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Background: Observational studies have reported strongly protective effects of bariatric surgery on cardiovascular disease, but with oversimplified definitions of the intervention, eligibility criteria, and follow-up, which deviate from those in a randomized trial. We describe an attempt to estimate the effect of bariatric surgery on cardiovascular disease without introducing these sources of bias, which may not be entirely possible with existing observational data., Methods: We propose two target trials among persons with diabetes: (1) bariatric operation (vs. no operation) among individuals who have undergone preoperative preparation (lifestyle modifications and screening) and (2) preoperative preparation and a bariatric operation (vs. neither preoperative nor operative component). We emulated both target trials using observational data of US veterans., Results: Comparing bariatric surgery with no surgery (target trial #1; 8,087 individuals), the 7-year cardiovascular risk was 18.0% (95% CI = 6.9, 32.7) in the surgery group and 18.9% (95% CI = 17.7, 20.1) in the no-surgery group (risk difference -0.9, 95% CI = -12.0, 14.0). Comparing preoperative components plus surgery vs. neither (target trial #2; 10,065 individuals), the 7-year cardiovascular risk was 17.4% (95% CI = 13.6, 22.0) in the surgery group and 18.8% (95% CI = 17.8, 19.9) in the no-surgery group (risk difference -1.4, 95% CI = -5.1, 3.2). Body mass index and hemoglobin A1c were reduced with bariatric interventions in both emulations., Conclusions: Within limitations of available observational data, our estimates do not provide evidence that bariatric surgery reduces cardiovascular disease and support equipoise for a randomized trial of bariatric surgery for cardiovascular disease prevention., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Frailty, a syndrome of physiologic vulnerability, increases cardiovascular disease (CVD) risk. Whether in person or automated frailty tools are ideal for identifying CVD risk remains unclear. We calculated 3 distinct frailty scores and examined their associations with mortality and CVD events in the Million Veteran Program, a prospective cohort of nearly 1 million US veterans., Methods and Results: Veterans aged ≥50 years and enrolled from 2011 to 2018 were included. Two frailty indices (FI) based on the deficit accumulation theory were calculated: the questionnaire-based 36-item Million Veteran Program-FI and 31-item Veterans Affairs-FI using claims data. We calculated Fried physical frailty using the self-reported, 3-item Study of Osteoporotic Fractures. Multivariable-adjusted Cox models examined the association of frailty by each score with primary (all-cause and CVD mortality) and secondary (myocardial infarction, stroke, and heart failure) outcomes. In 190 688 veterans (69±9 years, 94% male, 85% White), 33, 233 (17%) all-cause and 10 115 (5%) CVD deaths occurred. Using Million Veteran Program-FI, 29% were robust, 42% pre-frail, and 29% frail. Frailty prevalence increased by age group (27% in 50-59 to 42% in ≥90 years). Using the Million Veteran Program-FI, over 6±2 years, frail veterans had a higher hazard of all-cause (hazard ratio [HR], 3.05 [95% CI, 2.95-3.16]) and CVD mortality (HR, 3.65 [95% CI, 3.43-3.90]). Findings were concordant for the Veterans Affairs-FI and Study of Osteoporotic Fractures frailty definitions, and remained significant even among younger veterans aged 50-59 years., Conclusions: Irrespective of frailty measure, frailty is associated with a higher risk of all-cause mortality and adverse CVD events. Further study of frailty in veterans aged <60 years old is warranted.

Background: Red meat consumption was associated with an increased risk of cardiovascular disease (CVD) in prospective cohort studies and a profile of biomarkers favoring high CVD risk in short-term controlled trials. However, several recent systematic reviews and meta-analyses concluded with no or weak evidence for limiting red meat intake., Objectives: To prospectively examine the associations between red meat intake and incident CVD in an ongoing cohort study with diverse socioeconomic and racial or ethnic backgrounds., Methods: Our study included 148,506 participants [17,804 female (12.0%)] who were free of cancer, diabetes, and CVD at baseline from the Million Veteran Program. A food frequency questionnaire measured red meat intakes at baseline. Nonfatal myocardial infarction and acute ischemic stroke were identified through a high-throughput phenotyping algorithm, and fatal CVD events were identified by searching the National Death Index., Results: Comparing the extreme categories of intake, the multivariate-adjusted relative risks of CVD was 1.18 (95% CI: 1.01, 1.38; P-trend < 0.0001) for total red meat, 1.14 (95% CI: 0.96, 1.36; P-trend = 0.01) for unprocessed red meat, and 1.29 (95% CI: 1.04, 1.60; P-trend = 0.003) for processed red meat. We observed a more pronounced positive association between red meat intake and CVD in African American participants than in White participants (P-interaction = 0.01). Replacing 0.5 servings/d of red meat with 0.5 servings/d of nuts, whole grains, and skimmed milk was associated with 14% (RR: 0.86; 95% CI: 0.83, 0.90), 7% (RR: 0.93; 95% CI: 0.89, 0.96), and 4% (RR: 0.96; 95% CI: 0.94, 0.99) lower risks of CVD, respectively., Conclusions: Red meat consumption is associated with an increased risk of CVD. Our findings support lowering red meat intake and replacing red meat with plant-based protein sources or low-fat dairy foods as a key dietary recommendation for the prevention of CVD., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Statins are part of long-term medical regimens for many older adults. Whether frailty modifies the protective relationship between statins, mortality, and major adverse cardiovascular events (MACE) is unknown., Methods: This was a retrospective study of US Veterans ≥65, without CVD or prior statin use seen in 2002-2012, followed through 2017. A 31-item frailty index was used. The co-primary endpoint was all-cause mortality or MACE (MI, stroke/TIA, revascularization, or cardiovascular death). Cox proportional hazards models were developed to evaluate the association of statin use with outcomes; propensity score overlap weighting accounted for confounding by indication., Results: We identified 710,313 Veterans (mean age (SD) 75.3(6.5), 98% male, 89% white); 86,327 (12.1%) were frail. Over mean follow-up of 8 (5) years, there were 48.6 and 72.6 deaths per 1000 person-years (PY) among non-frail statin-users vs nonusers (weighted Incidence Rate Difference (wIRD)/1000 person years (PY), -24.0[95% CI, -24.5 to -23.6]), and 90.4 and 130.4 deaths per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -40.0[95% CI, -41.8 to -38.2]). There were 51.7 and 60.8 MACE per 1000PY among non-frail statin-users vs nonusers (wIRD/1000PY, -9.1[95% CI, -9.7 to -8.5]), and 88.2 and 102.0 MACE per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -13.8[95% CI, -16.2 to -11.4]). There were no significant interactions by frailty for statin users vs non-users by either mortality or MACE outcomes, p-interaction 0.770 and 0.319, respectively. Statin use was associated with lower risk of all-cause mortality (HR, 0.61 (0.60-0.61)) and MACE (HR 0.86 (0.85-0.87))., Conclusions: New statin use is associated with a lower risk of mortality and MACE, independent of frailty. These findings should be confirmed in a randomized clinical trial., (© 2023 The American Geriatrics Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Morbidity and mortality following COVID-19 infection may be influenced by baseline atherosclerotic cardiovascular disease (ASCVD) risk, yet limited data are available to identify those at highest risk. We examined the association between baseline ASCVD risk with mortality and major adverse cardiovascular events (MACE) in the year following COVID-19 infection., Methods: We evaluated a nationwide retrospective cohort of US Veterans free of ASCVD who were tested for COVID-19. The primary outcome was absolute risk of all-cause mortality in the year following a COVID-19 test among those hospitalized vs. not stratified by baseline VA-ASCVD risk scores. Secondarily, risk of MACE was examined., Results: There were 393,683 Veterans tested for COVID-19 and 72,840 tested positive. Mean age was 57 years, 86% were male, and 68% were white. Within 30 days following infection, hospitalized Veterans with VA-ASCVD scores >20% had an absolute risk of death of 24.6% vs. 9.7% (P ≤0.0001) for those who tested positive and negative for COVID-19 respectively. In the year following infection, risk of mortality attenuated with no difference in risk after 60 days. The absolute risk of MACE was similar for Veterans who tested positive or negative for COVID-19., Conclusions: Veterans without clinical ASCVD experienced an increased absolute risk of death within 30 days of a COVID-19 infection compared to Veterans with the same VA-ASCVD risk score who tested negative, but this risk attenuated after 60 days. Whether cardiovascular preventive medications can lower the risk of mortality and MACE in the acute period following COVID-19 infection should be evaluated., Competing Interests: Declaration of Competing Interest No authors have any conflicts of interest for this work., (Published by Elsevier B.V.)

Importance: Primary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation., Objective: To determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population., Design, Setting, and Participants: This was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023., Exposures: PRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status., Main Outcomes and Measures: Incident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events., Results: A total of 79 151 participants (mean [SD] age, 57.8 [13.7] years; 68 503 male [86.5%]) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, -0.07% to 3.30%)., Conclusions and Relevance: Study results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.

Aims: Influenza vaccination is associated with reduced cardiopulmonary morbidity and mortality among patients with heart failure or recent myocardial infarction. The immune response to vaccination frequently results in mild adverse reactions (AR), which leads to vaccine hesitancy. This post hoc analysis explored the association between vaccine-related AR and morbidity and mortality in patients with high-risk cardiovascular disease., Methods and Results: The INVESTED trial randomized 5260 patients with recent heart failure hospitalization or acute myocardial infarction to high-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine. We examined the association between vaccine-related AR and adverse clinical outcomes across both treatment groups in propensity-adjusted models. Among 5210 participants with available information on post-vaccination symptoms, 1968 participants (37.8%) experienced a vaccine-related AR. Compared to those without AR, post-vaccination AR, most commonly injection site pain (60.3%), were associated with lower risk for the composite of all-cause death or cardiopulmonary hospitalization (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75-0.92, p < 0.001), cardiopulmonary hospitalizations (HR 0.85 [95% CI 0.76-0.95], p = 0.003), all-cause death (HR 0.77 [95% CI 0.62-0.96], p = 0.02), cardiovascular hospitalizations (HR 0.88 [95% CI 0.78-0.99], p = 0.03) and non-cardiopulmonary hospitalizations (HR 0.80 [95% CI 0.69-0.92], p = 0.003). While mild (76.4%) and moderate (20.6%) AR were most common and together associated with lower risk for the primary outcome (HR 0.81 [95% CI 0.74-0.90], p < 0.001), severe AR (2.9%) were related to increased risk (HR 1.68 [95% CI 1.17-2.42], p = 0.005)., Conclusion: Mild to moderate post-vaccination reactions after influenza vaccine were associated with reduced risk of cardiopulmonary hospitalizations and all-cause mortality in patients with high-risk cardiovascular disease, while severe reactions may indicate increased risk. Mild to moderate AR to influenza vaccination may be a marker of immune response and should not deter future vaccinations., (© 2022 European Society of Cardiology.)

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke., Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank., Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min -1 ·1.73 m -2 , compared with those with eGFR between 60 and 105 mL·min -1 ·1.73 m -2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min -1 ·1.73 m -2 , with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min -1 ·1.73 m -2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min -1 ·1.73 m -2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD., Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Background: Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program., Methods: An ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization., Results: The discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality., Conclusion: A set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CJO: Employed by Novartis Institutes for Biomedical Research. SMD: Research support to my institution from RenalytixAI and paid consulting from Calico Labs, both outside the current work. PN: Research support from Amgen, Apple, and Boston Scientific, and personal consulting fees from Apple and Blackstone Life Sciences, all unrelated to the present work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Risk prediction models for cardiovascular disease (CVD) death developed from patients without vascular disease may not be suitable for myocardial infarction (MI) survivors. Prediction of mortality risk after MI may help to guide secondary prevention. Using national electronic record data from the Veterans Health Administration 2002 to 2012, we developed risk prediction models for CVD death and all-cause death based on 5-year follow-up data of 100,601 survivors of MI using Cox proportional hazards models. Model performance was evaluated using a cross-validation approach. During follow-up, there were 31,622 deaths and 12,901 CVD deaths. In men, older age, current smoking, atrial fibrillation, heart failure, peripheral artery disease, and lower body mass index were associated with greater risk of death from CVD or all-causes, and statin treatment, hypertension medication, estimated glomerular filtration rate level, and high body mass index were significantly associated with reduced risk of fatal outcomes. Similar associations and slightly different predictors were observed in women. The estimated Harrell's C-statistics of the final model versus the cross-validation estimates were 0.77 versus 0.77 in men and 0.81 versus 0.77 in women for CVD death. Similarly, the C-statistics were 0.75 versus 0.75 in men, 0.78 versus 0.75 in women for all-cause mortality. The predicted risk of death was well calibrated compared with the observed risk. In conclusion, we developed and internally validated risk prediction models of 5-year risk for CVD and all-cause death for outpatient survivors of MI. Traditional risk factors, co-morbidities, and lack of blood pressure or lipid treatment were all associated with greater risk of CVD and all-cause mortality., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To examine the association between intakes of sodium and potassium and the ratio of sodium to potassium and incident myocardial infarction and stroke. Design, Setting and Participants: Prospective cohort study of 180,156 Veterans aged 19 to 107 years with plausible dietary intake measured by food frequency questionnaire (FFQ) who were free of cardiovascular disease (CVD) and cancer at baseline in the VA Million Veteran Program (MVP). Main outcome measures: CVD defined as non-fatal myocardial infarction (MI) or acute ischemic stroke (AIS) ascertained using high-throughput phenotyping algorithms applied to electronic health records. Results: During up to 8 years of follow-up, we documented 4090 CVD cases (2499 MI and 1712 AIS). After adjustment for confounding factors, a higher sodium intake was associated with a higher risk of CVD, whereas potassium intake was inversely associated with the risk of CVD [hazard ratio (HR) comparing extreme quintiles, 95% confidence interval (CI): 1.09 (95% CI: 0.99−1.21, p trend = 0.01) for sodium and 0.87 (95% CI: 0.79−0.96, p trend = 0.005) for potassium]. In addition, the ratio of sodium to potassium (Na/K ratio) was positively associated with the risk of CVD (HR comparing extreme quintiles = 1.26, 95% CI: 1.14−1.39, p trend < 0.0001). The associations of Na/K ratio were consistent for two subtypes of CVD; one standard deviation increment in the ratio was associated with HRs (95% CI) of 1.12 (1.06−1.19) for MI and 1.11 (1.03−1.19) for AIS. In secondary analyses, the observed associations were consistent across race and status for diabetes, hypertension, and high cholesterol at baseline. Associations appeared to be more pronounced among participants with poor dietary quality. Conclusions: A high sodium intake and a low potassium intake were associated with a higher risk of CVD in this large population of US veterans.

Aims: Frailty is associated with an increased risk of all-cause mortality and cardiovascular (CV) events. Limited data exist from the modern era of CV prevention on the relationship between frailty and CV mortality. We hypothesized that frailty is associated with an increased risk of CV mortality., Methods and Results: All US Veterans aged ≥65 years who were regular users of Veteran Affairs care from 2002 to 2017 were included. Frailty was defined using a 31-item previously validated frailty index, ranging from 0 to 1. The primary outcome was CV mortality with secondary analyses examining the relationship between frailty and CV events (myocardial infarction, stroke, revascularization). Survival analysis models were adjusted for age, sex, ethnicity, geographic region, smoking, hyperlipidaemia, statin use, and blood pressure medication use. There were 3 068 439 US Veterans included in the analysis. Mean age was 74.1 ± 5.8 years in 2002, 76.0 ± 8.3 years in 2014, 98% male, and 87.5% White. In 2002, the median (interquartile range) frailty score was 0.16 (0.10-0.23). This increased and stabilized to 0.19 (0.10-0.32) for 2006-14. The presence of frailty was associated with an increased risk of CV mortality at every stage of frailty. Frailty was associated with an increased risk of myocardial infarction and stroke, but not revascularization., Conclusion: In this population, both the presence and severity of frailty are tightly correlated with CV death, independent of underlying CV disease. This study is the largest and most contemporary evaluation of the relationship between frailty and CV mortality to date. Further work is needed to understand how this risk can be diminished., Key Question: Can an electronic frailty index identify adults aged 65 and older who are at risk of CV mortality and major CV events?, Key Finding: Among 3 068 439 US Veterans aged 65 and older, frailty was associated with an increased risk of CV mortality at every level of frailty. Frailty was also associated with an increased risk of myocardial infarction and stroke, but not revascularization., Take Home Message: Both the presence and severity of frailty are associated with CV mortality and major CV events, independent of underlying CV disease., (Published by Oxford University Press on behalf of the European Society of Cardiology 2021. This work is written by US Government employees and is in the public domain in the US.)

Recent guidelines restricted aspirin (ASA) in primary prevention of cardiovascular disease (CVD) to patients <70 years old and more recent guidance to <60.In the most comprehensive prior meta-analysis, the Antithrombotic Trialists Collaboration reported a significant 12% reduction in CVD with similar benefit-risk ratios at older ages. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, four trials were added to an updated meta-analysis.ASA produced a statistically significant 13% reduction in CVD with 95% confidence limits (0.83 to 0.92) with similar benefits at older ages in each of the trials.Primary care providers should make individual decisions whether to prescribe ASA based on benefit-risk ratio, not simply age. When the absolute risk of CVD is >10%, benefits of ASA will generally outweigh risks of significant bleeding. ASA should be considered only after implementation of therapeutic lifestyle changes and other drugs of proven benefit such as statins, which are, at the very least, additive to ASA. Our perspective is that individual clinical judgements by primary care providers about prescription of ASA in primary prevention of CVD should be based on our evidence-based solution of weighing all the absolute benefits and risks rather than age. This strategy would do far more good for far more patients as well as far more good than harm in both developed and developing countries. This new and novel strategy for primary care providers to consider in prescribing ASA in primary prevention of CVD is the same as the general approach suggested by Professor Geoffrey Rose decades ago., Competing Interests: Competing interests: CHH reports that he serves as an independent scientist in an advisory role to investigators and sponsors as Chair of data monitoring committees for Amgen, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, and Regeneron; to the US FDA and UpToDate; receives royalties for authorship or editorship of three textbooks and as co-inventor on patents for inflammatory markers and cardiovascular disease that are held by Brigham and Women’s Hospital; has an investment management relationship with the West- Bacon Group within SunTrust Investment Services, which has discretionary investment authority; does not own any common or preferred stock in any pharmaceutical or medical device company. JMG reports that he serves as a consultant to Bayer. MAP reports that he receives research support from Novartis. He serves as an independent scientist in an advisory role to AstraZeneca, Boehringer-Ingelheim and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, NHLBI CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge and Sanofi; and has equity in DalCor and Peerbridge. DLDM reports that he serves as an independent scientist in an advisory role to the National Institutes of Health, the US Food and Drug Administration (FDA) and the pharmaceutical and medical device industry on the design, monitoring and analysis of trials. He serves on data monitoring committees for Astra Zeneca, Amgen, Action, DalCor, GSK, Merck, Sanofi, Boehringer Ingelheim, Teva and AbbVie. He holds no stock in any pharmaceutical or device company. SKW reports that she serves as an independent scientist in an advisory role to investigators and sponsors as member of three data monitoring committees for Amgen., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cardiovascular disease (CVD), including stroke and coronary artery disease (CAD), is the major cause of mortality for Americans. Nuts have been shown to improve a variety of cardiovascular disease risk factors. This study aimed to test the hypothesis that nut consumption is inversely associated with risk of incidence of stroke, CAD, and CVD mortality in the prospective Million Veterans Program (MVP). A total of 179,827 MVP participants enrolled between 2011 and 2018 were free of CVD prior to assessment of nut consumption via the food frequency questionnaire. Incident stroke and CVD events were ascertained from the Veterans Affairs electronic medical health records and the National Death Index. We used the Cox regression model to compute multivariable adjusted hazard ratios. Over the 3.5-year median follow-up, 3362 new cases of ischemic stroke were identified. When compared with participants who rarely or never consumed nuts, those consuming nuts ≥ 5 times per week were 19% less likely to experience a stroke (95% CI: 8% to 28%); 22% less likely to suffer from CAD (95% CI: 16% to 28%); and 24% less likely to die from CVD (95% CI: 7% to 37%). Consumption of peanut butter was not associated with risk of stroke. Increased dietary intake of nuts, but not peanut butter, was associated with a lower risk of stroke, CAD, and CVD death.

Objective: Our primary objective was to examine the associations of the Mediterranean (MED), the Dietary Approaches to Stop Hypertension (DASH), and the Alternate Healthy Eating Index (AHEI) diet with total mortality. Our secondary objective was to examine the association of these three dietary patterns with cardiovascular disease (CVD) and cancer mortality., Research: Design and Methods: We prospectively studied 15,768 men from the Physicians' Health Study who completed a semi-quantitative food-frequency questionnaire. Scores from each dietary pattern were divided into quintiles. Multivariable Cox regression models were used to estimate hazard ratio's (95% confidence intervals) of mortality., Results: At baseline, average age was 65.9 ± 8.9 years. There were 1763 deaths, including 488 CVD deaths and 589 cancer deaths. All diet scores were inversely associated with risk for all-cause mortality: Hazard ratios (95% CI) of all-cause mortality from lowest to highest quintile for MED diet were 1.0 (reference), 0.85 (0.73-0.98), 0.80 (0.69-0.93), 0.77 (0.66-0.90), and 0.68 (0.58-0.79); corresponding values were 1.0 (reference), 0.96 (0.82-1.12), 0.95 (0.82-1.11), 0.88 (0.75-1.04), and 0.83 (0.71-0.99) for DASH diet and 1.0 (reference), 0.88 (0.77-1.02), 0.82 (0.71-0.95), 0.69 (0.59, 0.81), and 0.56 (0.47-0.67) for AHEI diet, after adjusting for age, energy, smoking, exercise, BMI, hypertension, coronary heart disease, congestive heart failure, diabetes, and atrial fibrillation. For cause-specific mortality, MED and AHEI scores were inversely associated with lower risk for CVD mortality, whereas AHEI and MED scores were inversely associated with lower risk for cancer mortality., Conclusion: Within this cohort of male physicians, AHEI, MED, and DASH scores were each inversely associated with mortality from all causes.

Background: The link between nut consumption and cardiovascular (CV) mortality remains unclear., Objective: to examine whether nut consumption is associated with CV mortality and estimate the proportion of reduced risk of CV mortality explained by intermediate factors., Methods: We studied 39,167 women from the Women's Health Study; 28,034 provided blood samples. Nut consumption was self-reported at baseline and at follow-up using a food frequency questionnaire. Our primary outcome was cardiovascular death, which was ascertained via medical records, confirmed with the national death index and death certificates., Results: During a mean follow-up of 19 years, 959 CV deaths occurred. In a multivariable Cox regression model adjusting for age, body mass index, smoking, alcohol use, physical activity, postmenopausal status, marital status, family history of premature myocardial infarction and the alternate healthy eating index score, hazard ratios for CV mortality were 0.93 (0.76-1.14) for nut consumption of 1-3 times/month, 0.84 (0.69-1.01) for nut intake of 1 time/week, and 0.73 (0.61-0.87) for nut consumption of ≥2 times/week when compared to women who did not consume nuts (p = 0.0004). LDL and total cholesterol accounted for about 19%, HbA1c 18% and all mediating factors together accounted for about 6.6% of the lower risk of CV mortality for those who consumed nuts ≥2 times/week. For the secondary outcome of CV events, although the effect was noted to be in the same direction with increasing nut consumption associated with lower risk of CV events, it was not statistically significant (p = 0.07)., Conclusion: This study suggests that nut consumption is inversely associated with cardiovascular mortality in women. Lipids, inflammatory markers and glucose metabolism account for a modest proportion of the lowered CV mortality observed with nut consumption, assuming a causal nut-CV mortality association., (Published by Elsevier Inc.)

Importance: Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness., Objective: To evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease., Design, Setting, and Participants: Pragmatic multicenter, double-blind, active comparator randomized clinical trial conducted in 5260 participants vaccinated for up to 3 influenza seasons in 157 sites in the US and Canada between September 21, 2016, and January 31, 2019. Patients with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor were eligible., Interventions: Participants were randomly assigned to receive high-dose trivalent (n = 2630) or standard-dose quadrivalent (n = 2630) inactivated influenza vaccine and could be revaccinated for up to 3 seasons., Main Outcomes and Measures: The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. The final date of follow-up was July 31, 2019. Vaccine-related adverse events were also assessed., Results: Among 5260 randomized participants (mean [SD] age, 65.5 [12.6] years; 3787 [72%] men; 3289 [63%] with heart failure) over 3 influenza seasons, there were 7154 total vaccinations administered and 5226 (99.4%) participants completed the trial. In the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years), whereas in the standard-dose quadrivalent vaccine group, there were 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17]; P = .21). In the high-dose vs standard-dose groups, vaccine-related adverse reactions occurred in 1449 (40.5%) vs 1229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) participants., Conclusions and Relevance: In patients with high-risk cardiovascular disease, high-dose trivalent inactivated influenza vaccine, compared with standard-dose quadrivalent inactivated influenza vaccine, did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations. Influenza vaccination remains strongly recommended in this population., Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally, improved digital access to health information has facilitated the conduct of efficient randomized controlled trials (RCTs) upon which clinical management decisions can be based, for instance, by permitting the identification of eligible patients for recruitment and/or linkage for follow-up via their EHRs. Given these advances in cardiovascular data science and the complexities they behold, it is important that health professionals have clarity on the appropriate use and interpretation of observational, so-called 'real-world', and randomized data in cardiovascular medicine. The Cardiovascular Roundtable of the European Society of Cardiology (ESC) held a workshop to explore the future of RCTs and the current and emerging opportunities for gathering and exploiting complex observational datasets in cardiovascular research. The aim of this article is to provide a perspective on the appropriate use of randomized and observational data and to outline the ESC plans for supporting the collection and availability of clinical data to monitor and improve the quality of care of patients with cardiovascular disease in Europe and provide an infrastructure for undertaking pragmatic RCTs. Moreover, the ESC continues to campaign for greater engagement amongst regulators, industry, patients, and health professionals in the development and application of a more efficient regulatory framework that is able to take maximal advantage of new opportunities for improving the design and efficiency of observational studies and RCT in patients with cardiovascular disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Importance: Data are limited regarding statin therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in adults 75 years and older., Objective: To evaluate the role of statin use for mortality and primary prevention of ASCVD in veterans 75 years and older., Design, Setting, and Participants: Retrospective cohort study that used Veterans Health Administration (VHA) data on adults 75 years and older, free of ASCVD, and with a clinical visit in 2002-2012. Follow-up continued through December 31, 2016. All data were linked to Medicare and Medicaid claims and pharmaceutical data. A new-user design was used, excluding those with any prior statin use. Cox proportional hazards models were fit to evaluate the association of statin use with outcomes. Analyses were conducted using propensity score overlap weighting to balance baseline characteristics., Exposures: Any new statin prescription., Main Outcomes and Measures: The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes included a composite of ASCVD events (myocardial infarction, ischemic stroke, and revascularization with coronary artery bypass graft surgery or percutaneous coronary intervention)., Results: Of 326 981 eligible veterans (mean [SD] age, 81.1 [4.1] years; 97% men; 91% white), 57 178 (17.5%) newly initiated statins during the study period. During a mean follow-up of 6.8 (SD, 3.9) years, a total 206 902 deaths occurred including 53 296 cardiovascular deaths, with 78.7 and 98.2 total deaths/1000 person-years among statin users and nonusers, respectively (weighted incidence rate difference [IRD]/1000 person-years, -19.5 [95% CI, -20.4 to -18.5]). There were 22.6 and 25.7 cardiovascular deaths per 1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, -3.1 [95 CI, -3.6 to -2.6]). For the composite ASCVD outcome there were 123 379 events, with 66.3 and 70.4 events/1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, -4.1 [95% CI, -5.1 to -3.0]). After propensity score overlap weighting was applied, the hazard ratio was 0.75 (95% CI, 0.74-0.76) for all-cause mortality, 0.80 (95% CI, 0.78-0.81) for cardiovascular mortality, and 0.92 (95% CI, 0.91-0.94) for a composite of ASCVD events when comparing statin users with nonusers., Conclusions and Relevance: Among US veterans 75 years and older and free of ASCVD at baseline, new statin use was significantly associated with a lower risk of all-cause and cardiovascular mortality. Further research, including from randomized clinical trials, is needed to more definitively determine the role of statin therapy in older adults for primary prevention of ASCVD.

Background: Walking pace is increasingly being used to assess functional status in ambulatory settings., Methods: We conducted a prospective analysis within the Physicians' Health Study to examine whether walking pace is associated with mortality and incident cardiovascular disease (fatal or nonfatal myocardial infarction, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty). Participants included 21,919 male physicians with a mean age of 67.8 ± 9.0 years., Results: After a median follow-up of 9.4 years (IQR: 7.9-10.3), 3906 deaths and 2487 incident CVD events occurred. In a multivariable Cox proportional hazards model adjusting for age, body mass index, smoking, exercise frequency, and prevalent hypertension, diabetes mellitus, heart failure, peripheral vascular disease, cancer, and total weekly walking time, hazard ratios for mortality were 0.72 (95% CI: 0.64-0.81) for walking pace of 2-2.9mph, 0.63 (95% CI: 0.55-0.73) for walking pace of 3-3.9mph and 0.63 (95% CI: 0.48-0.83) for walking pace of ≥4mph compared to the group that reported not walking regularly (p trend <0.0001). Similar findings were observed for incident CVD: HRs were 0.88 (95% CI: 0.75-1.03) for a walking pace of 2-2.9mph, 0.75 (95% CI: 0.63-0.89) for a walking pace of 3-3.9mph and 0.70 (0.53-0.94) for a walking pace of ≥4mph compared to the group that reported not walking regularly (p trend 0.0001). These associations persisted after excluding those who exercised regularly., Conclusion: We found that walking pace is inversely associated with risk of mortality and CVD among US male physicians., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Importance: Electronic health record (EHR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform drug discovery. Individuals with interleukin 6 receptor (IL6R) single-nucleotide polymorphisms (SNPs) who are not receiving IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. This gene-drug pair provides an example to test whether associations of IL6R SNPs with a broad range of phenotypes can inform which diseases may benefit from treatment with IL6R blockade., Objective: To determine whether screening for clinical associations with the IL6R SNP in a phenome-wide association study (PheWAS) using EHR biobank data can identify drug effects from IL6R clinical trials., Design, Setting, and Participants: Diagnosis codes and routine laboratory measurements were extracted from the VA Million Veteran Program (MVP); diagnosis codes were mapped to phenotype groups using published PheWAS methods. A PheWAS was performed by fitting logistic regression models for testing associations of the IL6R SNPs with 1342 phenotype groups and by fitting linear regression models for testing associations of the IL6R SNP with 26 routine laboratory measurements. Significance was reported using a false discovery rate of 0.05 or less. Findings were replicated in 2 independent cohorts using UK Biobank and Vanderbilt University Biobank data. The Million Veteran Program included 332 799 US veterans; the UK Biobank, 408 455 individuals from the general population of the United Kingdom; and the Vanderbilt University Biobank, 13 835 patients from a tertiary care center., Exposures: IL6R SNPs (rs2228145; rs4129267)., Main Outcomes and Measures: Phenotypes defined by International Classification of Diseases, Ninth Revision codes., Results: Of the 332 799 veterans included in the main cohort, 305 228 (91.7%) were men, and the mean (SD) age was 66.1 (13.6) years. The IL6R SNP was most strongly associated with a reduced risk of aortic aneurysm phenotypes (odds ratio, 0.87-0.90; 95% CI, 0.84-0.93) in the MVP. We observed known off-target effects of IL6R blockade from clinical trials (eg, higher hemoglobin level). The reduced risk for aortic aneurysms among those with the IL6R SNP in the MVP was replicated in the Vanderbilt University Biobank, and the reduced risk for coronary heart disease was replicated in the UK Biobank., Conclusions and Relevance: In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.

Background: A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes., Methods: Using individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (≤100 mg) and higher doses (300-325 mg or ≥500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial cancer., Results: Among ten eligible trials of aspirin in primary prevention (including 117 279 participants), bodyweight varied four-fold and trial median weight ranged from 60·0 kg to 81·2 kg (p<0·0001). The ability of 75-100 mg aspirin to reduce cardiovascular events decreased with increasing weight (p interaction =0·0072), with benefit seen in people weighing 50-69 kg (hazard ratio [HR] 0·75 [95% CI 0·65-0·85]) but not in those weighing 70 kg or more (0·95 [0·86-1·04]; 1·09 [0·93-1·29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1·33 [95% CI 1·08-1·64], p=0·0082). Higher doses of aspirin (≥325 mg) had the opposite interaction with bodyweight (difference p interaction =0·0013), reducing cardiovascular events only at higher weight (p interaction =0·017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (p interaction =0·0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (p interaction =0·038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (p interaction =0·0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75-100 mg aspirin (HR 1·52 [95% CI 1·04-2·21], p=0·031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1·20 [1·03-1·47], p=0·02), particularly in those weighing less than 70 kg (1·31 [1·07-1·61], p=0·009) and consequently in women (1·44 [1·11-1·87], p=0·0069)., Interpretation: Low doses of aspirin (75-100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required., Funding: Wellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC-BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

No data exist on the prevalence of ideal cardiovascular health metrics in a national sample of U.S. veterans. We assessed the prevalence of ideal Life's Simple Seven (LSS) metrics in a cross-sectional study of 554,855 U.S. veterans enrolled in the Million Veteran Program (MVP) from 2011 to 2017. We used the American Heart Association's established criteria to categorize each LSS metric as either poor, intermediate, or ideal for a veteran at time of MVP enrollment. Information on adiposity/body mass index, smoking status, diet, and physical activity was obtained from self-reported survey data, and clinical measurements for total cholesterol, blood pressure, and plasma glucose were obtained from electronic health records. Complete data on all LSS health factors were available for 201,745 veterans. The prevalence of having 0, 1, 2, 3, 4, 5, 6, and 7 ideal cardiovascular health metrics was 29.2%, 34.6%, 22.6%, 10.0%, 3.0%, 0.6%, <0.1%, and 0%, respectively. The frequency of ideal body mass index, physical activity, smoking status, total cholesterol, blood pressure, and plasma glucose was 19.4%, 3.8%, 27.0%, 21.8%, 17.8%, and 34.5%, respectively, in our study population. Among the 7 metrics, MVP participants were least likely to achieve ideal diet (0.4%), particularly the recommendation for fruit and vegetable (at least 4.5 cups/day) intake. Our data show an extremely low prevalence of ideal cardiovascular health factors among veterans in the MVP, especially for diet and physical activity. These findings underscore the need to improve adherence to modifiable lifestyle factors that could result in subsequent reduction in cardiovascular disease burden among veterans., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: Despite growing interest in using electronic health records (EHR) to create longitudinal cohort studies, the distribution and missingness of EHR data might introduce selection bias and information bias to such analyses. We aimed to examine the yield and potential for these healthcare process biases in defining a study baseline using EHR data, using the example of cholesterol and blood pressure (BP) measurements., Methods: We created a virtual cohort study of cardiovascular disease (CVD) from patients with eligible cholesterol profiles in the New England (NE) and Southeast (SE) networks of the Veterans Health Administration in the United States. Using clinical data from the EHR, we plotted the yield of patients with BP measurements within an expanding timeframe around an index date of cholesterol testing. We compared three groups: (1) patients with BP from the exact index date; (2) patients with BP not on the index date but within the network-specific 90th percentile around the index date; and (3) patients with no BP within the network-specific 90th percentile., Results: Among 589,361 total patients in the two networks, 146,636 (61.0%) of 240,479 patients from NE and 289,906 (83.1%) of 348,882 patients from SE had BP measurements on the index date. Ninety percent had BP measured within 11 days of the index date in NE and within 5 days of the index date in SE. Group 3 in both networks had fewer available race data, fewer comorbidities and CVD medications, and fewer health system encounters., Conclusions: Requiring same-day risk factor measurement in the creation of a virtual CVD cohort study from EHR data might exclude 40% of eligible patients, but including patients with infrequent visits might introduce bias. Data visualization can inform study-specific strategies to address these challenges for the research use of EHR data., (Published by Elsevier Inc.)

Frailty and cardiovascular disease are highly interconnected and increase in prevalence with age. Identifying frailty allows for a personalized cardiovascular risk prescription and individualized management of hypertension, hyperlipidemia, diabetes, and lifestyle in the aging population., (Copyright © 2018 Cleveland Clinic.)

Importance: Long-term multivitamin use had no effect on risk of cardiovascular disease (CVD) in the Physicians' Health Study II. Baseline nutritional status may have modified the lack of effect., Objective: To investigate effect modification by various baseline dietary factors on CVD risk in the Physicians' Health Study II., Design, Setting, and Participants: The Physicians' Health Study II was a randomized, double-blind, placebo-controlled trial testing multivitamin use (multivitamin [Centrum Silver] or placebo daily) among US male physicians. The Physicians' Health Study II included 14 641 male physicians 50 years or older, 13 316 of whom (91.0%) completed a baseline 116-item semiquantitative food frequency questionnaire and were included in the analyses. This study examined effect modification by baseline intake of key foods, individual nutrients, dietary patterns (Alternate Healthy Eating Index and Alternate Mediterranean Diet Score), and dietary supplement use. The study began in 1997, with continued treatment and follow-up through June 1, 2011., Interventions: Multivitamin or placebo daily., Main Outcomes and Measures: Major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, and CVD mortality. Secondary outcomes included myocardial infarction, total stroke, CVD mortality, and total mortality individually., Results: In total, 13 316 male physicians (mean [SD] age at randomization, 64.0 [9.0] years in those receiving the active multivitamin and 64.0 [9.1] years in those receiving the placebo) were observed for a mean (SD) follow-up of 11.4 (2.3) years. There was no consistent evidence of effect modification by various foods, nutrients, dietary patterns, or baseline supplement use on the effect of multivitamin use on CVD end points. Statistically significant interaction effects were observed between multivitamin use and vitamin B6 intake on myocardial infarction, between multivitamin use and vitamin D intake on CVD mortality, and between multivitamin use and vitamin B12 intake on CVD mortality and total mortality. However, there were inconsistent patterns in hazard ratios across tertiles of each dietary factor that are likely explained by multiple testing., Conclusions and Relevance: The results suggest that baseline nutritional status does not influence the effect of randomized long-term multivitamin use on major CVD events. Future studies are needed to investigate the role of baseline nutritional biomarkers on the effect of multivitamin use on CVD and other outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT00270647.

Background: Although multivitamins are widely used by US adults, few prospective studies have investigated their association with the long- and short-term risks of cardiovascular disease (CVD)., Objective: The aim of this study was to investigate how multivitamin use is associated with the risk of CVD in initially healthy men at baseline., Methods: We studied 18,530 male physicians aged ≥40 y from the Physicians' Health Study I cohort who were free of CVD and cancer at baseline (1982). All men provided a wide range of self-reported lifestyle and clinical factors plus intake of selected foods and dietary supplements. Cox proportional hazards models were used to calculate multivariable-adjusted HRs (95% CIs)., Results: During a mean follow-up of 12.2 y (total of 225,287 person-years), there were 1697 incident cases of major CVD (defined as nonfatal myocardial infarction, nonfatal stroke, and CVD death). In multivariable-adjusted analyses, no significant associations were observed among baseline multivitamin users compared with nonusers for the risk of major CVD events (HR: 0.94; 95% CI: 0.84, 1.05), whereas a self-reported duration of ≥20 y at baseline was associated with lower risk (HR: 0.56; 95% CI: 0.35, 0.90; P-trend = 0.05). Baseline multivitamin use was also significantly inversely associated with the risk of cardiac revascularization (HR: 0.86; 95% CI: 0.75, 0.98). Baseline use of multivitamins was not significantly associated with other CVD endpoints., Conclusion: In this long-term prospective study in initially healthy men, multivitamin use for ≥20 y was associated with a lower risk of major CVD events., (© 2016 American Society for Nutrition.)

Fried food consumption and its effects on cardiovascular disease are still subjects of debate. The objective of this review was to summarize current evidence on the association between fried food consumption and cardiovascular disease, diabetes, hypertension and obesity and to recommend directions for future research. We used PubMed, Google Scholar and Medline searches to retrieve pertinent publications. Most available data were based on questionnaires as a tool to capture fried food intakes, and study design was limited to case-control and cohort studies. While few studies have reported a positive association between frequencies of fried food intake and risk of coronary artery disease, heart failure, diabetes or hypertension, other investigators have failed to confirm such an association. There is strong evidence suggesting a higher risk of developing chronic disease when fried foods are consumed more frequently (i.e., four or more times per week). Major gaps in the current literature include a lack of detailed information on the type of oils used for frying foods, stratification of the different types of fried food, frying procedure (deep and pan frying), temperature and duration of frying, how often oils were reused and a lack of consideration of overall dietary patterns. Besides addressing these gaps, future research should also develop tools to better define fried food consumption at home versus away from home and to assess their effects on chronic diseases. In summary, the current review provides enough evidence to suggest adverse health effects with higher frequency of fried food consumption. While awaiting confirmation from future studies, it may be advisable to the public to consume fried foods in moderation while emphasizing an overall healthy diet.

Objectives: The aim of this study is to assess the prevalence and changes over time of ideal Life's Simple Seven (LSS) in African-Americans., Methods: Prospective cohort of 5301 African-Americans from the Jackson Heart Study (JHS) from 2000 to 2013. Each of the LSS metrics was categorized as poor, intermediate, or ideal., Results: Among men, the prevalence of having 0, 1, 2, 3, 4, 5, 6, and 7 ideal LSS was 3.3%, 23.0%, 33.5%, 24.7%, 11.6%, 3.6%, 0.3%, and 0%, respectively. Corresponding values for women were 1.7%, 26.3%, 33.1%, 22.8%, 11.9%, 3.7%, 0.6%, and 0%. Prevalence of ideal diet was 0.9%. The proportions of those meeting LSS ideal recommendations for cholesterol and fasting glucose declined from the first through third JHS visits across all age groups, whereas prevalence of ideal BMI declined only in participants <40 years at a given visit. Prevalence of ideal blood pressure did not change over time and being ideal on physical activity improved from the first [18.3% (95% CI: 17.3% to 19.3%)] to third visit [24.8% (95% CI: 23.3% to 26.3%)]., Conclusions: Our data show a low prevalence of ideal LSS (especially diet, physical activity, and obesity) in the JHS and a slight improvement in adherence to physical activity recommendations over time., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Type 2 diabetes (T2DM) patients, including those in good glycemic control, have an increased risk of cardiovascular disease (CVD). Maintaining good glycemic control may reduce long-term CVD risk. However, other risk factors such as elevated vascular sympathetic tone and/or endothelial dysfunction may be stronger potentiators of CVD. This study evaluated the impact of bromocriptine-QR, a sympatholytic dopamine D2 receptor agonist, on progression of metabolic disease and CVD in T2DM subjects in good glycemic control (HbA1c ≤ 7.0%)., Methods: 1834 subjects (1219 bromocriptine-QR; 615 placebo) with baseline HbA1c ≤ 7.0% derived from the Cycloset Safety Trial (this trial is registered with ClinicalTrials.gov Identifier: NCT00377676), a 12-month, randomized, multicenter, placebo-controlled, double-blind study in T2DM, were evaluated. Treatment impact upon a prespecified composite CVD endpoint (first myocardial infarction, stroke, coronary revascularization, or hospitalization for angina/congestive heart failure) and the odds of losing glycemic control (HbA1c >7.0% after 52 weeks of therapy) were determined., Results: Bromocriptine-QR reduced the CVD endpoint by 48% (intention-to-treat; HR: 0.52 [0.28-0.98]) and 52% (on-treatment analysis; HR: 0.48 [0.24-0.95]). Bromocriptine-QR also reduced the odds of both losing glycemic control (OR: 0.63 (0.47-0.85), p = 0.002) and requiring treatment intensification to maintain HbA1c ≤ 7.0% (OR: 0.46 (0.31-0.69), p = 0.0002)., Conclusions: Bromocriptine-QR therapy slowed the progression of CVD and metabolic disease in T2DM subjects in good glycemic control.

Background: Although multivitamins are widely used, there are limited prospective studies investigating their association with both long- and short-term risk of cardiovascular disease (CVD)., Objective: The objective was to investigate how multivitamin use is associated with the long- and short-term risk of CVD., Design: A prospective cohort study was conducted of 37,193 women from the Women's Health Study aged ≥45 y and free of CVD and cancer at baseline who were followed for an average of 16.2 y. At baseline, women self-reported a wide range of lifestyle, clinical, and dietary factors. Women were categorized into 1) no current use and 2) current use of multivitamins. Duration and updated measures over the course of the follow-up to address short-term effects were also considered. Women were followed for major CVD events, including myocardial infarction (MI), stroke, and CVD death., Results: During the follow-up, 1493 incident cases of CVD [defined as myocardial infarction (MI), stroke, and CVD death] occurred. In multivariable analyses, multivitamin use compared with no use was not associated with major CVD events (HR: 1.01; 95% CI: 0.89, 1.15), MI (HR: 1.04; 95% CI: 0.84, 1.27), stroke (HR: 0.99; 95% CI: 0.83, 1.18), or CVD death (HR: 1.10; 95% CI: 0.84, 1.45). A nonsignificant inverse association was observed between baseline multivitamin use and major CVD events among women aged ≥70 y (P-interaction = 0.04) and those consuming <3 servings/d of fruit and vegetables (P-interaction = 0.01). When updating information on multivitamin use during the course of follow-up, no associations were observed for major CVD events (HR: 0.91; 95% CI: 0.82, 1.02), MI (HR: 0.89; 95% CI: 0.74, 1.06), stroke (HR: 0.91; 95% CI: 0.78, 1.06), and CVD death (HR: 0.91; 95% CI: 0.71, 1.16)., Conclusions: In this study of middle-aged and elderly women, neither baseline nor time-varying multivitamin use was associated with the long-term risk of major CVD events, MI, stroke, cardiac revascularizations, or CVD death. Additional studies are needed to clarify the role of multivitamins on CVD., (© 2015 American Society for Nutrition.)

Over the last 2 decades, observational evidence largely supports an association between light to moderate alcohol consumption (up to 1 drink per day in women and up to 2 drinks per day in men) and a lower risk of cardiovascular disease (CVD), largely driven by a reduction in coronary heart disease. Most studies suggest a nadir in risk in the light to moderate range of alcohol intake, which is then countered by an increase in cardiomyopathy, sudden death, and hemorrhagic stroke at higher drinking levels that offsets potential benefits. The mechanisms of cardioprotective effects of alcohol are complex and there are multiple pathways by which moderate alcohol consumption reduces the risk of CVD. Recent evidence continues to emerge on the physiologic and genetic mechanisms through which alcohol may reduce the risk of developing CVD. Ongoing debate also lingers whether there are important differences in cardiovascular effects according to alcoholic beverage type (beer vs red wine vs liquor). Another emerging area of interest is the role of alcohol consumption on the development of intermediate cardiovascular endpoints such as hypertension and diabetes that lead to the development of CVD as well as other important cardiovascular sequelae. Alcohol consumption has also been shown to impact the risk of other CVD endpoints including congestive heart failure, alcoholic cardiomyopathy, atrial fibrillation, and peripheral artery disease. Overall, alcohol still carries significant public health implications given its plausible benefits on CVD along with its well-documented adverse effects, warranting continued caution and a discussion with one's primary care provider regarding intake.

Background: Previous studies evaluating the association of cardiovascular disease and vascular risk factors with restless legs syndrome showed inconsistent results, especially for the potential relation between various vascular risk factors and restless legs syndrome. We therefore aimed to analyze the relationships between vascular risk factors, prevalent cardiovascular disease, and restless legs syndrome., Methods: This is a cross-sectional study of 30,262 female health professionals participating in the Women's Health Study (WHS). Restless legs syndrome was defined according to diagnostic criteria of the International Restless Legs Study Group. Information on vascular risk factors (diabetes, hypertension, hypercholesterolemia, body mass index [BMI], alcohol, smoking, exercise, and family history of myocardial infarction) was self-reported. Cardiovascular disease events (coronary revascularization, myocardial infarction, and stroke) were confirmed by medical record review. Prevalent major cardiovascular disease was defined as nonfatal stroke or nonfatal myocardial infarction. Logistic regression models were used to evaluate the association between vascular risk factors, prevalent cardiovascular disease, and restless legs syndrome., Results: Of the 30,262 participants (mean age: 63.6 years), 3624 (12.0%) reported restless legs syndrome. In multivariable-adjusted models, BMI (odds ratio [OR] for BMI ≥35 kg/m(2), 1.35; 95% confidence interval [CI], 1.17-1.56), diabetes (OR, 1.19; 95% CI, 1.04-1.35), hypercholesterolemia (OR, 1.17; 95% CI, 1.09-1.26), smoking status (OR for ≥15 cigarettes/day, 1.41; 95% CI, 1.19-1.66), and exercise (OR for exercise ≥4 times/week, 0.84; 95% CI, 0.74-0.95) were associated with restless legs syndrome prevalence. We found no association between prevalent cardiovascular disease (major cardiovascular disease, myocardial infarction, and stroke) and restless legs syndrome prevalence. Women who underwent coronary revascularization had a multivariable-adjusted OR of 1.39 (1.10-1.77) for restless legs syndrome., Conclusions: In this large cohort of female health professionals, various vascular risk factors are associated with the prevalence of restless legs syndrome. We could not confirm the results of previous reports indicating an association between prevalent cardiovascular disease and restless legs syndrome., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The prevalence of vascular risk factors, cardiovascular disease, and restless legs syndrome increases with age. Prior studies analyzing the associations between vascular risk factors, cardiovascular disease, and restless legs syndrome found controversial results. We therefore aim to evaluate the associations between prevalent vascular risk factors, prevalent cardiovascular disease, and restless legs syndrome., Methods: We conducted a cross-sectional study among 22,786 participants of the US Physicians' Health Studies I and II. Restless legs syndrome was classified according to the 4 minimal diagnostic criteria. Vascular risk factors and restless legs syndrome symptoms were self-reported. Prevalent cardiovascular disease events, including major cardiovascular disease, stroke, and myocardial infarction, were confirmed by medical record review. Age- and multivariable-adjusted logistic regression models were used to evaluate the association among vascular risk factors, prevalent cardiovascular disease events, and restless legs syndrome., Results: The mean age of the cohort was 67.8 years. The prevalence of restless legs syndrome was 7.5% and increased significantly with age. Diabetes significantly increased the odds of restless legs syndrome (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.21-1.65), whereas frequent exercise (OR, 0.78; 95% CI, 0.67-0.91) and alcohol consumption of 1 or more drinks per day (OR, 0.80; 95% CI, 0.69-0.92) significantly reduced the odds of restless legs syndrome in multivariable-adjusted models. Prevalent stroke showed an increased multivariable-adjusted OR of 1.40 (1.05-1.86), whereas men with prevalent myocardial infarction had a decreased OR of 0.73 (0.55-0.97) for restless legs syndrome., Conclusions: The restless legs syndrome prevalence among US male physicians is similar to that of men of the same age group in other western countries. A history of diabetes is the most consistent risk factor associated with restless legs syndrome. Prevalent stroke and myocardial infarction are related to restless legs syndrome prevalence., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Context: Although multivitamins are used to prevent vitamin and mineral deficiency, there is a perception that multivitamins may prevent cardiovascular disease (CVD). Observational studies have shown inconsistent associations between regular multivitamin use and CVD, with no long-term clinical trials of multivitamin use., Objective: To determine whether long-term multivitamin supplementation decreases the risk of major cardiovascular events among men., Design, Setting, and Participants: The Physicians' Health Study II, a randomized, double-blind, placebo-controlled trial of a common daily multivitamin, began in 1997 with continued treatment and follow-up through June 1, 2011. A total of 14,641 male US physicians initially aged 50 years or older (mean, 64.3 [SD, 9.2] years), including 754 men with a history of CVD at randomization, were enrolled., Intervention: Daily multivitamin or placebo., Main Outcome Measures: Composite end point of major cardiovascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, and CVD mortality. Secondary outcomes included MI and stroke individually., Results: During a median follow-up of 11.2 (interquartile range, 10.7-13.3) years, there were 1732 confirmed major cardiovascular events. Compared with placebo, there was no significant effect of a daily multivitamin on major cardiovascular events (11.0 and 10.8 events per 1000 person-years for multivitamin vs placebo, respectively; hazard ratio [HR], 1.01; 95% CI, 0.91-1.10; P = .91). Further, a daily multivitamin had no effect on total MI (3.9 and 4.2 events per 1000 person-years; HR, 0.93; 95% CI, 0.80-1.09; P = .39), total stroke (4.1 and 3.9 events per 1000 person-years; HR, 1.06; 95% CI, 0.91-1.23; P = .48), or CVD mortality (5.0 and 5.1 events per 1000 person-years; HR, 0.95; 95% CI, 0.83-1.09; P = .47). A daily multivitamin was also not significantly associated with total mortality (HR, 0.94; 95% CI, 0.88-1.02; P = .13). The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD (P = .62 for interaction)., Conclusion: Among this population of US male physicians, taking a daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up., Trial Registration: clinicaltrials.gov Identifier: NCT00270647.

Background: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events., Methods: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen., Results: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years., Conclusions: In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).

Background: 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)., Conclusions: 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.

Genes functioning in folate-mediated 1-carbon metabolism are hypothesized to play a role in cardiovascular disease (CVD) risk beyond the current narrow focus on the MTHFR 677 C→T (rs1801133) polymorphism. Using a cohort study design, we investigated whether sequence variants in the network of folate-related genes, particularly in genes encoding proteins related to SHMT1, predict CVD risk in 1131 men from the Normative Aging Study. A total of 330 single nucleotide polymorphisms (SNPs) in 52 genes, selected for function and gene coverage, were assayed on the Illumina GoldenGate platform. Age- and smoking-adjusted genotype-phenotype associations were estimated in regression models. Using a nominal P ≤ 5.00 × 10(-3) significance threshold, 8 SNPs were associated with CVD risk in single locus analyses. Using a false discovery rate (FDR) threshold (P-adjusted ≤1.00 × 10(-1)), a SNP in the GGH gene remained associated with reduced CVD risk, with a stronger association in early onset CVD cases (<55 y). A gene × folate interaction (MAT2B) and 2 gene × vitamin B-12 interactions (BHMT, SLC25A32) reached the FDR P-adjusted ≤2.00 × 10(-1) threshold. Three biological hypotheses related to SHMT1 were explored and significant gene × gene interactions were identified for TYMS by UBE2N, FTH1 by CELF1, and TYMS by MTHFR. Variations in genes other than MTHFR and those directly involved in homocysteine metabolism are associated with CVD risk in non-Hispanic white males. This work supports a role for SHMT1-related genes and nuclear folate metabolism, including the thymidylate biosynthesis pathway, in mediating CVD risk.

Background: Most incident cardiovascular disease (CVD) occurs after patients reach the age of 65. The additive benefits of aggressive risk factor management with advancing age are not well established., Objective: To evaluate the relationship between control of four modifiable risk factors (smoking, non-high density lipoprotein cholesterol, blood pressure, and aspirin use) and risk of CVD in a primary prevention population of older men., Materials and Methods: U.S. male physicians from the Physicians' Health Study (n = 4182; an epidemiologic follow-up of a randomized trial of aspirin and beta-carotene) who in 1997 were ≥ 65 years, free of CVD and diabetes, and had a blood sample on file were studied. Cox proportional hazard models were adjusted for age and competing causes of death. The first of any CVD event, defined as cardiovascular death, nonfatal myocardial infarction, angina, coronary revascularization, nonfatal stroke, transient ischemic attack, carotid artery surgery, and other peripheral vascular disease surgery, was measured., Results: Mean follow-up was 9.3 years, mean age was 73 years, and 96% were nonsmokers. Compared with when 4 of 4 risk factors were controlled (6.0% of participants), control of 0 of 4 risk factors almost quadrupled the risk of CVD (0.4% of participants; event rate 41.2%; hazard ratio [HR] 3.83, 95% confidence interval [95% CI] 1.72-8.55); control of 1 of 4 risk factors more than doubled the risk (14.2% of participants; HR 2.53, 95% CI 1.80-3.57); control of 2 of 4 risk factors almost doubled the 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 = .002). Depending on the number of risk factors controlled, the number-needed to control to prevent one CVD event ranged from 5 to 22., Conclusion: Control of 4 treatable risk factors (nonsmoking, control of non-high density lipoprotein cholesterol and blood pressure, and aspirin use) was associated with substantial protection against incident cardiovascular events in older men even after adjustment for competing causes of mortality., (Copyright © 2012 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: It is unclear whether models that include hemoglobin A(1c) (HbA(1c)) levels only for diabetic patients improve the ability to predict cardiovascular disease (CVD) risk compared with the currently recommended classification of diabetes as a cardiovascular risk equivalent., Methods: A total of 24 674 women (including 685 diabetic participants at baseline) and 11 280 men (including 563 diabetic participants at baseline) were followed up prospectively for cardiovascular disease (CVD). One hundred twenty-five CVD events occurred in diabetic women (666 in nondiabetic women), and 170 events occurred in diabetic men (1382 in nondiabetic 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 HbA(1c) levels only for diabetic individuals. In diabetic participants, the resulting predicted risks were compared with classification of diabetes as a cardiovascular risk equivalent (10-year CVD risk of at least 20%)., Results: In women, the models including HbA(1c) levels in diabetic participants improved the C statistic by 0.177 (P < .001) over the risk equivalence model and showed improved reclassification (net reclassification improvement [NRI] of 26.7% [P = .001]). In men, the improvements were more modest but still statistically significant (C statistic change of 0.039 [P = .02]; NRI of 9.2% [P = .04]). Including HbA(1c) levels also improved prediction over a dichotomous term for diabetes in women (NRI of 11.8% [P = .03]) but not in men., Conclusions: In both women and men with diabetes at baseline, we observed significant improvements in predictive ability of CVD risk using models incorporating HbA(1c) levels compared with classification of diabetes as a cardiovascular risk equivalent.

Background: We sought to examine whether ε4 carrier status modifies the relation between body mass index (BMI) and HDL. The National Heart, Lung, and Blood Institute Family Heart Study included 657 families with high family risk scores for coronary heart disease and 588 randomly selected families of probands in the Framingham, Atherosclerosis Risk in Communities, and Utah Family Health Tree studies. We selected 1402 subjects who had ε4 carrier status available. We used generalized estimating equations to examine the interaction between BMI and ε4 allele carrier status on HDL after adjusting for age, gender, smoking, alcohol intake, mono- and poly-unsaturated fat intake, exercise, comorbidities, LDL, and family cluster., Results: The mean (standard deviation) age of included subjects was 56.4(11.0) years and 47% were male. Adjusted means of HDL for normal, overweight, and obese BMI categories were 51.2(± 0.97), 45.0(± 0.75), and 41.6(± 0.93), respectively, among 397 ε4 carriers (p for trend < 0.0001) and 53.6(± 0.62), 51.3(± 0.49), and 45.0(± 0.62), respectively, among 1005 non-carriers of the ε4 allele (p-value for trend < 0.0001). There was no evidence for an interaction between BMI and ε4 status on HDL(p-value 0.39)., Conclusion: Our findings do not support an interaction between ε4 allele status and BMI on HDL.