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Background The association of social isolation or lack of social network ties in older adults is unknown. This knowledge gap is important since the risk of heart failure (HF) and social isolation increase with age. The study examines whether social isolation is associated with incident HF in older women, and examines depressive symptoms as a potential mediator and age and race and ethnicity as effect modifiers. Methods and Results This study included 44 174 postmenopausal women of diverse race and ethnicity from the WHI (Women's Health Initiative) study who underwent annual assessment for HF adjudication from baseline enrollment (1993–1998) through 2018. We conducted a mediation analysis to examine depressive symptoms as a potential mediator and further examined effect modification by age and race and ethnicity. Incident HF requiring hospitalization was the main outcome. Social isolation was a composite variable based on marital/partner status, religious ties, and community ties. Depressive symptoms were assessed using CES‐D (Center for Epidemiology Studies‐Depression). Over a median follow‐up of 15.0 years, we analyzed data from 36 457 women, and 2364 (6.5%) incident HF cases occurred; 2510 (6.9%) participants were socially isolated. In multivariable analyses adjusted for sociodemographic, behavioral, clinical, and general health/functioning; socially isolated women had a higher risk of incident HF than nonisolated women (HR, 1.23; 95% CI, 1.08–1.41). Adding depressive symptoms in the model did not change this association (HR, 1.22; 95% CI, 1.07–1.40). Neither race and ethnicity nor age moderated the association between social isolation and incident HF. Conclusions Socially isolated older women are at increased risk for developing HF, independent of traditional HF risk factors. Registration URL: http://www.clinicaltrials.gov ; Unique identifier: NCT00000611.

Background: Evidence that higher sedentary time is associated with higher risk for cardiovascular disease (CVD) is based mainly on self-reported measures. Few studies have examined whether patterns of sedentary time are associated with higher risk for CVD. Methods: Women from the OPACH Study (Objective Physical Activity and Cardiovascular Health; n=5638, aged 63–97 years, mean age 79±7 years) with no history of myocardial infarction or stroke wore accelerometers for 4 to 7 days and were followed up for up to 4.9 years for CVD events. Average daily sedentary time and mean sedentary bout duration were the exposures of interest. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs for CVD using models adjusted for covariates and subsequently adjusted for potential mediators (body mass index, diabetes mellitus, hypertension, and CVD risk biomarkers [fasting glucose, high-density lipoprotein, triglycerides, and systolic blood pressure]). Restricted cubic spline regression characterized dose-response relationships. Results: There were 545 CVD events during 19 350 person-years. With adjustment for covariates, women in the highest (≈11 h/d or more) versus the lowest (≈9 h/d or less) quartile of sedentary time had higher risk for CVD (HR, 1.62; 95% CI, 1.21–2.17; P trend P trend P trend=0.003) after adjustment for covariates. Additional adjustment for CVD risk biomarkers attenuated associations, resulting in a quartile 4 versus quartile 1 HR of 1.36 (95% CI, 1.01–1.83; P trend=0.10). Dose-response associations of sedentary time and bout duration with CVD were linear ( P nonlinear >0.05, each). Women jointly classified as having both high sedentary time and long bout durations had significantly higher risk for CVD (HR, 1.34; 95% CI, 1.08–1.65) than women with low sedentary time and short bout duration. All analyses were repeated for incident coronary heart disease (myocardial infarction or CVD death), and associations were similar, with notably stronger HRs. Conclusions: Both high sedentary time and long mean bout durations were associated in a dose-response manner with increased CVD risk in older women, which suggests that efforts to reduce CVD burden might benefit from addressing either or both components of sedentary behavior.

Background: Obesity is associated with an increased risk of heart failure (HF); however, how metabolic weight groups relate to HF risk, especially in postmenopausal women, has not been demonstrated. Methods: We included 19 412 postmenopausal women ages 50 to 79 without cardiovascular disease from the Women’s Health Initiative. Normal weight was defined as a body mass index ≥18.5 and 2 and waist circumference 2 or waist circumference ≥88 cm. Metabolically healthy was based on Results: Among our sample, 455 (2.34%) participants experienced HF hospitalizations over a mean follow-up time of 11.3±1.1 years. Compared with metabolically healthy normal weight individuals, HF risk was greater in metabolically unhealthy normal weight (HR, 1.66 [95% CI, 1.01–2.72], P =0.045) and metabolically unhealthy overweight/obese individuals (HR, 1.95 [95% CI, 1.35–2.80], P =0.0004), but not metabolically healthy overweight/obese individuals (HR, 1.15 [95% CI, 0.78–1.71], P =0.48). Subdividing the overweight/obese into separate groups showed HRs for metabolically unhealthy obese of 2.62 (95% CI, 1.80–3.83; P P =0.06). Conclusions: Metabolically unhealthy overweight/obese and metabolically unhealthy normal weight are associated with an increased risk of HF in postmenopausal women.

Background: The higher risk of heart failure (HF) in African-American and Hispanic women compared with white women is related to the higher burden of risk factors (RFs) in minorities. However, it is unclear if there are differences in the association between the number of RFs for HF and the risk of development of HF and death within racial/ethnic groups. Methods and Results: In the WHI (Women’s Health Initiative; 1993–2010), African-American (n=11 996), white (n=18 479), and Hispanic (n=5096) women with 1, 2, or 3+ baseline RFs were compared with women with 0 RF within their respective racial/ethnic groups to assess risk of developing HF or all-cause mortality before and after HF, using survival analyses. After adjusting for age, socioeconomic status, and hormone therapy, the subdistribution hazard ratio (95% confidence interval) of developing HF increased as number of RFs increased ( P P =0.18)—African-Americans 1 RF: 1.80 (1.01–3.20), 2 RFs: 3.19 (1.84–5.54), 3+ RFs: 7.31 (4.26–12.56); Whites 1 RF: 1.27 (1.04–1.54), 2 RFs: 1.95 (1.60–2.36), 3+ RFs: 4.07 (3.36–4.93); Hispanics 1 RF: 1.72 (0.68–4.34), 2 RFs: 3.87 (1.60–9.37), 3+ RFs: 8.80 (3.62–21.42). Risk of death before developing HF increased with subsequent RFs ( P P =0.001). The number of RFs was not associated with the risk of death after developing HF in any group ( P =0.25; interaction P =0.48). Conclusions: Among diverse racial/ethnic groups, an increase in the number of baseline RFs was associated with higher risk of HF and death before HF but was not associated with death after HF. Early RF prevention may reduce the burden of HF across multiple racial/ethnic groups.

Background Among women aged 50 to 59 years at baseline in the Women's Health Initiative (WHI) Estrogen‐Alone (E‐Alone) trial, randomization to conjugated equine estrogen‐alone versus placebo was associated with lower risk of myocardial infarction and mortality, and, in an ancillary study, the WHI‐CACS (WHI Coronary Artery Calcification Study) with lower CAC, measured by cardiac computed tomography ≈8.7 years after baseline randomization. We hypothesized that higher CAC would be related to post‐trial coronary heart disease (CHD), cardiovascular disease (CVD), and total mortality, independent of baseline randomization or risk factors. Methods and Results WHI‐CACS participants (n=1020) were followed ≈8 years from computed tomography scan in 2005 (mean age=64.4) through 2013 for incident CHD (myocardial infarction and fatal CHD, n=17), CVD (n=69), and total mortality (n=55). Incident CHD and CVD analyses excluded women with CVD before scan (n=89). Women with CAC=0 (n=54%) had very low age‐adjusted rates/1000 person‐years of CHD (0.91), CVD (5.56), and mortality (3.45). In comparison, rates were ≈2‐fold higher for women with any CAC (>0). Associations were not modified by baseline randomization to conjugated equine estrogen–alone versus placebo. Adjusted for baseline randomization and risk factors, the hazard ratio (95% confidence interval) for CAC >100 (19%) was 4.06 (2.11, 7.80) for CVD and 2.70 (1.26, 5.79) for mortality. Conclusions Among a subset of postmenopausal women aged 50 to 59 years at baseline in the WHI E‐Alone Trial, CAC at mean age of 64 years was strongly related to incident CHD, CVD, and to total mortality over ≈8 years, independent of baseline randomization to conjugated equine estrogen–alone versus placebo or CVD risk factors. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00000611.

Objectives The Women's Health Initiative (WHI) randomized trial of calcium/vitamin D supplementation found reduced bone loss with active treatment compared to placebo. Now we examine whether the treatment affected self-reported physical functioning and objective measures of physical functioning. Design A randomized, double-blind, placebo-controlled trial of 1,000 mg calcium carbonate plus 400 IU vitamin D 3 per day or matching placebo pills. Subjects/setting The study included 33,067 women (50 to 79 years old) at 40 US study centers. Main outcome measures Physical functioning was assessed by questionnaire at enrollment in WHI, 1 year prior to calcium/vitamin D trial randomization and at study close-out (average follow-up 7.1 years). Objective physical performance and self-reported exercise measures were collected at WHI baseline (1 year prior to calcium/vitamin D enrollment) and 2 years and 4 years after calcium/vitamin D trial enrollment in a subsample (n=3,137). Statistical analyses performed Calcium/vitamin D effects were tested in unadjusted and interaction linear models for each of the physical function measures. Covariates were baseline total calcium intake, fracture risk score, treatment arm in the hormone therapy and dietary modification trials (ie, active drug or placebo, low-fat diet intervention or usual diet, respectively) and age. Results Neither intention to treat nor high adherence analyses produced substantial effects of calcium/vitamin D compared to placebo on physical functioning or performance. The interaction analyses also did not result in differences because of calcium/vitamin D. Conclusions As the first long-term randomized trial to examine the effectiveness of calcium and vitamin D in protecting against decline of physical functioning in older women, the results did not support benefit.

The evaluation of women with chest pain for the presence of important coronary artery disease may be challenging. Coronary artery disease is the leading cause of death, but it is much more prevalent in women of older age. However, chest discomfort is a very common symptom among women of all ages. Younger women are much less likely (but not completely immune) from having significant coronary disease, but the existing forms of cardiac testing are more likely to yield false results when applied to low-risk groups. Women should be assessed for their overall level of risk for coronary disease and the severity and nature of symptoms. Noninvasive cardiac testing is best applied to women at intermediate risk. There are strengths and weaknesses for each of the available imaging modalities, but both nuclear scans and echocardiography have reasonable accuracy and reliability for detecting serious coronary disease in women. Importantly, a negative study imparts an excellent prognosis. The application of a systematic and comprehensive evaluation of women will improve detection of important coronary disease and permit reassurance to women who do not have evidence for ischemia producing coronary disease. For women whose symptoms are determined not to be caused by significant coronary disease, additional evaluation for noncardiac causes can then be undertaken. Key Words: Coronary artery disease, women, chest pain Dis Mon 2002;48:647-658

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or

Background Several prospective studies have reported a positive association for both long and short sleep duration with coronary heart disease (CHD) risk. Insomnia may also be a CHD risk factor. Our aims were to identify whether sleep duration and insomnia symptoms are associated with greater incident CHD among postmenopausal women. Methods Participants were 86,329 postmenopausal women, aged 50-79 at enrollment into the Women's Health Initiative (WHI) observational study, who reported information regarding sleep habits at baseline (1993-1998) and were followed for first occurrence of a coronary event. Cox proportional hazards models were developed using sleep duration and insomnia as the primary exposures. Person-years of follow up were calculated from the screening visit through August 2009. Results Compared to mid-range sleep duration (7-8 hours) women reporting shorter sleep (≤5 hours) and longer sleep (≥10 hours) had higher incident CHD (HR=1.21, 95% CI 1.09-1.33; HR=1.51, 95% CI 1.08-2.11), respectively, after adjusting for age and race. Only longer sleep remained significantly associated with incident CHD in fully adjusted models (HR=1.53, 95% CI 1.09-2.14). Women that scored high (≥9) for insomnia on the WHI Insomnia Rating Scale (WHIIRS) demonstrated the highest risk of CHD (HR=1.35, 95% CI 1.24-1.47, age- and race-adjusted; HR=1.18, 95% CI 1.08-1.30, fully adjusted models). When the analyses are stratified by the WHIIIRS, among those with high insomnia scores (≥9), long sleep almost doubled the risk of CHD (HR=1.97, 95% CI 1.18-3.30) versus mid-range sleep duration, whereas among those with lower WHIIRS scores ( Conclusions Women reporting ≥10 hours of sleep per night with high insomnia scores had a higher risk for incident CHD. A significant interaction between sleep duration and insomnia was observed (p Table 1. Cox proportional hazards models - sleep duration and incident CHD * among WHI participants stratified by level of insomnia Cases N High level of perceived insomnia (WHIIRS ≥ 9) Model adjusted for age, race Model fully adjusted † HR 95% CI P-value HR 95% CI P-value Sleep time ≤5 h 347 4580 1.16 1.02, 1.32 0.03 1.05 0.93, 1.18 0.46 6 h 679 9610 1.08 0.97, 1.20 0.14 1.00 0.91, 1.10 0.98 7-8 h (ref) 734 10919 REF REF REF REF REF REF 9 h 48 517 1.38 1.03, 1.85 0.03 1.26 0.97, 1.65 0.08 ≥10 h 12 114 1.98 1.12, 3.51 0.02 1.97 1.18, 3.30 0.01 Cases N Low level for perceived insomnia (WHIIRS < 9) Model adjusted for age, race Model fully adjusted † HR 95% CI P-value HR 95% CI P-value Sleep time ≤5 h 130 2209 1.12 0.96, 1.31 0.16 0.92 0.77, 1.09 0.34 6 h 768 13,416 0.99 0.92, 1.07 0.88 0.94 0.87, 1.02 0.12 7-8 h (ref) 2418 41347 REF REF REF REF REF REF 9 h 171 2934 1.06 0.93, 1.21 0.38 0.98 0.85, 1.13 0.73 ≥10 h 23 357 1.67 1.22, 2.28 0.01 1.49 1.08, 2.06 0.02 * Outcome includes myocardial infarction, CHD death, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting or hospitalized angina † Model adjusted for age, race, education, income, smoking, BMI, physical activity, alcohol intake, depression, diabetes, high blood pressure, cholesterol medication, comorbid conditions

The Studies of Left Ventricular Dysfunction (SOLVD) trials were designed to evaluate the effects of enalapril on long-term mortality in patients with severe left ventricular (LV) dysfunction. Patients with LV ejection fractions less than or equal to 0.35 and symptoms of congestive heart failure (CHF) were enrolled in the treatment trial, whereas those with no history of overt CHF and taking no treatment directed for LV dysfunction were enrolled in the prevention trial. The baseline clinical characteristics of SOLVD patients were compared to characterize differences between patients in these 2 separate but concurrent trials. From over 70,000 patients screened with LV dysfunction, 4,228 patients were enrolled in the prevention trial and 2,569 patients in the treatment trial. Ischemic heart disease was the primary cause of LV dysfunction in both prevention (83%) and treatment (71%) trial patients. Prior myocardial infarction was present in 80% of the prevention and 66% of the treatment trial patients (p less than 0.001). In the prevention trial, infarction was recent (less than or equal to 6 months) in 27% patients and remote (greater than 6 months) in 57% patients. Treatment trial patients had proportionately more women (20 vs 13%; p less than 0.001) and non-Caucasians (20 vs 14%; p less than 0.001), as well as the coexisting risk factors of hypertension (42 vs 37%; p less than 0.001) and diabetes (26 vs 15%; p less than 0.001) than did prevention trial patients. Clinical characteristics of patients in both trials were influenced by the gender and race of enrolled patients. Similarly, coronary artery bypass surgery was performed less often in women and non-Caucasians.(ABSTRACT TRUNCATED AT 250 WORDS)

Context: Women discharged with a diagnosis of nonspecific chest pain (NSCP) may have an increased risk of subsequent coronary heart disease (CHD) events. The influence of hormone therapy on NSCP is unknown. Methods: The WHI enrolled postmenopausal women aged 50 –79 years. After excluding women with prior cardiovascular disease, 9427 women in the estrogen alone (E-Alone) trial and 15,105 women in the estrogen plus progestin (E + P) trial were included in this analysis. NSCP, defined as having a primary hospital discharge diagnosis of NSCP by ICD-9 code, was reported in 322 E-Alone and 249 E + P women. Risks of subsequent CHD events were estimated using intent-to-treat Cox proportional hazard ratio (HR) models stratified by clinic and adjusted for age and other risk factors. Results: In the fully adjusted models of the combined trials, women with NSCP had a 2-fold greater risk of subsequent nonfatal CHD events including nonfatal myocardial infarction [2.3% vs 1.7%, HR 2.10 (1.11–3.98)], revascularization [3.5% vs 2.6%, HR 1.99 (1.20 –3.30)], and hospitalized angina [3.7% vs 2.3%, HR 2.39 (1.46 –3.92)]. Hormone therapy did not have a significant effect on either the incidence of NSCP hospitalizations [HRs (95% CIs): E-Alone 1.04 (0.81–1.32); E + P 0.78 (0.59 –1.02)] or on the risk of a subsequent CHD event over 7.1 or 5.6 years of follow-up, respectively. Conclusion: A NSCP hospitalization doubles the risk of a subsequent CHD event in postmenopausal women over the next 5 to 7 years. Further research is needed to identify appropriate diagnosis and treatment strategies for women with NSCP.

The evaluation of women with chest pain for the presence of important coronary artery disease may be challenging. Coronary artery disease is the leading cause of death, but it is much more prevalent in women of older age. However, chest discomfort is a very common symptom among women of all ages. Younger women are much less likely (but not completely immune) from having significant coronary disease, but the existing forms of cardiac testing are more likely to yield false results when applied to low-risk groups. Women should be assessed for their overall level of risk for coronary disease and the severity and nature of symptoms. Noninvasive cardiac testing is best applied to women at intermediate risk. There are strengths and weaknesses for each of the available imaging modalities, but both nuclear scans and echocardiography have reasonable accuracy and reliability for detecting serious coronary disease in women. Importantly, a negative study imparts an excellent prognosis. The application of a systematic and comprehensive evaluation of women will improve detection of important coronary disease and permit reassurance to women who do not have evidence for ischemia producing coronary disease. For women whose symptoms are determined not to be caused by significant coronary disease, additional evaluation for noncardiac causes can then be undertaken.

ContextThe Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group.ObjectiveTo assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers.DesignMulticenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls.InterventionsParticipants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102).Main Outcome MeasuresOverall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists.ResultsOne hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk.ConclusionsEstrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.