Biomarkers, menopausal hormone therapy and risk of venous thrombosis: The Women's Health Initiative.

BACKGROUND: Oral menopausal hormone therapy causes venous thrombosis but whether biomarkers of thrombosis risk can identify women at risk is unknown. METHODS: We completed a nested case control study in the two Women's Health Initiative hormone trials; 27 347 women aged 50-79 were randomized to hormone therapy (conjugated equine estrogen with or without medroxyprogesterone acetate) or placebo. With 4 years follow-up, biomarkers were measured using stored baseline samples prior to starting treatment, and one-year later, in 215 women who developed thrombosis and 867 controls. RESULTS: Overall, lower protein C and free protein S, and higher D-dimer, prothrombin fragment 1.2 and plasmin-antiplasmin complex were associated with risk of future thrombosis with odds ratios ranging from 1.9 to 3.2. Compared to women with normal biomarkers assigned to placebo, the risk of thrombosis with hormone therapy was increased among women with abnormal biomarkers, especially elevated D-dimer, elevated plasmin-antiplasmin, and low free protein S; the largest association was for D-dimer: odds ratio 6.0 (95% CI 3.6-9.8). Differences in associations by hormone use were not significant on the multiplicative scale. Considering a multi-marker score of eight biomarkers, women with three or more abnormal biomarkers had 15.5-fold increased odds of VT (95% CI 6.8-35.1). One-year changes in biomarkers were not robustly associated with subsequent thrombosis risk. CONCLUSION: Abnormal levels of biomarkers of thrombosis risk identified women at increased risk of future venous thrombosis with oral menopausal hormone therapy. Findings support the potential for clinical use of D-dimer testing in advance of hormone therapy prescription.

Effects of self-reported age at nonsurgical menopause on time to first fracture and bone mineral density in the Women's Health Initiative Observational Study.

OBJECTIVE: Menopause is a risk factor for fracture; thus, menopause age may affect bone mass and fracture rates. We compared bone mineral density (BMD) and fracture rates among healthy postmenopausal women with varying ages at self-reported nonsurgical menopause. METHODS: We compared hazard ratios for fractures and differences in BMD among 21,711 postmenopausal women from the Women's Health Initiative Observational Study cohort who had no prior hysterectomy, oophorectomy, or hormone therapy and had varying self-reported ages at menopause (<40, 40-49, or ≥50 y). RESULTS: Before multivariable adjustments, we found no differences in absolute fracture risk among menopause age groups. After multivariable adjustments for known risk factors for fracture, women who underwent menopause before age 40 years had a higher fracture risk at any site compared with women who underwent menopause at age 50 years or older (hazard ratio, 1.21; 95% CI, 1.02 to 1.44; P = 0.03). In a subset with BMD measurements (n = 1,351), whole-body BMD was lower in women who reported menopause before age 40 years than in women who reported menopause at ages 40 to 49 years (estimated difference, -0.034 g/cm; 95% CI, -0.07 to -0.004; P = 0.03) and women who reported menopause at age 50 years or older (estimated difference, -0.05 g/cm; 95% CI, -0.08 to -0.02; P < 0.01). Left hip BMD was lower in women who underwent menopause before age 40 years than in women who underwent menopause at age 50 years or older (estimated difference, -0.05 g/cm; 95% CI, -0.08 to -0.01; P = 0.01), and total spine BMD was lower in women who underwent menopause before age 40 years than in women who underwent menopause at age 50 years or older (estimated difference, -0.11 g/cm; 95% CI, -0.16 to -0.06; P < 0.01) and women who underwent menopause at ages 40 to 49 years (estimated difference, -0.09 g/cm; 95% CI, -0.15 to -0.04; P < 0.01). CONCLUSIONS: In the absence of hormone therapy, younger age at menopause may be a risk factor contributing to decreased BMD and increased fracture risk in healthy postmenopausal women. Our data suggest that menopause age should be taken into consideration, along with other osteoporotic risk factors, when estimating fracture risk in postmenopausal women.

Late-life factors associated with healthy aging in older men.

OBJECTIVES: To identify potentially modifiable late-life biological, lifestyle, and sociodemographic factors associated with overall and healthy survival to age 85. DESIGN: Prospective longitudinal cohort study with 21 years of follow-up (1991-2012). SETTING: Hawaii Lifespan Study. PARTICIPANTS: American men of Japanese ancestry (mean age 75.7, range 71-82) without baseline major clinical morbidity and functional impairments (N = 1,292). MEASUREMENTS: Overall survival and healthy survival (free from six major chronic diseases and without physical or cognitive impairment) to age 85. Factors were measured at late-life baseline examinations (1991-1993). RESULTS: Of 1,292 participants, 1,000 (77%) survived to 85 (34% healthy) and 309 (24%) to 95 (<1% healthy). Late-life factors associated with survival and healthy survival included biological (body mass index, ankle-brachial index, cognitive score, blood pressure, inflammatory markers), lifestyle (smoking, alcohol use, physical activity), and sociodemographic factors (education, marital status). Cumulative late-life baseline risk factor models demonstrated that age-standardized (at 70) probability of survival to 95 ranged from 27% (no factors) to 7% (≥ 5 factors); probability of survival to 100 ranged from 4% (no factors) to 0.1% (≥ 5 factors). Age-standardized (at 70) probability of healthy survival to 90 ranged from 4% (no factors) to 0.01% (≥ 5 factors). There were nine healthy survivors at 95 and one healthy survivor at 100. CONCLUSION: Several potentially modifiable risk factors in men in late life (mean age 75.7) were associated with markedly greater probability of subsequent healthy survival and longevity.

Correlation of a self-report and direct measure of physical activity level in the electron-beam tomography and risk assessment among Japanese and US Men in the post World War II birth cohort (ERA JUMP) study.

BACKGROUND: Physical activity (PA) is complex and a difficult behavior to assess as there is no ideal assessment tool(s) that can capture all contexts of PA. Therefore, it is important to understand how different assessment tools rank individuals. We examined the extent to which self-report and direct assessment PA tools yielded the same ranking of PA levels. METHODS: PA levels were measured by the Modifiable Activity Questionnaire (MAQ) and pedometer at baseline among 855 white (W), African-American (AA), Japanese-American (JA), and Korean (K) men (mean age 45.3 years) in 3 geographic locations in the ERA JUMP study. RESULTS: Korean men were more active than W, AA, and JA men, according to both the MAQ and pedometer (MAQ total PA [mean ± SD]: 41.6 ± 17.8, 20.9 ± 9.9, 20.0 ± 9.1, and 29.4 ± 10.3 metabolic equivalent [MET] hours/week, respectively; pedometer: 9584.4 ± 449.4, 8363.8 ± 368.6, 8930.3 ± 285.6, 8335.7 ± 368.6 steps/day, respectively). Higher levels of total PA in Korean men, as shown by MAQ, were due to higher occupational PA. Spearman correlations between PA levels reported on the MAQ and pedometer indicated positive associations ranging from rho = 0.29 to 0.42 for total activity, rho = 0.13 to 0.35 for leisure activity, and rho = 0.10 to 0.26 for occupational activity. CONCLUSIONS: The 2 assessment methods correlated and were complementary rather than interchangeable. The MAQ revealed why Korean men were more active. In some subpopulations it may be necessary to assess PA domains other than leisure and to use more than 1 assessment tool to obtain a more representative picture of PA levels.

Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

Factors relating to eating style, social desirability, body image and eating meals at home increase the precision of calibration equations correcting self-report measures of diet using recovery biomarkers: findings from the Women's Health Initiative.

BACKGROUND: The extent to which psychosocial and diet behavior factors affect dietary self-report remains unclear. We examine the contribution of these factors to measurement error of self-report. METHODS: In 450 postmenopausal women in the Women's Health Initiative Observational Study doubly labeled water and urinary nitrogen were used as biomarkers of objective measures of total energy expenditure and protein. Self-report was captured from food frequency questionnaire (FFQ), four day food record (4DFR) and 24 hr. dietary recall (24HR). Using regression calibration we estimated bias of self-reported dietary instruments including psychosocial factors from the Stunkard-Sorenson Body Silhouettes for body image perception, the Crowne-Marlowe Social Desirability Scale, and the Three Factor Eating Questionnaire (R-18) for cognitive restraint for eating, uncontrolled eating, and emotional eating. We included a diet behavior factor on number of meals eaten at home using the 4DFR. RESULTS: Three categories were defined for each of the six psychosocial and diet behavior variables (low, medium, high). Participants with high social desirability scores were more likely to under-report on the FFQ for energy (ß = -0.174, SE = 0.054, p < 0.05) and protein intake (ß = -0.142, SE = 0.062, p < 0.05) compared to participants with low social desirability scores. Participants consuming a high percentage of meals at home were less likely to under-report on the FFQ for energy (ß = 0.181, SE = 0.053, p < 0.05) and protein (ß = 0.127, SE = 0.06, p < 0.05) compared to participants consuming a low percentage of meals at home. In the calibration equations combining FFQ, 4DFR, 24HR with age, body mass index, race, and the psychosocial and diet behavior variables, the six psychosocial and diet variables explained 1.98%, 2.24%, and 2.15% of biomarker variation for energy, protein, and protein density respectively. The variations explained are significantly different between the calibration equations with or without the six psychosocial and diet variables for protein density (p = 0.02), but not for energy (p = 0.119) or protein intake (p = 0.077). CONCLUSIONS: The addition of psychosocial and diet behavior factors to calibration equations significantly increases the amount of total variance explained for protein density and their inclusion would be expected to strengthen the precision of calibration equations correcting self-report for measurement error. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00000611.

Ethnic difference in liver fat content: a cross-sectional observation among Japanese American in Hawaii, Japanese in Japan, and non-Hispanic whites in United States.

BACKGROUND: We recently reported that Japanese had higher liver fat at a lower level of BMI compared with non-Hispanic whites (NHW). OBJECTIVE: We hypothesize that ethnic difference in fat storage capacity contributes to this ethnic difference in liver fat. DESIGN: To examine this, we assessed liver fat among 244 Japanese-American aged 40-49, using regional computed-tomography images, along with metabolic variables. RESULTS: Despite the similar BMI between Japanese-Americans and NHW men, Japanese-Americans had more liver fat (liver to spleen attenuation ratio: 1.03 ± 0.22 for Japanese-Americans, and 1.07 ± 0.15 for NHW men; p < 0.05) and tended to have a greater disposition for fatty liver with an increase in BMI than NHW, indicating a clear difference between the two groups. In addition, liver fat is less in Japanese-Americans compared with Japanese men (1.03 ± 0.22 vs. 1.01 ± 0.16; p < 0.05), despite of a much higher BMI. These ethnic differences support the hypothesis that higher fat storage capacity indeed seems to be associated with less liver fat. In all the groups, liver fat content strongly correlated with triglycerides, homeostasis model assessment-insulin resistance, and C-reactive protein (CRP). Nevertheless, these metabolic variables were worse in Japanese-Americans, despite of less liver fat, compared with Japanese. Moreover, CRP levels were least among Japanese with highest liver fat, and highest among NHW men with least liver fat, despite of a strong positive association between CRP and fatty liver within each population. CONCLUSIONS: Fat content in the liver is intermediate for Japanese-Americans compared with Japanese and NHW men, which supports the hypothesis of less fat storage capacity among Japanese, closely linked to ethnic difference in predisposition to fatty liver.

Relationship of dietary monounsaturated fatty acids to blood pressure: the International Study of Macro/Micronutrients and Blood Pressure.

OBJECTIVE: In short-term feeding trials, replacement of other macronutrients with monounsaturated fatty acid reduces blood pressure. However, observational studies have not clearly demonstrated a relationship between monounsaturated fatty acid intake and blood pressure. We report associations of monounsaturated fatty acid intake of individuals with blood pressure in a cross-sectional study. METHODS: The International Study of Macro/Micronutrients and Blood Pressure is a cross-sectional epidemiologic study of 4680 men and women ages 40-59 years from 17 population samples in China, Japan, UK and USA. Nutrient intake data were based on four in-depth multipass 24-h dietary recalls/person and two-timed 24-h urine collections/person. Blood pressure was measured eight times at four visits. RESULTS: Mean monounsaturated fatty acid intake ranged from 8.1%kcal (China) to 12.2%kcal (USA). With sequential models to control for possible confounders (dietary, other), linear regression analyses showed significant inverse relationship of total monounsaturated fatty acid intake with DBP for all participants; for 2238 'nonintervened' individuals, the relationship was stronger. Estimated DBP differences with 2-SD higher monounsaturated fatty acids (5.35%kcal) were -0.82 mmHg (P < 0.05) for all participants and -1.70 mmHg (P < 0.01) for nonintervened individuals. Inverse associations of dietary total oleic acid (main monounsaturated) with blood pressure in nonintervened individuals were not significant, but those of oleic acid from vegetable sources were stronger and significant (P < 0.05). CONCLUSION: Dietary monounsaturated fatty acid intake, especially oleic acid from vegetable sources, may contribute to prevention and control of adverse blood pressure levels in general populations.

Geriatric syndromes and incident disability in older women: results from the women's health initiative observational study.

OBJECTIVES: To determine how the number of geriatric syndromes is associated with incident disability in community-based populations of older adults. DESIGN: Longitudinal analysis from the Women's Health Initiative Observational Study (WHI-OS). SETTING: Community. PARTICIPANTS: Twenty-nine thousand five hundred forty-four women aged 65 and older enrolled in the WHI-OS and free of disability in activities of daily living (ADLs) at baseline. MEASUREMENTS: Geriatric syndromes (high depressive symptoms, dizziness, falls, hearing or visual impairment, osteoporosis, polypharmacy, syncope, sleep disturbance, and urinary incontinence) were self-reported at baseline and 3-year follow-up. Disability was defined as dependence in any ADL and was assessed at baseline and follow-up. Chronic diseases were measured according to a modified Charlson Index. RESULTS: Geriatric syndromes were common in this population of women; 76.3% had at least one syndrome at baseline. Greater number of geriatric syndromes at baseline was significantly associated with greater risk of incident ADL disability at follow-up (P ≤ .001). Adjusted risk ratios were 1.21 (95% confidence interval (CI) = 0.78-1.87) for a single syndrome and 6.64 (95% CI = 4.15-10.62) for five or more syndromes compared with no syndromes. These results were only slightly attenuated after adjustment for number of chronic diseases or pain. CONCLUSION: Geriatric syndromes are significantly associated with onset of disability in older women; this association is not simply a result of chronic disease or pain. A better understanding of how these conditions contribute to disablement is needed. Geriatric syndrome assessment should be considered along with chronic disease management in the prevention of disability in older women.

Physical activity assessment: biomarkers and self-report of activity-related energy expenditure in the WHI.

We used a biomarker of activity-related energy expenditure (AREE) to assess measurement properties of self-reported physical activity and to determine the usefulness of AREE regression calibration equations in the Women's Health Initiative. Biomarker AREE, calculated as the total energy expenditure from doubly labeled water minus the resting energy expenditure from indirect calorimetry, was assessed in 450 Women's Health Initiative participants (2007-2009). Self-reported AREE was obtained from the Arizona Activity Frequency Questionnaire (AAFQ), the 7-Day Physical Activity Recall (PAR), and the Women's Health Initiative Personal Habits Questionnaire (PHQ). Eighty-eight participants repeated the protocol 6 months later. Reporting error, measured as log(self-report AREE) minus log(biomarker AREE), was regressed on participant characteristics for each instrument. Body mass index was associated with underreporting on the AAFQ and PHQ but overreporting on PAR. Blacks and Hispanics underreported physical activity levels on the AAFQ and PAR, respectively. Underreporting decreased with age for the PAR and PHQ. Regressing logbiomarker AREE on logself-reported AREE revealed that self-report alone explained minimal biomarker variance (R(2) = 7.6, 4.8, and 3.4 for AAFQ, PAR, and PHQ, respectively). R(2) increased to 25.2, 21.5, and 21.8, respectively, when participant characteristics were included. Six-month repeatability data adjusted for temporal biomarker variation, improving R(2) to 79.4, 67.8, and 68.7 for AAFQ, PAR, and PHQ, respectively. Calibration equations "recover" substantial variation in average AREE and valuably enhance AREE self-assessment.

The prevalence of aortic calcification in Japanese compared to white and Japanese-American middle-aged men is confounded by the amount of cigarette smoking.

BACKGROUND: The prevalence of coronary artery calcification (CAC) in Japanese men is lower than in white and Japanese-American men. It is unclear if aortic calcification (AC) strongly linked to smoking is also lower in Japanese men who have many times higher smoking prevalence compared to US men. METHODS: We conducted a population-based study of 903 randomly-selected men aged 40-49 years: 310 Japanese men in Kusatsu, Japan, 301 white men in Allegheny County, US, and 292 Japanese men in Hawaii, US (2002-2006). The presence of AC was assessed by electron-beam tomography. AC was defined as Agatston aortic calcium scores (AoCaS) >0 and ≥ 100. RESULTS: Japanese (35.8%) had significantly less AoCaS>0 compared to both white (68.8%, p<0.001) and Japanese-American (62.3%, p<0.001) but similar AoCaS ≥ 100 (19.4%, 18.3%, 22.6%, respectively, p=0.392). The pack-years of smoking, which was highest in Japanese, was the most important single associate of AC in all populations. Additionally age, low-density-lipoprotein cholesterol (LDL-C), and triglycerides in Japanese; body-mass index (BMI) in white; and BMI, LDL-C, hypertension, diabetes, and lipid medications in Japanese-American were independent associates of AC. The risk of AC using either cut points adjusted for pack-years of smoking and additional risk factors was lower in Japanese compared to both white and Japanese-American. AC and CAC had moderately positive and significant correlations in Japanese (r=0.26), white (r=0.39), and Japanese-American (r=0.45). CONCLUSIONS: The prevalence of AC defined both >0 and ≥ 100 was significantly lower in Japanese than in white and Japanese-American men after adjusting for cigarette smoking and additional risk factors.

Influence of cigarette smoking on coronary artery and aortic calcium among random samples from populations of middle-aged Japanese and Korean men.

BACKGROUND: Cigarette smoking is a risk factor of coronary heart disease. Vascular calcification such as coronary artery calcium (CAC) and aortic calcium (AC) is associated with coronary heart disease. The authors hypothesised that cigarette smoking is associated with coronary artery and aortic calcifications in Japanese and Koreans with high smoking prevalence. METHODS: Random samples from populations of 313 Japanese and 302 Korean men aged 40-49 years were examined for calcification of the coronary artery and aorta using electron beam CT. CAC and AC were quantified using the Agatston score. The authors examined the associations of cigarette smoking with CAC and AC after adjusting for conventional risk factors and alcohol consumption. Current and past smokers were combined and categorised into two groups using median pack-years as a cut-off point in each of Japanese and Koreans. The never-smoker group was used as a reference for the multiple logistic regression analyses. RESULTS: The ORs of CAC (score ≥10) for smokers with higher pack-years were 2.9 in Japanese (p<0.05) and 1.3 in Koreans (non-significant) compared with never-smokers. The ORs of AC (score ≥100) for smokers with higher pack-years were 10.4 in Japanese (p<0.05) and 3.6 in Koreans (p<0.05). CONCLUSION: Cigarette smoking with higher pack-years is significantly associated with CAC and AC in Japanese men, while cigarette smoking with higher pack-years is significantly associated with AC but not significantly with CAC in Korean men.

Calcium, magnesium and potassium intake and mortality in women with heart failure: the Women's Health Initiative.

Although diet is thought to affect the natural history of heart failure (HF), nutrient intake in HF patients has not been well studied. Based on prior research linking high intake of Ca, Mg and K to improved cardiovascular health, we hypothesised that these nutrients would be inversely associated with mortality in people with HF. Of the 161 808 participants in the Women's Health Initiative (WHI), we studied 3340 who experienced a HF hospitalisation. These participants were followed for post-hospitalisation all-cause mortality. Intake was assessed using questionnaires on food and supplement intake. Hazard ratios (HR) and 95 % CI were calculated using Cox proportional hazards models adjusted for demographics, physical function, co-morbidities and dietary covariates. Over a median of 4·6 years of follow-up, 1433 (42·9 %) of the women died. HR across quartiles of dietary Ca intake were 1·00 (referent), 0·86 (95 % CI 0·73, 1·00), 0·88 (95 % CI 0·75, 1·04) and 0·92 (95 % CI 0·76, 1·11) (P for trend = 0·63). Corresponding HR were 1·00 (referent), 0·86 (95 % CI 0·71, 1·04), 0·88 (95 % CI 0·69, 1·11) and 0·84 (95 % CI 0·63, 1·12) (P for trend = 0·29), across quartiles of dietary Mg intake, and 1·00 (referent), 1·20 (95 % CI 1·01, 1·43), 1·06 (95 % CI 0·86, 1·32) and 1·16 (95 % CI 0·90, 1·51) (P for trend = 0·35), across quartiles of dietary K intake. Results were similar when total (dietary plus supplemental) nutrient intakes were examined. In summary, among WHI participants with incident HF hospitalisation, intakes of Ca, Mg and K were not significantly associated with subsequent mortality.

Impact of ancestry and common genetic variants on QT interval in African Americans.

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN. CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

Risk factors for sudden cardiac death in post-menopausal women.

OBJECTIVES: The aim of this study was to estimate the annual incidence rate of sudden cardiac death (SCD) and to identify risk factors for SCD in post-menopausal women. BACKGROUND: With the aging U.S. population, post-menopausal women now have the greatest population burden of cardiovascular disease including SCD. METHODS: We examined 161,808 women who participated in the Women's Health Initiative clinical trials and observational study. The women were recruited at 40 clinical sites across the United States, enrolled between 1993 and 1998, and followed until August 2009. Our primary endpoint is incident SCD, defined as death occurring within 1 h of symptom onset or within 1 h after the participant was last seen without symptoms and death that occurred in the absence of a potentially lethal non-coronary disease process. RESULTS: Four hundred eighteen women experienced adjudicated SCD. The incidence rate of SCD was 2.4/10,000 women/year (95% confidence interval: 2.2 to 2.7). We identified the following independent risk factors for SCD: older age, African-American race, tobacco use, higher pulse, higher waist-to-hip ratio, elevated white blood cell count, history of heart failure, diabetes, history of myocardial infarction, previous carotid artery disease, and hypertension. Population-attributable fractions were greatest for hypertension, waist-to-hip ratio, and myocardial infarction. CONCLUSIONS: Besides traditional risk factors for coronary heart disease, risk factors for sudden cardiac death in post-menopausal women include African-American race, higher pulse, higher waist-to-hip ratio, elevated white blood cell count, and heart failure. Nearly one-half of women who experienced sudden cardiac death had no previous diagnosis of coronary heart disease.

Effects of postmenopausal hormone therapy on incident atrial fibrillation: the Women's Health Initiative randomized controlled trials.

BACKGROUND: Atrial fibrillation (AF) is less prevalent in women versus men, but associated with higher risks of stroke and death in women. The role hormone therapy plays in AF is not well understood. METHODS AND RESULTS: The Women's Health Initiative randomized postmenopausal women to placebo or conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) if they had a uterus (N=16 608) or to conjugated equine estrogens only if they had prior hysterectomy (N=10 739). Incident AF was identified by ECG and diagnosis codes from Medicare claims or hospitalization records. Hazard ratios for incident AF were estimated using Cox proportional hazards regression. After excluding participants with baseline AF, there were 611 incident AF cases over a mean of 5.6 years among 16 128 estrogen plus progestin participants, and 683 cases over a mean of 7.1 years among 10 251 conjugated equine estrogens alone participants. Incident AF was more frequent in the active groups of both trials, reaching statistical significance in the trial of conjugated equine estrogens alone in women with prior hysterectomy (hazard ratio, 1.17; CI, 1.00-1.36; P=0.045) and in the pooled analysis (hazard ratio, 1.12; CI, 1.00-1.24; P=0.05), but not in the estrogen plus progestin trial (hazard ratio, 1.07; CI, 0.91-1.25; P=0.44). These results were only minimally affected by adjustment for incident stroke, coronary heart disease, and heart failure. CONCLUSIONS: Incident AF was modestly elevated in hysterectomized women randomized to postmenopausal E-alone, and in the pooled group randomized to E-alone or estrogen plus progestin. The trend in women with intact uterus receiving estrogen plus progestin, considered separately, was not statistically significant. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; Identifier: NCT00000611.

Adiponectin, systolic blood pressure, and alcohol consumption are associated with more aortic stiffness progression among apparently healthy men.

OBJECTIVE: Limited data are available about risk factors for the progression of aortic stiffness in healthy population. We examined several risk factors as possible independent predictors of aortic stiffness progression among a population-based sample of US men. METHODS: A total of 240 men (40-49 years) free of CVD at baseline from the Pittsburgh site of the ERA JUMP study were evaluated. Aortic stiffness was measured as carotid-femoral pulse wave velocity at baseline and after 4.6 ± 0.2 (mean ± SD) years of follow-up. Progression of aortic stiffness was evaluated as relative annual change in carotid-femoral pulse wave velocity (% change/year). Using linear regression, both baseline potential risk factors and their annual changes were evaluated as possible risk factors for aortic stiffness progression. Baseline age, follow-up time, race, heart rate, and medications use were forced in all models. RESULTS: During follow-up, relative to baseline level, aortic stiffness increased 0.3% ± 5.3% per year. In final models, the independent predictors of degree of aortic stiffness progression were lower levels of adiponectin (P = 0.03), higher levels of systolic blood pressure (P = 0.03), greater annual change in systolic blood pressure (P = 0.04), and alcohol consumption ≥ 2 times/week (P = 0.02). Adiponectin levels within the third (9.8 µg/Ml ≤ adiponectin < 13.0 µg/mL) and the fourth (adiponectin ≥ 13.0 µg/mL) quartiles were associated with an improvement in relative annual aortic stiffness progression (P = 0.02, P = 0.01, respectively) compared to levels within the first quartile (adiponectin ≤ 7.0 µg/mL). CONCLUSION: Among apparently healthy men, lower levels of baseline adiponectin could be a novel marker for greater risk of aortic stiffness progression. Longitudinal research is required to evaluate whether adiponectin change over time would have similar association with aortic stiffness progression.

Use of the dietary supplement 5-aminiolevulinic acid (5-ALA) and its relationship with glucose levels and hemoglobin A1C among individuals with prediabetes.

OBJECTIVE: This study examined the association between 5-aminolevulinic acid (5-ALA) and glucose tolerance. DESIGN: A double blinded, randomized prospective parallel-group comparison study. SETTING: Participants were recruited from the community in Honolulu, Hawaii, using radio and TV ads, and at community events. PARTICIPANTS: One hundred fifty-four males and females ages 40-70 years, with evidence of prediabetes: hemoglobin A1c (HbA1c) 5.8%-7.0% at the screening visit. INTERVENTION: Participants were randomized equally to one of three study groups: (1) low dose 5-ALA supplement (15 mg capsule); (2) high dose 5-ALA (50 mg capsule); and (3) control (placebo capsule of identical size and color). MAIN OUTCOME MEASURES: HbA1c and 2 hours post-oral glucose tolerance test (OGTT) glucose levels. RESULTS: Among individuals taking 5-ALA supplements for 12 weeks, 2 hours post-OGTT glucose levels declined significantly compared to those not taking the supplement (p= 0.02). The relationships were stronger among those with baseline glucose intolerance, or 2 hours post-OGTT glucose measurements greater than 140 mg/dL (p= 0.005 and p= 0.02 for the low and high dose group, respectively). Similar trends were observed for HbA1c but results were of borderline significance (p= 0.07). No untoward effects were reported. CONCLUSIONS: Further studies are indicated. The potential benefits of 5-ALA dietary supplementation are affirmed by this investigation.

Hormone therapy, estrogen metabolism, and risk of breast cancer in the Women's Health Initiative Hormone Therapy Trial.

BACKGROUND: In the Women's Health Initiative Hormone Trials (WHI-HT), breast cancer risk was increased with estrogen plus progestin (E+P) but not with unopposed estrogen (E-alone). We hypothesized that E+P would preferentially metabolize to 16α-hydroxyestrone (16α-OHE1) rather than 2-hydroxyestrone (2-OHE1), and that breast cancer risk would be associated with baseline and 1 year changes in estrogen metabolites: positively for 16α-OHE1 levels and negatively for levels of 2-OHE-1 and the 2:16 ratio. METHODS: In a prospective case-control study nested in the WHI-HT, 845 confirmed breast cancer cases were matched to 1,690 controls by age and ethnicity. Using stored serum, 2-OHE1 and 16α-OHE1 levels were measured by enzyme immunoassay at baseline, and for those randomized to active treatment (n = 1,259), at 1 year. RESULTS: The 1-year increase in 16α-OHE1 was greater with E+P than E-alone (median 55.5 pg/mL vs. 43.5 pg/mL, P < 0.001), but both increased 2-OHE1 by ∼300 pg/mL. Breast cancer risk was modestly associated with higher baseline levels of 2-OHE1 and the 2:16 ratio, and for estrogen receptor+/progesterone+ cases only, higher baseline 16α-OHE1 levels. For those randomized to active treatment, breast cancer risk was associated with greater increase in 2-OHE-1 and the 2:16 ratio, but associations were not significant. CONCLUSIONS: Although E+P modestly increased 16α-OHE1 more than E-alone, increase in 16α-OHE1 was not associated with breast cancer. IMPACT: Study results do not explain differences between the WHI E+P and WHI E-alone breast cancer results but metabolism of oral HT, which may explain smaller than expected increase in breast cancer compared with endogenous estrogens.

A prospective study of leukocyte telomere length and risk of type 2 diabetes in postmenopausal women.

Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women's Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90-1.11) in whites, 0.95 (0.85-1.06) in blacks, 0.96 (0.79-1.17) in Hispanics, and 0.88 (0.70-1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women.