an individual’s capacity, is associated with reduced coronary heart disease (CHD) rates. Methods and Results— We followed 7337 men (mean age, 66 years) from 1988 to 1995. At baseline, men reported their actual activities and, using the Borg Scale, the perceived level of exertion when exercising (relative intensity). During follow-up, 551 men developed CHD. After multivariate adjustment, the relative risks of CHD among men who perceived their exercise exertion as “moderate,” “somewhat strong,” and “strong” or more intense were 0.86 (95% confidence interval, 0.66 to 1.13), 0.69 (0.51 to 0.94), and 0.72 (0.52 to 1.00), respectively ( P trend =0.02), compared with “weak” or less intense. This inverse association extended to men not fulfilling current recommendations, ie, expending P trend =0.03 and 0.007, respectively). Conclusions— There is an inverse association between relative intensity of physical activity (an individual’s perceived level of exertion) and risk of CHD, even among men not satisfying current activity recommendations. Recommendations for “moderate”-intensity physical activity may need to consider individual fitness levels instead of globally prescribing activities of ≥3 METs.

Background —The quantity and intensity of physical activity required for the primary prevention of coronary heart disease (CHD) remain unclear. Therefore, we examined the association of the quantity and intensity of physical activity with CHD risk and the impact of other coronary risk factors. Methods and Results —We followed 12 516 middle-aged and older men (mean age 57.7 years, range 39 to 88 years) from 1977 through 1993. Physical activity was assessed at baseline in kilojoules per week (4.2 kJ=1 kcal) from blocks walked, flights climbed, and participation in sports or recreational activities. During follow-up, 2135 cases of incident CHD, including myocardial infarction, angina pectoris, revascularization, and coronary death, occurred. Compared with men expending P for trend=0.003). When we considered the independent effects of specific physical activity components, only total sports or recreational activities ( P for trend=0.042) and vigorous activities ( P for trend=0.02) were inversely associated with the risk of CHD. These associations did not differ within subgroups of men defined by coronary risk factors. Finally, among men with multiple coronary risk factors, those expending ≥4200 kJ/wk had reduced CHD risk compared with men expending Conclusions —Total physical activity and vigorous activities showed the strongest reductions in CHD risk. Moderate and light activities, which may be less precisely measured, showed nonsignificant inverse associations. The association between physical activity and a reduced risk of CHD also extends to men with multiple coronary risk factors.

P83 Background: Alcohol drinking is associated with a dose-dependent increase in blood pressure, and JNC VI advises limiting alcohol consumption in patients with hypertension. Data are sparse on relationship between alcohol consumption and mortality in hypertensive patients. We therefore assessed whether alcohol consumption is associated with decrease in total, and cardiovascular mortality among subjects with hypertension. Methods: From the enrollment cohort of 89,251 men from the Physicians’ Health Study who provided self-reported information on alcohol intake and were free of myocardial infarction, stroke, cancer or liver disease at baseline, we identified a group of 14,125 persons with a history of current or past treatment for hypertension. Results: During 75,710 person-years of follow up, there were 1,018 deaths including 579 from cardiovascular disease and 224 from cancer. In multivariate analyses that controlled for several potential confounders, moderate alcohol intake was associated with significant decrease in cardiovascular mortality (P= 1 drink per day the RR was 0.57 (CI 0.44-0.72, P