Sleep Quality in Individuals with and without Persistent Postpartum Hypertension.

OBJECTIVE: This study aimed to compare sleep quality at 1 year postpartum following a hypertensive disorder of pregnancy (HDP) among individuals with persistent postpartum hypertension (HTN) compared with those with normal blood pressures (BPs). STUDY DESIGN: We combined data from the Heart Health 4 New Moms pilot randomized trial (n = 118) and the Pathways prospective cohort study (n = 36). Individuals with a singleton pregnancy complicated by gestational HTN or preeclampsia underwent a research study visit at a mean 48.7 ± 9.5 weeks postpartum with standardized BP measurement and assessment of subjective sleep quality with the Pittsburgh Sleep Quality Index (PSQI). Persistent postpartum HTN was defined as Stage 1 HTN or greater (mean systolic BP ≥ 130 mm Hg or mean diastolic BP ≥ 80 mm Hg over three measurements at rest) or requiring antihypertensive medication. Statistical analysis was performed using univariate and multivariable logistic regression analyses. RESULTS: Of 154 individuals with an HDP included in the analysis, 84 (55%) were normotensive at 1 year postpartum and 70 (45%) had persistent postpartum HTN. Individuals with persistent postpartum HTN were more likely to be older, self-identify as Black race, have higher prepregnancy and 1-year postpartum body mass index (BMI), be multiparous, and deliver at an earlier gestational age. The mean global PSQI score was 8.7 ± 3.7, with 81% reporting poor sleep (PSQI > 5), and scores were higher among individuals who were persistently hypertensive (9.6 ± 3.5) compared with those who were normotensive at 1 year postpartum (7.9 ± 3.6), p < 0.01. Findings were unchanged in a multivariable model adjusting for age, self-reported race, prepregnancy BMI, and parity. CONCLUSION: Following an HDP, individuals reported poor sleep quality at 1 year postpartum. Individuals with persistent postpartum HTN reported lower sleep quality, suggesting that sleep behavior may be a target for intervention to improve maternal cardiovascular health following an HDP. KEY POINTS: · After an HDP, poor sleep quality was common at 1 year postpartum.. · Those with persistent postpartum HTN reported worse sleep quality at 1 year postpartum.. · Sleep behavior may be a target for intervention to improve maternal cardiovascular health..

Inflammatory markers are elevated in early pregnancy, but not late pregnancy, in women with overweight and obesity that later develop preeclampsia.

PROBLEM: Obesity and preeclampsia both involve a pathological inflammatory response, which may be how obesity increases preeclampsia risk. Previous studies have failed to assess robust measurements of inflammatory markers across gestation, specifically in overweight/ obese women in the context of preeclampsia. METHOD OF STUDY: We measured 20 inflammatory markers in plasma via multiplex assay (ThermoFisher Inflammation 20 plex Human ProcartaPlex Panel) across the three trimesters of pregnancy in an existing cohort of overweight and obese women who developed preeclampsia (n = 37) and without preeclampsia (n = 74). Mann-Whitney U tests examined differences in inflammatory marker concentrations between cases and controls. Repeated measures ANOVA tests were used to explore differences in inflammatory marker concentrations over time within cases and controls. RESULTS: Pro-inflammatory markers (IL-1α, IL-1ß, IL-6, IFN-α, IFN-γ, GM-CSF, IL-12p70, IL-17α, TNF-α, IL-8) and anti-inflammatory markers (IL-4, IL-10, IL-13) were higher in the first and second trimester in participants who later developed preeclampsia compared to those who did not (p < .05). Only TNF-α and IL-8 remained elevated in the third trimester. Inflammatory markers did not change across pregnancy in preeclampsia cases but did increase across pregnancy in controls. CONCLUSION: Our findings diverge from prior studies, predominantly of non-obese women, that report lower circulating concentrations of anti-inflammatory cytokines in preeclampsia versus normotensive pregnancy, particularly by late pregnancy. We posit that women with overweight and obesity who develop preeclampsia entered pregnancy with a heightened pro-inflammatory state likely related to obesity, which increased risk for preeclampsia. Further studies are needed to investigate if inflammatory maker profiles differ between obese and non-obese women.

A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy.

Background: While preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study's purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls). Results: In the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases, n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significance p value threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases, n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated with TRAF3IP2-AS1/TRAF3IP2 genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample. Conclusions: The discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1-2 and significant DMRs that were not examined in the replication phase.

Small extracellular vesicles from plasma of women with preeclampsia increase myogenic tone and decrease endothelium-dependent relaxation of mouse mesenteric arteries.

Preeclampsia (PE) is a common syndrome of pregnancy, characterized by new-onset hypertension and proteinuria after gestational week 20, or new onset of hypertension and significant end-organ dysfunction. In the worst cases, it can threaten the survival of both mother and baby. Extracellular vesicles (EVs) are lipid-bilayer nanoparticles released from cells. They are involved in cell-cell communication and transport of diverse cargo molecules. Small extracellular vesicles (sEVs, exosomes) are defined by their size and biogenesis within the endocytic compartment of the cell or reverse budding of the plasma membrane. The function of circulating gestational EVs, released from maternal organs or the placenta, remains to be explored. Here, we focused on sEVs that circulate in the maternal blood in the third trimester of human pregnancy and hypothesized that sEVs from pregnant women with PE play a role in regulation of vessel tone. When compared to sEVs from women with uncomplicated pregnancies, ex vivo exposure of isolated mouse mesenteric arteries to sEVs purified from the plasma of pregnant women with PE led to constriction in response to intraluminal pressure. This effect was not observed using microvesicles from the plasma of women with PE or using PE plasma that was depleted of EVs. Blood vessels exposed to sEVs from women with PE were also more resistant to methacholine-stimulated relaxation. Immunofluorescence microscopy confirmed the presence of sEVs within the vessel wall. Together, these data support the notion that circulating sEVs from pregnant women play a role in the regulation of arterial tone.

Maternal Vascular Lesions in the Placenta Predict Vascular Impairments a Decade After Delivery.

Women with adverse pregnancy outcomes later experience excess hypertension and cardiovascular disease, but how the events are linked is unknown. Examination of the placenta may provide clues to vascular impairments after delivery. Maternal vascular malperfusion lesions (MVMs) were abstracted from clinical reports, validated and characterized using clinical guidelines and severity score. A total of 492 women (170 with MVMs and 322 without MVMs) participated in a study visit 8 to 10 years after delivery to assess blood pressure, cardiometabolic factors, and sublingual microvascular features using sidestream dark field imaging. Covariates included age, race, adverse pregnancy outcomes (preeclampsia, small for gestational age, and preterm birth), and health behaviors. Women with versus without MVM had a distinct sublingual microvascular profile comprised of (1) lower microvascular density (-410 µm/mm2, P=0.015), (2) higher red blood cell filling as a marker of perfusion (2%, P=0.004), and (3) smaller perfused boundary region (-0.07 µm, P=0.025) as a measure of glycocalyx integrity, adjusted for covariates including adverse pregnancy outcomes. Women with MVM also had higher adjusted diastolic blood pressure (+2.6 mm Hg, P=0.021), total and LDL (low-density lipoprotein)-cholesterol (+11.2 mg/dL, P=0.016; +8.7 mg/dL, P=0.031). MVM associations with subsequent cardiovascular measures did not vary by type of adverse pregnancy outcome, except among women with preterm births where blood pressure was higher only among those with MVM. Results were similar when evaluated as MVM severity. A decade after delivery, women with placental vascular lesions had an adverse cardiovascular profile comprised of microvascular rarefaction, higher blood pressure and more atherogenic lipids. Placental histopathology may reveal a woman's early trajectory toward subsequent vascular disease.

An exploratory study of white blood cell proportions across preeclamptic and normotensive pregnancy by self-identified race in individuals with overweight or obesity.

Objective: Examine white blood cell (WBC) proportions across preeclamptic (n = 28 cases) and normotensive (n = 28 controls) pregnancy in individuals with overweight/obesity.Methods: WBC proportions were inferred from genome-wide DNA methylation data and compared by case/control status and self-identified race.Results: In Trimester 1, ean B cell proportions were suggestively lower in cases in the overall sample and significantly lower in White participants but not in Black participants. More significant WBC proportion changes were observed across normotensive than preeclamptic pregnancy.Conclusions: These findings in a small sample demonstrate need for additional studies investigating the relationship between self-identified race and WBCs in pregnancy.

An Exploratory Study of Epigenetic Age in Preeclamptic and Normotensive Pregnancy Reveals Differences by Self-Reported Race but Not Pregnancy Outcome.

Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. Chronological age and race are associated with preeclampsia, but the role of these factors is not entirely understood. We hypothesized that DNA methylation age, a measure of biological age, would be higher in individuals with preeclampsia than in individuals with normotensive pregnancy and that DNA methylation age would differ by race across pregnancy. This was a longitudinal, exploratory study of 56 pregnant individuals (n = 28 preeclampsia cases and n = 28 normotensive controls). Genome-wide DNA methylation data were generated from trimester-specific peripheral blood samples. DNA methylation age was estimated using the "Improved Precision" clock, and ∆age, the difference between DNA methylation age and chronological age, was computed. DNA methylation age was compared with chronological age using Pearson correlations. The relationships between ∆age and preeclampsia status, self-reported race, and covariates were tested using multiple linear regression and performed both with and without consideration of cell-type heterogeneity. We observed strong correlation between chronological age and DNA methylation age across pregnancy, with significantly stronger correlation observed in White participants than in Black participants. We observed no association between ∆age and preeclampsia status. However, ∆age was higher in participants with higher pre-pregnancy body mass index in trimester 1 and lower in Black participants than in White participants in trimesters 2 and 3. Observations were largely consistent when controlling for cell-type heterogeneity. Our findings in a small sample support the need for additional studies to investigate the relationship between race and biological age, which could provide further insight into racial disparities across pregnancy. However, this study does not support an association between ∆age and preeclampsia status.

Go Red for Women Strategically Focused Research Network: Summary of Findings and Network Outcomes.

The Go Red for Women movement was initiated by the American Heart Association (AHA) in the early 2000s to raise awareness concerning cardiovascular disease (CVD) risk in women. In 2016, the AHA funded 5 research centers across the United States to advance our knowledge of the risks and presentation of CVD that are specific to women. This report highlights the findings of the centers, showing how insufficient sleep, sedentariness, and pregnancy-related complications may increase CVD risk in women, as well as presentation and factors associated with myocardial infarction with nonobstructive coronary arteries and heart failure with preserved ejection fraction in women. These projects were augmented by collaborative ancillary studies assessing the relationships between various lifestyle behaviors, including nightly fasting duration, mindfulness, and behavioral and anthropometric risk factors and CVD risk, as well as metabolomic profiling of heart failure with preserved ejection fraction in women. The Go Red for Women Strategically Focused Research Network enhanced the evidence base related to heart disease in women, promoting awareness of the female-specific factors that influence CVD.

DNA Methylation of Endoglin Pathway Genes in Pregnant Women With and Without Preeclampsia.

OBJECTIVE: We compared blood-based DNA methylation levels of endoglin (ENG) and transforming growth factor beta receptor 2 (TGFßR2) gene promoter regions between women with clinically-overt preeclampsia and women with uncomplicated, normotensive pregnancies. METHODS: We used EpiTect Methyl II PCR Assays to evaluate DNA methylation of CpG islands located in promoter regions of ENG (CpG Island 114642) and TGFßR2 (CpG Island 110111). Preeclampsia was diagnosed based on blood pressure, protein, and uric acid criteria. N = 21 nulliparous preeclampsia case participants were 1:1 frequency matched to N = 21 nulliparous normotensive control participants on gestational age at sample collection (±2 weeks), smoking status, and labor status at sample collection. Methylation values were compared between case and control participant groups [(ENG subset: n = 20 (9 cases, 11 controls); TGFßR2 subset: n = 28 (15 cases, 13 controls)]. RESULTS: The majority of the preeclampsia cases delivered at ⩾34 weeks' gestation (83%). Average methylation levels for ENG ([M ± (SD)]; Case Participant Group = 6.54% ± 4.57 versus Control Participant group = 4.81% ± 5.08; P = .102) and TGFßR2 (Case Participant Group = 1.50% ± 1.37 vs Control Participant Group = 1.70% ± 1.40; P = .695) promoter CpG islands did not differ significantly between the participant groups. Removal of 2 extreme outliers in the ENG analytic subset revealed a trend between levels of ENG methylation and pregnancy outcome (Case Participant Group = 5.17% ± 2.16 vs Control Participant Group = 3.36% ± 1.73; P = .062). CONCLUSION: Additional epigenetic studies that include larger sample sizes, investigate preeclampsia subtypes, and capture methylation status of CpG island shores and shelves are needed to further inform us of the potential role that ENG and TGFßR2 DNA methylation plays in preeclampsia pathophysiology.

Life Course Changes in Cardiometabolic Risk Factors Associated With Preterm Delivery: The 30-Year CARDIA Study.

Background Women who deliver preterm infants (<37 weeks) have excess cardiovascular risk; however, it is unclear whether the unfavorable changes in the cardiometabolic profile associated with preterm delivery initiate before, during, or after childbearing. Methods and Results We identified 1306 women (51% Black) with births between baseline (1985-1986) and year 30 in the CARDIA (Coronary Artery Risk Development in Young Adults) study. We compared life course changes in blood pressure, body mass index, waist circumference, and lipids in women with preterm deliveries (n=318) with those with all term deliveries (n=988), using piecewise linear mixed-effects models. Specifically, we evaluated group differences in rates of change before and after the childbearing period and change in level across the childbearing period. After adjusting for the covariates, women with preterm deliveries had a higher change in diastolic blood pressure across the childbearing period than those with all term deliveries (1.59 versus -0.73 mm Hg, P<0.01); the rates of change did not differ by group, both prechildbearing and postchildbearing. Women with preterm deliveries had a larger body mass index increase across the childbearing period (1.66 versus 1.22 kg/m2, P=0.03) compared with those with all term deliveries, followed by a steeper increase after the childbearing period (0.22 versus 0.17 kg/m2 per year, P=0.02). Conclusions Preterm delivery was associated with unfavorable patterns of change in diastolic blood pressure and adiposity that originate during the childbearing years and persist or exacerbate later in life. These adverse changes may contribute to the elevated cardiovascular risk among women with preterm delivery.

Noninvasive sublingual microvascular imaging reveals sex-specific reduction in glycocalyx barrier properties in patients with coronary artery disease.

BACKGROUND: Risk factors for coronary artery disease (CAD) have been associated with endothelial dysfunction and degradation of the endothelial glycocalyx. This study was designed to compare sublingual microvascular perfusion and glycocalyx barrier properties in CAD patients and controls using noninvasive side stream darkfield imaging. METHODS: Imaging of the sublingual microvasculature was performed in 52 case subjects (CAD confirmed by left heart catheterization) and 63 controls (low Framingham risk score). Red blood cell (RBC) filling percentage and functional microvascular density, measures of microvascular perfusion, and perfused boundary region (PBR), an index of glycocalyx barrier function, were measured in microvessels with a diameter ranging from 5-25 µm. RESULTS: RBC filling percentage was lower in patients with CAD compared to controls (p < .001). Functional microvascular density did not differ between groups. The overall PBR was marginally greater in the CAD group compared to the control group (p = .08). PBR did not differ between male CAD cases and controls (p = .17). However, PBR was greater in females with CAD compared with female controls (p = .04), indicating reduced glycocalyx barrier function. This difference became more pronounced after adjusting for potential confounders. CONCLUSIONS: Our data suggest that patients with CAD are characterized by a reduction in percentage of time microvessels are occupied by RBCs. In addition, CAD is significantly associated with impaired sublingual microvascular glycocalyx barrier function in women but not men. More research is needed to determine the significance of peripheral microvascular dysfunction in the pathophysiology of CAD, and how this may differ by sex.

Clinical Course, Associated Factors, and Blood Pressure Profile of Delayed-Onset Postpartum Preeclampsia.

OBJECTIVE: To identify clinical risk factors associated with development of delayed-onset postpartum preeclampsia, and to characterize management and subsequent risk of cardiovascular disease. METHODS: This is a case-control study of women admitted to the hospital with delayed-onset postpartum preeclampsia (defined as a new diagnosis of preeclampsia presenting between 48 hours and 6 weeks postpartum) compared with women with full-term, uncomplicated pregnancies without a hypertensive diagnosis or diabetes. Included women delivered between January 2014 and June 2018 at a single tertiary care center. Women with an antenatal diagnosis of preeclampsia or chronic hypertension were excluded. Univariate analysis was used to identify risk factors associated with delayed-onset postpartum preeclampsia and to compare rates of hypertension and antihypertensive medication use, with follow-up beyond 3 months postpartum among a subset of women in the control group who were matched 2:1 with women in the case group. Multivariable logistic regression was performed and included covariates identified in a backward stepwise approach. RESULTS: Compared with women in the control group (n=26,936), women with delayed-onset postpartum preeclampsia (n=121) were significantly more likely to be of non-Hispanic black race (31.4% vs 18.0%), obese (39.7% vs 20.1%), and deliver by cesarean (40.5% vs 25.8%), all P<.01. For women diagnosed with delayed-onset postpartum preeclampsia, the median postpartum day of presentation was 7.0 (interquartile range 5.0-9.0), with 93.4% presenting secondary to symptoms, which was most commonly a headache. A majority (73.6%) underwent imaging studies, and 49.6% received intravenous antihypertensive agents. A total of 86 (71.0%) women with delayed-onset postpartum preeclampsia and 169 (72.8%) women in the control group had longer term information available, with a median follow-up time of 1.5 years (interquartile range 0.8-2.8). Delayed-onset postpartum preeclampsia was associated with higher blood pressures at 3 months postpartum or later (median systolic 130 mm Hg vs 112 mm Hg and median diastolic 80 mm Hg vs 70 mm Hg, P<.001). CONCLUSION: Delayed-onset postpartum preeclampsia is associated with variable management strategies. There is substantial overlap between the clinical risk factors for delayed-onset postpartum preeclampsia and antepartum preeclampsia. Our findings suggest that delayed-onset postpartum preeclampsia is also associated with an increased risk of progression to chronic hypertension.

Preeclampsia-Associated Alteration of DNA Methylation in Fetal Endothelial Progenitor Cells.

OBJECTIVE: The pregnancy complication preeclampsia represents an independent risk factor for cardiovascular disease. Our previous research shows a diminished function of fetal endothelial colony-forming cells (ECFC), a proliferative subgroup of endothelial progenitor cells (EPC) in preeclampsia. The aim of this study was to further investigate whether DNA methylation of fetal EPC is affected in preeclampsia. METHODS: The genomic methylation pattern of fetal ECFC from uncomplicated and preeclamptic pregnancies was compared for 865918 CpG sites, and genes were classified into gene networks. Low and advanced cell culture passages were compared to explore whether expansion of fetal ECFC in cell culture leads to changes in global methylation status and if methylation characteristics in preeclampsia are maintained with increasing passage. RESULTS: A differential methylation pattern of fetal ECFC from preeclampsia compared to uncomplicated pregnancy was detected for a total of 1266 CpG sites in passage 3, and for 2362 sites in passage 5. Key features of primary networks implicated by methylation differences included cell metabolism, cell cycle and transcription and, more specifically, genes involved in cell-cell interaction and Wnt signaling. We identified an overlap between differentially regulated pathways in preeclampsia and cardiovascular system development and function. Cell culture passages 3 and 5 showed similar gene network profiles, and 1260 out of 1266 preeclampsia-associated methylation changes detected in passage 3 were confirmed in passage 5. CONCLUSION: Methylation modification caused by preeclampsia is stable and detectable even in higher cell culture passages. An epigenetically modified endothelial precursor may influence both normal morphogenesis and postnatal vascular repair capacity. Further studies on epigenetic modifications in complicated pregnancies are needed to facilitate development of EPC based therapies for cardiovascular alterations.

Plasma concentrations of soluble endoglin in the maternal circulation are associated with maternal vascular malperfusion lesions in the placenta of women with preeclampsia.

We evaluated the association between plasma soluble endoglin (sENG) and maternal vascular malperfusion (MVM) lesions of the placenta in women with preeclampsia. We measured sENG (sCD105) by ELISA in N = 70 women diagnosed with preeclampsia (median [IQR] GA at sampling = 36.4 [6.0] weeks) and available placental pathology. Placental pathology reports were reviewed for evidence of MVM based on the presence of ≥1 of the following: villous infarct, decidual vasculopathy, accelerated villous maturation, intervillous fibrin deposition, and/or low placental weight (<10th percentile for GA). We categorized plasma sENG concentrations into tertiles and used a modified Poisson regression approach to estimate the prevalence of MVM associated with sENG. We separately estimated the association between sENG and accelerated villous maturation, villous infarct, and low placental weight, the three most frequent lesions in the sample. We adjusted all models for age, parity, pre-pregnancy obesity, smoking, and infant sex. The prevalence of MVM in our sample of women with preeclampsia was 74%. Women in the highest sENG tertile had a higher prevalence of MVM (aPR[adjusted prevalence ratio] 1.70, 95% CI 1.15-2.52), low placental weight (aPR 3.26, 95% CI 1.25-8.50), and villous infarcts (aPR 2.93, 95% CI 1.27-6.73) compared with women in the lowest sENG tertile, after adjusting for covariates. Medium (aPR 2.57, 95% CI 1.17-5.66) and high (aPR 3.14, 95% CI 1.47-6.70) tertile concentrations of sENG were associated with higher accelerated villous maturation. Our results suggest that sENG may mark a more severe placental phenotype of preeclampsia, although findings should be replicated in larger cohorts.

Risk of hypertension and abnormal biomarkers in the first year postpartum associated with hypertensive disorders of pregnancy among overweight and obese women.

OBJECTIVES: Hypertension and obesity are common cardiometabolic risk factors in reproductive age women. The association of hypertensive disorders of pregnancy with later-life cardiovascular disease is well-established, however, it is unknown how obesity and hypertensive disorders of pregnancy converge to accelerate development of hypertension in the postpartum period. The aim of this study was to characterize rates of sustained hypertension at one year postpartum using the new American Heart Association/American College of Cardiology Guidelines among overweight and obese women with a normotensive pregnancy or hypertensive disorder of pregnancy. STUDY DESIGN: 315 early pregnant women were enrolled prospectively and followed up to 12 months after delivery (mean 7.0 ±â€¯1.8 months). At a postpartum research visit, we measured blood pressure and collected blood samples to measure cystatin C and high sensitivity C-reactive protein. RESULTS: A total of 254 women had a normotensive pregnancy, 39 had gestational hypertension (12.4%) and 22 had preeclampsia (7.0%). 91 women had hypertension at the postpartum study visit (28.9%). After adjustment for maternal age, BMI, lactation and time postpartum, preeclampsia was associated with an aOR 2.35 (95%CI 1.63-3.41) of development of sustained hypertension and an aOR 3.23 (95%CI 1.56-6.68) of hypertension with abnormal biomarkers compared to women with normotensive pregnancies. CONCLUSIONS: We demonstrate a high prevalence of hypertension and abnormal biomarkers associated with hypertensive disorders of pregnancy among overweight and obese women. Our findings support the need for structured follow up and risk reduction in overweight and obese women with hypertensive disorders of pregnancy as early as the first year postpartum.

Endoglin pathway genetic variation in preeclampsia: A validation study in Norwegian and Latina cohorts.

OBJECTIVE: The purpose of this study was to validate our previous genetic association findings related to the endoglin (ENG) pathway from an American Caucasian preeclampsia cohort in independent preeclampsia cohorts. We also sought to explore the ENG pathway for new genetic associations in these independent cohorts. STUDY DESIGN: We used a tagging single nucleotide (tSNP) approach to assess genetic variability across five ENG pathway genes (ENG, TGFß1, TGFßR1, ALK1, and TGFßR2) in a Caucasian cohort from Norway (n = 77 preeclampsia cases & n = 63 normotensive controls) and a White Hispanic cohort from Southern California (n = 69 preeclampsia cases & n = 106 normotensive controls). MAIN OUTCOME MEASURES: Univariate analyses (Chi Square, Fisher's Exact) and multivariate logistic regression were conducted to evaluate the association between tSNP genotype distributions and pregnancy outcome in each cohort. Logistic regression models were adjusted for maternal age at delivery, infant sex, parity, smoking during pregnancy, and pre-pregnancy BMI. RESULTS: Although we were unable to replicate our previous SNP-specific findings (ENG rs11792480, rs10121110; TGFßR2 rs6550005; p's > 0.05), we found that genetic variation in TGFßR1[ALK5] (rs6478974) and TGFßR2 (rs11129420, rs6802220, rs1155708, rs3773640, rs3773663) was significantly associated with preeclampsia in the Norwegian cohort and genetic variation in ALK1 (rs706819) and TGFßR2 (rs9843942) was significantly associated with preeclampsia in the Latina cohort. CONCLUSION: Overall, our results provide further support for the involvement and investigation of the endoglin pathway in preeclampsia.

Adverse pregnancy outcomes and future maternal cardiovascular disease.

Cardiovascular disease (CVD) remains the leading cause of death in women. Although traditional risk factors increase later-life CVD, pregnancy-associated complications additionally influence future CVD risk in women. Recent guidelines for the prevention of CVD in women have added adverse pregnancy outcomes as major CVD risk factors. Studies have shown that women with a history of preeclampsia, gestational diabetes, preterm delivery, and delivery of a small-for-gestational-age infant have an increased risk of developing cardiometabolic risk factors and subsequent CVD. A history of multiple adverse pregnancy outcomes further increases this risk. It has been suggested that these pregnancy complications may unmask preexisting elevated CVD risk; however, whether the pathophysiologic changes underlying these conditions directly result in long-term cardiovascular damage is unclear. The purpose of this review was to highlight the associations between adverse pregnancy outcomes and future CVD, and to emphasize the importance of considering pregnancy history in assessing a woman's CVD risk. Targeted efforts to initiate screening and risk-reduction strategies in women with prior history of pregnancy complications, particularly lifestyle modification, may help decrease the burden of CVD in women.

Low Soluble Syndecan-1 Precedes Preeclampsia.

INTRODUCTION: Syndecan-1 (Sdc1; CD138) is a major transmembrane heparan sulfate proteoglycan expressed on the extracellular, luminal surface of epithelial cells and syncytiotrophoblast, thus comprising a major component of the glycocalyx of these cells. The "soluble" (shed) form of Sdc1 has paracrine and autocrine functions and is normally produced in a regulated fashion. We compared plasma soluble Sdc1 concentrations, in relation to placental Sdc1 expression, in uncomplicated (control) and preeclamptic pregnancies. METHODS: We evaluated soluble Sdc1 across uncomplicated pregnancy, and between preeclamptic, gestational hypertensive and control patients at mid-pregnancy (20 weeks) and 3rd trimester by ELISA. Placental expression level of Sdc1 was compared between groups in relation to pre-delivery plasma soluble Sdc1. Participants were recruited from Magee-Womens Hospital. RESULTS: In uncomplicated pregnancy, plasma soluble Sdc1 rose significantly in the 1st trimester, and reached an approximate 50-fold increase at term compared to post pregnancy levels. Soluble Sdc1 was lower at mid-pregnancy in women who later developed preeclampsia (P<0.05), but not gestational hypertension, compared to controls, and remained lower at late pregnancy in preeclampsia (P<0.01) compared to controls. Sdc1 was prominently expressed on syncytiotrophoblast of microvilli. Syncytiotrophoblast Sdc1 immunostaining intensities, and mRNA content in villous homogenates, were lower in preeclampsia vs. controls (P<0.05). Soluble Sdc1 and Sdc1 immunostaining scores were inversely associated with systolic blood pressures, and positively correlated with infant birth weight percentile. CONCLUSION: Soluble Sdc1 is significantly lower before the clinical onset of preeclampsia, with reduced expression of Sdc1 in the delivered placenta, suggesting a role for glycocalyx disturbance in preeclampsia pathophysiology.

Evaluating the effects of preanalytical variables on the stability of the human plasma proteome.

High quality clinical biospecimens are vital for biomarker discovery, verification, and validation. Variations in blood processing and handling can affect protein abundances and assay reliability. Using an untargeted LC-MS approach, we systematically measured the impact of preanalytical variables on the plasma proteome. Time prior to processing was the only variable that affected the plasma protein levels. LC-MS quantification showed that preprocessing times <6h had minimal effects on the immunodepleted plasma proteome, but by 4 days significant changes were apparent. Elevated levels of many proteins were observed, suggesting that in addition to proteolytic degradation during the preanalytical phase, changes in protein structure are also important considerations for protocols using antibody depletion. As to processing variables, a comparison of single- vs double-spun plasma showed minimal differences. After processing, the impact ⩽3 freeze-thaw cycles was negligible regardless of whether freshly collected samples were processed in short succession or the cycles occurred during 14-17 years of frozen storage (-80 °C). Thus, clinical workflows that necessitate modest delays in blood processing times or employ different centrifugation steps can yield valuable samples for biomarker discovery and verification studies.