Comparative vascular effects of hormone replacement therapy and raloxifene in women at increased cardiovascular risk.

Hormone replacement therapy (HRT) improves endothelial function in postmenopausal women while the effects of raloxifene, a selective estrogen receptor modulator, are still under debate. The aim of this study was to evaluate endothelium-dependent flow-mediated vasodilatation in the brachial artery and plasma levels of nitrite, nitrate and endothelin-1 in 20 postmenopausal women with increased cardiovascular risk treated with either HRT or raloxifene for 4 weeks in a randomized double-blind single cross-over study. Patients had an endothelium-dependent flow-mediated dilatation of 4% prior to initiation of the study. Treatment with HRT resulted in a 67% increase in dilatation compared with baseline (from a 7.4% increase to a 12.4% increase, p < 0.01). Raloxifene treatment resulted in no change in vasodilatation from baseline. Endothelium-dependent dilatation was significantly improved by HRT compared with raloxifene treatment (12.4+/-0.6% vs. 6.1+/-2.0%; p < 0.01). Compared with baseline values, nitrate plus nitrite levels increased significantly (p < 0.05) with HRT but not with raloxifene. Similarly, endothelin-1 decreased from baseline with both treatments, but only the HRT-induced decrease was statistically significant (p < 0.05). In conclusion, HRT improved endothelial function and reduced plasma levels of endothelin-1 in postmenopausal women at risk of coronary artery disease. These beneficial effects were not shared by raloxifene.

Can menopause be considered an independent risk factor for cardiovascular disease?

Following the menopause, women develop coronary artery disease at the same rate as men. The best documented change observed in the risk factors linked to ovarian exhaustion is an alteration in lipid composition. More recent studies, however, suggest that the increased cardiovascular morbidity and mortality after menopause cannot be fully explained by changes in plasma lipoproteins, and support the concept that ovarian hormone deprivation has a widespread impact on the cardiovascular system, with a direct harmful effect on vessel-wall physiology. After the menopause, subjects free from cardiovascular diseases show vascular hyperactivity and a poor vasodilator reserve; the rate of increase in the incidence of arterial hypertension in women is higher than that observed among males of the same age; altogether, cardiovascular diseases become the number one cause of death among women. A large number of mechanistic studies have shown that estrogens, through either direct or genomic-dependent activities, produce beneficial effects on the factors controlling blood flow and plaque formation. Nevertheless, results from recent randomized clinical trials are challenging the belief that postmenopausal hormone therapy protects against coronary artery disease.

Cardiac dysfunction in acromegaly: evidence by pulsed wave tissue Doppler imaging.

OBJECTIVE: To verify whether the accuracy of data on myocardial function provided by pulsed-wave tissue Doppler imaging (PWTDI), a new echocardiographic application that allows quantitative measurements of myocardial wall velocities, could help towards a better understanding of the natural history of acromegalic cardiomyopathy. DESIGN: Eighteen patients with active acromegaly (ten men and eight women; mean age 48.0+/-15.0 years) with no other detectable cause of heart disease underwent PWTDI. Thirteen healthy individuals matched for age and body mass index acted as a control group. METHODS: Ejection fraction (EF), transmitral early/late diastolic velocity (E/A) ratio and isovolumic relaxation time (IVRT) were measured by conventional echocardiography; systolic peak (Sv) and early (Ev) and late (Av) diastolic peak velocities, Ev/Av ratio and regional IVRT (IVRTs) were obtained by PWTDI. RESULTS: All patients showed appreciably abnormal left ventricular global diastolic function represented by prolongation of the IVRT (P<0.001). Using PWTDI we found a prolongation of IVRTs and inversion of the Ev/Av ratio. In addition, the Ev/Av ratio proved to be significantly negatively correlated with IVRT; this correlation was not present in the case of the E/A ratio. Furthermore, a decrease in Sv was detected in the basal segment of the lateral wall (P<0.01), which had the greatest degree of diastolic dysfunction. CONCLUSIONS: PWTDI confirmed the acknowledged diastolic dysfunction that accompanies acromegalic cardiomyopathy and highlighted the greater sensitivity of regional PWTDI with respect to global Doppler diastolic indexes. Furthermore, by revealing an impairment of regional systolic function in presence of a normal EF, the findings with PWTDI contradicted the largely accepted theory that systolic function remains normal for several years in patients affected by acromegalic cardiomyopathy.

The relative effects of progesterone and progestins in hormone replacement therapy.

Hormone replacement therapy (HRT) was initially given to protect women against osteoporosis and alleviate menopausal symptoms, such as hot flashes, depression, sleep disturbances, and vaginal dryness. In view of the understanding of oestrogen deficiency as a major trigger for the acceleration of cardiovascular risk after menopause, HRT may also be proposed as a substantial beneficial cardioprotective agent. Progestins, which may be added to oestrogen in combined HRT to reduce the risk of uterine malignancy, have a number of potential adverse effects on the cardiovascular system which could even attenuate the benefit of unopposed oestrogen replacement therapy in post-menopausal women.

Evidence of a role of endogenous estrogen in the modulation of autonomic nervous system.

We studied heart rate variability in 14 healthy women before and after oophorectomy compared with 14 matched women who underwent hysterectomy with ovarian conservation. Surgical menopause induced a decline in cardiac vagal modulation with a shift toward sympathetic hyperactivity. Recovery of the baseline condition after 3 months of estrogen replacement therapy in oophorectomized women suggests a role of estrogen in the autonomic nervous control of the cardiovascular system.

Effects of acute administration of natural progesterone on peripheral vascular responsiveness in healthy postmenopausal women.

Peripheral vascular responses to acute administration of natural progesterone were studied in 12 postmenopausal women (mean +/- SD age 50.3 +/- 4.8 years) with no evidence of cardiovascular disease. According to a randomized, double-blind protocol, all subjects were given natural progesterone as a vaginal cream, able to produce a rapid peak and decay of plasma hormone concentrations, or matched placebo, with crossover after a 1-week washout period. Forearm blood flow and peak flow after ischemic stress (ml/100 ml/min), local vascular resistance (mm Hg/ml/100 ml/min), venous volume (ml/100 ml), and venous compliance (ml/100 ml/mm Hg) were measured by strain-gauge venous occlusion plethysmography at baseline and after progesterone or placebo administration. Plasma norepinephrine concentrations were determined by high-performance liquid chromatography with electrochemical detection. Progesterone sharply decreased forearm blood flow (p <0.01) through an increase in local vascular resistance (p <0.01). Measures of venous function remained unchanged. Although the hormone increased circulating norepinephrine concentrations (p <0.05), there were no significant changes in mean arterial pressure or heart rate. Furthermore, progesterone reduced the local vasodilator capacity, shown by a decrease in forearm delta flow (difference between peak flow and basal flow, p <0.05). Compared with the well-known effect of estrogen, progesterone exerted an opposite action on peripheral vascular responsiveness. Peripheral circulatory changes may be attributed to a direct activity of progesterone on the arterial wall and may in part reflect a modulation of the hormone on peripheral sympathetic tone. Consideration must be given to the hypothesis that the addition of progestin may attenuate the beneficial effects of unopposed estrogen replacement therapy in postmenopausal women.

Study of myocardial contractility by pulsed wave Doppler tissue imaging does not reveal an inotropic effect of estrogen at physiologic dose.

We studied myocardial contractility by pulsed wave Doppler tissue imaging in 6 postmenopausal healthy women. According to a crossover, double-blind protocol, we randomized patients to treatment with transdermal patches of estradiol-17beta or matched placebo. Estradiol-17beta did not modify local systolic and diastolic functions. Thus, at least when acutely administered, estrogen seems to be unable to determine hemodynamic changes at the myocardial level, in opposition to what occurs in the peripheral vascular system.

Impaired forearm blood flow and vasodilator reserve in healthy postmenopausal women.

BACKGROUND: The natural process of cessation of ovarian estrogen production is associated with an increasing incidence of cardiovascular disease. OBJECTIVE: We aimed to determine whether postmenopausal women had menopause-associated vasomotor disturbances develop. METHODS: We studied the vascular forearm function using strain-gauge venous occlusion plethysmography in 12 healthy postmenopausal women (mean age +/- SD, 47 +/- 3 years; time-lapse from menopause >1 year). Twelve premenopausal subjects matched for age and biophysical characteristics were used as a control group. RESULTS: No differences were observed in heart rate or mean blood pressure between the 2 groups of women. Forearm blood flow at supine resting was lower in postmenopausal than in premenopausal women (2.4 +/- 0.8 vs 3.1 +/- 0.5 mL/100 mL/min; P <.05). Local vascular resistance was higher in postmenopausal than in premenopausal women (43.5 +/- 17.5 vs 31.1 +/- 4.3 mm Hg/mL/100 mL/min; P <.05). Moreover, peak forearm flow in response to forearm ischemia was 20.8 +/- 7.9 mL/100 mL/min in postmenopausal women and 26.6 +/- 9.7 mL/100 mL/min in premenopausal women (P <.01). Plasma concentration of noradrenaline in the supine position was significantly higher in postmenopausal than in premenopausal women (286 +/- 22 pg/mL vs 195 +/- 33 pg/mL; P <.01). Finally, a significant positive relation was revealed in postmenopausal women between the amount of vasodilator reserve (D flow) in local peripheral circulation and levels of circulating estradiol-17beta. CONCLUSIONS: Abnormalities observed in forearm blood flow and vasodilator capacity in postmenopausal women may be attributed to a critical loss of the vasodilating property of physiologic estrogen. Our data support the possibility that reduction in dilator capacity of the vasculature may contribute to the increase of cardiovascular disease after menopause.

Estradiol-17beta reduces blood pressure and restores the normal amplitude of the circadian blood pressure rhythm in postmenopausal hypertension.

After menopause, both systolic (SBP) and diastolic (DBP) blood pressure (BP) become higher in women than in men of the same age, suggesting that estrogen deficiency may influence the age-related increase in BP. We studied 30 postmenopausal women (mean age, 55 +/- 5.7 years; time from menopause, 2-5 years) affected by mild hypertension with no target-organ complications by means of 24-h BP monitoring. None of the group were undergoing estrogen replacement therapy or taking antihypertensive drugs. According to a randomized, double-blind protocol, subjects received patches of transdermal estradiol-17beta (E2) or a matched placebo, with crossover after a 7-day washout period. In 12 patients the 24-h peak-to-trough variation in SBP and DBP amounted to less than 10% (nondippers). Administration of E2 significantly decreased 24-h SBP and DBP in the whole cohort (P < .05). Furthermore, E2 restored the expected reduction in BP during nighttime in the nondipper subgroup. It is well known that estrogen replacement therapy protects against the development of both cardiovascular diseases and stroke. Our data suggest that this activity could be attributed, at least in part, to the activity of E2 in preserving physiologic circadian fluctuation of BP.

Effects of acute administration of transdermal estrogen on postmenopausal women with systemic hypertension.

We studied 16 postmenopausal women with mild to moderate hypertension according to a randomized, double-blind protocol. They received patches of transdermal estradiol-17beta rated to deliver 100 mg/day of substance or matched placebo. A 24-hour ambulatory blood pressure (BP) monitoring was performed at baseline and after drug administrations. Our data show that estradiol-17beta exerts beneficial effects, both in lowering elevated BP levels and in maintaining a uniform BP control over 24 hours. Estrogen replacement therapy could be considered when significant changes in BP occur during the postmenopausal period.

Association between psychiatric disorders and Marfan's syndrome in a large Sardinian family with a high prevalence of cardiac abnormalities.

BACKGROUND: Marfan's syndrome is an inherited disorder of connective tissue associated with characteristic abnormalities of the skeletal, ocular, and cardiovascular systems. Marked clinical variability and age dependency of all manifestations of Marfan's syndrome may render the unequivocal diagnosis difficult in mildly affected, young subjects. HYPOTHESIS: The study and care of a 32-year-old woman with evidence of Marfan's syndrome, several cardiac abnormalities, and paranoid schizophrenia led to an investigation of her consenting relatives to verify the penetrance of Marfan's syndrome and the degree of comorbidity between the disease and psychiatric disorders. METHODS: The patient and 12 subjects belonging to three generations of her family underwent cardiovascular, skeletal, ophthalmologic, and psychiatric examinations. Two-dimensional and Doppler echocardiography were performed. RESULTS: One female index patient and six of her first-degree relatives were found to be affected by Marfan's syndrome. All seven patients were found to have mitral valve prolapse associated with other cardiac abnormalities. Four of these patients were affected by the following psychiatric disorders: generalized anxiety disorder, major depressive disorder, paranoid schizophrenia (two cases). Six more relatives without Marfan's syndrome showed mitral valve prolapse in association with other echocardiographic features. Two of these were found to be affected by a major depressive disorder. CONCLUSIONS: The present data support the hypothesis that a psychiatric condition, associated with a significantly high frequency of cardiac involvement, may be part of the phenotype of Marfan's syndrome.