Aditi R. Saxena

Increased Sensitivity to Angiotensin II Is Present Postpartum in Women With a History of Hypertensive Pregnancy

Pregnancies complicated by new-onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear whether this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high- and low-sodium balance. Ten women had a history of hypertensive pregnancy (5 with preeclampsia; 5 with transient hypertension of pregnancy), and 15 women had a history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone, and soluble fms-like tyrosine kinase 1 levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with a history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 versus 104 mm Hg and 73 versus 65 mm Hg, respectively; P<0.05). Women with a history of hypertensive pregnancy had a pressor response to salt loading, demonstrated by an increase in systolic blood pressure on a high-salt diet. They also had greater systolic pressor response (10 versus 2 mm Hg; P=0.03), greater increase in aldosterone (56.8 versus 30.8 ng/dL; P=0.03), and increase in soluble fms-like tyrosine kinase 1 levels (11.0 versus −18.9 pg/mL; P=0.02) after infusion of angiotensin II in low-sodium balance compared with controls. Thus, women with a history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal, and soluble fms-like tyrosine kinase 1 responses to infused angiotensin II in low-sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women.

Luteinizing hormone correlates with adrenal function in postmenopausal women.

ObjectiveIn postmenopausal women, a relationship between luteinizing hormone (LH) and cortisol levels has been suggested. Furthermore, LH receptors in the adrenal gland have been shown to mediate adrenocorticotropic hormone–independent Cushing syndrome. In contrast, follicle-stimulating hormone (FSH) receptors have not been found in the adrenal gland. Our objective was to explore the relationship of LH with adrenal function in postmenopausal women, as assessed by 24-hour urinary free cortisol (UFC) and aldosterone excretion rate (AER). MethodsParticipants were studied at a single time point in the fasting state in the Clinical Research Center of Brigham and Women’s Hospital. We studied 36 postmenopausal women in sodium balance to control for variation in endogenous levels of plasma renin activity and angiotensin II. Serum cortisol, aldosterone, LH, and FSH levels were measured, as were 24-hour UFC and AER. Correlations were performed by calculation of Pearson’s correlation coefficient. ResultsSerum LH correlated significantly with log-transformed UFC (r = 0.43, P = 0.01) and inversely with log AER (r = −0.50, P = 0.002). We found no correlation of serum LH with serum cortisol or aldosterone, nor did we find correlation of FSH with these parameters. ConclusionsIn postmenopausal women, serum LH levels correlate significantly with UFC (positively) and AER (negatively). LH stimulation may induce subtle shifts in adrenal function toward cortisol secretion.

Correlation of cystatin-C with glomerular filtration rate by inulin clearance in pregnancy.

Objective. To test utility of cystatin-C as a marker of glomerular filtration rate during pregnancy, we performed serial correlations with inulin clearance during pregnancy and postpartum. Methods. Twelve subjects received inulin infusions and serum cystatin-C at three time points. Pearsons correlation coefficient was calculated. Results. Cystatin-C levels ranged 0.66–1.48 mg/L during pregnancy, and 0.72–1.26 mg/L postpartum. Inulin clearance ranged 130–188 mL/min during pregnancy, and 110–167 mL/min postpartum. Cystatin-C did not correlate with inulin clearance at any time point. Conclusion. Serum cystatin-C did not correlate with inulin clearance during pregnancy or postpartum.

First trimester PAPP-A levels correlate with sFlt-1 levels longitudinally in pregnant women with and without preeclampsia

BackgroundFirst trimester Pregnancy Associated Plasma Protein A (PAPP-A) levels, routinely measured for aneuploidy screening, may predict development of preeclampsia. This study tests the hypothesis that first trimester PAPP-A levels correlate with soluble fms-like tyrosine kinase-1 (sFlt-1) levels, an angiogenic marker associated with preeclampsia, throughout pregnancy.MethodssFlt-1 levels were measured longitudinally in 427 women with singleton pregnancies in all three trimesters. First trimester PAPP-A and PAPP-A Multiples of Median (MOM) were measured. Student’s T and Wilcoxon tests compared preeclamptic and normal pregnancies. A linear mixed model assessed the relationship between log PAPP-A and serial log sFlt-1 levels.ResultsPAPP-A and PAPP-A MOM levels were significantly lower in preeclamptic (n = 19), versus normal pregnancies (p = 0.02). Although mean third trimester sFlt-1 levels were significantly higher in preeclampsia (p = 0.002), first trimester sFlt-1 levels were lower in women who developed preeclampsia, compared with normal pregnancies (p = 0.03). PAPP-A levels correlated significantly with serial sFlt-1 levels. Importantly, low first trimester PAPP-A MOM predicted decreased odds of normal pregnancy (OR 0.2, p = 0.002).ConclusionsLow first trimester PAPP-A levels suggests increased future risk of preeclampsia and correlate with serial sFlt-1 levels throughout pregnancy. Furthermore, low first trimester PAPP-A status significantly predicted decreased odds of normal pregnancy.

Cardiovascular risk factors and menstrual cycle phase in pre-menopausal women.

BACKGROUND Exogenous estrogens have been shown to affect markers of cardiovascular risk in women. AIM The objective of this study was to determine the effect of menstrual cycle phase on markers of cardiovascular risk in young, healthy women with regular menstrual cycles. SUBJECTS AND METHODS This prospective cohort study examined 20 healthy pre-menopausal women at 2 time-points in the menstrual cycle, in early follicular phase and early luteal phase. RESULTS In the early luteal phase, levels of estrogen, progesterone, LH, total cholesterol, and HDL were significantly higher, compared with the early follicular phase. In contrast, there were no significant differences in LDL or triglyceride levels between the 2 phases. Furthermore, there were no significant effects of menstrual cycle phase on glycemic indices (fasting blood glucose, glycohemoglobin or homeostatic model assessment of insulin resistance), markers of inflammation (C-reactive protein, soluble CD40 ligand, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, or adiponectin), or vascular function, as measured by brachial artery reactivity. CONCLUSIONS Although menstrual cycle phase affects total cholesterol and HDL levels, it does not affect other markers of cardiovascular risk in young women with regular menstrual cycles.

The Association of Estrogen Receptor-β Gene Variation With Salt-Sensitive Blood Pressure

Context: Hypertension in young women is uncommon compared with young men and older women. Estrogen appears to protect most women against hypertension, with incidence increasing after menopause. Because some premenopausal women develop hypertension, estrogen may play a different role in these women. Genetic variations in the estrogen receptor (ER) are associated with cardiovascular disease. ER‐&bgr;, encoded by ESR2, is the ER predominantly expressed in vascular smooth muscle. Objective: To determine an association of single nucleotide polymorphisms in ESR2 with salt sensitivity of blood pressure (SSBP) and estrogen status in women. Methods: Candidate gene association study with ESR2 and SSBP conducted in normotensive and hypertensive women and men in two cohorts: International Hypertensive Pathotype (HyperPATH) (n = 584) (discovery) and Mexican American Hypertension‐Insulin Resistance Study (n = 662) (validation). Single nucleotide polymorphisms in ESR1 (ER‐&agr;) were also analyzed. Analysis conducted in younger (<51 years, premenopausal, “estrogen‐replete”) and older women (≥51 years, postmenopausal, “estrogen‐deplete”). Men were analyzed to control for aging. Results: Multivariate analyses of HyperPATH data between variants of ESR2 and SSBP documented that ESR2 rs10144225 minor (risk) allele carriers had a significantly positive association with SSBP driven by estrogen‐replete women (&bgr; = +4.4 mm Hg per risk allele, P = 0.004). Findings were confirmed in Hypertension Insulin‐Resistance Study premenopausal women. HyperPATH cohort analyses revealed risk allele carriers vs noncarriers had increased aldosterone/renin ratios. No associations were detected with ESR1. Conclusions: The variation at rs10144225 in ESR2 was associated with SSBP in premenopausal women (estrogen‐replete) and not in men or postmenopausal women (estrogen‐deplete). Inappropriate aldosterone levels on a liberal salt diet may mediate the SSBP.

Labor therapeutics and BMI as risk factors for postpartum preeclampsia: A case-control study

OBJECTIVES This study aims at identifying associations between therapeutics used during labor and the occurrence of postpartum preeclampsia (PPPE), a poorly understood entity. STUDY DESIGN AND MAIN OUTCOME MEASURES This is a case-control study of women who received an ICD-9 code for PPPE (cases) during the years 2009-2011, compared to women with a normotensive term pregnancy, delivery and postpartum period until discharge (controls), matched on age (±1year) and delivery date (±3months). Cases were defined as women having a normotensive term pregnancy, delivery and initial postpartum period (48h post-delivery) but developing hypertension between 48h and 6weeks postpartum. Single variable and multiple variable models were used to determine significant risk factors. RESULTS Forty-three women with PPPE were compared to 86 controls. Use of vasopressors and oxytocin did not differ between cases and controls, but rate of fluids administered during labor (OR=1.68 per 100cc/h; 95% CI: 1.09-2.59, p=0.02) and an elevated pre-pregnancy/first trimester BMI (OR=1.18 per kg/m2, 95% CI: 1.07-1.3, p=0.001) were identified as significant risk factors in multivariate analysis. CONCLUSIONS We identified two potentially modifiable risk factors for PPPE; further studies are needed to better define the role of these two variables in the development of PPPE.