Usefulness of the American Heart Association's Ideal Cardiovascular Health Measure to Predict Long-term Major Adverse Cardiovascular Events (From the Heart SCORE Study).

To further reduce the burden of cardiovascular disease (CVD) and expand prevention efforts, the American Heart Association (AHA) introduced in 2010 the concept of Ideal Cardiovascular Health (ICH), which includes 7 metrics (smoking status, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting plasma glucose). Limited data exist on the relation between ICH and long-term CVD risk. The Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study cohort was used to examine the relation between ICH and incident major adverse cardiovascular events (MACE: first occurrence of death, myocardial infarction, stroke, acute ischemic syndrome, or coronary revascularization). The 7 factors of the ICH were scored at study entry on a 0 to 2 scale, resulting in possible range of 0 to 14, with higher scores representing "better" health. Cox regression analyses were used to estimate hazard ratios (HR) of MACE, along with 95% confidence intervals. Over a median follow-up of 12 years, the study population (n = 1,863, 67% women, 42% Black race, mean age 59 years [range 45 to 75]) had 218 MACE. In unadjusted analysis, the ICH score (per 1 unit) was associated with an estimated 12% lower risk of MACE (HR [95% Confidence Interval]: 0.88 [0.82, 0.93]). Adjusting for demographics, education, and quality of life, ICH score was associated with a 10% lower risk of MACE (HR 0.90 [0.84, 0.96]). In a community-based sample of adults, the AHA ICH construct, which includes 7 modifiable CVD risk factors, appears to be a valid measure for predicting long-term risk of MACE.

Risk factors for heart failure in women with ischemia and no obstructive coronary artery disease.

Study objective: Women with ischemia and no obstructive coronary artery disease (INOCA) are at increased risk for heart failure (HF) hospitalizations, which is predominantly HF with preserved ejection fraction (HFpEF). We aimed to identify predictors for the development of heart failure HF in a deeply phenotyped cohort of women with INOCA and long-term prospective follow-up. Design setting and participants: Women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) were evaluated for baseline characteristics including clinical history, medications, physical exam, laboratory data and angiographic data. Using a multivariate Cox analysis, we assessed the association between baseline characteristics and the occurrence of HF hospitalizations in 493 women with evidence of ischemia but no obstructive coronary disease, no prior history of HF, and available follow-up data. Results: During a median follow-up of 6-years, 18 (3.7%) women were hospitalized for HF. Diabetes mellitus and tobacco use were associated with HF hospitalization. In a multivariate analysis adjusting for known HFpEF predictors including age, diabetes, hypertension, tobacco use, and statin use, novel predictive variables included higher resting heart rate, parity and IL-6 levels and lower coronary flow reserve (CFR) and poor functional status. Conclusions: There is a considerable incidence of HF hospitalization at longer term follow-up in women with INOCA. In addition to traditional risk factors, novel risk variables that independently predict HF hospitalization include multi-parity, high IL-6, low CFR, and poor functional status. These novel risk factors may be useful to understand mechanistic pathways and future treatment targets for prevention of HFpEF.

Lactation and Maternal Subclinical Atherosclerosis Among Women With and Without a History of Hypertensive Disorders of Pregnancy.

Background: We evaluated subclinical cardiovascular disease in relation to lactation history among women with normotensive pregnancies and women with hypertensive pregnancies, a distinction not previously examined. Materials and Methods: The POUCHmoms study included 678 women from a pregnancy cohort who were followed 7-15 years after delivery. We measured blood pressure, lipid levels, carotid intima-media thickness (CIMT), and lactation duration for each live birth (LB) at follow-up. We categorized lactation as never, <6 months/LB, or ≥6 months/LB. We analyzed associations between lactation and cardiometabolic risk factors and CIMT by using analysis of variance and multivariable linear regression (adjusted for age, race, socioeconomic status, smoking, time from last pregnancy, and total parity), which produced adjusted least square mean differences (LSMdiff) between groups. Results: In the normotensive pregnancies group with women who never lactated as the referent (n = 157): Women with some lactation but <6 months/LB (n = 284) had higher high density lipoprotein (HDL) (LSMdiff = +4.47 mg/dL, p = 0.013), lower triglycerides (LSMdiff = -38.1 mg/dL, p = 0.02), and thinner mean CIMT (LSMdiff = -0.03 mm, p = 0.005); women who lactated for ≥6 months/LB (n = 133) also had higher HDL (LSMdiff = +7.59 mg/dL, p < 0.001), lower triglycerides (LSMdiff = -41.6 mg/dL, p = 0.01), and thinner mean CIMT (LSMdiff = -0.03 mm, p = 0.003). After further adjustment for body mass index, associations between lactation and HDL, triglycerides, and mean CIMT persisted. These associations were not detected in women with prior hypertensive pregnancies. Conclusions: Women with a history of normotensive pregnancies and lactation for any duration had a more favorable cardiometabolic profile and were at decreased risk of subclinical atherosclerosis compared with those who never lactated.

Ideal Cardiovascular Health Metrics in Couples: A Community-Based Study.

BACKGROUND: Determination of the correlation of ideal cardiovascular health variables among spousal or cohabitating partners may guide the development of couple-based interventions to reduce cardiovascular disease risk. METHOD AND RESULTS: We used data from the HeartSCORE (Heart Strategies Concentrating on Risk Evaluation) study. Ideal cardiovascular health, defined by the American Heart Association, comprises nonsmoking, body mass index <25 kg/m2, physical activity at goal, diet consistent with guidelines, untreated total cholesterol <200 mg/dL, untreated blood pressure <120/80 mm Hg, and untreated fasting glucose <100 mg/dL. McNemar test and logistic regression were used to assess concordance patterns in these variables among partners (ie, concordance in achieving ideal factor status, concordance in not achieving ideal factor status, or discordance-only one partner achieving ideal factor status). Overall, there was a low prevalence of ideal cardiovascular health among the 231 couples studied (median age 61 years, 78% white). The highest concordances in achieving ideal factor status were for nonsmoking (26.1%), ideal fruit and vegetable consumption (23.9%), and ideal fasting blood glucose (35.6%). The strongest odds of intracouple concordance were for smoking (odds ratio, 3.6; 95% confidence interval, 1.9-6.5), fruit and vegetable consumption (odds ratio, 4.8; 95% confidence interval, 2.5-9.3) and blood pressure (odds ratio, 3.0; 95% confidence interval, 1.2-7.9). A participant had 3-fold higher odds of attaining ≥3 ideal cardiovascular health variables if he or she had a partner who attained ≥3 components (odds ratio 3.0; 95% confidence interval, 1.6-5.6). CONCLUSIONS: Intracouple concordance of ideal cardiovascular health variables supports the development and testing of couple-based interventions to promote cardiovascular health. Fruit and vegetable consumption and smoking may be particularly good intervention targets.

Particulate Matter Air Pollution and Racial Differences in Cardiovascular Disease Risk.

OBJECTIVE: We aimed to assess racial differences in air pollution exposures to ambient fine particulate matter (particles with median aerodynamic diameter <2.5 µm [PM2.5]) and black carbon (BC) and their association with cardiovascular disease (CVD) risk factors, arterial endothelial function, incident CVD events, and all-cause mortality. APPROACH AND RESULTS: Data from the HeartSCORE study (Heart Strategies Concentrating on Risk Evaluation) were used to estimate 1-year average air pollution exposure to PM2.5 and BC using land use regression models. Correlates of PM2.5 and BC were assessed using linear regression models. Associations with clinical outcomes were determined using Cox proportional hazards models, adjusting for traditional CVD risk factors. Data were available on 1717 participants (66% women; 45% blacks; 59±8 years). Blacks had significantly higher exposure to PM2.5 (mean 16.1±0.75 versus 15.7±0.73µg/m3; P=0.001) and BC (1.19±0.11 versus 1.16±0.13abs; P=0.001) compared with whites. Exposure to PM2.5, but not BC, was independently associated with higher blood glucose and worse arterial endothelial function. PM2.5 was associated with a higher risk of incident CVD events and all-cause mortality combined for median follow-up of 8.3 years. Blacks had 1.45 (95% CI, 1.00-2.09) higher risk of combined CVD events and all-cause mortality than whites in models adjusted for relevant covariates. This association was modestly attenuated with adjustment for PM2.5. CONCLUSIONS: PM2.5 exposure was associated with elevated blood glucose, worse endothelial function, and incident CVD events and all-cause mortality. Blacks had a higher rate of incident CVD events and all-cause mortality than whites that was only partly explained by higher exposure to PM2.5.

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study.

BACKGROUND: Sudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Women's Ischemia Syndrome Evaluation) study. METHODS AND RESULTS: Overall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and as SCD or non-SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person-hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P<0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively (P value not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression (P=0.018) and longer corrected QT interval (P=0.023) were independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD (P=0.033). CONCLUSIONS: SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women.

Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries.

A recent genome-wide association study (GWAS) for dental caries nominated the chromosomal region 4q21 near ABCG2, PKD2 and the SIBLING (small integrin-binding ligand N-linked glycoprotein) gene family. In this investigation, we followed up and fine-mapped this region using a tag-SNP (single-nucleotide polymorphism) approach in 13 age- and race-stratified samples from 6 independent studies (N=4089). Participants were assessed for dental caries via intraoral examination and 49 tag-SNPs were genotyped capturing much of the variation in the 4q21 locus. Linear models were used to test for genetic association, while adjusting for sex, age and components of ancestry. SNPs in and near PKD2 showed significant evidence of association in individual samples of black adults (rs17013735, P-value=0.0009) and white adults (rs11938025; P-value=0.0005; rs2725270, P-value=0.003). Meta-analyses across black adult samples recapitulated the association with rs17013735 (P-value=0.003), which occurs at low frequency in non-African populations, possibly explaining the race specificity of the effect. In addition to race-specific associations, we also observed evidence of gene-by-fluoride exposure interaction effects in white adults for SNP rs2725233 upstream of PKD2 (P=0.002). Our results show evidence of regional replication, though no single variant clearly accounted for the original GWAS signal. Therefore, while we interpret our results as strengthening the hypothesis that chromosome 4q21 may impact dental caries, additional work is needed.

Cardiovascular Disease and 10-Year Mortality in Postmenopausal Women with Clinical Features of Polycystic Ovary Syndrome.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) have greater cardiac risk factor clustering but the link with mortality is incompletely described. OBJECTIVE: To evaluate outcomes in 295 postmenopausal women enrolled in the National Institutes of Health-National Heart, Lung, and Blood Institute (NIH-NHLBI) sponsored Women's Ischemia Syndrome Evaluation (WISE) study according to clinical features of PCOS. MATERIALS AND METHODS: A total of 25/295 (8%) women had clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia, defined as the top quartile of androstenedione (≥701 pg/mL), testosterone (≥30.9 ng/dL), or free testosterone (≥4.5 pg/mL). Cox proportional hazard model estimated death (n = 80). RESULTS: Women with clinical features of PCOS had an earlier menopause (p = 0.01), were more often smokers (p < 0.04), and trended toward more angiographic coronary artery disease (CAD) (p = 0.07) than women without these features. Cumulative 10-year mortality was 28% for women with (n = 25) versus 27% without clinical features of PCOS (n = 270) (p = 0.85). PCOS was not a significant predictor (p = NS) in prognostic models including diabetes, waist circumference, hypertension, and angiographic CAD. CONCLUSION: From this longer-term follow up of a relatively small cohort of postmenopausal women with suspected ischemia, the prevalence of PCOS is similar to the general population, and clinical features of PCOS are not associated with CAD or mortality. These findings question whether identification of clinical features of PCOS in postmenopausal women who already have known cardiovascular disease provides any additional opportunity for risk factor intervention.

Endothelial Dysfunction and Racial Disparities in Mortality and Adverse Cardiovascular Disease Outcomes.

BACKGROUND: The contribution of arterial endothelial dysfunction (ED) to increased cardiovascular disease (CVD) risk among Blacks is not known. HYPOTHESIS: We investigated whether peripheral arterial ED explains racial disparity in CVD events. METHODS: Data from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study was used. Endothelial dysfunction was assessed by the Framingham reactive hyperemia index (fRHI), measured using pulse amplitude tonometry (PAT). Lower values of fRHI indicate more severe ED. The primary outcome of interest was combined CVD events and all-cause mortality. RESULTS: 1454 individuals (62% female, 40% Black, mean age 59 ± 8 years) had available data on fRHI (mean [SD]: 0.74 [0.46]). Over a mean follow-up period of 8.0 ± 2.4 years (11,186 person-years), 116 events were observed. Black race, male sex, smoking, diabetes, blood pressure, triglycerides, C-reactive protein, and interleukin-6 were inversely correlated with fRHI in univariate models. In an unadjusted Cox regression model, fRHI was associated with 20% lower risk of the primary outcome events (hazard ratio [HR] per 1-SD higher fRHI: 0.80, 95% confidence interval [CI]: 0.66-0.97). However, this association was no longer significant after adjustment for CVD risk factors (HR: 0.90, 95% CI: 0.74-1.11). In an age- and sex-adjusted model, Blacks had 1.68 (95% CI: 1.16-2.43) higher risk of primary outcome compared with Whites. This association was not significantly attenuated by addition of fRHI to the multivariable models. CONCLUSION: Black race is associated with increased risk of CVD events and mortality independent of its associations with ED, as measured by PAT.

Traditional and nontraditional cardiovascular risk factors in comorbid insomnia and sleep apnea.

OBJECTIVES: Insomnia and sleep apnea frequently co-occur and are independently associated with an increased risk of cardiovascular disease, but little is known about cardiovascular disease risk among individuals with comorbid insomnia and sleep apnea. The current study examined traditional risk factors and a physiologic biomarker of cardiovascular risk in comorbid insomnia and sleep apnea. DESIGN: Community-based participatory research study. PARTICIPANTS: The sample comprised 795 participants without preexisting cardiovascular disease from the Heart Strategies Concentrating On Risk Evaluation (Heart SCORE) study. MEASUREMENTS AND RESULTS: Participants were assessed for symptoms of insomnia and sleep apnea risk, as well as for presence of obesity, smoking, a sedentary lifestyle, hypertension, dyslipidemia, and diabetes. Baseline resting brachial artery diameter was measured by B-mode ultrasonography. A total of 138 participants (17.4%) met criteria for insomnia syndrome alone, 179 (22.5%) were at high risk for sleep apnea alone, 95 (11.9%) reported both insomnia syndrome and high sleep apnea risk, and 383 (48.2%) reported having neither insomnia nor sleep apnea symptoms Both high sleep apnea risk alone and comorbid insomnia and high sleep apnea risk groups had greater frequencies of obesity, sedentary lifestyle, hypertension, and three or more traditional cardiovascular risk factors and significantly larger brachial artery diameters than the insomnia alone group and those without insomnia or sleep apnea symptoms. No differences in traditional cardiovascular risk factors or brachial artery diameter were found between the high sleep apnea risk and comorbid groups. CONCLUSIONS: These findings suggest that sleep apnea is a major contributor to cardiovascular risk and co-occurring insomnia does not appear to add to this risk.

The µ-opioid receptor variant N190K is unresponsive to peptide agonists yet can be rescued by small-molecule drugs.

The µ-opioid receptor (MOR) plays an important role in modulating analgesia, feeding behavior, and a range of autonomic functions. In the current study, we investigated the degree to which 13 naturally occurring missense mutations affect the pharmacological properties of the human MOR. After expression of each receptor in human embryonic kidney 293 cells, signaling (Gα(i/o)-mediated) induced by peptide agonists was assessed using luciferase reporter gene assays. Multiple mutants (S66F, S147C, R260H, R265C, R265H, and S268P) show a significant reduction in agonist potency. At the N190K variant, agonist-mediated signaling was essentially absent. Enzyme-linked immunosorbent assay, microscopic analysis, and radioligand binding assays revealed that this mutant shows markedly reduced cell-surface expression, whereas all other receptor variants were expressed at normal levels. Surface expression of the N190K variant could be increased by incubation with the alkaloid agonist buprenorphine or with either naltrexone or naloxone, structurally related MOR antagonists. We were surprised to find that both putative antagonists, despite being inactive at the wild-type MOR, triggered a concentration-dependent increase in N190K receptor-mediated signaling. In contrast, peptidic ligands failed to promote expression or rescue function of the N190K mutant. Subsequent analysis of the N190K variant in an ethnically diverse cohort identified this isoform in a subgroup of African Americans. Taken together, our studies reveal that the N190K mutation leads to severe functional alterations and, in parallel, changes the response to established MOR ligands. The extent to which this mutation results in physiological abnormalities or affects drug sensitivity in selected populations (e.g., those with chronic pain or addiction) remains to be investigated.

Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study.

OBJECTIVES: We investigated whether coronary microvascular dysfunction predicts major adverse outcomes during follow-up among women with signs and symptoms of ischemia. BACKGROUND: Altered coronary reactivity occurs frequently in women evaluated for suspected ischemia, and the endothelium-dependent component is linked with adverse outcomes. Possible links between endothelium-independent microvascular coronary reactivity and adverse outcomes remain uncertain. METHODS: As part of the National Heart, Lung and Blood Institute-sponsored WISE (Women's Ischemia Syndrome Evaluation), we investigated relationships between major adverse outcomes and baseline coronary flow reserve (CFR) after intracoronary adenosine in 189 women referred to evaluate suspected ischemia. RESULTS: At a mean of 5.4 years, we observed significant associations between CFR and major adverse outcomes (death, nonfatal myocardial infarction, nonfatal stroke, or hospital stay for heart failure). An exploratory receiver-operator characteristic analysis identified CFR <2.32 as the best discriminating threshold for adverse outcomes (event rate 26.7%; and >or=2.32 event rate 12.2%; p = 0.01). Lower CFR was associated with increased risk for major adverse outcomes (hazard ratio: 1.16, 95% confidence interval: 1.04 to 1.30; p = 0.009). This held true among the 152 women without obstructive coronary artery disease (CAD) (hazard ratio: 1.20, 95% confidence interval: 1.05 to 1.38; p = 0.008). The CFR significantly improved prediction of adverse outcomes over angiographic CAD severity and other risk conditions. CONCLUSIONS: Among women with suspected ischemia and atherosclerosis risk factors, coronary microvascular reactivity to adenosine significantly improves prediction of major adverse outcomes over angiographic CAD severity and CAD risk factors. These findings suggest that coronary microvessels represent novel targets for diagnostic and therapeutic strategies to predict and limit adverse outcomes in women. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00000554).

Acute physiologic effects of secondhand smoke exposure in children.

INTRODUCTION: We investigated the hypothesis that exhaled carbon monoxide (eCO), heart rate (HR), and blood pressure (BP) would increase acutely in exposed but not in unexposed children. METHODS: In a nonrandomized controlled design, parent-child dyads were assigned to groups based on exposure: child subjects, 7-18 years of age, exposed to smoking daily in the home (exposed) or with no household exposure (unexposed control). HR, BP, and eCO were measured before and after exposure to a parent smoking 1 cigarette (exposed) or a time-lapse equivalent (control). The primary analysis compared mean acute changes in physiological measures following intervention or control procedure. RESULTS: Forty-one dyads were enrolled. At baseline, no differences in child gender, race, ethnicity, HR, BP, lipids, or fasting glucose were noted between exposure groups. Following experimental or control procedures, the median change in eCO was similar between groups (-0.1 ppm exposed vs. 0.0 ppm unexposed, p = .27). Acute hemodynamic changes were also similar between exposed and unexposed children, respectively: (HR change 4.2 vs. 2.6 beats per minute, p = .62; systolic blood pressure change 0.08 vs. 0.41 mm Hg, p = .91; diastolic blood pressure 0.08 vs. 2.27 mm Hg, p = .37). DISCUSSION: This is the first study to report on acute physiologic changes of secondhand smoke exposure in children in a naturalistic setting. A single acute dose of passive smoke exposure in children did not alter the physiologic variables of HR or BP. Further in-home study using continuous monitoring is needed. Demonstration of acute effects may serve as clinical feedback to motivate parents to quit smoking.

Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer.

The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)-approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05-1.47) and for noninvasive disease, 1.22 (95% CI, 0.95-1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36-0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12-0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60-0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer.

Total estrogen time and obstructive coronary disease in women: insights from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE).

OBJECTIVE: It has been suggested that both endogenous reproductive hormones and hormone therapy may play a protective role against coronary artery disease (CAD). However, recent clinical trials have failed to demonstrate the benefit of a variety of forms of hormone therapy. The observational data on the role of endogenous reproductive hormones, using surrogate measures such as number of birth, age at menarche, and age at menopause are inconsistent. In addition, the longer-term associations have not been evaluated. The aim of this study was to evaluate the relationships between detailed measurements of endogenous and exogenous estrogen exposure time with angiographic CAD and major adverse cardiovascular events. METHODS: We assessed total estrogen exposure time, quantitative CAD by a core angiography laboratory, and prospectively measured major adverse cardiovascular events in 646 postmenopausal women undergoing coronary angiography for evaluation for suspected ischemia in the Women's Ischemia Syndrome Evaluation (WISE) study. RESULTS: Timing of postmenopausal exogenous hormone therapy (HT) use was associated with reduced CAD. Two summarized total estrogen time scores (TET and sTET) were not related to angiographic CAD after accounting for HT use. In addition, these scores were not related to cardiovascular events over a median of 6.0 years of follow-up. CONCLUSIONS: There was no independent relation of estrogen exposure time to angiographic CAD or major adverse cardiovascular events in a contemporary cohort of postmenopausal women evaluated for suspected ischemia. Our results suggest that the paradigm of estrogen protection from CAD in women may be more complex than estrogen exposure duration alone.

Multimarker approach predicts adverse cardiovascular events in women evaluated for suspected ischemia: results from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation.

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 >or= 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.

Coronary vasospasm and atrial fibrillation associated with ondansetron therapy.

OBJECTIVE: To provide further evidence of cardiovascular adverse effects of ondansetron, including new-onset atrial fibrillation, ST segment elevation, and chest pain subsequent to ondansetron administration, and to review cardiovascular adverse events related to several 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonists. CASE SUMMARY: A 51-year-old male with an uncomplicated past medical history was admitted for an elective inguinal hernia repair and septoplasty. His maintenance medications were discontinued prior to surgery. After a second 4-mg dose of intravenous ondansetron was administered, he developed nausea and diaphoresis. His electrocardiograph revealed new-onset atrial fibrillation and inferolateral ST segment elevation with ST segment alternans. During emergent cardiac catheterization, no obstructive coronary artery disease was evident. The patient's heart rhythm was electrically converted to normal sinus rhythm. During 3 years of follow-up, he has had no return of chest pain or hypotension. DISCUSSION: Although considered a safe class of medications by many clinicians, several of the 5-HT(3) receptor antagonists have been associated with serious cardiovascular effects. Three case reports described cardiac dysrhythmias and 9 documented coronary vasospasm and chest pain, possibly resulting from ondansetron. This is the first reported case of a combination of hypotension, atrial fibrillation, ST segment elevation, and chest pain following ondansetron administration after elective surgery in a healthy adult male with a nonconfounding medication profile. The Naranjo probability scale indicated that ondansetron was the probable cause of these cardiovascular events. CONCLUSIONS: This case report supports the concern regarding cardiovascular adverse effects of ondansetron. Clinicians should be aware of cardiovascular adverse reactions that may be associated with intravenous ondansetron and monitor for electrocardiographic changes as indicated. Further investigation is needed to delineate the actual incidence of cardiovascular effects associated with ondansetron and whether the intravenous rate of administration is a contributing factor.

Social networks and incident stroke among women with suspected myocardial ischemia.

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 > or =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.

Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health--National Heart, Lung, and Blood Institute sponsored Women's Ischemia Syndrome Evaluation.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) have a greater clustering of cardiac risk factors. However, the link between PCOS and cardiovascular (CV) disease is incompletely described. OBJECTIVE: The aim of this analysis was to evaluate the risk of CV events in 390 postmenopausal women enrolled in the National Institutes of Health-National Heart, Lung, and Blood Institute (NIH-NHLBI) sponsored Women's Ischemia Syndrome Evaluation (WISE) study according to clinical features of PCOS. METHODS: A total of 104 women had clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia. Hyperandrogenemia was defined as the top quartile of androstenedione (> or = 701 pg/ml), testosterone (> or = 30.9 ng/dl), or free testosterone (> or = 4.5 pg/ml). Cox proportional hazard model was fit to estimate CV death or myocardial infarction (n = 55). RESULTS: Women with clinical features of PCOS were more often diabetic (P < 0.0001), obese (P = 0.005), had the metabolic syndrome (P < 0.0001), and had more angiographic coronary artery disease (CAD) (P = 0.04) compared to women without clinical features of PCOS. Cumulative 5-yr CV event-free survival was 78.9% for women with clinical features of PCOS (n = 104) vs. 88.7% for women without clinical features of PCOS (n = 286) (P = 0.006). PCOS remained a significant predictor (P < 0.01) in prognostic models including diabetes, waist circumference, hypertension, and angiographic CAD as covariates. CONCLUSION: Among postmenopausal women evaluated for suspected ischemia, clinical features of PCOS are associated with more angiographic CAD and worsening CV event-free survival. Identification of postmenopausal women with clinical features of PCOS may provide an opportunity for risk factor intervention for the prevention of CAD and CV events.

Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study.

OBJECTIVES: The purpose of this study was to examine prospectively whether inflammation explains the relationship between depression and cardiovascular disease (CVD). BACKGROUND: It is unclear whether inflammation is a mechanism linking depression to CVD. METHODS: We measured C-reactive protein (CRP) and interleukin (IL)-6 in 559 women with suspected coronary ischemia who completed the Beck Depression Inventory (BDI) at baseline and were followed over 5.9 years. We considered indicators of past and current depression to classify women into 3 groups: 1) depression, having both elevated depressive symptoms (BDI > or =10) and a previous diagnosis of depression requiring treatment; 2) possible depression, having either indicator but not both; and 3) no depression, having neither indicator of depression. The main outcome was incidence of CVD events (hospital stays for nonfatal myocardial infarction, stroke, congestive heart failure, and CVD-related mortality). RESULTS: Compared with women without depression, women with depression had a 70% higher CRP (p = 0.0008) and a 25% higher IL-6 (p = 0.04), whereas women with possible depression had 30% higher CRP (p = 0.02) and 28% higher IL-6 (p = 0.01). Depression was a significant predictor of CVD (hazard ratio 2.58, p = 0.0009), but possible depression was not (hazard ratio 1.12, p = 0.68). Adjustment for other patient factors did not substantially affect the results. Addition of CRP decreased the estimate for depression by 13% and addition of IL-6 decreased it by 4%. Both depression and inflammatory biomarkers remained independent predictors of outcome. CONCLUSIONS: Despite their robust association with depression, inflammatory biomarkers explain only a small portion of the association between depression and CVD incidence.