Ellen W. Seely

Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function.

BackgroundRecent clinical trial data indicate that the use of angiotensin converting enzyme (ACE) inhibitors among patients with left ventricular dysfunction results in reduced rates of coronary thrombosis, a provocative finding that suggests a potential interaction between the renin-angiotensin system and fibrinolytic function Methods and ResultsIn four normotensive subjects and six hypertensive patients, we investigated whether infusion of angiotensin II (Ang II) affected circulating levels of plasminogen activator inhibitor-i (PAI-1), the most important physiological inhibitor of tissue-type plasminogen activator (t-PA). Overall, mean levels of PAI-1 antigen increased significantly from 20.1 ng/mL before Ang H infusion to 36.0 ng/mL at the end of Ang II infusion (p=0.008), whereas no change in PAI-1 was observed for control subjects infused with 5% dextrose (p=0.46). Among the normotensive subjects for whom graded doses of Ang II were infused at 0, 1, 3, and 10 ng · kg-1 · min-1, mean PAI-1 levels increased sequentially from 14.7 ng/mL to 23.0, 26.8, and 33.5 ng/mL, a dose-response relation that, compared with controls, was highly significant (p<0.001). Among the hypertensive patients for whom a single 45-minute infusion of Ang II was given at a dose of 3 ng · kg-1 · min-1, PAI-1 levels increased from 23.7 to 37.7 ng/mL, whereas PAI-1 levels among control subjects infused with 5% dextrose decreased from 16.9 to 10.8 ng/mL (p=0.04). Finally, when compared with infusion of 5% dextrose solution, infusion of Ang II appeared to have little effect on circulating levels of t-PA antigen. ConclusionThese in vivo data suggest that infusion of Ang H results in a rapid increase in circulating levels of PAI-1, a finding that may help to explain clinical observations linking the renin-angiotensin system and thrombotic risk. (Circulation 1993;87:1969-1973)

Estradiol Therapy Combined With Progesterone and Endothelium-Dependent Vasodilation in Postmenopausal Women

BACKGROUND Epidemiological studies indicate that estrogen replacement therapy decreases the risk of cardiovascular events in postmenopausal women. Estrogen may confer cardiovascular protection by improving endothelial function because it increases endothelium-dependent vasodilation. It is not known whether progesterone attenuates the beneficial effects of estrogen on endothelial function. METHODS AND RESULTS Seventeen postmenopausal women with mild hypercholesterolemia were enrolled in a placebo-controlled, crossover trial to evaluate the effect of transdermal estradiol, with and without vaginal micronized progesterone, on endothelium-dependent vasodilation in a peripheral conduit artery. Brachial artery diameter was measured with high-resolution B-mode ultrasonography. To assess endothelium-dependent vasodilation, brachial artery diameter was determined at baseline and after a flow stimulus induced by reactive hyperemia. To assess endothelium-independent vasodilation, brachial artery diameter was measured after administration of sublingual nitroglycerin. During estradiol therapy, reactive hyperemia caused an 11.1+/-1.0% change in brachial artery diameter compared with 4. 7+/-0.6% during placebo therapy (P<0.001). Progesterone did not significantly attenuate this improvement. During combined estrogen and progesterone therapy, flow-mediated vasodilation of the brachial artery was 9.6+/-0.8% (P=NS versus estradiol alone). Endothelium-independent vasodilation was not altered by estradiol therapy, either with or without progesterone, compared with placebo. There was a modest decrease in total and LDL cholesterol during treatment both with estradiol alone and when estradiol was combined with progesterone (all P<0.001 versus placebo). In a multivariate analysis that included serum estradiol, progesterone, total and LDL cholesterol concentrations, blood pressure, and heart rate, only the estradiol level was a significant predictor of endothelium-dependent vasodilation. CONCLUSIONS The addition of micronized progesterone does not attenuate the favorable effect of estradiol on endothelium-dependent vasodilation. The vasoprotective effect of hormone replacement therapy may extend beyond its beneficial actions on lipids.

Brief Review: Hypertension in Pregnancy : A Manifestation of the Insulin Resistance Syndrome?

Pregnancy-induced hypertension (PIH), which includes both gestational hypertension and preeclampsia, is a common and morbid pregnancy complication for which the pathogenesis remains unclear. Emerging evidence suggests that insulin resistance, which has been linked to essential hypertension, may play a role in PIH. Conditions associated with increased insulin resistance, including gestational diabetes, polycystic ovary syndrome, and obesity, may predispose to hypertensive pregnancy. Furthermore, metabolic abnormalities linked to the insulin resistance syndrome are also observed in women with PIH to a greater degree than in normotensive pregnant women: These include glucose intolerance, hyperinsulinemia, hyperlipidemia, and high levels of plasminogen activator inhibitor-1, leptin, and tumor necrosis factor-alpha. These observations suggest the possibility that insulin resistance may be involved in the pathogenesis of PIH and that approaches that improve insulin sensitivity might have benefit in the prevention or treatment of this syndrome, although this requires further study.

Relations of thyroid function to body weight: cross-sectional and longitudinal observations in a community-based sample.

BACKGROUND Overt hypothyroidism and hyperthyroidism may be associated with weight gain and loss. We assessed whether variations in thyroid function within the reference (physiologic) range are associated with body weight. METHODS Framingham Offspring Study participants (n=2407) who attended 2 consecutive routine examinations, were not receiving thyroid hormone therapy, and had baseline serum thyrotropin (TSH) concentrations of 0.5 to 5.0 mIU/L and follow-up concentrations of 0.5 to 10.0 mIU/L were included in this study. Baseline TSH concentrations were related to body weight and body weight change during 3.5 years of follow-up. RESULTS At baseline, adjusted mean weight increased progressively from 64.5 to 70.2 kg in the lowest to highest TSH concentration quartiles in women (P< .001 for trend), and from 82.8 (lowest quartile) to 85.6 kg (highest quartile) in men (P= .007 for trend). During 3.5 years of follow-up, mean (SD) body weight increased by 1.5 (5.6) kg in women and 1.0 (5.0) kg in men. Baseline TSH concentrations were not associated with weight change during follow-up. However, an increase in TSH concentration at follow-up was positively associated with weight gain in women (0.5-2.3 kg across increasing quartiles of TSH concentration change; P< .001 for trend) and men (0.4-1.3 kg across quartiles of TSH concentration change; P= .007 for trend). CONCLUSIONS Thyroid function (as assessed by serum TSH concentration) within the reference range is associated with body weight in both sexes. Our findings raise the possibility that modest increases in serum TSH concentrations within the reference range may be associated with weight gain.

Estradiol With or Without Progesterone and Ambulatory Blood Pressure in Postmenopausal Women

The purpose of this study was to determine whether transdermal estradiol and intravaginal progesterone given in doses to mimic the premenopausal state would lower blood pressure (BP) in postmenopausal women. Fifteen healthy postmenopausal women were studied in each of 3 conditions: on placebo, after 8 weeks of transdermal estradiol 0.2 mg twice per week, and again 2 weeks after addition of intravaginal progesterone 300 mg/d. Women were studied at each point after 2 days of 100 mmol/d sodium intake. Twenty-four-hour ambulatory BP monitoring was performed, and blood was assayed for estradiol, progesterone, and hormones of the renin-angiotensin-aldosterone system (RAAS). ANOVA with pairwise comparisons was used for analysis. Urinary sodium excretion was similar at each time point. Levels of estrogen and progesterone similar to those in premenopausal women were achieved. On estradiol, nocturnal systolic BP (110+/-3 mm Hg), diastolic BP (63+/-2 mm Hg), and mean BP (77+/-2 mm Hg) fell significantly (P<0.02) compared with placebo systolic BP (116+/-2 mm Hg), diastolic BP (68+/-2 mm Hg), and mean BP (82+/-2 mm Hg). Daytime BP followed the same trend but was significantly lower only for mean BP. There was no activation of the RAAS. The addition of progesterone resulted in no further fall in BP but a significant activation of the RAAS. Thus, contrary to what is often assumed, administration of estradiol with or without progesterone not only did not raise BP but rather substantially lowered BP. This BP-lowering effect may be responsible for the lower incidence of hypertension in premenopausal than in postmenopausal women.

Glucose intolerance as a predictor of hypertension in pregnancy.

Insulin resistance is associated with and may be causal in essential hypertension, but the relation between insulin resistance and hypertension arising de novo in pregnancy is unclear. Transient hypertension of pregnancy (new-onset nonproteinuric hypertension of late pregnancy) is associated with a high risk of later essential hypertension and thus may have similar pathophysiology. To assess the association between glucose intolerance and subsequent development of proteinuric and nonproteinuric hypertension in pregnancy in women without underlying essential hypertension or overt glucose intolerance, we performed a retrospective case-control study comparing glucose levels on routine screening for gestational diabetes mellitus among women subsequently developing hypertension. Women who developed hypertension in pregnancy (n = 97) had significantly higher glucose levels on 50-g oral glucose loading test (P < .01) and a significantly higher frequency of abnormal glucose loading tests (> or = 7.8 mmol/L) (P < .01) than women who remained normotensive (n = 77). Relative glucose intolerance was particularly common in women who developed nonproteinuric hypertension. Women who developed hypertension also had greater prepregnancy body mass index (P < or = .0001) and baseline systolic and diastolic blood pressures (P < or = .0001 for both), although all subjects were normotensive at baseline by study design. However, after adjustment for these and other potential confounders, an abnormal glucose loading test remained a significant predictor of development of hypertension (P < .05) and, specifically, nonproteinuric hypertension in pregnancy (P < .01). Among a subgroup of women in whom insulin levels were also measured (n = 80), there was a nonsignificant trend toward higher insulin levels in women developing hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

First Trimester Vitamin D, Vitamin D Binding Protein, and Subsequent Preeclampsia

Previous studies report an association between vitamin D deficiency and hypertension, including the pregnancy-specific disorder preeclampsia. Circulating vitamin D is almost entirely bound to vitamin D binding protein, which increases 2-fold during pregnancy and previous studies have not examined vitamin D binding protein or free vitamin D levels. We performed a nested case-control study within the Massachusetts General Hospital Obstetric Maternal Study, measuring first trimester total 25-hydroxyvitamin D (25[OH]D) and vitamin D binding protein and calculating free 25(OH)D levels. We compared these levels from pregnancies complicated by subsequent preeclampsia (cases, n=39) with those from normotensive pregnancies (controls, n=131). First trimester total 25(OH)D levels were similar in cases and controls (27.4±1.9 versus 28.8±0.80 ng/mL; P=0.435). Despite an association between higher first trimester blood pressures and subsequent preeclampsia, first trimester total 25(OH)D was not associated with first trimester systolic (r=0.11; P=0.16) or diastolic blood pressures (r=0.03; P=0.72). Although there was a trend toward increased risk of preeclampsia with 25(OH)D levels <15 ng/mL (odds ratio: 2.5 [95% CI: 0.89 to 6.90]), this was attenuated after adjustment for body mass index and other covariates (odds ratio: 1.35 [95% CI: 0.40 to 4.50]). First trimester vitamin D binding protein and free 25(OH)D levels were similar in cases and controls and were not associated with first trimester blood pressures. These data suggest that first trimester total and free 25(OH)D levels are not independently associated with first trimester blood pressure or subsequent preeclampsia.

A prospective study of calciotropic hormones in pregnancy and post partum: Reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D

OBJECTIVE The purpose of this study was to examine the hormones regulating calcium homeostasis longitudinally in pregnancy and post partum. STUDY DESIGN Twenty-three women with normal pregnancies were studied in the second and third trimesters and post partum. At each time blood was analyzed for ionized calcium, vitamin D metabolites, and intact parathyroid hormone, and a 24-hour urine specimen was analyzed for creatinine, calcium, and sodium. RESULTS Urinary calcium excretion was 250% to 300% higher during pregnancy than post partum (p < 0.00001). 1,25-Dihydroxyvitamin D levels were equivalent in the second and third trimesters but were twofold higher than postpartum values (p < 0.01). Ionized calcium was similar at all time points. Intact parathyroid hormone in the second and third trimesters was 50% of postpartum levels (p < 0.001). CONCLUSION Pregnancy is associated with an increase in the levels of 1,25-dihydroxyvitamin D and a concomitant reciprocal fall in intact parathyroid hormone levels. The increase in serum 1,25-dihydroxyvitamin D values appears to be a key factor in providing for the increase in maternal calcium requirements during pregnancy.

Vasomotor symptoms and cardiovascular events in postmenopausal women

Objective:Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Womens Health Initiative Observational Study (WHI-OS). Methods:We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N = 60,027): (1) no VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]), (2) VMS at menopause onset but not at WHI-OS enrollment (early VMS), (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]), and (4) VMS at WHI-OS enrollment but not at menopause onset (late VMS). Results:For women with early VMS (n = 24,753), compared with no VMS (n = 18,799), hazard ratios (95% CIs) in fully adjusted models were as follows: major coronary heart disease (CHD), 0.94 (0.84-1.06); stroke, 0.83 (0.72-0.96); total CVD, 0.89 (0.81-0.97); and all-cause mortality, 0.92 (0.85-0.99). For women with persistent VMS (n = 15,084), there was no significant association with clinical events. For women with late VMS (n = 1,391), compared with no VMS, hazard ratios (95% CIs) were as follows: major CHD, 1.32 (1.01-1.71); stroke, 1.14 (0.82-1.59); total CVD, 1.23 (1.00-1.52); and all-cause mortality, 1.29 (1.08-1.54). Conclusions:Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with the onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from the classic perimenopausal VMS.

Congenital anomaly rate in offspring of mothers with diabetes treated with insulin lispro during pregnancy

Aim  To determine the rate of major congenital anomalies in offspring of a large group of women with diabetes mellitus treated with insulin lispro (Humalog®).