Inflammation and Cardiometabolic Risk in African American Women Is Reduced by a Pilot Community-Based Educational Intervention.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death for women, and African Americans have higher rates of CVD mortality than do other racio/ethnic groups. Women in community settings can benefit from preventive interventions, yet few investigations of successful programs have been conducted and evaluated in high-risk women, especially for metabolic syndrome. The purpose of our study was to pilot and assess the effectiveness of a 4-month pre-/post-CVD preventive educational intervention in improving knowledge, clinical risk profiles, adoption of heart-healthy lifestyles, inflammatory burden, and cardiometabolic risk in African American women in local communities. METHODS: Forty-two African American women (mean age 59 years) enrolled in the 4-month educational Cardiovascular Disease Preventive Intervention Program in Sacramento, CA, in 2010. Participants completed knowledge-based surveys pre-/postintervention, provided clinical measures (weight, waist circumference, body mass index (BMI), blood pressure and blood samples for analysis of fasting glucose and lipids, and inflammatory markers: tumor necrosis factor (TNF)-α±, high-sensitivity C-reactive protein (hs-CRP), and interleukin (IL)-12. RESULTS: The CVD risk profile of participants confirmed a high-risk cohort. Postintervention (n=31), there were significant (p<0.05) gains in knowledge for all symptoms of a heart attack and calling 911; improvements in clinical risk parameters, especially for waist circumference and low-density lipoprotein (LDL) cholesterol (p<0.05); and reductions in all the inflammatory markers assessed: TNF-α±by 16%, IL-12 by 20%, and hs-CRP by 26% (p<0.05). There was also a 60% reduction in the number of participants with metabolic syndrome (MetS) (p<0.05), driven primarily by reductions in triglycerides and glucose and a rise in high-density lipoprotein (HDL) cholesterol. CONCLUSIONS: We demonstrated the efficacy of a pilot community-based educational cardiovascular program in reducing cardiometabolic risk and inflammation in high-risk African American women. Our successful culturally appropriate and sustainable model could be implemented as part of comprehensive efforts to improve community-based health outcomes.

Community-based cardiovascular disease prevention to reduce cardiometabolic risk in Latina women: a pilot program.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women, yet significant health disparities exist for high-risk groups, including Latinas, and comprehensive, culturally relevant, and effective prevention intervention models are lacking. We used a systems approach to develop, assess, and pilot a community-based education program for improving outcomes for knowledge/awareness of CVD, cardiometabolic risk, and health behaviors in Latinas. METHODS: Latinas (n=35, mean age 50) participated in a 4-month community-based bilingual preventive cardiovascular education program. Pre/post analyses were for knowledge/awareness of CVD risk factors, symptoms, calling 911; personal risk factors (smoking, physical inactivity, family history of CVD); clinical parameters (weight, body mass index [BMI], waist, blood pressure, fasting lipids, and glucose); diagnosis of metabolic syndrome (MetS); and serum inflammatory markers (tumor necrosis factor [TNF]-α, high-sensitivity C reactive protein [hsCRP], and interleukin [IL]-12). RESULTS: Baseline knowledge/awareness was relatively low, risk factors and MetS prevalent, and serum inflammatory markers elevated. Postintervention, participants demonstrated significant (p<0.05) improvements in knowledge of symptoms, risk factors for CVD, calling 911, and knowledge/adoption of heart-healthy behaviors. Clinical health status also improved, especially for serum triglycerides (p<0.05; 21% decline), prevalence of MetS (from 43% to 37% of participants), and serum levels of the proinflammatory TNF-α (from 16.9 ± 1.11 pg/mL to 13.5 ± 0.8 pg/mL, p<0.05). CONCLUSION: A bilingual culturally appropriate community-based CVD-prevention program based on health education, medical screenings, and empowerment is a successful, effective, adaptable, and replicable model to significantly improve cardiometabolic risk in Latinas.

Testosterone-derived estradiol production by male endothelium is robust and dependent on p450 aromatase via estrogen receptor alpha.

Vascular endothelium expresses both the estrogen receptors (ERs) α and ß, and ERα mediates development of early atherosclerosis in male mice. This process is thought to be testosterone-dependent. We hypothesized that male murine aortic endothelium produces robust levels of estradiol by aromatase conversion of testosterone, and that regulation of this process is mediated by the presence of ERs, primarily ERα. Aortic endothelium was isolated from ERα knockout (ERα -/-) and wild-type (ERα +/+) male mice and treated with testosterone or the 5α reduction product dihydrotestosterone (DHT), with or without the P450 aromatase inhibitor anastrazole, or a non-specific estrogen receptor antagonist. Aromatase gene expression and estradiol production were assayed. Treatment with testosterone, but not DHT, caused increased aromatase expression and estradiol production in ERα +/+ endothelium that was attenuated by disruption of ERα in the ERα -/- group. Anastrazole inhibition of aromatase reduced testosterone-induced aromatase expression and estradiol levels in both ERα -/- and ERα +/+ endothelium. Antagonism of both ERs decreased testosterone-induced aromatase expression in both wild-type and knockout groups. The effects of the receptor antagonist on estradiol production differed between the two groups, however, with a reduction in estradiol release from the ERα +/+ cells and complete abolition of estradiol release from the ERα -/- cells. Thus, estradiol production in vascular endothelium from male mice is robust, depends on the aromatic conversion of testosterone and requires functional ERα to achieve maximal levels of estradiol generation. Local vascular production of aromatase-mediated estradiol in response to circulating testosterone may affect ERα-dependent mechanisms to increase susceptibility to early atheroma formation in male mice. This pathway may have important therapeutic relevance for reducing the risk of atherosclerotic cardiovascular disease in human males.

The DHHS Office on Women's Health Initiative to Improve Women's Heart Health: focus on knowledge and awareness among women with cardiometabolic risk factors.

UNLABELLED: Abstract Background: The diversity of the U.S. population and disparities in the burden of cardiovascular disease (CVD) require that public health education strategies must target women and racial/ethnic minority groups to reduce their CVD risk factors, particularly in high-risk communities, such as women with the metabolic syndrome (MS). METHODS: The data reported here were based on a cross-sectional face-to-face survey of women recruited from four participating sites as part of the national intervention program, Improving, Enhancing and Evaluating Outcomes of Comprehensive Heart Care in High-Risk Women. Measures included baseline characteristics, sociodemographics, CVD related-knowledge and awareness, and Framingham risk score (FRS). RESULTS: There were 443 of 698 women (63.5%) with one or more risk factors for the MS: non-Hispanic white (NHW), 51.5%; non-Hispanic black (NHB), 21.0%; Hispanic, 22.6%. Greater frequencies of MS occurred among Hispanic women (p<0.0001), those with less than a high school education (70.0%) (p<0.0001), Medicaid recipients (57.8%) (p<0.0001), and urbanites (43.3%) (p<0.001). Fewer participants with MS (62.6%) knew the leading cause of death compared to those without MS (72.1%) (p<0.0001). MS was associated with a lack of knowledge of the composite of knowing the symptoms of a heart attack plus the need to call 911 (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.17-0.97, p=0.04). CONCLUSIONS: Current strategies to decrease CVD risk are built on educating the public about traditional factors, including hypertension, smoking, and elevated low-density lipoprotein cholesterol (LDL-C). An opportunity to broaden the scope for risk reduction among women with cardiometabolic risk derives from the observation that women with the MS have lower knowledge about CVD as the leading cause of death, the symptoms of a heart attack, and the ideal option for managing a CVD emergency.

Atherosclerosis and sex hormones: current concepts.

CVD (cardiovascular disease) is the leading cause of death for women. Considerable progress has been made in both our understanding of the complexities governing menopausal hormone therapy and our understanding of the cellular and molecular mechanisms underlying hormone and hormone receptor function. Understanding the interplay of atherosclerosis and sex steroid hormones and their cognate receptors at the level of the vessel wall has important ramifications for clinical practice. In the present review, we discuss the epidemiology of CVD in men and women, the clinical impact of sex hormones on CVD, and summarize our current understanding of the pathogenesis of atherosclerosis with a focus on gender differences in CVD, its clinical presentation and course, and pathobiology. The critical animal and human data that pertain to the role of oestrogens, androgens and progestins on the vessel wall is also reviewed, with particular attention to the actions of sex hormones on each of the three key cell types involved in atherogenesis: the endothelium, smooth muscle cells and macrophages. Where relevant, the systemic (metabolic) effects of sex hormones that influence atherogenesis, such as those involving vascular reactivity, inflammation and lipoprotein metabolism, are discussed. In addition, four key current concepts in the field are explored: (i) total hormone exposure time and coronary heart disease risk; (ii) the importance of tissue specificity of sex steroid hormones, critical timing and the stage of atherosclerosis in hormone action; (iii) biomarkers for atherosclerosis with regard to hormone therapy; and (iv) the complex role of sex steroids in inflammation. Future studies in this field will contribute to guiding clinical treatment recommendations for women and help define research priorities.

Maternal and neonatal exposure to environmental tobacco smoke targets pro-inflammatory genes in neonatal arteries.

Maternal mainstream tobacco smoking is known to have adverse outcomes on fetal respiratory function; however, no data is currently available on the effects of passive exposure to tobacco smoking and environmental tobacco smoke (ETS) on fetal systemic arterial structure and function. Eight pregnant rhesus macaque monkeys were studied at the California Regional Primate Research Center breeding colony. The estimated gestational age for each dam was established by sonography performed before gestational day 40. Two inhalation chambers were used, each with an air capacity of 3.5 m(3), and each housed two dams. Aged and diluted sidestream smoke was used as a surrogate for ETS. Exposure to ETS (1 mg/m(3)) occurred for 6 h/day, 5 days/week, beginning on gestational day 100. All dams were allowed to give birth spontaneously and then ETS exposure continued 70-80 days postnatally with the chamber containing both the mother and infant. Carotid arteries from four control (C) and four ETS-treated newborns were analyzed for mRNA by gene macroarray and for protein by Western blotting. A total of 588 cardiovascular genes were studied. Four genes were upregulated by ETS compared to C, and nine genes were downregulated (≥2-fold change). Three genes were selected for further study. Following ETS exposure, neonatal carotid arteries of non-human primates manifested evidence of inflammation with increased gene and protein expression of LFA-1 and RANTES, proteins that are recognized to be important in vascular adhesion and inflammation, and downregulation of expression for the receptor for VEGF, which has a key role in angiogenesis. Prenatal and postnatal exposure to ETS increases expression of pro-inflammatory genes and may be responsible for early arterial vascular remodeling that is predisposing to a subsequent vascular disease.

Outcomes of national community organization cardiovascular prevention programs for high-risk women.

The purpose of this study was to reduce cardiovascular disease (CVD) risk in women by implementing a cardiovascular prevention health promotion program in faith- and community-based sites. The primary outcomes were reducing obesity and increasing physical activity. A longitudinal cohort of high-risk (age > 40, ethnic minority) women (n = 1,052) was enrolled at 32 sites across the USA. The pre- or post-educational intervention consisted of eight biweekly counseling sessions conducted over 4 months each addressing one of six of the major CVD risk factors (smoking, diabetes, hypertension, cholesterol, obesity, and physical inactivity) as well as signs and symptoms of a heart attack and stroke; plus 4-6 maintenance sessions over three additional months. A multifaceted approach delivered by lay and medically trained personnel involving medical screenings, health behavior counseling, risk behavior modification, and stage of change were determined at baseline and end of counseling or maintenance. Following list-wise deletion, data were analyzed on 423 women who completed all follow-up time-points. Overall, significant improvement was attained in most of 28 secondary outcomes but not in the primary outcomes. Knowledge and awareness of heart disease as the leading killer or women, all of the signs and symptoms of a heart attack, calling 911, and CVD risk factors increased significantly (p < 0.05) by 8.8%, 13.6%, 5.8%, and 10%, respectively. There was a 10% (p < 0.05) increase in participants attaining control for hypertension (blood pressure < 140/90) coupled with a significant reduction in mean blood pressure in the entire cohort. Knowledge of effective CVD risk modification strategies for all CVD risk factors increased significantly (p < 0.05), except for obesity. In addition, there were significant (p < 0.05) increases in forward movement in stage of change for each CVD risk factor (range +10% to +39%). Thus, a heart disease prevention intervention built around a model of community engagement, advocacy, self-efficacy, resource knowledge, and health promotion in faith- and community-based organizations is successful at improving cardiovascular knowledge and awareness outcomes in high-risk women. Limitations of our study include the high dropout rate, significant time demands on site coordinators, limited resources for program implementation, lack of morbidity and mortality endpoints, and failure to attain the primary outcomes of weight loss and physical activity. Future studies should not only assess the effect of community education interventions on lifestyle change and knowledge and awareness of participants but should also address program duration, cost, and resources required to attain improved outcomes.

17beta-estradiol prevents early-stage atherosclerosis in estrogen receptor-alpha deficient female mice.

Estrogen is atheroprotective and a high-affinity ligand for both known estrogen receptors, ERalpha and ERbeta. However, the role of the ERalpha in early-stage atherosclerosis has not been directly investigated and is incompletely understood. ERalpha-deficient (ERalpha-/-) and wild-type (ERalpha+/+) female mice consuming an atherogenic diet were studied concurrent with estrogen replacement to distinguish the actions of 17beta-estradiol (E(2)) from those of ERalpha on the development of early atherosclerotic lesions. Mice were ovariectomized and implanted with subcutaneous slow-release pellets designed to deliver 6 or 8 mug/day of exogenous 17beta-estradiol (E(2)) for a period of up to 4 months. Ovariectomized mice (OVX) with placebo pellets (E(2)-deficient controls) were compared to mice with endogenous E(2) (intact ovaries) and exogenous E(2). Aortas were analyzed for lesion area, number, and distribution. Lipid and hormone levels were also determined. Compared to OVX, early lesion development was significantly (p < 0.001) attenuated by E(2) with 55-64% reduction in lesion area by endogenous E(2) and >90% reduction by exogenous E(2). Compared to OVX, a decline in lesion number (2- to 4-fold) and lesser predilection (~4-fold) of lesion formation in the proximal aorta also occurred with E(2). Lesion size, development, number, and distribution inversely correlated with circulating plasma E(2) levels. However, atheroprotection was independent of ERalpha status, and E(2) athero-protection in both genotypes was not explained by changes in plasma lipid levels (total cholesterol, triglyceride, and high-density lipoprotein cholesterol). The ERalpha is not essential for endogenous/exogenous E(2)-mediated protection against early-stage atherosclerosis. These observations have potentially significant implications for understanding the molecular and cellular mechanisms and timing of estrogen action in different estrogen receptor (ER) deletion murine models of atherosclerosis, as well as implications to human studies of ER polymorphisms and lipid metabolism. Our findings may contribute to future improved clinical decision-making concerning the use of hormone therapy.

Compromised aortic vasoreactivity in male estrogen receptor-alpha-deficient mice during acute lipopolysaccharide-induced inflammation.

Activation of the estrogen receptor-alpha (ERalpha) mediates the vasculoprotective effects of estrogen, in part, through modulating nitric oxide (NO) production and vasodilation. Whereas inflammation is accompanied by altered vascular reactivity and underlies the pathogenesis of vascular disease, the role of the ERalpha in the vascular responses associated with acute systemic inflammation remains poorly characterized. Contractile and relaxation responses of isolated aortic segments were investigated 12 h after ip injection of saline or lipopolysaccharide (LPS, 10 mg/kg) in male wild-type (ERalpha(+/+)) and ERalpha-deficient (ERalpha(-/-)) mice. As previously observed, LPS-injected ERalpha(+/+) mice displayed reduced contractile responses to phenylephrine and enhanced vasodilation in response to acetylcholine. In contrast, aortic tissues from LPS-injected ERalpha(-/-) mice displayed enhanced contractile responses and reduced sensitivity to acetylcholine- and sodium nitroprusside-induced vasodilation. LPS treatment in ERalpha(+/+) and ERalpha(-/-) mice resulted in similar increased levels of systemic NO production and inducible NO synthase expression in the vascular wall. However, expression of mRNA and protein for endothelial NOS and soluble guanylate cyclase (alpha- and beta-subunits) were significantly reduced in aortic tissues from LPS-treated ERalpha(-/-) animals, possibly accounting for reduced endothelial NO production and reduced smooth muscle responses to NO. These findings represent new evidence of the functional role of ERalpha in the male vasculature and suggest that during acute LPS-induced inflammatory responses, the ERalpha mediates the sustained expression of the molecular machinery essential for endothelial NO synthesis (i.e. endothelial NOS) and the vascular responses to NO (i.e. soluble guanylate cyclase).

Cardiovascular actions of selective estrogen receptor modulators and phytoestrogens.

Cardiovascular disease is the leading cause of death among men and women in Western societies. Over the past decade, interest in a better understanding of gender differences in cardiovascular disease has heightened. Concomitantly, the use of hormone therapy for cardiovascular risk reduction in postmenopausal women has come into question in light of recent landmark clinical studies casting doubt on the benefits of this therapy. As a consequence, alternatives to conventional hormone replacement, including selective estrogen receptor modulators and phytoestrogens, have attracted considerable attention. The authors provide an up-to-date review of the clinical actions of selective estrogen receptor modulators on cardiovascular disease. The actions of tamoxifen, raloxifene, droloxifene, and soy phytoestrogens are discussed in the context of cardiovascular disease epidemiology, coronary events, clinical markers of cardiovascular risk, and vascular function. In addition, the authors' current understanding of the mechanism of action of these agents is discussed and recommendations for clinical practice are reviewed.

Soy protein with isoflavones has favorable effects on endothelial function that are independent of lipid and antioxidant effects in healthy postmenopausal women.

BACKGROUND: Controversy exists about the ability of soy protein and isoflavones to modulate vascular reactivity and biochemical cardiovascular disease risk markers in healthy, normolipidemic postmenopausal women. OBJECTIVE: The objective was to investigate whether the consumption of soy protein with isoflavones would result in improved vascular reactivity and decreased biochemical markers of endothelial dysfunction and inflammation, independent of enhanced lipid and antioxidant effects. DESIGN: Healthy postmenopausal women (n = 28) were enrolled in a randomized, double-blind, crossover study, and they consumed 25 g of 3 protein products/d for 6 wk each, with intervening washout periods. The products were isolated soy protein with isoflavones, ethanol-washed isolated soy protein with trace isoflavones, and total milk protein, which supplied 107, 2, and 0 mg total isoflavone (aglycone) units/d, respectively. We studied vascular function by using brachial artery reactivity values, plasma concentrations of vasoactive factors, endothelial inflammatory markers, and plasma isoflavone concentrations. The resistance of whole plasma and isolated LDL to copper-mediated oxidation was measured by conjugated diene formation. RESULTS: Postocclusion peak flow velocity of the brachial artery was significantly (P = 0.03) lower after treatment with isolated soy protein with isoflavones, which is consistent with a vasodilatory response, than after treatment with total milk protein. Plasma isoflavones and metabolites were significantly (P < 0.01) higher after treatment with isolated soy protein with isoflavones. There were no significant changes in biochemical cardiovascular disease risk markers or conjugated diene formation between the 3 dietary groups. CONCLUSION: Daily consumption of soy protein with isoflavones can result in positive vascular effects that are independent of lipid and antioxidant effects in healthy postmenopausal women.

Time- and dose-dependent differential upregulation of three genes by 17 beta-estradiol in endothelial cells.

The purpose of this study was to identify genetic targets in the vasculature for estrogen by profiling genes expressed in female human aortic endothelial cells exposed to various doses of 17 beta-estradiol at differing concentrations and for differing periods of time. Our approach employed a RT-PCR-based cloning strategy of DNA differential display analysis, with differential expression verified by semiquantitative PCR performed with gene-specific primers. A significant increase in mRNA expression in response to 17 beta-estradiol was observed for the following three genes: aldose reductase (3.4-fold), caspase homologue-alpha protein (4.2-fold), and plasminogen activator inhibitor-1 intron e (2.3-fold). For all three upregulated genes, estradiol-induced upregulation occurred with a similar time course and temporally clustered to the first 24 h after hormone treatment. In addition, the effect of estradiol dose on gene expression was consistent and occurred at physiological concentrations. Our results describe previously uncharacterized estradiol-sensitive time- and dose-dependent regulation of genes with potential importance to vascular function in human endothelial cells.

Estrogens and lipids. Can HRT designer estrogens, and phytoestrogens reduce cardiovascular risk markers after menopause?

HRT may act preventively to reduce morbidity and mortality from cardiovascular disease in primary prevention. The development of SERMs adds a new, exciting, and promising therapeutic option to this field, as does the enhanced availability of soy phytoestrogen products. Although clinical trial data are incomplete, epidemiologic studies suggest that HRT raises HDL-C and triglyceride levels and lowers LDL-C levels. In addition, HRT lowers levels of Lp(a). These changes account for up to 50% of the cardiovascular risk reduction observed with HRT. In contrast, SERMs have less uniform effects. Both SERMs and phytoestrogens are less potent than HRT but have greater tissue selectivity. Although further study is needed, current information suggests that SERMs and phytoestrogens have significant potential to reduce CAD risk and may be a viable alternative to HRT for modest lowering of lipid levels. Phytoestrogens may be particularly useful for reducing CAD risk in men because they do not cause the side effects associated with estrogen. Additional clinical trials are necessary to determine whether the favorable lipid effects associated with HRT, SERMs, and phytoestrogens are linked to protection against cardiovascular disease. Nonetheless, physicians should consider the use of HRT, SERMs, and phytoestrogens for lowering lipid levels and reducing cardiovascular risk in women.