Systolic Blood Pressure and Survival to Very Old Age: Results From the Women's Health Initiative.

BACKGROUND: The relationship between systolic blood pressure (SBP) and longevity is not fully understood. We aimed to determine which SBP levels in women ≥65 years of age with or without blood pressure medication were associated with the highest probability of surviving to 90 years of age. METHODS: The study population consisted of 16 570 participants enrolled in the Women's Health Initiative who were eligible to survive to 90 years of age by February 28, 2020, without a history of cardiovascular disease, diabetes, or cancer. Blood pressure was measured at baseline (1993 through 1998) and then annually through 2005. The outcome was defined as survival to 90 years of age with follow-up. Absolute probabilities of surviving to 90 years of age were estimated for all combinations of SBP and age using generalized additive logistic regression modeling. The SBP that maximized survival was estimated for each age, and a 95% CI was generated. RESULTS: During a median follow-up of 19.8 years, 9723 of 16 570 women (59%) survived to 90 years of age. Women with an SBP between 110 and 130 mm Hg at attained ages of 65, 70, 75, and 80 years had a 38% (95% CI, 34%-48%), 54% (52%-56%), 66% (64%-67%), or 75% (73%-78%) absolute probability to survive to 90 years of age, respectively. The probability of surviving to 90 years of age was lower for greater SBP levels. Women at the attained age of 80 years with 0%, 20%, 40%, 60%, 80%, or 100% time in therapeutic range (defined as an SBP between 110 and 130 mm Hg) had a 66% (64%-69%), 68% (67%-70%), 71% (69%-72%), 73% (71%-74%), 75% (72%-77%), or 77% (74%-79%) absolute survival probability to 90 years of age. CONCLUSIONS: For women >65 years of age with low cardiovascular disease and other chronic disease risk, an SBP level <130 mm Hg was found to be associated with longevity. These findings reinforce current guidelines targeting an SBP target <130 mm Hg in older women.

Subjective cognitive decline and total energy intake: Talk too much?

The increasing longevity of the population has resulted in dementia becoming a leading cause of both death and disability. Dementia is not a single disease. Studies of rare Mendelian disorders have documented that Alzheimer's disease, the most common cause of dementia, is associated with a long incubation period from amyloid deposition to neurodegeneration to mild cognitive impairment and dementia. There are three broad hypotheses related to the causes of Alzheimer's dementia: (1) an aging process; (2) brain vascular disease; and (3) metabolic abnormalities associated with either increased production of amyloid-ß or decreased clearance from the brain. Therefore, research on the early stages of the dementia process are of high priority. This paper reports that higher energy intake in both the Nurses' Health Study and Health Professionals Follow-up Study is associated with very early symptoms that lead to mild cognitive impairment and dementia. The results are very interesting but hard to interpret because they also show that higher energy intake is not related to body mass index, a very unusual observation. A likely hypothesis is that there is an association between reporting of dietary intake and subjective symptoms, i.e. reporting bias, accounting for their results.

Low untreated systolic blood pressure over 18 years is associated with survival free of dementia age 90.

INTRODUCTION: We hypothesized that lower untreated systolic blood pressure (SBP) would be associated with a lower risk of dementia and death up to age 95. METHODS: SBP measured between 2000 and 2006 was evaluated in relationship to dementia risk and brain biomarkers from 2009-2020 (n = 177) in the Gingko Evaluation of Memory Study (GEMS), mean age 95 in 2020. Participants had measurements of brain amyloid beta (Aß) and repeat clinical-cognitive evaluations every 6 months. RESULTS: By 2020, only 9 of 177 patients (5%) were alive and cognitively unimpaired (CU). Mean SBP from 2000 to 2006 was 120 mm Hg for nine alive/CU, 125 mm Hg for alive/mild cognitive impairment (MCI), and 130 mm Hg for alive/dementia (P = .03). The amount of Aß was directly related to SBP levels. In multivariate analysis, Aß+ in 2009 and thinner cortex were significant predictors of dementia. Excluding Aß, SBP became a significant predictor of dementia. DISCUSSION: Low SBP untreated by antihypertensive medications was associated with significant decreased risk of dementia and less Aß.

Randomized Trial Evaluation of the Benefits and Risks of Menopausal Hormone Therapy Among Women 50-59 Years of Age.

The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women's Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy postmenopausal women aged 50-79 years at 40 US clinical centers during 1993-1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens and 16,608 participants with a uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over a (median) 18-year follow-up period (1993-2016), risk for a global index (defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality) was reduced with conjugated equine estrogens with a hazard ratio of 0.82 (95% confidence interval: 0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture, and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (95% confidence interval: 0.95, 1.19) were nonsignificant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50-59 years of age, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.

Estrogen, brain structure, and cognition in postmenopausal women.

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.

Peripheral inflammatory biomarkers predict the deposition and progression of amyloid-ß in cognitively unimpaired older adults.

INTRODUCTION: Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer's disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aß deposition in oldest-old cognitively unimpaired (CU) adults. METHODS: A large sample of 139 CU older adults (mean age (range) = 85.4 (82-95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aß deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aß status and hippocampal volume, were incorporated to assess conditional associations. RESULTS: At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aß burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aß deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions. DISCUSSION: In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aß deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aß pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment.

ENGAGE and EMERGE: Truth and consequences?

The potential benefit of the anti-amyloid drug aducanumab based on results of recent EMERGE and ENGAGE clinical trials has generated great controversy and has very important implications for the future of anti-amyloid drug therapies. The two trials of 18-month duration were done in patients with mild cognitive impairment (MCI) and early dementia. The ENGAGE trial showed no benefit while the high-dose EMERGE trial initially also showed no benefit but with longer follow-up there was a significant positive benefit. A recent review form the U.S. Food and Drug Administration (FDA) Advisory Committee was negative while the FDA Office of Neurological Drugs was positive and the statisticians negative. This has generated debate about whether the drug should be approved, disapproved, require a new clinical trial, or approved for a subsample only. The implications for treating both MCI and Alzheimer's disease (AD) patients with anti-amyloid drugs is very substantial as well as the brain amyloid-AD-dementia hypothesis.

Ophthalmic conditions associated with dementia risk: The Cardiovascular Health Study.

INTRODUCTION: Ophthalmic conditions and dementia appear to overlap and may share common pathways, but research has not differentiated dementia subtypes. METHODS: Diagnoses of cataracts, age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma were based on medical histories and International Classification of Diseases, Ninth Revision (ICD-9) codes for 3375 participants from the Cardiovascular Health Study. Dementia, including Alzheimer's disease (AD) and vascular dementia (VaD), was classified using standardized research criteria. RESULTS: Cataracts were associated with AD (hazard ratio [HR] = 1.34; 95% confidence interval [CI] = 1.01-1.80) and VaD/mixed dementia (HR = 1.41; 95% CI = 1.02-1.95). AMD was associated with AD only (HR = 1.87; 95% CI = 1.13-3.09), whereas DR was associated with VaD/mixed dementia only (HR = 2.63; 95% CI = 1.10-6.27). DISCUSSION: Differential associations between specific ophthalmic conditions and dementia subtypes may elucidate pathophysiologic pathways. Lack of association between glaucoma and dementia was most surprising from these analyses.

High density lipoprotein and its apolipoprotein-defined subspecies and risk of dementia.

Whether HDL is associated with dementia risk is unclear. In addition to apoA1, other apolipoproteins are found in HDL, creating subspecies of HDL that may have distinct metabolic properties. We measured apoA1, apoC3, and apoJ levels in plasma and apoA1 levels in HDL that contains or lacks apoE, apoJ, or apoC3 using a modified sandwich ELISA in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 995 randomly selected participants and 521 participants who developed dementia during a mean of 5.1 years of follow-up. The level of total apoA1 was not significantly related to dementia risk, regardless of the coexistence of apoC3, apoJ, or apoE. Higher levels of total plasma apoC3 were associated with better cognitive function at baseline (difference in Modified Mini-Mental State Examination scores tertile 3 vs. tertile 1: 0.60; 95% CI: 0.23, 0.98) and a lower dementia risk (adjusted hazard ratio tertile 3 vs. tertile 1: 0.73; 95% CI: 0.55, 0.96). Plasma concentrations of apoA1 in HDL and its apolipoprotein-defined subspecies were not associated with cognitive function at baseline or with the risk of dementia during follow-up. Similar studies in other populations are required to better understand the association between apoC3 and Alzheimer's disease pathology.

Invited Commentary: Can You Do Trials of Behavioral Modification, Such as Diet or Exercise Intervention, With Hard Endpoints?

Blackburn (Am J Epidemiol. 2020;189(6):491-498) describes the evolution from the Makarska Conference in 1968 to the planning of the JUMBO trial and the decision by the National Institutes of Health (NIH) to do the Multiple Risk Factor Intervention Trial. He attributes the failure of the Multiple Risk Factor Intervention Trial to show a significant reduction in coronary heart disease or total mortality to the design of the trial, the multiple centers involved, and continued bureaucracy. The paper is important in raising 3 issues of continued relevance: 1) What is the relationship of the NIH staff in both development and monitoring of large cooperative studies, especially clinical trials, outside of the walls of the NIH? 2) Can clinical trials that utilize individual randomization to intervention and comparison be successful in evaluating a common-source epidemic, such as diet and coronary heart disease, especially in populations with readily available foods and competing advertising, etc.? 3) How much information obtained from, e.g., observational studies, animal models, and genetic studies, is necessary given limits of human population clinical trials of behavioral intervention to develop recommendations for strong public health programs to reduce morbidity and mortality, and what is the measure of successful intervention?

APOL1 Kidney Risk Variants and Cardiovascular Disease: An Individual Participant Data Meta-Analysis.

BACKGROUND: Two coding variants in the apo L1 gene (APOL1) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results. METHODS: We conducted a two-stage individual participant data meta-analysis to assess the association of APOL1 kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts. RESULTS: Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two APOL1 kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by APOL1 genotype. APOL1 genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index. CONCLUSIONS: In this large, two-stage individual participant data meta-analysis, APOL1 kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.

Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.

AIMS: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. METHODS AND RESULTS: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. CONCLUSION: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials.

Importance: The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. Objective: To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials. Design, Setting, and Participants: Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017. Interventions: In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration. Main Outcomes and Measures: The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer. Results: Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11). Conclusions and Relevance: In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

Association Between Depressive Symptoms and Incident Cardiovascular Diseases.

Importance: It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVDs). Objective: To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood. Design, Setting, and Participants: A pooled analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 162 036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and the UK Biobank (401 219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline. Exposures: Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Center for Epidemiological Studies Depression (CES-D) scale (range, 0-60; ≥16 indicates possible depressive disorder). The UK Biobank recorded the 2-item Patient Health Questionnaire 2 (PHQ-2; range, 0-6; ≥3 indicates possible depressive disorder). Main Outcomes and Measures: Primary outcomes were incident fatal or nonfatal coronary heart disease (CHD), stroke, and CVD (composite of the 2). Hazard ratios (HRs) per 1-SD higher log CES-D or PHQ-2 adjusted for age, sex, smoking, and diabetes were reported. Results: Among 162 036 participants from the ERFC (73%, women; mean age at baseline, 63 years [SD, 9 years]), 5078 CHD and 3932 stroke events were recorded (median follow-up, 9.5 years). Associations with CHD, stroke, and CVD were log linear. The HR per 1-SD higher depression score for CHD was 1.07 (95% CI, 1.03-1.11); stroke, 1.05 (95% CI, 1.01-1.10); and CVD, 1.06 (95% CI, 1.04-1.08). The corresponding incidence rates per 10 000 person-years of follow-up in the highest vs the lowest quintile of CES-D score (geometric mean CES-D score, 19 vs 1) were 36.3 vs 29.0 for CHD events, 28.0 vs 24.7 for stroke events, and 62.8 vs 53.5 for CVD events. Among 401 219 participants from the UK Biobank (55% were women, mean age at baseline, 56 years [SD, 8 years]), 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1 years). The HR per 1-SD higher depression score for CHD was 1.11 (95% CI, 1.08-1.14); stroke, 1.10 (95% CI, 1.06-1.14); and CVD, 1.10 (95% CI, 1.08-1.13). The corresponding incidence rates per 10 000 person-years of follow-up among individuals with PHQ-2 scores of 4 or higher vs 0 were 20.9 vs 14.2 for CHD events, 15.3 vs 10.2 for stroke events, and 36.2 vs 24.5 for CVD events. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors. Conclusions and Relevance: In a pooled analysis of 563 255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels lower than the threshold indicative of a depressive disorder. However, the magnitude of associations was modest.

Associations of body composition with incident dementia in older adults: Cardiovascular Health Study-Cognition Study.

INTRODUCTION: A body of literature reported associations between late-life general adiposity measures (eg, body mass index) and dementia. Little is known about the association of late-life body composition with dementia risk. METHODS: We determined this association among cognitively normal participants from the Cardiovascular Health Study- Cognition Study. Body composition was assessed by dual-energy x-ray absorptiometry in 1994-1995. Dementia was ascertained at annual follow-up from 1998-1999 to 2013. Associations of body composition with incident dementia were assessed by the Fine-Gray model. RESULT: Among 344 participants (mean age 78, 62.2% women), body composition was significantly different between men and women, despite similar body mass indexes (BMIs). Increased dementia risk was significantly associated with lower lean mass in men and marginally with low appendicular lean mass in women. DISCUSSION: Decreased lean mass was an indicator of increased dementia risk in older adults. Studies should test whether preventing lean mass loss in older adults reduces dementia risk.

Inflammatory joint diseases and atherosclerosis: time to look beyond the 'lipid paradox'.

PURPOSE OF REVIEW: Uncertainty persists about the contribution of lipids to the increased risk of cardiovascular disease (CVD) among rheumatoid arthritis and other inflammatory joint disease (IJD) patients. In reviewing recent research, we consider potential insights gained by quantifying lipoprotein particles directly, rather than by their lipid content. RECENT FINDINGS: Although inflammation often decreases LDL cholesterol (LDL-C), and anti-inflammatory medications often increase LDL-C, both inflammation and anti-inflammatory medications can increase atherogenic Apolipoprotein B (ApoB)-containing lipoprotein particles, attenuated by statins. CVD risk factors, that is, smoking, obesity, ApoB, may increase years prior to IJD diagnosis. Increased risks of nonatherosclerotic myocardial and pulmonary disease, heart failure and mortality may be directly related to disease activity, inflammation, and possibly to HDL particles and function. SUMMARY: For IJD patients, higher cumulative lifetime exposure to CVD risk factors accelerates atherosclerosis and subsequent CVD risk that is underestimated by current risk factor levels. CVD risk reduction in IJD requires aggressive and earlier reduction in CVD risk factors (ApoB lipoproteins, smoking, hypertension, diabetes, lack of physical activity), in addition to control of disease activity and inflammation. Lipid-lowering medications can attenuate anti-inflammatory medication-induced increases in ApoB and LDL-C, but can also reduce CVD risk due to cumulative lifetime exposure.

Sex and Race Differences in Lifetime Risk of Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Lifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known. METHODS: Participant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF <45%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks. RESULTS: We included 12 417 participants >45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction. CONCLUSIONS: Lifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

Epidemiologists of the Future: Data Collectors or Scientists?

Epidemiology is the study of epidemics. It is a biological science that includes expertise in many disciplines in social and behavioral sciences. Epidemiology is also a key component of preventive medicine and public health. Unfortunately, over recent years, academic epidemiology has lost its relationship with preventive medicine, as well as much of its focus on epidemics. The new "-omics" technologies to measure risk factors and phenotypes, and advances in genomics (e.g., host susceptibility) consistent with good epidemiology methods will likely enhance epidemiology research. There is a need based on these new technologies to modify training, especially for the first-level doctorate epidemiologist.

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Circulating estrogens and postmenopausal ovarian and endometrial cancer risk among current hormone users in the Women's Health Initiative Observational Study.

PURPOSE: Menopausal hormone therapy (MHT) use induces alterations in circulating estrogens/estrogen metabolites, which may contribute to the altered risk of reproductive tract cancers among current users. Thus, the current study assessed associations between circulating estrogens/estrogen metabolites and ovarian and endometrial cancer risk among MHT users. METHODS: We conducted a nested case-control study among postmenopausal women using MHT at baseline in the Women's Health Initiative Observational Study (179 ovarian cancers, 396 controls; 230 endometrial cancers, 253 controls). Multivariable logistic regression was utilized to estimate odds ratios and 95% confidence intervals overall and by subtype. RESULTS: Estrogen/estrogen metabolite levels were not associated with overall or serous ovarian cancer risk, examined separately. However, unconjugated estradiol was positively associated with non-serous ovarian cancer risk [quintile 5 vs. quintile 1: 3.01 (1.17-7.73); p-trend = 0.03; p-het < 0.01]. Endometrial cancer risk was unrelated to estrogen/estrogen metabolite levels among women who took combined estrogen/progestin therapy (EPT). CONCLUSIONS: These findings provide novel evidence that may support a heterogeneous hormonal etiology across ovarian cancer subtypes. Circulating estrogens did not influence endometrial cancer risk among women with EPT-induced high-estrogen levels. Larger studies are needed to delineate the relationship between ovarian/endometrial cancer subtypes and estrogen levels in the context of MHT use.