Effect of multivitamin-mineral supplementation versus placebo on cognitive function: results from the clinic subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial and meta-analysis of 3 cognitive studies within COSMOS.

BACKGROUND: Longer effects of multivitamin-mineral (MVM) supplementation on late-life cognitive function remain untested using in-person, detailed neuropsychological assessments. Furthermore, insufficient evidence exists for healthcare providers to recommend daily MVM supplements to prevent cognitive decline. OBJECTIVES: This study aimed to test MVM effects on cognitive change using in-person, detailed neuropsychological assessments and conduct a meta-analysis within COSMOS (COcoa Supplement and Multivitamin Outcomes Study) cognitive substudies for a robust evaluation of MVM effects on cognition. METHODS: COSMOS is a 2 × 2 factorial trial of cocoa extract (500 mg flavanols/d) and/or a daily MVM supplement for cardiovascular disease and cancer prevention among 21,442 United States adults aged ≥60 y. There were 573 participants in the clinic subcohort of COSMOS (that is, COSMOS-Clinic) who completed all cognitive tests administered at baseline. For the meta-analysis, we included nonoverlapping participants across 3 COSMOS cognitive substudies: COSMOS-Clinic (n = 573); COSMOS-Mind (n = 2158); COSMOS-Web (n = 2472). RESULTS: In COSMOS-Clinic, we observed a modest benefit of MVM compared with placebo on global cognition over 2 y {mean difference [95% confidence interval (CI)] = 0.06 SD units (SU) (-0.003, 0.13)}, with a significantly more favorable change in episodic memory [mean difference (95% CI) = 0.12 SU (0.002, 0.23)] but not in executive function or attention [mean difference (95% CI) = 0.04 SU (-0.04, 0.11)]. The meta-analysis of COSMOS substudies showed clear evidence of MVM benefits on global cognition [mean difference (95% CI) = 0.07 SU (0.03, 0.11); P = 0.0009] and episodic memory [mean difference (95% CI) = 0.06 SU (0.03, 0.10); P = 0.0007]; the magnitude of effect on global cognition was equivalent to reducing cognitive aging by 2 y. CONCLUSIONS: In COSMOS-Clinic, daily MVM supplementation leads to a significantly more favorable 2-y change in episodic memory. The meta-analysis within COSMOS cognitive substudies indicates that daily MVM significantly benefits both global cognition and episodic memory. These findings within the COSMOS trial support the benefits of a daily MVM in preventing cognitive decline among older adults. This trial was registered at COSMOS-clinicaltrials.gov as NCT02422745, at COSMOS-Mind-clinicaltrials.gov as NCT03035201, and at COSMOS-Web-clinicaltrials.gov as NCT04582617.

Effect of cocoa extract supplementation on cognitive function: results from the clinic subcohort of the COSMOS trial.

BACKGROUND: Some prior randomized clinical trials (RCTs) that tested the effects of cocoa extract (CE), a source of flavanols, on late-life cognition have yielded promising findings. A long-term RCT using in-person neuropsychological tests covering multiple cognitive domains may clarify the cognitive effects of CE. OBJECTIVES: To test whether daily supplementation with CE, compared with placebo, produces better cognitive change over 2 y. METHODS: The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a 2 × 2 factorial RCT of CE [500 mg flavanols/d, including 80 mg (-)-epicatechin] and/or a daily multivitamin-mineral supplement for cardiovascular disease and cancer prevention among 21,442 United States adults aged ≥60 y. There were 573 participants in the clinic subcohort of COSMOS (that is, COSMOS-Clinic) who completed all cognitive tests at baseline; of these, 492 completed 2-y follow-up assessments. The primary outcome was global cognition (averaging z-scores across 11 tests). Secondary outcomes were episodic memory and executive function/attention. Repeated measures models were used to compare randomized groups. RESULTS: Participants' mean age (standard deviation) was 69.6 (5.3); 49.2% were females. Daily supplementation with CE, compared with placebo, had no significant effect on 2-y change in global cognition {mean difference [95% confidence interval (CI)]: -0.01 (-0.08, 0.05) standard deviation units (SU)}. CE, compared with placebo, had no significant effects on 2-y change in episodic memory [mean difference (95% CI): -0.01 (-0.13, 0.10) SU] or executive function/attention [mean difference (95% CI): 0.003 (-0.07, 0.08) SU]. Subgroup analyses uncorrected for multiple-testing suggested cognitive benefits of CE supplementation, compared with placebo among those with poorer baseline diet quality. CONCLUSIONS: Among 573 older adults who underwent repeat in-person, detailed neuropsychological assessments over 2 y, daily CE supplementation, compared with placebo, showed no overall benefits for global or domain-specific cognitive function. Possible cognitive benefits of CE among those with poorer diet quality warrant further study. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov with identifier - NCT02422745.

The Mediterranean Diet, Cardiometabolic Biomarkers, and Risk of All-Cause Mortality: A 25-Year Follow-Up Study of the Women's Health Study.

Background: Higher consumption of Mediterranean diet (MED) intake has been associated with reduced risk of all-cause mortality but limited data are available examining long-term outcomes in women or the underlying molecular mechanisms of this inverse association in human populations. We aimed to investigate the association of MED intake with long-term risk of all-cause mortality in women and to better characterize the relative contribution of traditional and novel cardiometabolic factors to the MED-related risk reduction in morality. Methods: In a prospective cohort study of 25,315 initially healthy women from the Women's Health Study, we assessed dietary MED intake using a validated semiquantitative food frequency questionnaire according to the usual 9-category measure of MED adherence. Baseline levels of more than thirty cardiometabolic biomarkers were measured using standard assays and targeted nuclear magnetic resonance spectroscopy, including lipids, lipoproteins, apolipoproteins, inflammation, glucose metabolism and insulin resistance, branched-chain amino acids, small metabolites, and clinical factors. Mortality and cause of death was ascertained prospectively through medical and death records. Results: During a mean follow-up of 25 years, 3,879 deaths were ascertained. Compared to the reference group of low MED intake (0-3, approximately the bottom tertile), and adjusting for age, treatment, and energy intake, risk reductions were observed for the middle and upper MED groups with respective HRs of 0.84 (95% CI 0.78-0.90) and 0.77 (95% CI 0.70-0.84), p for trend <0.0001. Further adjusting for smoking, physical activity, alcohol intake and menopausal factors attenuated the risk reductions which remained significant with respective HRs of 0.92 (95% CI 0.85-0.99) and 0.89 (95% CI 0.82-0.98), p for trend 0.0011. Risk reductions were generally similar for CVD and non-CVD mortality. Small molecule metabolites (e.g., alanine and homocysteine) and inflammation made the largest contributions to lower mortality risk (accounting for 14.8% and 13.0% of the benefit of the MED-mortality association, respectively), followed by triglyceride-rich lipoproteins (10.2%), adiposity (10.2%) and insulin resistance (7.4%), with lesser contributions (<3%) from other pathways including branched-chain amino acids, high-density lipoproteins, low-density lipoproteins, glycemic measures, and hypertension. Conclusions: In the large-scale prospective Women's Health Study of 25,315 initially healthy US women followed for 25 years, higher MED intake was associated with approximately one fifth relative risk reduction in mortality. The inverse association was only partially explained by known novel and traditional cardiometabolic factors.

Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial.

BACKGROUND: Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested. OBJECTIVES: We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults. METHODS: We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina. RESULTS: During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns. CONCLUSIONS: Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.

Multivitamins in the prevention of cancer and cardiovascular disease: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial.

BACKGROUND: Although older adults commonly take multivitamin-multimineral (MVM) supplements to promote health, evidence on the use of daily MVMs on invasive cancer is limited. OBJECTIVES: The study objective was to determine if a daily MVM decreases total invasive cancer among older adults. METHODS: We performed a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of a daily MVM and cocoa extract for prevention of cancer and cardiovascular disease (CVD) among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y) free of major CVD and recently diagnosed cancer. The intervention phase was from June 2015 through December 2020. This article reports on the MVM intervention. Participants were randomly assigned to daily MVM or placebo. The primary outcome was total invasive cancer, excluding nonmelanoma skin cancer. Secondary outcomes included major site-specific cancers, total CVD, all-cause mortality, and total cancer risk among those with a baseline history of cancer. RESULTS: During a median follow-up of 3.6 y, invasive cancer occurred in 518 participants in the MVM group and 535 participants in the placebo group (HR: 0.97; 95% CI: 0.86, 1.09; P = 0.57). We observed no significant effect of a daily MVM on breast cancer (HR: 1.06; 95% CI: 0.79, 1.42) or colorectal cancer (HR: 1.30; 95% CI: 0.80, 2.12). We observed a protective effect of a daily MVM on lung cancer (HR: 0.62; 95% CI: 0.42, 0.92). The composite CVD outcome occurred in 429 participants in the MVM group and 437 participants in the placebo group (HR: 0.98; 95% CI: 0.86, 1.12). MVM use did not significantly affect all-cause mortality (HR: 0.93; 95% CI: 0.81, 1.08). There were no safety concerns. CONCLUSIONS: A daily MVM supplement, compared with placebo, did not significantly reduce the incidence of total cancer among older men and women. Future studies are needed to determine the effects of MVMs on other aging-related outcomes among older adults. This trial is registered at www.clinicaltrials.gov as NCT02422745.

Exercise-Induced Ventricular Ectopy and Cardiovascular Mortality in Asymptomatic Individuals.

BACKGROUND: The prognosis of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals is unclear. OBJECTIVES: This study sought to investigate whether high-grade PVCs during stress testing predict mortality in asymptomatic individuals. METHODS: A cohort of 5,486 asymptomatic individuals who took part in the Lipid Research Clinics prospective cohort had baseline interview, physical examination, blood tests, and underwent Bruce protocol treadmill testing. Adjusted Cox survival models evaluated the association of exercise-induced high-grade PVCs (defined as either frequent (>10 per minute), multifocal, R-on-T type, or ≥2 PVCs in a row) with all-cause and cardiovascular mortality. RESULTS: Mean baseline age was 45.4 ± 10.8 years; 42% were women. During a mean follow-up of 20.2 ± 3.9 years, 840 deaths occurred, including 311 cardiovascular deaths. High-grade PVCs occurred during exercise in 1.8% of individuals, during recovery in 2.4%, and during both in 0.8%. After adjusting for age, sex, diabetes, hypertension, lipids, smoking, body mass index, and family history of premature coronary disease, high-grade PVCs during recovery were associated with cardiovascular mortality (hazard ratio [HR]: 1.82; 95% CI: 1.19-2.79; P = 0.006), which remained significant after further adjusting for exercise duration, heart rate recovery, achieving target heart rate, and ST-segment depression (HR: 1.68; 95% CI: 1.09-2.60; P = 0.020). Results were similar by clinical subgroups. High-grade PVCs occurring during the exercise phase were not associated with increased risk. Recovery PVCs did not improve 20-year cardiovascular mortality risk discrimination beyond clinical variables. CONCLUSIONS: High-grade PVCs occurring during recovery were associated with long-term risk of cardiovascular mortality in asymptomatic individuals, whereas PVCs occurring only during exercise were not associated with increased risk.

Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial.

Importance: Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking. Objective: To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF. Design, Setting, and Participants: An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017. Interventions: Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed). Main Outcomes and Measures: The primary outcome was incident AF confirmed by medical record review. Results: Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39). Conclusions and Relevance: Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF. Trial Registration: ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259.

Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women.

Importance: Risk profiles for premature coronary heart disease (CHD) are unclear. Objective: To examine baseline risk profiles for incident CHD in women by age at onset. Design, Setting, and Participants: A prospective cohort of US female health professionals participating in the Women's Health Study was conducted; median follow-up was 21.4 years. Participants included 28 024 women aged 45 years or older without known cardiovascular disease. Baseline profiles were obtained from April 30, 1993, to January 24, 1996, and analyses were conducted from October 1, 2017, to October 1, 2020. Exposures: More than 50 clinical, lipid, inflammatory, and metabolic risk factors and biomarkers. Main Outcomes and Measures: Four age groups were examined (<55, 55 to <65, 65 to <75, and ≥75 years) for CHD onset, and adjusted hazard ratios (aHRs) were calculated using stratified Cox proportional hazard regression models with age as the time scale and adjusting for clinical factors. Women contributed to different age groups over time. Results: Of the clinical factors in the women, diabetes had the highest aHR for CHD onset at any age, ranging from 10.71 (95% CI, 5.57-20.60) at CHD onset in those younger than 55 years to 3.47 (95% CI, 2.47-4.87) at CHD onset in those 75 years or older. Risks that were also noted for CHD onset in participants younger than 55 years included metabolic syndrome (aHR, 6.09; 95% CI, 3.60-10.29), hypertension (aHR, 4.58; 95% CI, 2.76-7.60), obesity (aHR, 4.33; 95% CI, 2.31-8.11), and smoking (aHR, 3.92; 95% CI, 2.32-6.63). Myocardial infarction in a parent before age 60 years was associated with 1.5- to 2-fold risk of CHD in participants up to age 75 years. From approximately 50 biomarkers, lipoprotein insulin resistance had the highest standardized aHR: 6.40 (95% CI, 3.14-13.06) for CHD onset in women younger than 55 years, attenuating with age. In comparison, weaker but significant associations with CHD in women younger than 55 years were noted (per SD increment) for low-density lipoprotein cholesterol (aHR, 1.38; 95% CI, 1.10-1.74), non-high-density lipoprotein cholesterol (aHR, 1.67; 95% CI, 1.36-2.04), apolipoprotein B (aHR, 1.89; 95% CI, 1.52-2.35), triglycerides (aHR, 2.14; 95% CI, 1.72-2.67), and inflammatory biomarkers (1.2- to 1.8-fold)-all attenuating with age. Some biomarkers had similar CHD age associations (eg, physical inactivity, lipoprotein[a], total high-density lipoprotein particles), while a few had no association with CHD onset at any age. Most risk factors and biomarkers had associations that attenuated with increasing age at onset. Conclusions and Relevance: In this cohort study, diabetes and insulin resistance, in addition to hypertension, obesity, and smoking, appeared to be the strongest risk factors for premature onset of CHD. Most risk factors had attenuated relative rates at older ages.

Premature Myocardial Infarction in the Middle East and North Africa: Rationale for the Gulf PREVENT Study.

The Middle East and North Africa (MENA) region has a high burden of morbidity and mortality due to premature (≤55 years in men; ≤65 years in women) myocardial infarction (MI) and acute coronary syndrome (ACS). Despite this, the prevalence of risk factors in patients presenting with premature MI or ACS is incompletely described. We compared lifestyle, clinical risk factors, and biomarkers associated with premature MI/ACS in the MENA region with selected non-MENA high-income countries. We identified English-language, peer-reviewed publications through PubMed (up to March 2018). We used the World Bank classification system to categorize countries. Patients with premature MI/ACS in the MENA region had a higher prevalence of smoking than older patients with MI/ACS but a lower prevalence of diabetes, hypertension, and dyslipidemia. Men with premature MI/ACS had a higher prevalence of smoking than women but a lower prevalence of diabetes and hypertension. The MENA region had sparse data on lifestyle, diet, psychological stress, and physical activity. To address these knowledge gaps, we initiated the ongoing Gulf Population Risks and Epidemiology of Vascular Events and Treatment (Gulf PREVENT) case-control study to improve primary and secondary prevention of premature MI in the United Arab Emirates, a high-income country in the MENA region.

Menopausal age, postmenopausal hormone therapy and incident atrial fibrillation.

OBJECTIVE: Limited data exist on the association between menopause and atrial fibrillation (AF). We sought to examine the relationship between menopausal age, postmenopausal hormone therapy (PHT) use and incident AF. METHODS: The Women's Health Study (WHS) enrolled 39 876 female health professionals between 1992 and 1995. We prospectively examined 30 034 women in WHS using Cox proportional-hazard models. Participants were free of cardiovascular disease and AF at baseline and had not undergone hysterectomy without bilateral oophorectomy prior to menopause. Incident AF was confirmed by medical record review. RESULTS: At baseline, median age was 53 years (IQR 49-60), median menopausal age was 50 years (IQR 46-52) and 14 415 (48.0%) had prior PHT use. Over a median follow-up of 20.5 years, 1350 AF events occurred. In multivariable analysis, relative hazards for AF were lower among women with younger age at menopause but did not differ significantly from women with the oldest menopausal age (<45: HR 0.82, 95% CI 0.67 to 1.02; 45-49: HR 0.90, 95% CI 0.74 to 1.08; 50-54: HR 0.89, 95% CI 0.75 to 1.06; >54 years: referent). Use of oestrogen-alone PHT, but not oestrogen and progesterone, was independently associated with AF risk (HR 1.22; 95% CI 1.02 to 1.45 vs HR 1.04; 95% CI 0.86 to 1.26). This relationship was not attenuated by intermediary cardiovascular events. CONCLUSIONS: In this large prospective study, menopausal age was not significantly related to incident AF, while use of oestrogen monotherapy was associated with increased AF risk. Our findings suggest a pathophysiological link between unopposed oestrogen exposure and AF in women. CLINICAL TRIAL REGISTRATION: NCT000000479; Post-results.

Modifiable Risk Factors for Incident Heart Failure in Atrial Fibrillation.

OBJECTIVES: This study sought to identify modifiable risk factors and estimate the impact of risk factor modification on heart failure (HF) risk in women with new-onset atrial fibrillation (AF). BACKGROUND: Incident HF is the most common nonfatal event in patients with AF, although strategies for HF prevention are lacking. METHODS: We assessed 34,736 participants in the Women's Health Study who were free of prevalent cardiovascular disease at baseline. Cox models with time-varying assessment of risk factors after AF diagnosis were used to identify significant modifiable risk factors for incident HF. RESULTS: Over a median follow-up of 20.6 years, 1,495 women developed AF without prevalent HF. In multivariable models, new-onset AF was associated with an increased risk of HF (hazard ratio [HR]: 9.03; 95% confidence interval [CI]: 7.52 to 10.85). Once women with AF developed HF, all-cause (HR: 1.83; 95% CI: 1.37 to 2.45) and cardiovascular mortality (HR: 2.87; 95% CI: 1.70 to 4.85) increased. In time-updated, multivariable models accounting for changes in risk factors after AF diagnosis, systolic blood pressure >120 mm Hg, body mass index ≥30 kg/m2, current tobacco use, and diabetes mellitus were each associated with incident HF. The combination of these 4 modifiable risk factors accounted for an estimated 62% (95% CI: 23% to 83%) of the population-attributable risk of HF. Compared with women with 3 or 4 risk factors, those who maintained or achieved optimal risk factor control had a progressive decreased risk of HF (HR for 2 risk factors: 0.60; 95% CI: 0.37 to 0.95; 1 risk factor: 0.40; 95% CI: 0.25 to 0.63; and 0 risk factors: 0.14; 95% CI: 0.07 to 0.29). CONCLUSIONS: In women with new-onset AF, modifiable risk factors including obesity, hypertension, smoking, and diabetes accounted for the majority of the population risk of HF. Optimal levels of modifiable risk factors were associated with decreased HF risk. Prospective assessment of risk factor modification at the time of AF diagnosis may warrant future investigation.

Association of N-Linked Glycoprotein Acetyls and Colorectal Cancer Incidence and Mortality.

BACKGROUND: Acute phase proteins highlight the dynamic interaction between inflammation and oncogenesis. GlycA, a novel nuclear magnetic resonance (NMR) inflammatory marker that identifies primarily circulating N-acetyl glycan groups attached to acute phase proteins, may be a future CRC risk biomarker. METHODS: We examined the association between GlycA and incident CRC and mortality in two prospective cohorts (N = 34,320); Discovery cohort: 27,495 participants from Women's Health Study (WHS); Replication cohort: 6,784 participants from Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable Cox models were adjusted for clinical risk factors and compared GlycA to acute phase proteins (high-sensitivity C-reactive protein [hsCRP], fibrinogen, and soluble intercellular adhesion molecule-1 [sICAM-1]). RESULTS: In WHS (median follow-up 19 years, 337 cases, 103 deaths), adjusted HRs (95% CIs) per SD increment of GlycA for CRC incidence and mortality were 1.19 (1.06-1.35; p = 0.004) and 1.24 (1.00-1.55; p = 0.05), respectively. We replicated findings in MESA (median follow-up 11 years, 70 cases, 23 deaths); HRs (95% CIs) per SD of GlycA for CRC incidence and mortality were 1.32 (1.06-1.65; p = 0.01) and 1.54 (1.06-2.23; p = 0.02), respectively, adjusting for age, sex, and race. Pooled analysis, adjusted HR (95% CI) per SD of GlycA for CRC incidence and mortality was 1.26 (1.15-1.39; p = 1 x 10-6). Other acute phase proteins (hsCRP, fibrinogen, and sICAM-1) had weaker or no association with CRC incidence, while only fibrinogen and GlycA were associated with CRC mortality. CONCLUSIONS: The clinical utility of GlycA to personalize CRC therapies or prevention warrants further study. TRIAL REGISTRATION: ClinicalTrials.gov: WHS NCT00000479, MESA NCT00005487.

Lipid biomarkers and long-term risk of cancer in the Women's Health Study.

BACKGROUND: Lipid biomarkers, such as HDL-cholesterol concentrations, have been shown to have positive, inverse, and null associations with total, breast, and colorectal cancer risks. Studies of novel lipid biomarkers, such as apolipoprotein A-I (apo A-I) and apolipoprotein B-100 (apo B-100), and cancer risk have been sparse, to our knowledge. OBJECTIVES: We evaluated the prospective association of total, breast, colorectal, and lung cancers and cancer mortality with circulating lipid biomarkers in 15,602 female health professionals in the Women's Health Study (aged ≥45 y, free of cardiovascular disease and cancer, and without hormone replacement therapy or lipid-lowering medications at baseline). DESIGN: Cox regression models estimated HRs of cancer endpoints (19 y median follow-up) across quartiles 1 (reference) to 4 of each lipid biomarker after adjustment for cancer risk factors. RESULTS: Confirmed cases included 2163 incident cancer cases (864 breast, 198 colorectal, and 190 lung cancers) and 647 cancer deaths. Total cancer risk was significantly lower in the highest quartile of apo A-I (adjusted HR: 0.79; 95% CI: 0.70, 0.90; P-trend = 0.0008) and HDL cholesterol (HR: 0.85; 95% CI: 0.75, 0.97; P-trend = 0.01). For site-specific cancers, significant associations included colorectal cancer risk with HDL cholesterol (HR: 0.63; 95% CI; 0.41, 0.98; P-trend = 0.03), triglycerides (HR: 1.86; 95% CI: 1.17, 2.97; P-trend = 0.02), and apo B-100 (HR: 1.60; 95% CI: 1.03, 2.49; P-trend = 0.006) and lung cancer risk with HDL cholesterol (HR: 0.59; 95% CI: 0.38, 0.93; P-trend = 0.01). LDL cholesterol was not significantly associated with risk of total cancer or any site-specific cancers. In time-dependent models that were adjusted for the use of a lipid-lowering medication after baseline, these associations remained. CONCLUSIONS: Lipids were associated with total, lung, and colorectal cancer risks in women. Lifestyle interventions for heart-disease prevention, which reduce apo B-100 or raise HDL cholesterol, may be associated with reduced cancer risk. The Women's Health Study was registered at clinicaltrials.gov as NCT00000479.

Circulating N-Linked Glycoprotein Acetyls and Longitudinal Mortality Risk.

RATIONALE: Circulating glycoprotein N-acetyl glucosamine residues have recently been associated with incident cardiovascular disease and diabetes mellitus. OBJECTIVE: Using a plasma glycan biosignature (GlycA) to identify circulating N-acetyl glycan groups, we examined the longitudinal association between GlycA and mortality among initially healthy individuals. METHODS AND RESULTS: We quantified GlycA by 400 MHz (1)H nuclear magnetic resonance spectroscopy in 27,524 participants in the Women's Health Study (NCT00000479). The primary outcome was all-cause mortality. We replicated the findings in an independent cohort of 12,527 individuals in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681). We also undertook secondary examination of cardiovascular disease and cancer mortality in the Women's Health Study. In the Women's Health Study, during 524,515 person-years of follow-up (median, 20.5 years), there were 3523 deaths. Risk factor-adjusted multivariable Cox proportional hazard ratio (95% confidence interval) per SD increment in GlycA for all-cause mortality was significantly increased at 5 years (1.21 [1.06-1.40]) and during maximal follow-up (1.14 [1.09-1.16]). Similar risk for all-cause mortality was observed in the replication cohort (1.33 [1.21-1.45]). In the Women's Health Study, risk of cardiovascular disease mortality was increased at 5 years (1.43 [1.05-1.95]) and during maximal follow-up (1.15 [1.04-1.26]) and of cancer mortality at 5 years (1.23 [1.02-1.47]) and during maximal follow-up (1.08 [1.01-1.16]). Examination of correlations and mortality associations adjusted for high-sensitivity C-reactive protein, fibrinogen, and intercellular adhesion molecule-1, suggested that GlycA reflects summative risk related to multiple pathways of systemic inflammation. CONCLUSIONS: Among initially healthy individuals, elevated baseline circulating glycoprotein N-acetyl methyl groups were associated with longitudinal risk of all-cause, cardiovascular, and cancer mortality.

Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial.

BACKGROUND: Recent evidence suggests that daily aspirin use decreases cancer risk, particularly for colorectal cancer, but evidence for alternate-day use is scant. OBJECTIVE: To examine the association between long-term, alternate-day, low-dose aspirin and cancer in healthy women. DESIGN: Observational follow-up of a randomized trial. SETTING: Female health professionals. PARTICIPANTS: 39,876 women aged 45 years or older in the Women's Health Study (ClinicalTrials.gov: NCT00000479), 33 682 of whom continued observational follow-up. INTERVENTION: 100 mg of alternate-day aspirin or placebo through March 2004, with a median 10-year follow-up. Posttrial follow-up continued through March 2012. MEASUREMENTS: Cancer incidence. RESULTS: A total of 5071 cancer cases (including 2070 breast, 451 colorectal, and 431 lung cancer cases) and 1391 cancer deaths were confirmed. Over the entire follow-up, aspirin had no association with total (hazard ratio [HR], 0.97 [95% CI, 0.92 to 1.03]; P = 0.31), breast (HR, 0.98 [CI, 0.90 to 1.07]; P = 0.65), or lung (HR, 1.04 [CI, 0.86 to 1.26]; P = 0.67) cancer. Colorectal cancer was reduced in the aspirin group (HR, 0.80 [CI, 0.67 to 0.97]; P = 0.021), primarily for proximal colon cancer (HR, 0.73 [CI, 0.55 to 0.95]; P = 0.022). The difference emerged after 10 years, with a posttrial reduction of 42% (HR, 0.58 [CI, 0.42 to 0.80]; P < 0.001). There was no extended effect on cancer deaths or colorectal polyps. More gastrointestinal bleeding (HR, 1.14 [CI, 1.06 to 1.22]; P < 0.001) and peptic ulcers (HR, 1.17 [CI, 1.09 to 1.27]; P < 0.001) occurred in the aspirin group. LIMITATIONS: Not all women received extended follow-up, and posttrial ascertainment bias cannot be ruled out. Gastrointestinal bleeding, peptic ulcers, and polyps were self-reported during extended follow-up. CONCLUSION: Long-term use of alternate-day, low-dose aspirin may reduce risk for colorectal cancer in healthy women.