BACKGROUND:We previously reported in a cross-sectional analysis an adverse relationship between weight cycling and HDL-cholesterol but not angiographic obstructive coronary artery disease (CAD) among women undergoing coronary angiography for suspected ischemia in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE). We now examine the relationship between weight cycling and prospective adverse cardiovascular outcome in this group.METHODS:795 women enrolled between 1996-2001 in the WISE undergoing coronary angiography for evaluation of suspected ischemia and followed for a median of 6.0 years (interquartile range = 3.4 years). Adverse outcome was defined as a composite of all-cause death, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure. Weight cycling was defined as the intentional loss of at least 10 lbs. (4.5 kgs.) at least three times during the women's lifetime.RESULTS:Women (n = 224) who reported a history of weight cycling were younger; more often white and better educated compared those without this history. At baseline, women with a weight cycling history had lower HDL-C values, higher body mass index, larger waist circumferences and higher values for fasting blood sugar, but no difference in obstructive CAD prevalence or severity. There was an inverse relationship between weight cycling and adverse composite cardiovascular outcome, whereby fewer of women with a history of weight cycling experienced an adverse outcome as compared to non-cyclers (21% vs 29%, respectively, p = 0.03).CONCLUSIONS:Despite an adverse association with HDL-cholesterol in women undergoing coronary angiography for suspected ischemia, weight cycling was associated with a lower adverse outcome rate in women with suspected ischemia.

hristopher B. Arant, MD,* Timothy R. Wessel, MD,* Marian B. Olson, MS,‡ . Noel Bairey Merz, MD, FACC,¶ George Sopko, MD,# William J. Rogers, MD, FACC, arry L. Sharaf, MD, FACC,§ Steven E. Reis, MD, FACC,‡ Karen M. Smith, MD, FACC,* . Delia Johnson, PHD,‡ Eileen Handberg, PHD,* Sunil Mankad, MD, FACC,† arl J. Pepine, MD, MACC* ainesville, Florida; Pittsburgh, Pennsylvania; Providence, Rhode Island; Birmingham, Alabama; os Angeles, California; and Bethesda, Maryland

OBJECTIVES:To assess the prognostic value of a left ventricular energy-model in women with suspected myocardial ischemia.BACKGROUND:The prognostic value of internal energy utilization (IEU) of the left ventricle in women with suspected myocardial ischemia is unknown.METHODS:Women (n=227, mean age 59±12 years, range 31-86), with symptoms of myocardial ischemia, underwent myocardial perfusion imaging (MPI) assessment for regional perfusion defects along with measurement of ventricular volumes separately by gated Single Photon Emission Computed Tomography (SPECT) (n= 207) and magnetic resonance imaging (MRI) (n=203). During follow-up (40±17 months), time to first major adverse cardiovascular event (MACE, death, myocardial infarction or hospitalization for congestive heart failure) was analyzed using MRI and gated SPECT variables.RESULTS:Adverse events occurred in 31 (14%). Multivariable Cox models were formed for each modality: IEU and wall thickness by MRI (Chi-squared 34, p<0.005) and IEU and systolic blood pressure by gated SEPCT (Chi-squared 34, p<0.005). The models remained predictive after adjustment for age, disease history and Framingham risk score. For each Cox model, patients were categorized as high-risk if the model hazard was positive and not high-risk otherwise. Kaplan-Meier analysis of time to MACE was performed for high-risk vs. not high-risk for MR (log rank 25.3, p<0.001) and gated SEPCT (log rank 18.2, p<001) models.CONCLUSIONS:Among women with suspected myocardial ischemia a high internal energy utilization has higher prognostic value than either a low EF or the presence of a myocardial perfusion defect assessed using two independent modalities of MR or gated SPECT.

Prescribing exercise at intensities that improve fitness is difficult in children with cystic fibrosis (CF) due to ventilatory limitations and fluctuating health status. Our aim was to determine if children with CF could regulate the intensity of cycle ergometer and treadmill exercise using target ratings of perceived exertion (RPE) derived from the Children's OMNI Scale. We examined prescription congruence (similar oxygen consumption [VO₂] and heart rate [HR] for target RPE) and intensity discrimination (different VO₂ and HR for different RPEs), from cycle to cycle and cycle to treadmill. Subjects were 24 children (12 male, 12 female), aged 10-17 years with varying disease severity. Each child participated in one orientation, one estimation trial (graded maximal exercise test), and two production trials (cycle and treadmill, alternating between RPE 4 and 7). At RPE 4, congruence was evident for both VO₂ and HR on the treadmill. On the cycle at RPE 4, VO₂ was significantly higher only in the first production trial, although HRs tended to be higher in the production trials than the estimation trial. Prescription congruence was also supported at RPE 7, with no significant differences in VO₂ or HR between estimation and production trials on cycle or treadmill. Results fully supported intensity discrimination, with significant differences between VO₂ and HR at RPE 4 and 7 (P < 0.0001). Children with CF appear capable of using the OMNI Scale to regulate cycle and treadmill exercise intensity. Training using this methodology has the potential to promote fitness in children with CF of varying severity.

Objective: To determine the association between self-rated health and major cardiovascular events in a sample of women with suspected myocardial ischemia. Previous studies showed that self-rated health is a predictor of objective health outcomes, such as mortality. Method: At baseline, 900 women rated their health on a 5-point scale ranging from poor to excellent as part of a protocol that included quantitative coronary angiography, cardiovascular disease (CVD) risk factor assessment, cardiac symptoms, psychotropic medication use, and functional impairment. Participants were followed for a maximum of 9 years (median, 5.9 years) to determine the prevalence of major CVD events (myocardial infarction, heart failure, stroke, and CVD-related death). Results: A total of 354 (39.3% of sample) participants reported their health as either poor or fair. After adjusting for demographic factors, CVD risk factors, and coronary artery disease severity, women who rated their health as poor (hazard ratio, 2.1 [1.1-4.2]) or fair (hazard ratio, 2.0 [1.2-3.6]) experienced significantly shorter times to major CVD events compared with women who rated their health as excellent or very good. Further adjustment for functional impairment, however, attenuated the self-rated health relationships with major CVD events. Conclusions: Among women with suspected myocardial ischemia, self-rated health predicted major CVD events independent of demographic factors, CVD risk factors, and angiogram-defined disease severity. However, functional impairment seemed to explain much of the self-rated health association. These results support the clinical utility of self-rated health scores in women and encourage a multidimensional approach to conceptualizing these measures. CAD = coronary artery disease; CVD = cardiovascular disease; DASI = Duke Activity Status Index; HR = hazard ratio; SES = socioeconomic status; WISE = Women’s Ischemia Syndrome Evaluation.

Background Compared with men, women have more evidence of myocardial ischemia with no obstructive coronary artery disease. Although low endogenous estrogen levels are associated with endothelial dysfunction, the role of low-dose hormone therapy has not been fully evaluated. We postulate that a 12-week duration of low-dose hormone replacement therapy is associated with myocardial ischemia and endothelial dysfunction.Methods and Results Using a multicenter, randomized, placebo-controlled design, subjects were randomized to receive either 1 mg norethindrone/10 mu g ethinyl estradiol or placebo for 12 weeks. Chest pain and menopausal symptoms, cardiac magnetic resonance spectroscopy, brachial artery reactivity, exercise stress testing, and psychosocial questionnaires were evaluated at baseline and exit. Recruitment was closed prematurely because of failure to recruit after publication of the Women's Health Initiative hormone trial. Of the 35 women who completed the study, there was less frequent chest pain in the treatment group compared with the placebo group (P=.02) at exit. Women taking 1 mg norethindrone/10 mu g ethinyl estradiol also had significantly fewer hot flashes/night sweats (P=.003), less avoidance of intimacy (P=.05), and borderline differences in sexual desire and vaginal dryness (P=.06). There were no differences in magnetic resonance spectroscopy, brachial artery reactivity, compliance, or reported adverse events between the groups.Conclusions These data suggest that low-dose hormone therapy improved chest pain symptoms, menopausal symptoms, and quality of life, but did not improve ischemia or endothelial dysfunction. Given that it was not possible to enroll the prespecified sample size, these results should not be considered definitive. (Am Heart J 2010; 159: 987.e1-987.e7.)

OBJECTIVESTo determine the efficacy of skin protection wheelchair seat cushions in preventing pressure ulcers in the elderly nursing home population.DESIGNClinical trial with participants assigned at random to a skin protection or segmented foam cushion. Two hundred thirty-two participants were recruited between June 2004 and May 2008 and followed for 6 months or until pressure ulcer incidence.SETTINGTwelve nursing homes.PARTICIPANTSNursing home residents aged 65 and older who were using wheelchairs for 6 or more hours per day and had a Braden score of 18 or less and a combined Braden activity and mobility score of 5 or less. Participants were recruited from a referred sample.INTERVENTIONAll participants were provided with a fitted wheelchair and randomized into skin protection (SPC, n=113) or segmented foam (SFC, n=119) cushion groups. The SPC group received an air, viscous fluid and foam, or gel and foam cushion. The SFC group received a 7.6-cm crosscut foam cushion.MEASUREMENTSPressure ulcer incidence over 6 months for wounds near the ischial tuberosities (IT ulcers) were measured. Secondary analysis was performed on combined IT ulcers and ulcers over the sacrum and coccyx (sacral ulcers).RESULTSOne hundred eighty participants reached a study end point, and 42 were lost to follow-up. Ten did not receive the intervention. There were eight (6.7%) IT ulcers in the SFC group and one (0.9%) in the SPC group (P=.04). There were 21 (17.6%) combined IT and sacral ulcers in the SFC group and 12 (10.6%) in the SPC group (P=.14).CONCLUSIONSkin protection cushions used with fitted wheelchairs lower pressure ulcer incidence for elderly nursing home residents and should be used to help prevent pressure ulcers.

BACKGROUND Although extensive research has been conducted on both smoking and low exercise capacity alone, few studies have examined the joint impact or interaction of these two risk factors. We examined the joint and interactive effects of smoking and self-reported exercise capacity on subsequent clinical events (heart failure, myocardial infarction [MI], stroke, and cardiovascular-related mortality) among women with suspected myocardial ischemia. METHODS At baseline (1996-1999), 789 women completed angiographic testing of coronary artery disease (CAD) severity and provided self-report information about their smoking history and exercise capacity as well as demographic and other risk factor data. Incidence of clinical events among the women was tracked for a median of 5.9 years; this analysis was conducted in 2008. RESULTS In an adjusted survival analysis, women with a positive smoking history and self-reported low exercise capacity had the greatest risk of experiencing a clinical event (HR = 7.7, 95% CI 2.3, 25.5), followed by women with a positive smoking history and self-reported high exercise capacity (HR = 6.9, 95% CI 2.0, 24.6) and those with a negative smoking history and self-reported low exercise capacity (HR = 4.9, 95% CI 1.5, 15.8), relative to women with a negative smoking history and self-reported high exercise capacity. Additional analyses revealed a significant interaction between smoking history and exercise capacity, such that (1) women with a positive smoking history did not experience an additional significantly greater risk due to low exercise capacity, unlike those with a negative smoking history, and (2) all women experienced a significantly greater risk due to a positive smoking history regardless of their exercise capacity. CONCLUSIONS Among women with suspected myocardial ischemia, the combined protective health effects of self-reported high exercise capacity and a negative smoking history remained significant after controlling for preexisting CAD severity and other established risk factors. These findings highlight the importance of studying behavioral risk factors in combination.

Background: Inflammatory marker and hemoglobin levels (eg biomarkers) considered separately, predict adverse events in selected populations.Hypothesis: A multiple biomarker approach predicts adverse events in women referred for evaluation of ischemia.Methods: We investigated associations between biomarkers (high sensitivity C-reactive protein, interleukin-6, serum amyloid-A, and hemoglobin levels) with adverse outcomes in women referred for coronary angiography for suspected ischemia in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE).Results: Among 595 women (mean age 58 years, ejection fraction [EF] 65%, majority without coronary stenosis >= 50%) followed for 3.6 +/- 1.8 years (mean +/- SD), those without abnormal markers had fewer events (11.6%) compared to those with 1 (18.4%), 2 (20.9%), Or 3 (37%) abnormal markers (p<0.001 for trend). Women without abnormal markers had fewer deaths (1.6%) than women with 1 (6.1%), 2 (9.1%), or 3 (17%) abnormal markers (p<0.001 for trend). Adding low hemoglobin was associated with higher adverse event and all-cause mortality rates. In multivariate analysis, as the number of abnormal biomarkers increased risk increased. Women with 3 or 4 abnormal biomarkers were approximately 10-20 times more likely to die (P<0.05). Biomarkers added to the predictive information provided by the Framingham Risk Score.Conclusions: Among women undergoing coronary angiography for suspected ischemia, a multibiomarker approach predicted adverse events. Biomarkers added prognostic information beyond that obtained from traditional risk factors.

ObjectivesThis study evaluated 3 novel questions in a prospective clinical cohort of women undergoing evaluation for suspected myocardial ischemia: 1) What is the relationship between depression and cardiovascular costs? 2) Does the relationship vary by definition of depression? 3) Do depression-cost relationship patterns differ among women with versus without coronary artery disease (CAD)?BackgroundComorbid depression has been linked to higher medical costs in previous studies of cardiovascular patients.MethodsA total of 868 women presenting with suspected myocardial ischemia completed an extensive baseline examination including cardiovascular risk factor assessment and coronary angiogram. Depression was defined by: 1) current use of antidepressants; 2) a reported history of depression treatment; and 3) Beck Depression Inventory scores. Direct (hospitalizations, office visits, procedures, and medications) and indirect (out-of-pocket, lost productivity, and travel) costs were collected through 5 years of follow-up to estimate cardiovascular costs.ResultsUsing the study criteria, 17% to 45% of the women studied met study depression criteria. Depressed women showed adjusted annual cardiovascular costs $1,550 to $3,300 higher than nondepressed groups (r = 0.08 to 0.12, p < 0.05). Depression-cost relationships also varied by CAD status, with stronger associations present among women without evidence of significant CAD.ConclusionsDepression was associated with 15% to 53% increases in 5-year cardiovascular costs, and cost differences were present using 3 definitions of depression. The results reinforce the importance of assessing depression in clinical populations and support the hypothesis that improved management of depression in women with suspected myocardial ischemia could reduce medical costs. (J Am Coll Cardiol 2009; 53: 176-83) (C) 2009 by the American College of Cardiology Foundation

Objective: To describe the prospective relationship between social networks and nonfatal stroke events in a sample of women with suspected myocardial ischemia. Social networks are an independent predictor of all-cause and cardiovascular mortality, but their relationship with stroke events in at-risk populations is largely unknown. Method: A total of 629 women (mean age = 59.6 ± 11.6 years) were evaluated at baseline for cardiovascular disease risk factors as part of a protocol including coronary angiography; the subjects were followed over a median 5.9 years to track the incidence of cardiovascular events including stroke. Participants also completed the Social Network Index (SNI), measuring the presence/absence of 12 types of common social relationships. Results: Stroke events occurred among 5.1% of the sample over follow-up. More isolated women were older and less educated, with higher rates of smoking and hypertension, and increased use of cardiovascular medications. Women with smaller social networks were also more likely to show elevations (scores of ≥10) on the Beck Depression Inventory (54% versus 41%, respectively; p = .003). Relative to women with higher SNI scores, Cox regression results indicated that more isolated women experienced strokes at greater than twice the rate of those with more social relationships after adjusting for covariates (hazard ratio = 2.7; 95% Confidence Interval = 1.1–6.7). Conclusions: Smaller social networks are a robust predictor of stroke in at-risk women, and the magnitude of the association rivals that of conventional risk factors. CAD = coronary artery disease; SES = socioeconomic status; CVD = cardiovascular disease; WISE = Women's Ischemia Syndrome Evaluation; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft; SNI = Social Network Index; BDI = Beck Depression Inventory; HR = hazard ratio.

AIM The aim of this study was to examine the association between the use of lipid-lowering medication and aggressive responding, hostility, cynicism, and depression scores in women undergoing coronary angiography. METHODS The cohort included 498 women from the National Heart, Lung and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. WISE is a four-center study of women with chest pain who underwent quantitative coronary angiography for suspected myocardial ischemia. The psychosocial indices included the Cook Medley Hostility questionnaire, measuring aggression, hostility, and cynicism, and the Beck Depression Inventory (BDI). RESULTS Compared to those not on lipid-lowering medication, women receiving lipid-lowering pharmacotherapy were older (62 vs. 55 years, p < 0.001) and had more hypertension, dyslipidemia, diabetes, and coronary artery disease (CAD, defined as > or =50% stenoses in at least one epicardial artery) (all p < 0.003). Women on lipid-lowering medication had higher aggressive responding scores than those not on medication, 3.0 +/- 1.8 vs. 2.7 +/- 1.7, respectively (age-adjusted p < 0.003). This association persisted after adjustment for coronary risk factors, education, and extent of angiographic disease (CAD) (p < 0.005), and after exclusion of women using psychotropic medications (p < 0.001). Hostility, cynicism, and depression scores did not differ by medication use.

Background: The relationship between depression and the metabolic syndrome is unclear, and whether metabolic syndrome explains the association between depression and cardiovascular disease (CVD) risk is unknown. Methods: We studied 652 women who received coronary angiography as part of the Women's Ischemia Syndrome Evaluation (WISE) study and completed the Beck Depression Inventory (BDI). Women who had both elevated depressive symptoms (BD1 >= 10) and a previous diagnosis of depression were considered at highest risk, whereas those with one of the two conditions represented an intermediate group. The metabolic syndrome was defined according to the ATP-III criteria. The main outcome was incidence of adverse CVD events (hospitalizations for myocardial infarction, stroke, congestive heart failure, and CVD-related mortality) over a median follow-up of 5.9 years. Results: After adjusting for demographic factors, lifestyle and functional status, both depression categories were associated with about 60% increased odds for metabolic syndrome compared with no depression (p = .03). The number of metabolic syndrome risk factors increased gradually across the three depression categories (p = .003). During follow-up, 104 women (15.9%) experienced CVD events. In multivariable analysis, women with both elevated symptoms and a previous diagnosis of depression had 2.6 times higher risk of CVD. When metabolic syndrome was added to the model, the risk associated with depression only decreased by 7%, and both depression and metabolic syndrome remained significant predictors of CVD. Conclusions: In women with suspected coronary artery disease, the metabolic syndrome is independently associated with depression but explains only a small portion of the association between depression and incident CVD.

BACKGROUND:Altered coronary reactivity is frequent in women with findings of myocardial ischemia without significant obstructive disease. This suggests a defect in coronary microvascular function. The adenosine-related component of this altered reactivity has been described in male and mixed gender populations, while the factors influencing this component of coronary reactivity in symptomatic women have received limited attention. Accordingly, the relationship between adenosine-related microvascular coronary reactivity and risk factors in symptomatic women evaluated for suspected ischemia remains uncertain.HYPOTHESIS:Abnormal coronary microvascular reactivity to adenosine is predicted by atherosclerosis risk factors in women.METHODS:As part of the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE), we investigated the relationship between risk factors and coronary microvascular reactivity as flow velocity reserve to intracoronary adenosine (CFVR(Ado)) in 210 women referred for angiography to evaluate suspected ischemia.RESULTS:Univariate analyses identified associations between CFVR(Ado) and multiple risk conditions; however, after adjusting for age, none remained significant. The best multivariable model using combinations of risk conditions to predict CFVR(Ado) yielded an R2 of only 0.18.CONCLUSIONS:Among women with suspected ischemia, risk factors account for <20% of observed variability in CFVR(Ado). Therefore, other as yet unidentified factors must primarily account for coronary microvascular reactivity to adenosine.

Background: Compared with men, women have more evidence of myocardial ischemia in the setting of no obstructive coronary artery disease (CAD). While low endogenous estrogen levels are associated with endothelial dysfunction, the role of low dose hormone therapy has not been fully evaluated in women suffering from myocardial ischemia and no obstructive CAD. Objective: This WISE ancillary trial evaluated the effect of low dose hormone therapy in postmenopausal women with myocardial ischemia and no obstructive CAD on: endothelial dysfunction, assessed by brachial artery reactivity, physical functional disability assessed by exercise testing, and quality of life assessed by cardiac symptoms and psychological questionnaires. Methods: Using a multicenter, randomized, placebo-controlled design, seventy-four participants with normal/minimally diseased epicardial coronary arteries (<50% luminal diameter stenosis) who fulfilled the inclusion criteria were planned to be randomized to receive either 1 mg norethindrone/10 mcg ethinyl estradiol (1/10 NA/EE) or placebo for twelve weeks. Baseline and exit brachial artery reactivity (BART), exercise stress testing, WISE psychosocial questionnaires, SF-36, blood lipids and hormone levels were evaluated. Results: Recruitment was closed prematurely due to failure to recruit in the year following publication of the Women’s Health Initiative hormone trial results. Of the 37 women randomized, 35 completed the study. While there was no difference in the frequency of chest pain between groups at the baseline visit, at study exit there was less frequent chest pain in the 1/10 NA/EE group compared to the placebo group (p=0.02). Women taking 1/10 NA/EE also showed a trend to improved BART and exercise tolerance, and had significantly fewer hot flashes/night sweats (p=0.003), less avoidance of intimacy (p=0.05), and borderline differences in sexual desire and vaginal dryness (p=0.06). Conclusion: Among postmenopausal women with myocardial ischemia and no obstructive CAD, hormone therapy with 1/10 NA/EE is associated with reduced chest pain symptoms, menopausal symptoms and improved quality of life with trends for improved endothelial function and exercise performance.

OBJECTIVE:To determine the relationship of anger and hostility to angiographic coronary artery disease (CAD), symptoms, and functional status among women with suspected CAD.METHODS:Data were collected from 636 women with suspected CAD referred for diagnostic angiography in the Women's Ischemia Syndrome Evaluation (WISE) Study. CAD was assessed as angiographic presence/absence of disease (> or =50% stenosis in any epicardial coronary artery). Hostility/anger, angina, symptoms, and functional status were assessed by the Cook-Medley Hostility Inventory, Spielberger Anger Expression Scale, cardiovascular symptom history, and the Duke Activity Status Index.RESULTS:Logistic regression revealed that anger-out (i.e., aggressive behavior in response to angry feelings) was independently associated with the presence/absence of angiographic CAD (OR = 1.09, CI 1.01-1.17). Anger and hostility were higher among women reporting increased cardiovascular symptoms. In women without angiographic CAD, those with nonanginal cardiac symptoms had the highest anger-out, anger expression, hostile affect, and aggressive responding scores, and those with typical angina reported the lowest functional status. Among women with CAD, functional status was lowest in women with atypical angina.CONCLUSIONS:Among women with suspected CAD, anger-out scores were associated with the presence of angiographic CAD. Anger/hostility traits were associated with increased symptoms, particularly with nonanginal chest pain in women without angiographic CAD. Relationships among psychosocial factors, cardiac symptoms, and angiographic CAD are potentially important in the management of women with suspected CAD.

PURPOSE:Relationships between body weight and disease are not straightforward. Central obesity appears to be a relatively greater cardiovascular risk factor than generalized obesity. The purpose of this study was to evaluate body mass index (BMI) and waist circumference and the association of obesity distribution with blood estrogen levels (estradiol, bioavailable estradiol, and estrone).METHODS:The study cohort consisted of 207 postmenopausal women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) undergoing angiography for evaluation of suspected ischemia.RESULTS:Both BMI and waist circumference were positively associated with all three blood estrogen levels (p < 0.01), with the highest estrogen levels found in the obese women with large waists (p < 0.01). Results from regression analyses confirmed significant associations of BMI and waist circumference with the estrogen levels.CONCLUSIONS:These results demonstrate differing relationships between blood estrogen levels and obesity distribution in a cohort of postmenopausal women with chest pain undergoing coronary angiography. The differing levels by general and central obesity may help explain in part observed epidemiological relationships between obesity and disease.