Giorgia Origliani

Prognostic Role of Flow-Mediated Dilation and Cardiac Risk Factors in Post-Menopausal Women

OBJECTIVES The aim of this study was to examine the association between brachial artery flow-mediated dilation (FMD) and cardiovascular events in a cohort of initially asymptomatic post-menopausal women, with adjustment for the presence of the major cardiovascular risk factors. BACKGROUND Conventional major cardiovascular risk factors (cigarette smoking, hypercholesterolemia, hypertension, and diabetes) fail to explain nearly 50% of cardiovascular events. Defining the magnitude of future risk for the development of clinical events is a major focus of effective primary prevention. Evaluation of endothelial function, utilizing the noninvasive measurement of the brachial artery FMD, may serve as a screening tool to individualize high-risk patients. METHODS We conducted a prospective study on 2,264 post-menopausal women, age 54 +/- 6 years. The length of the follow-up was 45 +/- 13 months (range 6 to 65 months). RESULTS During observation, 90 major events were recorded. Risk-adjusted relative risk values resulted 1.0, 1.33 (95% confidence interval [CI] 1.09 to 4.09), and 4.42 (95% CI 2.97 to 8.01) for women in the higher, intermediate, and lower tertile of FMD, respectively (p < 0.0001 for trend). The event rate for women in the lower tertile (FMD <or=4.5%) was greater than the combined event rate noted in the other 2 tertiles (women in the lower tertile accounted for 51 events [56.6% of total events]). When added to age and other conventional cardiovascular risk factors (smoking habits, presence of hypercholesterolemia, history of diabetes, hypertension), FMD contributed significantly to the model predicting cardiovascular events (likelihood ratio chi-square change: 10.22; p < 0.0001). CONCLUSIONS In post-menopausal women, the knowledge of FMD provided incremental prognostic information regarding the risk of developing cardiovascular events.

Menopause and cardiovascular risk.

Menopause is not a disease, but a physiologic phase of a womans life, due to the changes of their hormonal status. Fastidious symptoms may be associated with changes in the metabolism together with new cardiovascular risk factors, particularly aggressive for the female cardiovascular system, unprepared because of the protection due to the fertile period. Changes of the lipid profile, obesity, hypertension, glucose intolerance and diabetes mellitus may intervene as severe risk factors. Cardiovascular disease represents therefore the most frequent cause of mortality and morbidity also in the female gender more than cancer either in the United States as in Europe. The risks related to post-menopause are mainly due to the abrupt interruption of estrogen, which has indirect protective effects on lipid, glycidic metabolism and direct effects on vessel function. They have, in fact, vasodilator action due to nitric oxide release, calcium-antagonist like action and an antiproliferative effect on smooth muscle cells. Post-menopause is also frequently associated with hypertension, the most frequent related factor to coronary artery disease. Hypertension is due to increased body mass index, with insulin-resistance, sodium retention, increased blood viscosity and estrogen deficiency with increased smooth muscle cell proliferation which determines an increase in systemic vascular resistance. Age and estrogen deficiency are together the most important cause of cardiovascular risk in post-menopause. The discovery of alpha and recently beta estrogen receptors on coronary female vessels unaffected by atherosclerosis either during pre and post-menopause phase are possible key of interpretation of pathophysiology of coronary artery disease in women, with important therapeutic consequence.

Metabolic Syndrome Affects Cardiovascular Risk Profile and Response to Treatment in Hypertensive Postmenopausal Women

Metabolic syndrome is increasingly recognized as an important cardiovascular risk factor in hypertension, but its influence on the cardiovascular risk profile in hypertensive postmenopausal women has not been studied. The aim of the present study was to investigate the impact of metabolic syndrome on the cardiovascular risk profile and the response to treatment. We enrolled 350 hypertensive postmenopausal women, 55±6 years of age (range 47 to 60 years of age). Patients were divided into 2 groups according to the presence of metabolic syndrome. Compared with those without, women with metabolic syndrome had higher waist circumference, body mass index, and levels of glucose, triglycerides, and HDL cholesterol, as would be expected, based on definition. In addition, patients with metabolic syndrome had a cardiovascular risk profile less favorable, characterized by a significantly higher highly sensitive C-reactive protein (2.2±0.6 versus 1.7±0.7 ng/L; P<0.01), a more compromised endothelial function (flow-mediated vasodilation 2.4±2.2 versus 4.4±2.5%; P=0.01), and a significantly higher left ventricular mass (44±15 versus 41±16 g/m2.7). Also, antihypertensive treatment induced a more modest improvement of both endothelial dysfunction and subclinical inflammation in women with metabolic syndrome. The results of our study show that in postmenopausal women, there are 2 different forms of hypertension: that which is isolated, and that which is associated with metabolic syndrome. This last form is related to a more severe risk profile, and response to therapy is less favorable.

Endothelial function affects early carotid atherosclerosis progression in hypertensive postmenopausal women.

Objectives Endothelial dysfunction is known to be associated with atherosclerosis progression and cardiovascular events. Limited information exists regarding the importance of this topic in hypertensive postmenopausal women. In this particular population the influence of endothelial dysfunction on cardio-vascular end cerebro-vascular events is well demonstrated. Therefore, we investigated, in a prospective study, the influence of endothelial-dependent vasodilation on carotid intima–media thickness (IMT) progression in our population of hypertensive postmenopausal women. Methods In addition to common risk factors and pharmacological therapy, we measured carotid IMT and flow-mediated dilation (FMD) of the brachial artery at baseline and after 1 year of follow-up. Results Baseline and follow-up data were available for 618 hypertensive postmenopausal women with an age of 55 ± 8 years. The mean IMT at baseline was 754 ± 161 μm [interquartile range (IQR) from 600 to 838 μm]. The mean FMD at baseline was 5.8 ± 3.9% (IQR from 3.2 to 8.2%). There was a significant correlation between baseline FMD and carotid IMT (r = −0.16; P = 0.003). Mean IMT progression resulted in 103 μm (range from −250 to 567 μm; IQR from 0 to 200 μm) per year. Baseline FMD, FMD change and the amount of SBP reduction during follow-up remained the independent predictors of IMT progression in multivariable analysis. Conclusions In this prospective study we observed a significant interaction between baseline FMD, FMD change during follow-up and IMT progression in our population of hypertensive postmenopausal women. These results are in accordance with the suggestion that endothelial dysfunction is associated with enhanced atherosclerosis development. This hypothesis could provide a pathophysiological explanation for the increase in cardio-vascular and cerebro-vascular episodes recorded in hypertensive postmenopausal women with endothelial dysfunction.

Type 2 diabetes mellitus is a risk factor for the development of hypertension in postmenopausal women.

Objective Hypertension and type 2 diabetes mellitus are common diseases that are frequently found concomitantly in postmenopausal women. These findings suggest a close and/or synergistic nature in the relationship between the two disease processes; however, no prospective data exist on the incidence rate of hypertension in postmenopausal women with type 2 diabetes mellitus. Methods The present study assessed the risk of developing hypertension in 840 postmenopausal women: 102 women (12.1% of the cohort) with type 2 diabetes mellitus and 738 (87.9%) free of diabetes. The mean ± SD follow-up was 3.2 ± 0.9 years (range 0.5–6.0 years). Results The incidence rate (cases of hypertension per 100 person-years) was 1.1 for the group of women without diabetes versus 5.6 in women with diabetes (P < 0.0001). Compared with the non-diabetic group, women with type 2 diabetes mellitus had a statistically significant higher risk of developing hypertension. The relative risks for women with diabetes was 5.09 [crude: 95% confidence interval (CI) = 3.52–7.36; P < 0.0001]; 3.43 (adjusted for body mass index and waist circumference: 95% CI = 2.25–5.14; P < 0.001); and 2.95 (adjusted for all potential confounders: 95% CI = 1.86–4.32; P < 0.01). Conclusion In our prospective study, on the incidence of hypertension, the presence of type 2 diabetes was found to be a potent independent risk determinant. This suggests that postmenopausal women affected by type 2 diabetes mellitus comprise a population at high risk for the subsequent development of hypertension.

Parity as predictor of early hypertension during menopausal transition.

Objectives: Studies regarding the effects of parity on blood pressure in later life produced conflicting results. The aim of our study is to analyse whether parity influences the prevalence of hypertension in perimenopausal and postmenopausal women. Methods: One thousand perimenopausal and postmenopausal women (mean age 55.2 ± 5.4 years) were enrolled with a median follow-up of 63.0 months. The study sample consisted of patients who self-referred, in 1998–2009, to the BenEssere Donna Clinic, dedicated to menopause-related disorders. Results: One hundred and twenty-two (12.2%) women were nulliparous and 878 (87.8%) had at least one child. Thirty-four (27.9%) women among nulliparous and 326 (37.1%) among parous were hypertensive at baseline (P = 0.046) and 812 women (81.2%) were in their postmenopausal period. Univariate analysis showed that women with one or more children were at higher risk of being hypertensive [odds ratio (OR): 1.529; 95% confidence interval (CI): 1.006–2.324; P = 0.047]. Likewise, multivariate analysis revealed that parity (OR: 2.907; 95% CI: 1.290–6.547; P = 0.010), BMI (OR: 1.097; 95% CI: 1.048–1.149; P < 0.001) and family history of hypertension (OR: 3.623; 95% CI: 2.231–5.883; P < 0.001) were independently related to hypertension at baseline. In a subanalysis of 640 initially normotensive women, 109 (17.0%) patients developed hypertension after follow-up, without a statistically significant association with parity (13.6% in nulliparous versus 17.6% in parous; P = 0.362). Consistently, parity showed no relationship with the incidence of hypertension during follow-up (OR: 1.350; 95% CI: 0.707–2.579; P = 0.363). Conclusion: For the first time in a population of White perimenopausal and postmenopausal women, parity was demonstrated to be independently associated with early hypertension during menopausal transition. Conversely, postmenopausal hypertension was not related with parity.

Effects of antihypertensive treatment on endothelial function in postmenopausal hypertensive women. A significant role for aldosterone inhibition

Introduction: Endothelial dysfunction is a well-demonstrated independent predictor of cardiovascular events in hypertensive postmenopausal women. Accordingly, it is plausible that improving endothelial function could represent an adjunctive target for antihypertensive treatment. The aim of our study was to evaluate the effect of pharmacologic treatment on endothelial function in the specific population of hypertensive postmenopausal women. Methods: A total of 320 consecutive hypertensive postmenopausal women underwent a high-resolution ultrasound study of the brachial artery at baseline and after six months, while ‘optimal’ control of blood pressure (maintenance of blood pressure values below 140/90 mmHg at all follow-up visits) was achieved using antihypertensive therapy. Endothelial function was measured as flow-mediated dilation, using ultrasound method. Results: After six months of treatment, flow-mediated dilatation (FMD) had significantly improved in the majority of patients (n = 257 [80.3% of the entire population]; FMD = 8.1 ± 1.0% at baseline vs. 10.6 ± 1.5% after follow-up; p < 0.001), but it had not changed or worsened in others (n = 63 [19.7%]; FMD = 8.2 ± 1.2% at baseline vs. 7.6 ± 1.0% after six months; p = ns). Improvement of endothelial function, at multivariate analysis, resulted independently associated with the use of aldosterone inhibitors (odds ratio = 2.15; 95% confidence interval: 1.55–2.75; p = 0.001). Conclusions: This study demonstrates that a significant improvement in endothelial function may be obtained after six months of an optimal antihypertensive therapy. Among all hypertensive postmenopausal women that achieved an optimal control of blood pressure during follow-up, the use of drugs that inhibit aldosterone receptors was associated with an improvement of endothelial function, beyond the ‘optimal’ blood pressure control.