Association between global leukocyte DNA methylation and cardiovascular risk in postmenopausal women.

BACKGROUND: Genetic studies to date have not provided satisfactory evidence regarding risk polymorphisms for cardiovascular disease (CVD). Conversely, epigenetic mechanisms, including DNA methylation, seem to influence the risk of CVD and related conditions. Because postmenopausal women experience an increase in CVD, we set out to determine whether global DNA methylation was associated with cardiovascular risk in this population. METHODS: In this cross sectional study carried out in a university hospital, 90 postmenopausal women without prior CVD diagnosis (55.5 ± 4.9 years, 5.8 [3.0-10.0] years since menopause) were enrolled. DNA was extracted from peripheral leukocytes and global DNA methylation levels were obtained with an ELISA kit. Cardiovascular risk was estimated by the Framingham General Cardiovascular Risk Score (10-year risk) (FRS). Clinical and laboratory variables were assessed. Patients were stratified into two CVD risk groups: low (FRS: <10 %, n = 69) and intermediate/high risk (FRS ≥10 %, n = 21). RESULTS: Age, time since menopause, blood pressure, total cholesterol, and LDL-c levels were higher in FRS ≥10 % group vs. FRS <10 % group. BMI, triglycerides, HDL-c, HOMA-IR, glucose and hsC-reactive protein levels were similar in the two groups. Global DNA methylation (% 5mC) in the overall sample was 26.5 % (23.6-36.9). The FRS ≥10 % group presented lower global methylation levels compared with the FRS <10 % group: 23.9 % (20.6-29.1) vs. 28.8 % (24.3-39.6), p = 0.02. This analysis remained significant even after adjustment for time since menopause (p = 0.02). CONCLUSIONS: Our results indicate that lower global DNA methylation is associated with higher cardiovascular risk in postmenopausal women.

Relationship between endogenous testosterone and cardiovascular risk in early postmenopausal women.

Cardiovascular disease (CVD) is the leading cause of death among postmenopausal women. Changes in endothelial function play an important role in the pathophysiology of atherosclerosis, and evidence suggests that interventions to improve endothelial function could modify the rates of progression and the risk of cardiovascular events. In addition, a positive association between markers of endothelial dysfunction and androgenicity has been described in women with polycystic ovary syndrome, suggesting a correlation with the early-onset endothelial dysfunction found in these patients. We performed a cross-sectional study to verify whether endogenous testosterone levels are correlated with markers of inflammation and endothelial function and with anthropometric and metabolic profile in 53 postmenopausal women. Serum testosterone, sex hormone-binding globulin, C-reactive protein (CRP), fibrinogen, and plasma endothelin-1 (ET-1) were determined. Patients were stratified into 2 groups (higher or lower than the mean testosterone levels of the studied sample). Mean age was 55 years (+/-5), and median time since menopause was 5.5 years (interquartile range, 3-8 years). Body mass index and waist circumference were significantly higher in the group with testosterone levels >or=0.49 ng/mL. Median CRP levels were greater in the group with higher testosterone levels (1.17 [0.17-2.36] vs 0.17 [0.17-0.61] mg/L, P = .039). Median ET-1 levels were also higher in women with greater testosterone levels (0.84 [0.81-0.97] vs 0.81 [0.74-0.84] pg/mL, P = .023). An association of testosterone with CRP (r = 0.416, P = .004) and ET-1 (r = 0.323, P = .031) was observed. This association was dependent on homeostasis model assessment index for ET-1 but not CRP. Testosterone was also associated with waist circumference and blood pressure (P = .001). These data suggest that endogenous testosterone levels in recently postmenopausal women may be part of a proatherogenic profile. Longitudinal studies are needed to assess if androgenicity represents a risk factor for cardiovascular disease and the clinical relevance of its association with ET-1 and CRP in this population.

Menopause, estrogens, and endothelial dysfunction: current concepts.

Menopause is defined as the permanent cessation of menses. Cardiovascular disease is the leading cause of death among postmenopausal women in developed countries. The disparity between the incidence of cardiovascular disease among women in pre- and postmenopause has been ascribed to the actions of endogenous estrogen on the cardiovascular system and, particularly, on the vascular endothelium. The endothelium plays an important role in cardiovascular homeostasis, either through the vascular tonus and its regulation, or through coagulation and the inflammatory response. Endothelial dysfunction is implicated in the genesis of atherosclerosis and other chronic disorders, such as diabetes mellitus and hypertension. The pharmacological use of estrogen exerts influence on the circulating levels of markers of vascular tonus, and inflammation, as well as prothrombotic, and fibrinolytic markers, but the impact of these changes on the atherosclerotic disease is still uncertain.

Association between androgen receptor gene CAG repeat polymorphism and plasma testosterone levels in postmenopausal women.

OBJECTIVES: The biologic action of androgens in target cells depends on plasma androgen levels and receptor transcriptional activity. We investigated the relationship between androgen receptor (AR) CAG repeat polymorphism, serum androgen levels, and anthropometric, metabolic, and hormonal variables in 39 postmenopausal women, taking into consideration the patterns of X-chromosome inactivation. METHODS: Genomic DNA was extracted from peripheral leukocytes. Polymerase chain reactions (PCRs) were performed to amplify the polymorphic (CAG)n repeat of the human AR gene, which were analyzed with GeneScan software (Applied Biosystems, Foster City, CA). The X-chromosome inactivation analysis was based on the AR gene methylation patterns. RESULTS: The mean age of participants was 54.7 years; mean age at menopause was 48 years. The number of CAG repeats ranged from 15 to 30, with a median length of 23. Analysis of X-chromosome inactivation patterns showed 19 cases with a degree of skewing (DS) > or =70% and seven with a DS > or =90%. The X-weighted CAG repeat biallelic mean was significantly lower in individuals with total testosterone (TT) greater than 0.56 ng/mL (group mean) than in the group with TT < or =0.56 (P=.018). No difference was observed between the groups regarding dehydroepiandrosterone sulfate (DHEA-S). Plasma TT was significantly higher in the group with the smaller X-weighted CAG repeat biallelic mean (P=.01). Free androgen index (FAI) was also significantly higher in this group (P=.033). Testosterone levels and FAI were inversely correlated to X-weighted CAG repeat biallelic mean. CONCLUSION: Our data indicate an association between testosterone plasma levels and AR CAG repeats in postmenopausal women, and suggest that plasma levels of androgens in postmenopausal women may be related to variants of the AR gene.

Subclinical cardiovascular disease in postmenopausal women with low/medium cardiovascular risk by the Framingham risk score.

OBJECTIVES: To evaluate the prevalence of subclinical cardiovascular disease (CVD) and its association with clinical and hormone variables in postmenopausal women from Southern Brazil. STUDY DESIGN: Cross-sectional study. MAIN OUTCOME MEASURES: Coronary artery calcification (CAC) assessed by electron-beam computed tomography. Carotid intima-media thickness (IMT) and atheromatous plaques assessed using B-mode ultrasound. IMT was measured at three segments. Subclinical CVD was defined as the presence of plaque and/or IMT >0.9 mm. RESULTS: Ninety-seven postmenopausal women (mean age 55 ± 5 years, median duration of menopause 5.8 [3-10] years) were studied. A low/medium Framingham risk score (FRS) was present in 97.9% of participants; 35.1% had subclinical CVD on carotid ultrasound, and 24.7% had the presence of plaque. Seven women had a CAC score ≥ 100, and two had a score ≥ 200. CAC score (p<0.001) and FRS (p=0.013) were higher in patients with subclinical atherosclerosis. Positive correlations were found between IMT and age (rs=0.293 p=0.004), duration of menopause (rs=0.237, p=0.020), and CAC score (rs=0.468, p<0.001). Common carotid IMT (IMT-CC) was negatively associated with estradiol levels (ß=-0.237, p=0.018) and positively with age (ß=0.210, p=0.033), and BMI (ß=0.260, p=0.010). However, correlations with estradiol and age did not remain significant when adjusted for systolic blood pressure and LDL-cholesterol levels. CONCLUSION: A high prevalence of subclinical atherosclerosis was detected in this sample of postmenopausal women with low/medium CV risk by the FRS. The association between IMT-CC and age or endogenous estrogen levels was dependent of blood pressure and LDL-cholesterol in these postmenopausal women from Southern Brazil.

Association between hyperinsulinemia and endogenous androgen levels in peri- and postmenopausal women.

We evaluated the relationship between hyperinsulinemia and anthropometric, metabolic, and hormonal parameters that might contribute to the risk for coronary heart disease (CHD) in 104 peri- and postmenopausal women. Plasma glucose, insulin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), and total testosterone (TT) were determined. Free androgen index (FAI) and fasting insulin to glucose ratio (IGR) were calculated. The cut off point to define hyperinsulinemia was established at 23 microIU/mg. Mean age was 54.8 years. Mean age at menopause was 47.7 years. Body mass index (BMI) was greater than 25 in 46 patients, and 28 (26.9%) were hyperinsulinemic. BMI, waist circumference, triglycerides, and 2-hour postglucose insulin levels were significantly higher in hyperinsulinemic patients. Hyperinsulinemic patients had higher TT levels (P =.02), FAI (P =.0001), and lower SHBG levels (P =.003). Positive correlations were observed between IGR and BMI, waist-to-hip ratio (WHR), waist circumference, and triglycerides. IGR and high-density lipoprotein-cholesterol (HDL-C) were negatively correlated. IGR presented a positive association with TT and FAI and a negative association with SHBG. FAI contributed positively to IGR, independently of BMI, age, or time since menopause. In conclusion, androgen levels may be important determinants of risk factors for cardiovascular diseases in peri- and postmenopausal women. However, this observation should be confirmed by longitudinal studies.

Variations in the fat mass and obesity-associated (FTO) gene are related to glucose levels and higher lipid accumulation product in postmenopausal women from southern Brazil.

OBJECTIVE: To test the association between polymorphisms rs9939609 T>A and rs8050136 A>C of the fat mass and obesity-associated (FTO) gene and metabolic and cardiovascular variables in postmenopause. DESIGN: Cross-sectional study. SETTING: University hospital. PATIENT(S): A total of 135 postmenopausal women (mean age 52 ± 4 years). INTERVENTION(S): Anthropometric measurements and collection of blood samples. MAIN OUTCOME MEASURE(S): Blood pressure, metabolic variables, and FTO genotype. RESULT(S): The frequency of polymorphism rs9939609 was 43.7% for the wild TT genotype, 43.0% for TA, and 13.3% for AA. The frequency of the rs8050136 polymorphism was 12.6% for the wild AA genotype, 39.3% for AC, and 48.1% for CC. The polymorphic AA genotype of the SNP rs9939609 was associated with higher glucose levels and lipid accumulation product (LAP) index, whereas the wild AA genotype of the SNP rs8050136 was associated with higher LAP. CONCLUSION(S): The rs9939609 polymorphism in the FTO gene is related to abnormal glucose levels and with LAP, a surrogate marker of diabetes and cardiovascular risk in postmenopause. Further studies are needed in different ethnic backgrounds to confirm the clinical relevance of these associations.

Lipid accumulation product (LAP) is related to androgenicity and cardiovascular risk factors in postmenopausal women.

OBJECTIVES: To investigate whether lipid accumulation product (LAP) is related to androgen and sex hormone binding globulin (SHBG) levels and to cardiovascular risk factors in postmenopausal women with no evidence of established cardiovascular disease. STUDY DESIGN: Cross-sectional study. MAIN OUTCOME MEASURES: LAP (waist-58 × triglycerides [nmol/L]), LAP ≥ arbitrary cutoff point of 34.5, serum testosterone, SHBG, ultrasensitive C-reactive protein (us-CRP). RESULTS: Forty-nine women (mean age 55±5 years; median amenorrhea time 5.5 years [3-8]) were studied: 14% had the metabolic syndrome and 24.5% were hypertensive. Compared with LAP<34.5, LAP ≥ 34.5 (n=29, 59%) was associated with higher testosterone (p=0.021) and free androgen index (FAI) (p=0.003) and lower SHBG levels (p=0.013). Us-CRP (p=0.012), total cholesterol (p=0.041), glucose (p=0.020) and homeostasis model assessment (HOMA) (p=0.019) were higher, and high-density lipoprotein cholesterol (HDL-C) (p=0.001) was lower with LAP ≥ 34.5. LAP was positively correlated with total testosterone (r=0.349, p=0.014), FAI (rs=0.470, p=0.001), us-CRP (r=0.315, p=0.042), systolic (r=0.318, p=0.028) and diastolic (r=0.327, p=0.023) blood pressure, total cholesterol (r=0.498, p<0.001) and glucose (rs=0.319, p=0.026). LAP was negatively correlated with SHBG (rs=-0.430, p=0.003) and HDL-C (r=-0.319, p=0.026). CONCLUSIONS: LAP index seems to be associated with androgens and SHBG and with cardiovascular risk factors in postmenopausal women. Also, LAP seems to be a suitable method to screen for cardiovascular risk in postmenopause.

Impacto do uso de anticoncepcional oral nas características e na evolução clínica de mulheres submetidas à intervenção coronariana percutânea primária / Impact of oral contraceptive use on the characteristics and clinical evolution of women undergoing primary percutaneous coronary intervention

Em nosso, país estima-se que aproximadamente 27% das mulheres em idade fértil utilizemanticoncepcional oral (ACO). A apresentação e a evolução clínica do infarto agudo do miocárdio (IAM) nessasmulheres ainda não foi descrita em nosso meio. O objetivo do presente estudo foi analisar o perfil clínico, ascaracterísticas angiográficas, os aspectos técnicos do procedimento e os desfechos de usuárias de ACO quetiveram IAM e foram encaminhadas à intervenção coronariana percutânea (ICP) primária. Métodos: Mulheres < 55 anos que apresentaram IAM com supradesnivelamento do segmento ST e foram encaminhadas à ICP primária foram sequencialmente incluídas e categorizadas em dois grupos: com e sem uso atual de ACO. Resultados: Incluímos 257 pacientes, sendo que 19 (7,4%) usavam ACO. Estas eram mais jovens (42,3 ± 6,2 anos vs. 48,4 ± 5,7 anos; p < 0,001), com menos fatores de risco tradicionais para doença arterial coronariana, mas apresentavam proteína C-reativa e fibrinogênio séricos mais elevados. O delta T foi semelhante (4,00 [1,25 a 6,86] horas vs. 4,50 [2,50 a 7,64] horas; p = 0,54), mas o tempo porta-balão foi maior nas pacientes em uso de ACO (1,41 [0,58 a 1,73] hora vs. 1,16 [0,91 a 1,51] hora; p = 0,02). Estas pacientes foram mais frequentemente submetidas à tromboaspiração (52,6% vs. 25,6%; p = 0,04). Após o evento índice, elas não apresentaram desfechosaterotrombóticos em até 2 anos de acompanhamento (0 vs. 15,2%; p = 0,08). Conclusões: Neste estudo, encontramos perfil clínico e desfechos diferentes entre mulheres em idadereprodutiva, usuárias ou não de ACO, e submetidas à ICP primária. Estudos com maior número de pacientes sãonecessários para confirmar tais resultados...

In Brazil, it is estimated that approximately 27% of women of childbearing age use oral contraceptives (OC). The presentation and clinical course of acute myocardial infarction (AMI) in these women has yet to be described in Brazil. The aim of this study was to analyze the clinical profile, angiographic characteristics, technical aspects of the procedure, and the outcomes in women using OC who had an AMI and were submitted to primary percutaneous coronary intervention (PCI). Methods: Women aged < 55 years who had acute ST segment elevation myocardial infarct and were referred to primary PCI were sequentially included and categorized into two groups: with and without current use of OC. Results: We have included 257 patients, of whom 19 (7.4%) used OC. These patients were younger (42.3 ± 6.2 years vs. 48.4 ± 5.7 years; p < 0.001), with fewer traditional risk factors for coronary artery disease, but had higher serum levels of C-reactive protein and fibrinogen. The delta T was similar (4.00 [1.25 to 6.86] hours vs.4.50 [2.50 to 7.64] hours; p = 0.54), but the door-to-balloon time was longer in patients taking OC (1.41 [0.58 to 1.73] hour vs. 1.16 [0.91 to 1.51] hour, p = 0.02). These patients were more frequently submitted to thrombus aspiration (52.6% vs. 25.6%; p = 0.04). After the index event, they had no atherothrombotic outcomes in up to 2years of follow-up (0 vs. 15.2%; p = 0.08). Conclusions: In this study, different clinical profiles and outcomes were found among women of reproductive age, users or non-users of OC, and submitted to primary PCI. Studies with a larger number of patients are required to confirm these results...

Menopause, estrogens, and endothelial dysfunction: current concepts

Menopause is defined as the permanent cessation of menses. Cardiovascular disease is the leading cause of death among postmenopausal women in developed countries. The disparity between the incidence of cardiovascular disease among women in pre- and postmenopause has been ascribed to the actions of endogenous estrogen on the cardiovascular system and, particularly, on the vascular endothelium. The endothelium plays an important role in cardiovascular homeostasis, either through the vascular tonus and its regulation, or through coagulation and the inflammatory response. Endothelial dysfunction is implicated in the genesis of atherosclerosis and other chronic disorders, such as diabetes mellitus and hypertension. The pharmacological use of estrogen exerts influence on the circulating levels of markers of vascular tonus, and inflammation, as well as prothrombotic, and fibrinolytic markers, but the impact of these changes on the atherosclerotic disease is still uncertain.

A menopausa é definida como a cessação permanente das menstruações. A doença cardiovascular é a principal causa de mortalidade em mulheres na pós- menopausa, em países desenvolvidos. A disparidade entre a incidência de doença cardiovascular entre mulheres na pré e pós menopausa tem sido atribuída a ações do estrogênio endógeno sobre o sistema cardiovascular e, em especial, sobre a função do endotélio vascular. O endotélio tem importante papel na homestase cardiovascular, seja no controle do tônus e permeabilidade vascular, ou da coagulação e resposta inflamatória. A disfunção endotelial está implicada na gênese da aterosclerose e de outras doenças crônicas, como diabete melito e hipertensão arterial. O uso farmacológico de estrogênio exerce influência sobre concentrações circulantes de marcadores do tônus vascular, inflamatórios, pró-trombóticos e fibrinolíticos, porém o impacto destas alterações sobre a doença aterosclerótica ainda não está determinado.