Cardiovascular Disease In Men Research Articles

Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan.

Diseases of the cardiovascular system are the leading cause of morbidity and mortality in men and women in developed countries, and cardiovascular disease (CVD) is becoming more prevalent in developing countries. The prevalence of atherosclerotic CVD in men is greater than in women until menopause, when the prevalence of CVD increases in women until it exceeds that of men. Endothelial function is a barometer of vascular health and a predictor of atherosclerosis that may provide insights into sex differences in CVD as well as how and why the CVD risk drastically changes with menopause. Studies of sex differences in endothelial function are conflicting, with some studies showing earlier decrements in endothelial function in men compared with women, whereas others show similar age-related declines between the sexes. Because the increase in CVD risk coincides with menopause, it is generally thought that female hormones, estrogens in particular, are cardioprotective. Moreover, it is often proposed that androgens are detrimental. In truth, the relationships are more complex. This review first addresses female and male sex hormones and their receptors and how these interact with the cardiovascular system, particularly the endothelium, in healthy young women and men. Second, we address sex differences in sex steroid receptor-independent mechanisms controlling endothelial function, focusing on vascular endothelin and the renin-angiotensin systems, in healthy young women and men. Finally, we discuss sex differences in age-associated endothelial dysfunction, focusing on the role of attenuated circulating sex hormones in these effects.

What\u2019s the difference? A gender perspective on understanding educational inequalities in all-cause and cause-specific mortality

BackgroundMaterial and behavioural factors play an important role in explaining educational inequalities in mortality, but gender differences in these contributions have received little attention thus far. We examined the contribution of a range of possible mediators to relative educational inequalities in mortality for men and women separately.MethodsBaseline data (1991) of men and women aged 25 to 74 years participating in the prospective Dutch GLOBE study were linked to almost 23 years of mortality follow-up from Dutch registry data (6099 men and 6935 women). Cox proportional hazard models were used to calculate hazard ratios with 95% confidence intervals, and to investigate the contribution of material (financial difficulties, housing tenure, health insurance), employment-related (type of employment, occupational class of the breadwinner), behavioural (alcohol consumption, smoking, leisure and sports physical activity, body mass index) and family-related factors (marital status, living arrangement, number of children) to educational inequalities in all-cause and cause-specific mortality, i.e. mortality from cancer, cardiovascular disease, other diseases and external causes.ResultsEducational gradients in mortality were found for both men and women. All factors together explained 62% of educational inequalities in mortality for lowest educated men, and 71% for lowest educated women. Yet, type of employment contributed substantially more to the explanation of educational inequalities in all-cause mortality for men (29%) than for women (− 7%), whereas the breadwinner’s occupational class contributed more for women (41%) than for men (7%). Material factors and employment-related factors contributed more to inequalities in mortality from cardiovascular disease for men than for women, but they explained more of the inequalities in cancer mortality for women than for men.ConclusionsGender differences in the contribution of employment-related factors to the explanation of educational inequalities in all-cause mortality were found, but not of material, behavioural or family-related factors. A full understanding of educational inequalities in mortality benefits from a gender perspective, particularly when considering employment-related factors.

The Favorable Effect of Empagliflozin on Erectile Function in an Experimental Model of Type 2 Diabetes

IntroductionFollowing the results of the EMPA-REG Outcome trial, we hypothesized that empagliflozin, a highly potent and specific sodium/glucose cotransporteur 2 inhibitor, could improve type 2 diabetes mellitus (T2DM)-associated erectile dysfunction (ED), a highly prevalent complication of T2DM, very often coexisting with cardiovascular complications and considered as a prognostic factor of cardiovascular disease in men with diabetes. AimTo investigate the effects of chronic treatment with empagliflozin on ED in a T2DM rat model in the presence or absence of sildenafil. MethodsMale Goto-Kakizaki (GK), a model of T2DM, and age-matched Wistar rats received placebo or empagliflozin treatment at 25.3 ± 0.9 mg/kg/d for 4 weeks. Then, the in vivo effect of empagliflozin on erectile function was assessed by electrical stimulation of the cavernous nerve at different frequencies under anesthesia in the presence or absence of acute intravenous injection of sildenafil. Endothelium-dependent, -independent, and nitrergic relaxations of cavernosal strips from the rats were studied. Main Outcome MeasuresBody weight, food consumption, metabolic parameters, plasma inflammation biomarkers, and in vivo erectile responses elicited by electrical stimulation of the cavernous nerve in empagliflozin-treated and untreated GK rats and control Wistar rats were assessed and followed by concentration or frequency response curves to endothelium-dependent, -independent, and nitrergic relaxations of cavernosal strips from these rats. ResultsChronic empagliflozin followed by acute sildenafil significantly improved erectile responses in adult GK rats (n = 12–15/group). Ratios of intracavernous pressure and area under the curve/mean arterial pressure during the electrical stimulation were significantly increased in empagliflozin-treated vs untreated GK rats. Nitrergic relaxations of cavernosal strips from GK rats were significantly increased with empagliflozin compared with placebo. Moreover, the effect of sildenafil on erectile function was not altered by empagliflozin treatment. Clinical ImplicationsEmpagliflozin may benefit T2DM patient with ED. Strengths & LimitationsThe mechanism(s) by which empagliflozin shows favorable effect on erectile function in GK rats needs to be further elucidated. ConclusionEmpagliflozin shows favorable effect on erectile function in diabetic GK rats mediated by an improvement of nitrergic relaxation of erectile tissue. Whether this favorable effect on ED in the experimental context of T2DM is due to better glycemic control or to another effect of empagliflozin deserves further investigation.Assaly R, Gorny D, Compagnie S, et al. The Favorable Effect of Empagliflozin on Erectile Function in an Experimental Model of Type 2 Diabetes. J Sex Med 2018;15:1224–1234.

The association between eGFR in the normal or mildly impaired range and incident cadiovascular disease: Age and sex analysis

BackgroundWorse renal function, even in the normal or mildly impaired range, is associated with incident cardiovascular disease (CVD). Whether this association exists in both sexes across all ages is not known. MethodsA population based cohort of individuals >22 years with no prior CVD and with an eGFR 60–130 ml/min/1.73 m2. eGFR was calculated using the CKD-EPI formula. Incident CVD was defined as either myocardial infarction, unstable angina pectoris, coronary revascularization, or cerebrovascular event. Incident CVD was examined separately in men and women in 3 age-groups (young, 22–40 years; middle-aged, 41–60 years; and elderly, ≥61 years), during a median follow-up of 96.0 months. ResultsAmong 1,341,400 individuals (57% women, mean age 49.2 ± 16.6 years), men had more incident CVD as compared to women (34,968 vs. 23,515 total incident CVD) in all age-groups (0.6% vs. 0.2% in young; 6.2% vs. 2.0% in middle-aged; 13.4% vs. 8.4% in elderly, respectively). After adjustment for CVD risk factors, an increment of 10 units in eGFR was independently associated with a decrease of 5.4%, 3.4% and 5.4% in incident CVD in young, middle-aged and elderly men (p < 0.001 for each) and a decrease of 6.3%, 3.4% and 6.8% in the same age-groups in women (p < 0.001 for each). There was no significant age-sex interaction in the association between eGFR and incident CVD. ConclusionAlthough incident CVD differs in men and women, as well as in different age-groups, a higher eGFR even in the normal or mildly impaired range is associated with lesser incident CVD in men and women of all ages.

Testosterone to oestradiol ratio reflects systemic and plaque inflammation and predicts future cardiovascular events in men with severe atherosclerosis.

The effects of testosterone on cardiovascular disease (CVD) as reported in literature have been ambiguous. Recently, the interplay between testosterone and oestradiol as assessed by testosterone/oestradiol (T/E2) ratio was suggested to be better informative on the normal physiological balance. Considering the role in CVD, we hypothesized that a low T/E2 ratio in men with CVD is associated with increased inflammation, a more unstable plaque and a worse cardiovascular outcome. Testosterone and oestradiol concentrations were determined in blood samples of 611 male carotid endarterectomy patients included in the Athero-Express Biobank Study. T/E2 ratio was associated with baseline characteristics, atherosclerotic plaque specimens, inflammatory biomarkers, and 3 year follow-up information. Patients with low T/E2 ratio had more unfavourable inflammatory profiles compared with patients with high T/E2 as observed by higher levels of C-reactive protein [2.81 μg/mL vs. 1.22 μg/mL (P < 0.001)] and higher leucocyte counts [8.98*109/L vs. 7.75*109/L (P = 0.001)] in blood. In atherosclerotic plaques, a negative association between T/E2 ratio and number of neutrophils [B = -0.366 (P = 0.012)], plaque calcifications [OR: 0.816 (P = 0.044)], interleukin-6 (IL-6) [B = -0.15 (P = 0.009)], and IL-6 receptor [B = -0.13 (P = 0.024)] was found. Furthermore, in multivariate Cox regression analysis, low T/E2 ratio was independently associated with an increased risk for major cardiovascular events (MACE) during 3 year follow-up [hazard ratio 1.67 (95% confidence interval 1.02-2.76), P = 0.043]. In men with elevated body mass index (BMI), these effects were strongest. In male patients with manifest atherosclerotic disease, low T/E2 ratio was associated with increased systemic inflammation, increased inflammatory plaque proteins, and an increased risk of future MACE as compared to men with normal T/E2 ratio. These effects are strongest in men with elevated BMI and are expected to be affected by aromatase activity in white fat tissues. Normalization of T/E2 ratio may be considered as target for the secondary prevention of CVD in men.

Aortic Arch Width and Cardiovascular Disease in Men and Women in the Community.

BackgroundWe sought to determine whether increased aortic arch width (AAW) adds to standard Framingham risk factors and coronary artery calcium (CAC) for prediction of incident adverse cardiovascular disease (CVD) events in community‐dwelling adults.Methods and ResultsA total of 3026 Framingham Heart Study Offspring and Third Generation cohort participants underwent noncontrast multidetector computed tomography from 2002 to 2005 to quantify CAC. We measured AAW as the distance between the centroids of the ascending and descending thoracic aorta, at the level of main pulmonary artery bifurcation or the right pulmonary artery. We determined sex, age group, and body size specific cut points for high (≥90th percentile) AAW from a healthy referent group (N=1471) and dichotomized AAW as high or not high across all study participants. Clinical covariates were obtained at Offspring cycle 7 (1998–2001) or Third Generation cycle 1 (2002–2005) examinations. The primary CVD outcome was a composite of myocardial infarction, coronary insufficiency, cerebrovascular accident, first hospitalization for heart failure, or CVD death. Cox proportional hazards models were used to estimate hazard ratio of high AAW on time‐to‐incident CVD after adjustment for Framingham risk factors and CAC. Net reclassification improvement was used to assess the effect of adding AAW to the baseline Framingham risk factor+CAC model. A total of 2826 participants (aged 51±11 years, 48% women) had complete covariates and were free of CVD at multidetector computed tomography. Over a median 8.9 years of follow‐up, there were 135 incident CVD events. High AAW was independently predictive of CVD events (hazard ratio, 1.55; P=0.032) and appropriately reclassified participants at risk: net reclassification improvement, 0.31 (95% confidence interval, 0.15–0.48).Conclusion AAW augments traditional CVD risk factors and CAC for prediction of incident adverse CVD events among community‐dwelling adults.

Insights from outside BJOG

Insights from outside BJOG

A New Perspective on the Nitrate-Phosphodiesterase Type 5 Inhibitor Interaction.

Nitrates and nitrate-containing compounds are vasodilators used for the treatment of angina and heart failure. Phosphodiesterase type 5 inhibitors used for the treatment of erectile dysfunction are also vasodilators, and when taken together with nitrates, synergistic effects that enhance hypotensive effects may occur. Phosphodiesterase type 5 inhibitors are therefore contraindicated in patients taking organic nitrates. A literature review was performed to provide a historical overview of different phosphodiesterase type 5 inhibitors and nitrates and their interaction. The pharmacologic characteristics of phosphodiesterase type 5 inhibitors and nitrates are reviewed, and clinical recommendations for treating cardiovascular disease in men taking phosphodiesterase type 5 inhibitors are discussed. Pharmacologic and adverse drug reactions between nitrates and phosphodiesterase type 5 inhibitors are dependent on many variables. Organic nitrates remain an absolute contraindication in men treated with phosphodiesterase type 5 inhibitors. In general, nitrates may be taken 24 hours after the last dose of short-acting phosphodiesterase type 5 inhibitors and 48 hours after the last dose of long-acting phosphodiesterase type 5 inhibitors. This literature review determined that the use of phosphodiesterase type 5 inhibitors with nitrates is a contraindication, with the duration between the last dose of phosphodiesterase inhibitor and nitrate use generally varying between short- and long-acting phosphodiesterase type 5 formulations. Patients receiving nitrates who wish to use phosphodiesterase type 5 inhibitors should be educated regarding the interaction and should be evaluated to determine whether nitrate treatment can be discontinued. Further research is needed to determine how soon phosphodiesterase type 5 inhibitors can be restarted after a patient has taken a nitrate and the effect of high and low phosphodiesterase type 5 inhibitor doses on the interaction effect.

Abstract 267: Testosterone to Estradiol Ratio Reflects Systemic and Plaque Inflammation and Predicts Future Cardiovascular Events in Men With Severe Atherosclerosis

Objective: The effects of testosterone on cardiovascular disease (CVD) as reported in literature have been ambiguous. Recently, the interplay between testosterone and estradiol as assessed by testosterone/estradiol (T/E2) ratio was suggested to be better informative on the normal physiological balance. Considering the role in CVD, we hypothesized that a low T/E2 ratio in men with CVD is associated with increased inflammation, a more unstable plaque and a worse cardiovascular outcome. Approach: Testosterone and estradiol concentrations were determined in blood samples of 709 male carotid endarterectomy patients included in the Athero-Express Biobank Study. T/E2 ratio was associated with baseline characteristics, atherosclerotic plaque specimens, inflammatory biomarkers and three-year follow-up information. Results: Patients with low T/E2 ratio had more unfavorable inflammatory profiles compared to patients with high T/E2 as observed by higher levels of C-reactive protein (CRP) (3.08 μg/mL vs. 1.21 μg/mL (p&lt;0.001)) and higher leukocyte counts (8.95*109/L vs. 7.84*109/L (p&lt;0.001)) in blood. In atherosclerotic plaques, a negative association between T/E2 ratio and number of neutrophils (B=-0.56(p=0.010)), smooth muscle cells (B=-0.049(p=0.046)), interleukin-6 (IL-6) (B=-0.15 p=0.009) and Il-6receptor (B=-0.13 p=0.024) was found. Decreased T/E2 ratio showed an overall trend towards histological features that represent the vulnerability of atherosclerotic lesions. Furthermore, in multivariate cox regression analysis, low T/E2 ratio was independently associated with an increased risk for major cardiovascular events (MACE) during three-year follow-up (HR 1.77 (95%CI: 1.08 - 2.90 p=0.023)). Conclusion: In male patients with manifest atherosclerotic disease, low T/E2 ratio was associated with increased systemic inflammation, increased inflammatory plaque proteins and an increased risk of future major cardiovascular events as compared to men with normal T/E2 ratio. Normalization of T/E2 ratio may be a useful tool for the secondary prevention of CVD in men.

PHS4 - Effect of Fasting Serum Glucose Change on The Risk of Cardiovascular Disease in Men Without Type2 Diabetes

To find the effect of change in fasting serum glucose on the risk of cardiovascular disease without type2 diabetes(T2DM). We analyzed the data of 149,913 Korean men aged ≥40 years without T2DM and history of cardiovascular disease at baseline using National Health Insurance Service database. Participants were first grouped into normal fasting glucose (NFG, 70.0-99.9mg/dL) and impaired fasting glucose (IFG, 100.0-125.9mg/dL) according to the fasting serum glucose levels of the first health screening. Then, the subjects were categorized into five groups which were ≤-25.0, -10.0 to -24.9, -9.9 to 9.9 (a persistent group, reference), +10.0 to +24.9, and ≥+25.0 mg/dL according to change in fasting serum glucose levels between the second and first health screenings. Cox proportional hazards regression analyses were performed to calculate the hazard ratios for the risk of myocardial infarction and stroke after adjusting for potential confounders. Fasting serum glucose increasing ≥25.0mg/dL in the NFG group was associated with an elevated risk of stroke (adjusted hazard ratio, aHR 1.22, 95% confidential interval, CI 1.09-1.37). Fasting serum glucose increasing ≥25.0mg/dL in the IFG group was associated with an elevated risk of myocardial infarction (aHR 1.86, 95% CI 1.25-2.76) and stroke (aHR 1.34, 95% CI 1.09-1.66). Fasting serum glucose decreasing -10.0 to -24.9mg/dL in the NFG group was associated with an elevated risk of stroke (aHR 1.24, 95% CI 1.11-1.38), but decreasing fasting serum glucose in the IFG group was not significantly associated with the risk of myocardial infarction or stroke. Maintaining fasting serum glucose at normal level may contribute to lowering the risk of cardiovascular disease.

Endogenous testosterone does not improve prediction of incident cardiovascular disease in a community-based cohort of adult men: results from the Tehran Lipid and Glucose Study

Introduction: To explore the predictive value of testosterone added to the Framingham Risk Score (FRS) for cardiovascular disease (CVD).Methods: Among 816 men, 30–70 years/old, without prevalent CVD, from a community-based cohort (Tehran Lipid and Glucose Study), we assessed the predictive value of testosterone with incident CVD, using three multivariate Cox proportional-hazards models. Model I: FRS variables; model II: Model I plus total testosterone; model III: Model II plus Systolic blood pressure (SBP) * total testosterone (the best fit interaction-term between testosterone and FRS variables). Discriminations and goodness-of-fit were assessed by the C-statistic and the approach of Grønnesby, respectively. p Value <.05 was significant.Results: During 12 years of follow-up, 121 CVD events occurred. In all models, age, treated SBP, smoking, and diabetes were associated with increased CVD (p values <.05). Neither testosterone (models II and III), nor SBP * testosterone (model III) were associated with CVD (p values >.05). The C-statistics for models I, II, and III were 0.819, 0.820, and 0.821, respectively, indicating no significant improvement in the discrimination power. The models’ goodness-of-fit did not improve compared with the FRS.Conclusion: Testosterone could not add to the predictive value of FRS for CVD in men, either directly, or through interactions with FRS variables.

Management of Acute Coronary Syndromes

Management of Acute Coronary Syndromes

Cardiovascular Protection in People With Diabetes.

Cardiovascular Protection in People With Diabetes.

Null association between androgen-deprivation therapy and nonprostate cancer mortality among older men with nonmetastatic prostate cancer

BackgroundAndrogen-deprivation therapy (ADT) has been associated with cardiovascular risk factors and the development of cardiovascular disease in men with metastatic prostate cancer. We sought to examine the effect of ADT on nonprostate cancer mortality among patients with nonmetastatic prostate cancer. MethodsWe performed a population-based, retrospective cohort study of men aged 66 years and older treated with surgery or radiotherapy for nonmetastatic prostate cancer in Ontario, Canada from 2002 to 2009 using administrative datasets (including the Ontario Cancer Registry, Ontario Drug Benefit, and Ontario Health Insurance Plan). Analysis was performed between September 2016 and April 2017. ADT exposure was operationalized as a time-varying binary and cumulative dose exposure. Primary and secondary outcomes were nonprostate cancer mortality and cardiovascular mortality, respectively. The Fine and Gray subdistribution method with generalized estimating equations was used to calculate subdistribution hazard ratios (sdHR), while accounting for competing risks. ResultsWe examined 20,651 men treated for nonmetastatic prostate cancer. Median follow-up was 7.4 years and median ADT exposure was 6.4 months. ADT was not significantly associated with nonprostate cancer mortality (sdHR = 0.75, 95% CI: 0.37–1.50) or cardiovascular mortality (sdHR = 1.16, 95% CI: 0.37–3.63) when operationalized as a binary time-varying exposure. Similar results were obtained when we examined ADT cumulative dose exposure. ConclusionsADT is not associated with nonprostate cancer mortality or cardiovascular mortality in a large, population-based cohort of older men with localized prostate cancer treated by surgery or radiation therapy.

Risk factors control for primary prevention of cardiovascular disease in men: Evidence from the Aragon Workers Health Study (AWHS).

Benefits of cardiovascular disease (CVD) risk factors control are well known, but goals achievement remains low. The objective of this study is to evaluate the prevalence of CVD risk factors among men ina worker’s cohort with no previous CVD, to study control variations across time and the factors associated with poor control. To this end, we conducted a cohort reexamination (2010–2014) within the context of the Aragon Workers Health Study (AWHS). Data from working characteristics, analytical values and pharmacological prescription were included in the analysis. Prevalences of risk factor diagnosis and control were calculated, as well as factors associated with poor control. The prevalence of CVD risk factors was high. In 2014dyslipidaemia was the most prevalent (85.2%) followed by Hypertension (HT) (42.0%). People under treatment increased for the period analysed (p<0.001). The proportion of people treated varied from 72.2% in Diabetes Mellitus to 31.1% in dyslipidaemia in 2014. 46.2% of the workers with HT were controlled, decreasing to 21.9% in Diabetes and 11.0% in dyslipidaemia (2014). Working in a turn different to central shift was associated with poor control, especially for those working at night with HT (Odds Ratio in 2010: 3.6; Confidence Interval 95% 1.8–7.4) and dyslipidaemia (Odds Ratio 2010: 4.7; Confidence Interval 95% 1.3–16.4). We conclude that, although CVD control has increased significantly for the period studied, there are still many people that do not receive any treatment, and control goals are normally not achieved.

Diabetes and number of years of life lost with and without cardiovascular disease: a multi-state homogeneous semi-Markov model.

We quantified the impact of type 2 diabetes on incidence of non-fatal cardiovascular disease (CVD) and mortality, considering CVD as a continuum from occurrence of diabetes to the end point, and estimated the 15-year life expectancy with and without CVD. A total of 7239 Iranian adults (3246 men), aged ≥30years, were followed from 1999 to 2014. We applied a multi-state semi-Markov model with three transitions including CVD-free to non-fatal CVD, CVD-free to death and non-fatal CVD to death, and studied the influence of diabetes on each transition rate, stratifying by sex and adjusting for confounders. Diabetes was significantly associated with increased risk of non-fatal CVD in men [hazard ratio, 1.70 (1.36-3.53)] and women [2.19 (1.74-2.77)], and of all-cause death [2.72 (2.03-3.63) and 1.92 (1.37-2.67) in men and women, respectively]. An increased risk of mortality was found only among diabetic men, when non-fatal CVD was occurred [2.19 (1.36-3.53)]. Men with diabetes experienced first non-fatal CVD and death without CVD 1.7 and 1.4years, respectively, earlier than those without diabetes; the corresponding values were 1.4 and 0.7years for women. Moreover, diabetic men lived 1.3years less than non-diabetic counterparts when non-fatal CVD was occurred. Diabetes increased the risk of non-fatal CVD events and all-cause mortality and consequently decreased the number of years lived without CVD. A decrease in LE was found only among diabetic men compared to non-diabetics after non-fatal CVD occurred.

Stress in the family - association with prevalence of cardiovascular diseases in men of the open city population

Stress in the family - association with prevalence of cardiovascular diseases in men of the open city population

Is Corneal Arcus Independently Associated With Incident Cardiovascular Disease in Asians?

To examine the longitudinal relationship between baseline corneal arcus (CA) and incident cardiovascular disease (CVD) in ethnic Indian and Malay adults in Singapore. Population-based cohort study. Indian and Malay adults aged 40-80 years were recruited for baseline and 6-year follow-up visits between 2004-2009 and 2010-2015, respectively (follow-up response rate 73.9%). CA was assessed by ophthalmologists using slit-lamp biomicroscopy. The main outcome was self-reported incident CVD, defined as new myocardial infarction, angina pectoris, or stroke, which developed between baseline and follow-up. Multivariable logistic regression models assessed independent associations between baseline CA and incident CVD, adjusting for traditional CVD risk factors including age, sex, serum cholesterol, hypertension, diabetes, and smoking. We further conducted sex-stratified analyses to identify possible effect modifications. Of the total 3637 participants (overall mean [SD] age: 56 [9] years, 46% male) with available follow-up data, without history of CVD at baseline, 208 (5.7%) incident CVD cases were reported. Participants with CA were more likely to have incident CVD (7.5%) than those without (4.9%). After controlling for traditional CVD risk factors, CA was independently associated with incident CVD (odds ratio [95% confidence interval]: 1.52 [1.07-2.16]) in adjusted models. In sex-stratified models, associations between CA and incident CVD were seen in men (1.73 [1.12-2.67]) and not in women (1.05 [0.56-1.97]). CA is associated with incident CVD, independent of serum lipids and traditional CVD risk factors, in ethnic Malay and Indian men. Our finding suggests that CA is an additional observable indicator of CVD in men.

Perinatal testosterone exposure potentiates vascular dysfunction by ERβ suppression in endothelial progenitor cells.

Recent clinical cohort study shows that testosterone therapy increases cardiovascular diseases in men with low testosterone levels, excessive circulating androgen levels may play a detrimental role in the vascular system, while the potential mechanism and effect of testosterone exposure on the vascular function in offspring is still unknown. Our preliminary results showed that perinatal testosterone exposure in mice induces estrogen receptor β (ERβ) suppression in endothelial progenitor cells (EPCs) in offspring but not mothers, while estradiol (E2) had no effect. Further investigation showed that ERβ suppression is due to perinatal testosterone exposure-induced epigenetic changes with altered DNA methylation on the ERβ promoter. During aging, EPCs with ERβ suppression mobilize to the vascular wall, differentiate into ERβ-suppressed mouse endothelial cells (MECs) with downregulated expression of SOD2 (mitochondrial superoxide dismutase) and ERRα (estrogen-related receptor α). This results in reactive oxygen species (ROS) generation and DNA damage, and the dysfunction of mitochondria and fatty acid metabolism, subsequently potentiating vascular dysfunction. Bone marrow transplantation of EPCs that overexpressed with either ERβ or a SIRT1 single mutant SIRT1-C152(D) that could modulate SIRT1 phosphorylation significantly ameliorated vascular dysfunction, while ERβ knockdown worsened the problem. We conclude that perinatal testosterone exposure potentiates vascular dysfunction through ERβ suppression in EPCs.

Temporal Associations Between Smoking and Cardiovascular Disease, 1971 to 2006 (from the Framingham Heart Study)

Smoking has consistently been related to cardiovascular risk. Public health efforts have yielded reduced smoking prevalence and gains in cardiovascular disease (CVD) prevention. We hypothesized that the contribution of tobacco to CVD risk would be attenuated over prospective decades (1971 to 2006) in a community-based cohort. We evaluated 5,041 Framingham Heart Study Offspring Cohort participants (mean age 36.1 years, 52% women) without prevalent CVD. We collected prospective data on smoking status, relevant CVD risk factors, and incident CVD events across prospective decades. We used multivariable-adjusted, Cox proportional hazard models to measure the effect of smoking on incident CVD over 3 prospective 12-year follow-up periods. Our results demonstrated a consistent twofold increased risk of CVD in men who smoke compared with nonsmokers for each 12-year time period spanning from 1971 to 2006. Women who smoked had a 1.5-fold increased CVD risk. Smoking remains an important risk factor despite substantial improvements in the prevention and treatment of CVD. Significant, contemporary improvements in CVD prevention-such as gains in hypertension and cholesterol treatment-have not attenuated the strong and persistent associations between smoking and CVD observed here. In conclusion, our results highlight the importance of continued public health efforts to address smoking as a modifiable exposure that strongly contributes toward CVD risk.