Amparo C. Villablanca

Chronic consumption of flavanol-rich cocoa improves endothelial function and decreases vascular cell adhesion molecule in hypercholesterolemic postmenopausal women

Endothelial dysfunction characterizes many disease states including subclinical atherosclerosis. The consumption of flavanol-rich cocoa and cocoa-based products has been shown to improve endothelial function in both compromised and otherwise normal, healthy individuals when administered either acutely or over a period of several days, or weeks. Women experience increased risk for cardiovascular disease after menopause, which can be associated with endothelial dysfunction. Whether a flavanol-rich cocoa-based product can improve endothelial function in hypercholesterolemic postmenopausal women is not known. The purpose of the present study was to determine whether chronic dietary administration of flavanol-rich cocoa improves endothelial function and markers of cardiovascular health in hypercholesterolemic postmenopausal women. Thirty-two postmenopausal hypercholesterolemic women were randomly assigned to consume a high-flavanol cocoa beverage (high cocoa flavanols (CF)—446 mg of total flavanols), or a low-flavanol cocoa beverage (low CF—43 mg of total flavanols) for 6 weeks in a double-blind study (n=16 per group). Endothelial function was determined by brachial artery-reactive hyperemia. Plasma was analyzed for lipids (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol), hormones (follicle-stimulating hormone), total nitrate/nitrite, activation of cellular adhesion markers (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-Selectin, P-Selectin), and platelet function and reactivity. Changes in these plasma markers were then correlated to brachial reactivity. Brachial artery hyperemic blood flow increased significantly by 76% (P<0.05 vs. baseline) after the 6-week cocoa intervention in the high CF group, compared with 32% in the low CF cocoa group (P=ns vs. baseline). The 2.4-fold increase in hyperemic blood flow with high CF cocoa closely correlated (r2=0.8) with a significant decrease (11%) in plasma levels of soluble vascular cell adhesion molecule-1. Similar responses were not observed after chronic use of low CF. There were no significant differences between high and low CF in other biochemical markers and parameters measured. This study is the first to identify beneficial vascular effects of flavanol-rich cocoa consumption in hypercholesterolemic postmenopausal women. In addition, our results suggest that reductions in plasma soluble vascular cell adhesion molecule-1 after chronic consumption of a flavanol-rich cocoa may be mechanistically linked to improved vascular reactivity.

SMOKING AND CARDIOVASCULAR DISEASE

Mainstream and ETS exposure are strong risk factors for cardiovascular disease in men and women. The relationships between smoking and cardiovascular disease result from multiple mechanisms that interact to contribute to atherosclerosis, vascular injury, thrombosis, and vascular dysfunction. We are only now beginning to understand how smoking contributes to the genesis and progression of cardiovascular disease. Because of the complexity of the interactions between nicotine and the components of MSS, ETS, and sidestream smoke with the vasculature, it will take a great deal of time and effort to fully unravel the mechanisms by which smoking contributes to cardiovascular disease. In addition, cardiovascular risk in female smokers is complicated by hormonal variables that may contribute to greater relative risk. It is important that health care providers, educators, and policy makers recognize the changing patterns of smoking and the impact of smoking on cardiovascular disease, and continue campaigns aimed at enhancing smoking cessation in the general population and in teens. Rigorous research is needed on the changing cultural, psychosocial, and environmental factors that influence tobacco use to improve our understanding of racial/ethnic smoking patterns, and identify strategic tobacco control opportunities. The capacity of tobacco control efforts to keep pace with patterns of tobacco use and cessation depends on timely recognition of emerging prevalence and cessation patterns and the resulting development of appropriate community-based programs to address the factors involved. Smoking trends today will determine how heavy the health burden of cardiovascular disease and others will be among communities tomorrow. Programs that aim at early intervention and reflect cultural diversity will be the cornerstone in the battle against tobacco use. Continued interest in research, educational, and prevention efforts are needed to help curb the risk of cardiovascular disease from smoking in men and women.

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.

Growth-promoting effects of substance P on endothelial cells in vitro. Synergism with calcitonin gene-related peptide, insulin, and plasma factors.

The purpose of this study was to determine the effects of the vasoactive perivascular neuropeptide substance P (SP) on the growth and function of vascular endothelial cells in serum-free culture conditions with cells quiescent in the G0-G1 phase of the cell cycle and to characterize the response. In addition, interactions between SP and other growth factors and neuropeptides including insulin, platelet factors, neurokinin A, neurokinin B, and calcitonin gene-related peptide (CGRP) were studied on endothelial cell growth and compared. Growth effects were determined by stimulation of tritiated thymidine incorporation into DNA and cell proliferation. SP exhibited differential effects on cell growth that were a function of concentration, incubation time, interaction with other growth factors, and cell culture conditions. DNA synthesis in response to SP showed a bell-shaped distribution with a maximal effect that was 10.5-fold over control at 500 micrograms/mL of SP after 48 hours of incubation. The effect showed marked synergism with insulin (10 micrograms/mL) and with CGRP (0.01 to 10 micrograms/mL), which is colocalized with SP in vivo. Insulin and CGRP alone had no significant effect on endothelial cell growth. Furthermore, no synergism was observed between SP and platelet-derived growth factor or platelet-derived endothelial cell growth factor. Endothelial cell proliferation increased in response to SP to 2.6-fold over control at 48 hours, was maximal at 10 micrograms/mL SP, and also demonstrated synergism with insulin (10 micrograms/mL). Our studies indicate that neuropeptides play a significant role in regulating endothelial cell growth and proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

17β-estradiol stimulates substance P receptor gene expression

Abstract The actions of substance P (SP), a widely distributed tachykinin neuropeptide, are mediated by the NK1 receptor, a seven trans-membrane spanning domain cell surface receptor coupled to heterotrimeric G-proteins. SP regulates cellular processes in the CNS, placenta and vasculature including permeability, inflammation, mitogenesis and transformation. Examples of sexual dimorphism in tissue distribution and expression of SP and the SP receptor (SPR) in various organ systems (breast, uterus, brain) suggest the SPR may be under hormonal control. Using Northern blot analysis of SPR mRNA levels, we studied the effects of 17 β -estradiol (E 2 ) on SPR gene expression in AR42J (rat pancreatic acinar) cells which constitutively express high levels of SPR. E 2 (100 nM) led to a 2.5-fold increase in SPR mRNA levels (4.7 kb band) which was time- and concentration-dependent. The increase was inhibited by the RNA polymerase inhibitor actinomycin D (5 μ g/ml) but not by the translational inhibitor cycloheximide (10 μ g/ml). In addition, the antiestrogen tamoxifen (1 μ M) blocked the stimulatory effect of E 2 on SPR mRNA. Increased SPR mRNA levels in response to E 2 were linearly related to increased [ 3 H]SP binding to the SPR. This study has implications for understanding molecular mechanisms of hormonal control of receptor gene expression.

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

PREVIEW Cardiovascular disease may be a hormone-responsive disorder, as evidenced by the age-adjusted lower incidence of the disease in women than in men and the decrease in cardiovascular risk with hormone replacement therapy (HRT) found in observational studies. Also, evidence indicates that the incidence of cardiovascular disease rises sharply in the absence of estrogen after menopause. This response is accompanied by an increase in cardiovascular risk factors, including lipid levels. In this article, Drs Ariyo and Villabianca review the effect of HRT and its analogues on lipoprotein metabolism and discuss the influence of conventional HRT, selective estrogen receptor modulators (SERMs, sometimes called designer estrogens), and phytoestrogens on lipid parameters in women.

Outcomes of Comprehensive Heart Care Programs in High-Risk Women

OBJECTIVE The purpose of this study was to improve the fund of knowledge, reduce cardiovascular disease (CVD) risk, and attain Healthy People 2010 objectives among women in model womens heart programs. METHODS A 6-month pre/post-longitudinal educational intervention of high-risk women (n = 1310) patients at six U.S. womens heart programs consisted of comprehensive heart health counseling and use of American Heart Association/American College of Cardiology (AHA/ACC) Evidence-Based Guidelines as enhancement to usual care delivered via five integrated components: education/awareness, screening/risk assessment, diagnostic testing/treatment, lifestyle modification/rehabilitation, and tracking/evaluation. Demographics, before and after knowledge surveys, clinical diagnoses, laboratory parameters, and Framingham risk scores were also determined. Changes in fund of knowledge, awareness, and risk reduction outcomes and Healthy People 2010 objectives were determined. RESULTS At 6 months, there were statistically significant improvements in fund of knowledge, risk awareness, and clinical outcomes. Participants attained or exceeded >90% of the Healthy People 2010 objectives. Proportions of participants showing increased knowledge and awareness of CVD as the leading killer of women, of all signs and symptoms of a heart attack, and calling 911 increased significantly (11.1%, 25.4%, and 34.6%, respectively). Health behavior counseling for physical activity, diet, and diabetes as CVD risk factors increased significantly (28.3%, 28.2%, and 12.5%, respectively). There was a statistical 4.1% increase in participants with systolic blood pressure (SBP) <140/90 mm Hg, a 4.7% decrease in participants with total cholesterol (TC) >240 mg/dL, a 4.5% decrease in participants with TC >200 mg/dL, a 5.9% decrease in participants with high-density lipoprotein cholesterol (HDL-C) <50 mg/dL, a 4.4% decrease in participants with HDL-C <40 mg/dL, and an 8.8% increase in diabetics with low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. CONCLUSIONS CVD prevention built around a comprehensive heart care model program and AHA/ACC Evidence-Based Guidelines can be successful in improving knowledge and awareness, CVD risk factor reduction, and attainment of Healthy People 2010 objectives in high-risk women. Thus, these programs could have a dramatic and lasting impact on the health of women.

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.

Murine Cytomegalovirus (MCMV) Infection Upregulates P38 MAP kinase in Aortas of Apo E KO Mice: a Molecular Mechanism for MCMV-Induced Acceleration of Atherosclerosis

Multiple studies suggest an association between cytomegalovirus (CMV) infection and atherogenesis; however, the molecular mechanisms by which viral infection might exacerbate atherosclerosis are not well understood. Aortas of MCMV-infected and uninfected Apo E knockout (KO) mice were analyzed for atherosclerotic lesion development and differential gene expression. Lesions in the infected mice were larger and showed more advanced disease compared to the uninfected mice. Sixty percent of the genes in the MAPK pathway were upregulated in the infected mice. p38 and ERK 1/2 MAPK genes were 5.6- and 2.0-fold higher, respectively, in aortas of infected vs. uninfected mice. Levels of VCAM-1, ICAM-1, and MCP-1 were ~2.0–2.6-fold higher in aortas of infected vs. uninfected mice. Inhibition of p38 with SB203580 resulted in lower levels of pro-atherogenic molecules and MCMV viral load in aortas of infected mice. MCMV-induced upregulation of p38 may drive the virus-induced acceleration of atherogenesis observed in our model.

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 β, 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.