Differential effects of renin-angiotensine-aldosteron system inhibition, sympathoinhibition and low sodium diet on blood pressure in women with a history of preeclampsia: A double-blind, placebo-controlled cross-over trial (the PALM study).

Current guidelines lack sufficient evidence to recommend a specific blood pressure lowering strategy to prevent cardiovascular disease after preeclampsia. We conducted a double-blind cross-over trial to identify the most potent antihypertensive strategy: renin-angiotensin-aldosterone system (RAAS) inhibition (losartan), sympathoinhibition (moxonidine), low sodium diet and placebo (n = 10). Due to low inclusion rate our study stopped prematurely. Initiatory analyses showed no significant effect of antihypertensive strategy on office blood pressure and 24-hour blood pressure. However, nocturnal dipping was significantly higher on RAAS inhibition and low sodium diet compared to placebo and sympathoinhibition. Optimal cardiovascular prevention after preeclampsia should be further explored.

The etiology of cardiac hypertrophy in infants.

This study aimed to describe the variety of etiologies currently identified in infants with cardiac hypertrophy (CH) and investigate whether there is a relation with hyperinsulinism, echocardiographic characteristics and prognosis. This retrospective cohort study included infants born between 2005 and 2018 with CH measured by echocardiography [interventricular septum (IVS) and/or left ventricular posterior wall (LVPW) thickness with Z-score ≥ 2.0]. Children with congenital heart disease or hypertension were excluded. Underlying diagnosis, echocardiographic and follow-up data were extracted from patient files. Seventy-one infants with CH were included. An underlying cause of CH was identified in two-thirds (n = 47). Most common etiologies of CH were malformation syndromes (n = 23, including Noonan n = 12) and maternal diabetes mellitus (n = 13). Less common causes were congenital hyperinsulinism (n = 3), metabolic- (n = 5), sarcomeric- (n = 2) and neuromuscular disease (n = 1). In half of the identified causes (n = 22) an association with hyperinsulinism was described, including maternal diabetes mellitus (n = 13), malformation syndromes with insulin resistance (n = 6) and congenital hyperinsulinism (n = 3). CH associated with hyperinsulinism was echocardiographically characterized by lower LVPW thickness, higher IVS:LVPW ratio and more frequent sole involvement of the IVS (all, p ≤ 0.02). CH associated with hyperinsulinism normalized more often (41 vs. 0%) with lower mortality rates (14 vs. 44%) compared to CH not associated with hyperinsulinism (all, p ≤ 0.03). Nowadays, an etiology of CH can be identified in the majority of infants. The development of CH is often associated with hyperinsulinism which is mainly characterized by focal hypertrophy of the IVS on echocardiography. Prognosis depends on the underlying cause and is more favorable in CH associated with hyperinsulinism.

Developmental programming in human umbilical cord vein endothelial cells following fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR) is associated with an increased susceptibility for various noncommunicable diseases in adulthood, including cardiovascular and renal disease. During FGR, reduced uteroplacental blood flow, oxygen and nutrient supply to the fetus are hypothesized to detrimentally influence cardiovascular and renal programming. This study examined whether developmental programming profiles, especially related to the cardiovascular and renal system, differ in human umbilical vein endothelial cells (HUVECs) collected from pregnancies complicated by placental insufficiency-induced FGR compared to normal growth pregnancies. Our approach, involving transcriptomic profiling by RNA-sequencing and gene set enrichment analysis focused on cardiovascular and renal gene sets and targeted DNA methylation assays, contributes to the identification of targets underlying long-term cardiovascular and renal diseases. RESULTS: Gene set enrichment analysis showed several downregulated gene sets, most of them involved in immune or inflammatory pathways or cell cycle pathways. seven of the 22 significantly upregulated gene sets related to kidney development and four gene sets involved with cardiovascular health and function were downregulated in FGR (n = 11) versus control (n = 8). Transcriptomic profiling by RNA-sequencing revealed downregulated expression of LGALS1, FPR3 and NRM and upregulation of lincRNA RP5-855F14.1 in FGR compared to controls. DNA methylation was similar for LGALS1 between study groups, but relative hypomethylation of FPR3 and hypermethylation of NRM were present in FGR, especially in male offspring. Absolute differences in methylation were, however, small. CONCLUSION: This study showed upregulation of gene sets related to renal development in HUVECs collected from pregnancies complicated by FGR compared to control donors. The differentially expressed gene sets related to cardiovascular function and health might be in line with the downregulated expression of NRM and upregulated expression of lincRNA RP5-855F14.1 in FGR samples; NRM is involved in cardiac remodeling, and lincRNAs are correlated with cardiovascular diseases. Future studies should elucidate whether the downregulated LGALS1 and FPR3 expressions in FGR are angiogenesis-modulating regulators leading to placental insufficiency-induced FGR or whether the expression of these genes can be used as a biomarker for increased cardiovascular risk. Altered DNA methylation might partly underlie FPR3 and NRM differential gene expression differences in a sex-dependent manner.

Long-term Graft Survival and Graft Function Following Pregnancy in Kidney Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND: The incidence of pregnancy in kidney transplantation (KT) recipients is increasing. Studies report that the incidence of graft loss (GL) during pregnancy is low, but less data are available on long-term effects of pregnancy on the graft. METHODS: Therefore, we performed a meta-analysis and systematic review on GL and graft function, measured by serum creatinine (SCr), after pregnancy in KT recipients, stratified in years postpartum. Furthermore, we included studies of nulliparous KT recipients. RESULTS: Our search yielded 38 studies on GL and 18 studies on SCr. The pooled incidence of GL was 9.4% within 2 years after pregnancy, 9.2% within 2-5 years, 22.3% within 5-10 years, and 38.5% >10 years postpartum. In addition, our data show that, in case of graft survival, SCr remains stable over the years. Only within 2 years postpartum, Δ SCr was marginally higher (0.18 mg/dL, 95%CI [0.05-0.32], P = 0.01). Furthermore, no differences in GL were observed in 10 studies comparing GL after pregnancy with nulliparous controls. Systematic review of the literature showed that mainly prepregnancy proteinuria, hypertension, and high SCr are risk factors for GL. CONCLUSIONS: Overall, these data show that pregnancy after KT has no effect on long-term graft survival and only a possible effect on graft function within 2 years postpartum. This might be due to publication bias. No significant differences were observed between pre- and postpartum SCr at longer follow-up intervals.

Prenatal Amino Acid Supplementation to Improve Fetal Growth: A Systematic Review and Meta-Analysis.

Aberrant fetal growth remains a leading cause of perinatal morbidity and mortality and is associated with a risk of developing non-communicable diseases later in life. We performed a systematic review and meta-analysis combining human and animal studies to assess whether prenatal amino acid (AA) supplementation could be a promising approach to promote healthy fetal growth. PubMed, Embase and Cochrane libraries were searched to identify studies orally supplementing the following AA groups during gestation: (1) arginine family; (2) branched chain (BCAA); (3) methyl donors. Primary outcome was fetal/birth weight. 22 human and 89 animal studies were included in the systematic review. The arginine family, and especially arginine itself, was studied most. Our meta-analysis showed beneficial effects of arginine and (N-Carbamyl) glutamate (NCG), but not aspartic acid and citrulline on fetal/birth weight. However, no effects were reported when isonitrogenous control diet was included. BCAA and methyl donor supplementation did not affect fetal/birth weight. Arginine family supplementation, in particular arginine and NCG, improves fetal growth in complicated pregnancies. BCAA and methyl donor supplementation do not seem to be as promising to target fetal growth. Well controlled research in complicated pregnancies is needed before ruling out AA supplements or preferring arginine above other AAs.

Longitudinal follow-up of kidney function in patients with a history of preeclampsia: From 11 to 18 years postpartum.

Formerly preeclamptic (fPE) women are reported to have an increased risk to develop end stage kidney disease. To gain more insight in the course of kidney function after preeclampsia we assessed blood pressure, eGFR and urinary protein loss in 75 fPE women at 11 and 18 years postpartum. We found that during follow-up blood pressure did not increase and no cases of CKD were identified. Only a small decrease in eGFR (6-7 mL/min) and a small increase in urinary protein loss were observed, which fall within the expected range of normal aging. In conclusion, our data suggests that progression to kidney disease might not be a major concern in women after preeclampsia within 18 years postpartum.

Neonatal cardiac hypertrophy: the role of hyperinsulinism-a review of literature.

Hypertrophic cardiomyopathy (HCM) in neonates is a rare and heterogeneous disorder which is characterized by hypertrophy of heart with histological and functional disruption of the myocardial structure/composition. The prognosis of HCM depends on the underlying diagnosis. In this review, we emphasize the importance to consider hyperinsulinism in the differential diagnosis of HCM, as hyperinsulinism is widely associated with cardiac hypertrophy (CH) which cannot be distinguished from HCM on echocardiographic examination. We supply an overview of the incidence and treatment strategies of neonatal CH in a broad spectrum of hyperinsulinemic diseases. Reviewing the literature, we found that CH is reported in 13 to 44% of infants of diabetic mothers, in approximately 40% of infants with congenital hyperinsulinism, in 61% of infants with leprechaunism and in 48 to 61% of the patients with congenital generalized lipodystrophy. The correct diagnosis is of importance since there is a large variation in prognoses and there are various strategies to treat CH in hyperinsulinemic diseases.Conclusion: The relationship between CH and hyperinsulism has implications for clinical practice as it might help to establish the correct diagnosis in neonates with cardiac hypertrophy which has both prognostic and therapeutic consequences. In addition, CH should be recognized as a potential comorbidity which might necessitate treatment in all neonates with known hyperinsulinism.What is Known:• Hyperinsulinism is currently not acknowledged as a cause of hypertrophic cardiomyopathy (HCM) in textbooks and recent Pediatric Cardiomyopathy Registry publications.What is New:• This article presents an overview of the literature of hyperinsulinism in neonates and infants showing that hyperinsulinism is associated with cardiac hypertrophy (CH) in a broad range of hyperinsulinemic diseases.• As CH cannot be distinguished from HCM on echocardiographic examination, we emphasize the importance to consider hyperinsulinism in the differential diagnosis of HCM/CH as establishing the correct diagnosis has both prognostic and therapeutic consequences.

Association between parity and persistent weight gain at age 40-60 years: a longitudinal prospective cohort study.

OBJECTIVES: Physiological metabolic adaptations occur in the pregnant woman. These may persist postpartum and thereby contribute to an unfavourable cardiovascular disease (CVD) risk profile in parous women. The aim of the current study is to assess time-dependent changes of cardiometabolic health in parous women compared with nulliparous women. DESIGN AND SETTING: We studied data of 2459 women who participated in the Prevention of Renal and Vascular End-stage Disease study, a population-based prospective longitudinal cohort for assessment of CVD and renal disease in the general population. PARTICIPANTS: We selected women ≥40 years at the first visit, who reported no new pregnancies during the four follow-up visits. All women were categorised in parity groups, and stratified for age. OUTCOME MEASURES: We compared body mass index (BMI), high-density lipoprotein (HDL) cholesterol, blood pressure as continuous measurements and as clinical relevant CVD risk factors among parity groups over the course of 6 years using generalised estimating equation models adjusted for age. RESULTS: The BMI was significantly higher in women para 2 or more in all age categories: per child, the BMI was 0.6 kg/m2 higher. corresponding with 1.5-2.0 kg weight gain per child. HDL cholesterol was significantly lower in women para 2 or more aged 40-49 and 50-59 years: per child, the HDL cholesterol was up to 0.09 mmol/L lower. Blood pressure did not differ among parity groups in any of the age categories. CONCLUSIONS: Higher parity is associated with higher BMI, lower HDL cholesterol and a higher prevalence of cardiovascular risk factors, which is constant over time. These findings warrant for prospective research assessing determinants of cardiometabolic health at earlier age to understand the role of pregnancy in the development of CVD in women.

Prenatal Sildenafil Therapy Improves Cardiovascular Function in Fetal Growth Restricted Offspring of Dahl Salt-Sensitive Rats.

Fetal growth restriction (FGR) is associated with increased risk for cardiovascular and renal disorders in later life. Prenatal sildenafil improves birth weight in FGR animal models. Whether sildenafil treatment protects against long-term cardiovascular and renal disease in these offspring is unknown. The aim of this study is to test the hypothesis that prenatal sildenafil ameliorates cardiovascular and renal function in FGR offspring of Dahl salt-sensitive rats. Sildenafil citrate (60 mg/kg per day) or control gel diet (containing 0.3% salt) was administered from gestational day ten until birth. In male and female offspring, the mean arterial pressure was measured by telemetry in 1 subset from week 5 until week twenty. Echocardiographic parameters, glomerular filtration rate, and fractional electrolyte excretion were determined in another subset at week 9. Aortic and mesenteric artery rings were prepared to assess endothelial-dependent (acetylcholine) and -independent (sodium nitroprusside) vasorelaxation (week 10). The rise in mean arterial pressure per week was attenuated in treated versus untreated male offspring. Mesenteric arteries showed an increased endothelium-dependent relaxation and improved endothelium-independent relaxation in treated versus control male offspring. No differences in aortic relaxation, echocardiographic parameters or renal function were observed between groups. Prenatal sildenafil treatment subtly improves cardiovascular but not renal function in the offspring of this FGR rat model. Translationally, in utero treatment could be beneficial for cardiovascular programming in a sex-specific manner; however, caution is warranted since recent human trials have been halted because of potentially deleterious neonatal side effects when treating pregnancies complicated with severe FGR with sildenafil.

Elevated renal tissue oxygenation in premature fetal growth restricted neonates: An observational study.

BACKGROUND: Fetal growth restriction (FGR) is associated with an increased risk for kidney disease in later life. Studies reporting on early signs of renal disturbances in FGR are sparse and mostly include invasive measurements, which limit the possibility for early identification and prevention. We aim to investigate whether renal tissue oxygen saturation (rSO2) measured with near-infrared spectroscopy (NIRS) and the derived value fractional tissue oxygen extraction (FTOE) differ between premature FGR and control neonates in the first three days after birth. METHODS: Nine FGR and seven control neonates born <32 weeks of gestation were included. FGR was defined as biometry

Cardiovascular Sequels During and After Preeclampsia.

Preeclampsia is a pregnancy-specific disorder complicating 2%-8% of pregnancies worldwide and characterized by de novo development of hypertension and proteinuria. Current understanding of the pathophysiology of preeclampsia is limited. A main feature is disrupted spiral artery remodeling in the placenta, which restricts the blood flow to the placenta, which in turn leads to decreased uteroplacental perfusion. Impaired blood flow through the placenta might result in fetal growth restriction and secretion of several factors by the placenta-mainly pro-inflammatory cytokines and anti-angiogenic factors-which spread into the maternal circulation, leading to endothelial dysfunction, which subsequently results in disrupted maternal hemodynamics. To date, no treatment options are available apart from termination of pregnancy. Despite normalization of the maternal vascular disturbances after birth, it has become apparent that formerly preeclamptic women experience an increased risk to develop cardiovascular and kidney disease later in life. One well-accepted concept is that the development of preeclampsia is an indicator of maternal susceptibility to develop future cardiovascular conditions, although the increased risk might also be the result of organ damage caused during preeclampsia. Given the associations between preeclampsia and long-term complications, preeclampsia is acknowledged as woman-specific risk factor for cardiovascular disease. Current research focuses on finding effective screening and prevention strategies for the reduction of cardiovascular disease in women with a history of preeclampsia.

Postpartum increases in cerebral edema and inflammation in response to placental ischemia during pregnancy.

Reduced placental blood flow results in placental ischemia, an initiating event in the pathophysiology of preeclampsia, a hypertensive pregnancy disorder. While studies show increased mortality risk from Alzheimer's disease, stroke, and cerebrovascular complications in women with a history of preeclampsia, the underlying mechanisms are unknown. During pregnancy, placental ischemia, induced by reducing uterine perfusion pressure (RUPP), leads to cerebral edema and increased blood-brain barrier (BBB) permeability; however whether these complications persist after delivery is not known. Therefore, we tested the hypothesis that placental ischemia contributes to postpartum cerebral edema and neuroinflammation. On gestational day 14, time-pregnant Sprague Dawley rats underwent Sham (n = 10) or RUPP (n = 9) surgery and brain tissue collected 2 months post-delivery. Water content increased in posterior cortex but not hippocampus, striatum, or anterior cerebrum following RUPP. Using a rat cytokine multi-plex kit, posterior cortical IL-17, IL-1α, IL-1ß, Leptin, and MIP2 increased while hippocampal IL-4, IL-12(p70) and RANTES increased and IL-18 decreased following RUPP. Western blot analysis showed no changes in astrocyte marker, Glial Fibrillary Acidic Protein (GFAP); however, the microglia marker, ionized calcium binding adaptor molecule (Iba1) tended to increase in hippocampus of RUPP-exposed rats. Immunofluorescence staining revealed reduced number of posterior cortical microglia but increased activated (Type 4) microglia in RUPP. Astrocyte number increased in both regions but area covered by astrocytes increased only in posterior cortex following RUPP. BBB-associated proteins, Claudin-1, Aquaporin-4, and zonular occludens-1 expression were unaltered; however, posterior cortical occludin decreased. These results suggest that 2 months postpartum, neuroinflammation, along with decreased occludin expression, may partly explain posterior cortical edema in rats with history of placental ischemia.

Kidney Function After a Hypertensive Disorder of Pregnancy: A Longitudinal Study.

BACKGROUND: Registry-based studies report an increased risk for end-stage kidney disease after hypertensive disorders of pregnancy (HDPs). It is unclear whether HDPs lead to an increased incidence of chronic kidney disease (CKD) and/or progression of kidney function decline. STUDY DESIGN: Subanalysis of the Prevention of Renal and Vascular Endstage Disease (PREVEND) Study, a Dutch population-based cohort with follow-up of 5 visits approximately 3 years apart. SETTING & PARTICIPANTS: Women without and with patient-reported HDPs (non-HDP, n=1,805; HDP, n=977) were identified. Mean age was 50 years at baseline and median follow-up was 11 years. FACTOR: An HDP. OUTCOMES: (1) The incidence of CKD using Cox regression and (2) the course of kidney function (estimated glomerular filtration rate [eGFR] and 24-hour albuminuria) over 5 visits using generalized estimating equation analysis adjusted for age, mean arterial pressure, and renin-angiotensin system (RAS) blockade. CKD was defined as eGFR<60mL/min/1.73m2 and/or 24-hour albuminuria with albumin excretion > 30mg, and end-stage kidney disease was defined as receiving dialysis or kidney transplantation. RESULTS: During follow-up, none of the women developed end-stage renal disease and the incidence of CKD during follow-up was similar across HDP groups (HR, 1.04; 95% CI, 0.79-1.37; P=0.8). Use of RAS blockade was higher after HDP at all visits. During a median of 11 years, we observed a decrease in eGFR in both groups, with a slightly steeper decline in the HDP group (98±15 to 88±16 vs 99±17 to 91±15mL/min/1.73m2; Pgroup<0.01, Pgroup*visit<0.05). The group effect remained significant after adjusting for mean arterial pressure, but disappeared after adjusting for RAS blockade. The 24-hour albuminuria did not differ between groups. LIMITATIONS: No obstetric records available. HDPs defined by patient report rather than health records. CONCLUSIONS: HDPs did not detectably increase the incidence of CKD. During follow-up, we observed no differences in albuminuria, but observed a marginally lower eGFR after HDP that was no longer statistically significant after adjusting for the use of RAS blockers. In this population, we were unable to identify a significant risk for kidney function decline after patient-reported HDP.

Sildenafil During Pregnancy: A Preclinical Meta-Analysis on Fetal Growth and Maternal Blood Pressure.

Sildenafil is a new approach to treat fetal growth restriction (FGR) and preeclampsia. We performed a systematic meta-analysis to evaluate effects of sildenafil. Our search identified 22 animal studies (mouse, rat, rabbit, sheep, and guinea pigs) and 2 human randomized controlled trials. Data were pooled using ratio of means and mean differences with 95% confidence intervals for fetal growth and maternal blood pressure, respectively. Meta-regression analyses were performed for study-related factors that might affect efficacy of sildenafil, including the model used (healthy pregnancy versus FGR/preeclampsia) and route of administration. Dose-response curves with dose per metabolic weight (mg/kg0.75 per 24 hours) were fitted using splines. Our analyses show that sildenafil increases fetal growth during FGR/preeclampsia pregnancy compared with healthy pregnancy (1.10 [1.06-1.13] versus 1.03 [0.99-1.06]; P=0.006). There was no significant effect on fetal growth in the absence of FGR/preeclampsia. Effects were similar among different species and largest after oral and continuous administration. There was a positive relation between dose and fetal growth up to a human equivalent dose of ≈450 mg/d. A significant blood pressure-lowering effect of sildenafil is present during FGR/preeclampsia pregnancy only (-19 [-25 to -13] mm Hg; P<0.01), with the effect size being highly dependent on baseline blood pressure and without effect in the absence of hypertension. This meta-analysis supports that sildenafil improves fetal growth and maternal blood pressure regulation during FGR and preeclampsia pregnancy. The greatest beneficial effects on fetal growth are with dosages greater than those currently used in human studies.

Exposure to placental ischemia impairs postpartum maternal renal and cardiac function in rats.

Women with a history of preeclampsia (PE) have an increased risk to develop cardiovascular and renal diseases later in life, but the mechanisms underlying this effect are unknown. In rats, we assessed whether placental ischemia results in long-term effects on the maternal cardiovascular and renal systems using the reduced uterine perfusion pressure (RUPP) model for PE. Sprague-Dawley rats received either a Sham or RUPP operation at gestational day 14 The rats were followed for 8 wk after delivery (Sham n = 12, RUPP n = 21) at which time mean arterial pressure (MAP; conscious), 24-h albuminuria, glomerular filtration rate (GFR; transcutaneous, FITC-sinistrin), and cardiac function (Vevo 770 system) were assessed. Subsequently, all rats were euthanized for mesenteric artery vasorelaxation and histology of heart and kidney. At 8 wk after delivery, there was no difference in MAP and albuminuria. However, RUPP rats showed a significantly reduced GFR [2.61 ± 0.53 vs. 3.37 ± 0.74 ml/min; P = 0.01]. Ultrasound showed comparable cardiac structure, but RUPP rats had a lower left ventricular ejection fraction (62 ± 7 vs. 69 ± 10%; P = 0.04). Heart and kidney histology was not different between Sham or RUPP rats. Furthermore, there were no differences in endothelial-dependent or -independent vasorelaxation. We show that exposure to placental ischemia in rats is accompanied by functional disturbances in maternal renal and cardiac function 8 wk after a preeclamptic pregnancy. However, these changes were not dependent on differences in blood pressure, small artery vasorelaxation, or cardiac and renal structure at this time point postpartum.

High-Normal Estimated Glomerular Filtration Rate in Early-Onset Preeclamptic Women 10 Years Postpartum.

Women with a history of preeclampsia have a 5- to 12-fold increased risk to develop end-stage kidney disease. Previous observations in small cohorts suggest that former preeclamptic (fPE) women have subtle abnormalities in renal hemodynamics and renal function, which might predispose them to renal failure in later life. In this study, we analyzed renal function in a cross-sectional cohort consisting of former early-onset preeclamptic (fPE, n=339) and former healthy pregnant women (fHP, n=332), overall with a mean age of 39 years at 10 years postpartum. Estimated glomerular filtration rate (eGFR), assessed by the modification of diet in renal disease (MDRD) and chronic kidney disease-epidemiology (CKD-epi) equations, and urinary protein:creatinine ratios were assessed 10 years postpartum. Median MDRD and CKD-epi eGFR did not significantly differ between fHP and fPE groups, whereas a comparison of distribution of eGFR revealed a shift toward a high-normal MDRD eGFR in the fPE group (χ2, P=0.02) with the same trend for CKD-epi eGFR (χ2, P=0.18). The odds ratio for fPE women having MDRD eGFR >110 mL/min per 1.73 m2 was 1.6 (1.1-2.4). In addition, the median urinary protein:creatinine ratio was slightly higher in fPE (8.5 versus 7.1 mg/mmol; P<0.01) and correlated positively with both MDRD and CKD-epi eGFR in fPE women. No increased incidence of CKD in fPE women was observed. In conclusion, we demonstrate subtle changes in renal function in former early-onset preeclamptic women 10 years postpartum, characterized by a high-normal eGFR and a slightly higher protein excretion. Whether these subtle differences predispose to or predict long-term renal function loss in fPE women remains to be investigated. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR2668.

Impaired sodium-dependent adaptation of arterial stiffness in formerly preeclamptic women: the RETAP-vascular study.

Women with a history of preeclampsia have an increased risk for cardiovascular diseases later in life. Persistent vascular alterations in the postpartum period might contribute to this increased risk. The current study assessed arterial stiffness under low sodium (LS) and high sodium (HS) conditions in a well-characterized group of formerly early-onset preeclamptic (fPE) women and formerly pregnant (fHP) women. Eighteen fHP and 18 fPE women were studied at an average of 5 yr after pregnancy on 1 wk of LS (50 mmol Na(+)/day) and 1 wk of HS (200 mmol Na(+)/day) intake. Arterial stiffness was measured by pulse-wave analysis (aortic augmentation index, AIx) and carotid-femoral pulse-wave velocity (PWV). Circulating markers of the renin-angiotensin aldosterone system (RAAS), extracellular volume (ECV), nitric oxide (NO), and hydrogen sulfide (H2S) were measured in an effort to identify potential mechanistic elements underlying adaptation of arterial stiffness. AIx was significantly lower in fHP women on LS compared with HS while no difference in AIx was apparent in fPE women. PWV remained unchanged upon different sodium loads in either group. Comparable sodium-dependent changes in RAAS, ECV, and NO/H2S were observed in fHP and fPE women. fPE women have an impaired ability to adapt their arterial stiffness in response to changes in sodium intake, independently of blood pressure, RAAS, ECV, and NO/H2S status. The pathways involved in impaired adaptation of arterial stiffness, and its possible contribution to the increased long-term risk for cardiovascular diseases in fPE women, remain to be investigated.

Long-term renal and cardiovascular risk after preeclampsia: towards screening and prevention.

Preeclampsia (PE) is a hypertensive pregnancy disorder complicating up to 1-5% of pregnancies, and a major cause of maternal and fetal morbidity and mortality. In recent years, observational studies have consistently shown that PE carries an increased risk for the mother to develop cardiovascular and renal disease later in life. Women with a history of PE experience a 2-fold increased risk of long-term cardiovascular disease (CVD) and an approximate 5-12-fold increased risk of end-stage renal disease (ESRD). Recognition of PE as a risk factor for renal disease and CVD allows identification of a young population of women at high risk of developing of cardiovascular and renal disease. For this reason, current guidelines recommend cardiovascular screening and treatment for formerly preeclamptic women. However, these recommendations are based on low levels of evidence due to a lack of studies on screening and prevention in formerly preeclamptic women. This review lists the incidence of premature CVD and ESRD observed after PE and outlines observed abnormalities that might contribute to the increased CVD risk with a focus on kidney-related disturbances. We discuss gaps in current knowledge to guide optimal screening and prevention strategies. We emphasize the need for research on mechanisms of late disease manifestations, and on effective screening and therapeutic strategies aimed at reducing the late disease burden in formerly preeclamptic women.