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Abstract: Objective: To explore biomarkers indicating cardiovascular disease in pregnant women with diabetes or preeclampsia, since these women are at increased risk for future cardiovascular disease. Study design: EDTA-plasma from 262 women in gestational week 24–42 (healthy pregnancies n =71, preeclampsia n =105, type 2 diabetes n =17, gestational diabetes n =61, diabetes with preeclampsia n =8) was analyzed by immunoassay for neopterin, midregional pro-adrenomedullin (MR-proADM) and C-terminal pro-arginine vasopressin (CT-proAVP). The diabetes groups were also analyzed for midregional pro-atrial natriuretic peptide (MR-proANP), and compared to previously reported MR-proANP concentrations for healthy, normotensive and preeclamptic patients. Results: In contrast to preeclampsia, median plasma MR-proANP was not increased in pregnancies complicated by diabetes, but in fact lower, compared to healthy pregnancies. Neopterin was increased in diabetic pregnancies and in late onset preeclampsia, compared to healthy pregnancies. Median plasma MR-proADM was increased in pregnancies complicated by gestational diabetes or preeclampsia, compared to healthy pregnancies. Median plasma MR-proANP was increased in diabetic pregnancies complicated by preeclampsia compared to pregnant women with diabetes only. Conclusion: Women with pregnancies complicated by diabetes mellitus or preeclampsia are at risk for future cardiovascular disease, but differ in circulating cardiovascular biomarker profile. A cardiovascular biomarker profiling during pregnancy might prove helpful in identifying women at risk for future cardiovascular disease, thus enabling targeted prophylactic interventions and follow-up. [Copyright &y& Elsevier]

Introduction Preeclampsia complicates about 5% of all pregnancies worldwide and is the major cause of maternal, fetal and neonatal morbidity and mortality in the western world. Long-term morbidity has also been observed in former preeclamptic mothers, with a substantial increased risk for coronary heart disease. Recent studies demonstrate that women after preterm PE show echocardiographic signs of AHA classification stage B (asymptomatic heart failure) 2 years postpartum although they were normotensive. Objectives The main objective is to detect where and what kind of changes during preeclamptic pregnancy occur. Materials and methods We established a transgenic rat model for preeclampsia, featuring hypertension, proteinuria and intrauterine growth restriction (IUGR) where a female rat harbouring the human angiotensinogen gene is mated with a male transgenic for the human renin. For evaluation we used echocardiography, immunostaining and mRNA expression levels. Results Echocardiographic data show a decreasing ejection fraction and decreasing stroke volume in c ombination with a reduced left ventricular diameter during diastole stage at the end of pregnancy in the preeclamptic rat. The pathology is visible already at day 18, five days after blood pressure rises . In addition, speckle tracking analysis allows description of myocardial deformation normalized to its original shape (strain) and the speed at which this occurs (strain rate). In all dimensions (longitudinal, circumferential and radial) in long as well as in short axis significant reduced global function of strain and strain rate was observed in the heart of preeclamptic rats compared to controls. In the posterior part of the left ventricle we could detect a regional decrease of strain rate which was not found in septal part. Furthermore, an increased wall thickness and increased perivascular fibrosis was measured in this impaired part of the heart (posterior wall). Conclusion These results demonstrate alterations based on a pathological pregnancy leading to a change in structure and function of the left ventricle heart. Future studies will show how long these changes will remain postpartum and how big the impact on later cardiovascular health is. [ABSTRACT FROM AUTHOR]

Introduction and objectives Impaired placental development or function leads to intrauterine growth restriction (IUGR) resulting in fetal malnutrition and deprivation of oxygen supply. Since it is known that overexpression of the human anti-angiogenic molecule sFlt-1 in mice lead to preeclampsia and intrauterine growth restriction (IUGR) in mice we established two sFlt-1 mouse models: (1) placental overexpression of human sFlt-1 by lentiviral transduced blastocysts and (2) maternal ubiquitous inducible human sFlt-1 overexpression (sFlt-1/rtTA transgenic mice). We hypothesize that sFlt-1 influence placental morphology and physiology which led to fetal IUGR. Material and methods Therefore we examined the effect of human sFlt-1 on placental morphology and physiology at embryonic day 18.5 with histologic and morphometric analyses, transcript analyses, immunoblotting, and methylation studies. Results Interestingly, placental overexpression of sFlt-1 leads to IUGR in the fetus and results in lower placental weights. Moreover, we observed altered trophoblast differentiation with reduced expression of IGF2, resulting in a smaller placenta, a smaller labyrinth, and the loss of glycogen cells in the junctional zone. Changes in IGF2 are accompanied by small changes in its DNA methylation, whereas overall DNA methylation is unaffected. In addition, mostly the expression of placental glucose transporters, such as the glucose diffusion channel Cx26 and Glut-1 is significantly decreased. Conclusion Placental sFlt-1 overexpression resulted in a reduction in the differentiation of the spongiotrophoblast into glycogen cells. These findings of a reduced exchange area of the labyrinth and glycogen stores, as well as decreased expression of glucose transporter, could contribute to the intrauterine growth restriction phenotype. All of these factors change the intrauterine availability of nutrients. Thus, we speculate that the alterations triggered by increased anti-angiogenesis strongly affect fetal outcome and programming. [ABSTRACT FROM AUTHOR]

Objectives Vitamin D deficiency is associated with increased prevalence of hypertension and chronic inflammatory diseases both in the presence and absence of pregnancy. Preeclampsia (PE) is characterized by late-onset hypertension in pregnancy is also associated with increased CD4+ T cells, agonistic autoantibodies to the angiotensin type II receptor (AT1-AA) and decreases in T regulatory cells (TREGs). We tested the hypothesis that Vitamin D2 and D3 treatment would ameliorate hypertension and or other hallmarks of PE in the RUPP rat. Methods We utilized the Reduced Uterine Perfusion Pressure (RUPP) model of PE which exhibits hypertension (MAP), increased CD4+ T cells, AT1-AA and reduced TREGs. RUPP surgery was performed on gestation day 14 (GD14) with 50 μM VD2 or VD3 oral administration on GD14-18. Rats were sacrificed on GD19 with MAP measured by indwelling carotid catheter. Results MAP in RUPP rats was 122 ± 2.3 compared to 104.2 ± 2.4 mmHg in NP rats ( n = 12–18, p < 0.05). Supplementation with either VD2 or VD3 lowered MAP to 117.6 ± 3.9 or 114.3 ± 2.9 mmHg, respectively ( n = 9–12). CD4+ T cells increased from 2.8 ± 1.0% in NP to 8.5 ± 1.5% in RUPP ( n = 8–11, p < 0.05) which decreased to 1.2 ± 0.4% with VD2 and to 4.6 ± 3.7% with VD3 ( n = 2–3). AT1-AA, measured via chronotropic response in cardiomyocytes, were 19.5 ± 0.4 beats/min in RUPP rats and decreased to 15.4 ± 0.7 with VD3, and further to 8.3 ± 0.5 with VD2 ( n = 5, p < 0.05). Circulating B cells increased in RUPP rats compared to NP (9.0 ± 3.7% to 5.5 ± 2.3%, n = 5–10) while VD2 had no effect (11.6 ± 3.0%, n = 6) but VD3 treatment decreased B cells in RUPP rats (6.8 ± 3.3%, n = 7). Conclusions Taken together, these data indicate that Vitamin D supplementation reduced MAP and inflammation in a rat model of PE, thereby suggesting a role for Vitamin D as an agent to reduce the pathophysiology associated with PE. Disclosures J.L. Faulkner: None. M.M. Darby: None. D.C. Cornelius: None. A.C. Harmon: None. L.M. Amaral: None. J. Moseley: None. F. Herse: None. G. Wallukat: None. R. Dechend: None. B. LaMarca: None. [ABSTRACT FROM AUTHOR]

Introduction: Vitamin D may ameliorate hypertension and kidney disease through genomic and extra-genomic pathways. Objective: To investigate the impact of vitamin D in a transgenic rat model of angiotensin II-mediated hypertensive organ failure. Methods: In 4-week-old age-matched rats overexpressing the human renin and angiotensinogen genes, group 1 (n =18) received vitamin D depleted chow; group 2 (n =15) standard chow and intraperitoneal paricalcitol at 800ng/kg thrice weekly; and group 3 (n =15) standard chow and vehicle injections. Blood pressure (tail cuff) and 24-h albuminuria were determined once weekly. After three weeks, animals were sacrificed. Heart tissue was examined for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) by RT-PCR. Results: The vitamin D depleted group had higher blood pressure at week 1 (mean difference 23.4mmHg, 95% CI 9.1–37.7) and tended to have higher blood pressure in weeks 2 and 3 (mean difference 14.3mmHg 95% CI −0.02–28.7 and 15.2mmHg 95% CI −1.5–33). The depletion group had higher heart-to-body weight ratio, and a trend towards higher ANP and BNP levels. The group receiving paricalcitol did not perform better. No differences were found between groups in mortality or proteinuria. Conclusion: Short-term vitamin D depletion aggravated hypertension and end-organ damage in a rat model of angiotensin II-induced hypertension. Short-term interventions with high-dose vitamin D analogues had no protective effect. [Copyright &y& Elsevier]

Introduction: miRNAs are small ∼22nt RNAs, important in the fine-tuning of mRNA in many organs including placenta. Preeclampsia (PE) is a heterogenous disease which may be divided into early-onset PE, which is a more severe form with assumed placental origin, and late-onset PE, with assumed maternal origin. Objectives: The aim of this study was to investigate the differential expression of miRNAs in early and late-onset PE compared to controls using high throughput sequencing. Methods: Placentas were obtained from an ongoing biobank collection at Oslo University Hospital. 23 normotensive controls, 23 early-onset PE (delivery at gestational week <34) and 26 late-onset PE (week⩾34) samples were sequenced using Illumina sequencing technology. Differential expressed miRNAs were identified by the EdgeR package in R and predicted targets were estimated by miRWalk. Results: 3 placental miRNAs were differentially expressed between controls and late-onset PE, 4 miRNAs were differentially expressed between early- and late-onset PE and 51 miRNAs were differentially expressed between early-onset PE and controls. Combining with mRNA array data from a subgroup of the same patients, we identified predicted targets of some of these miRNAs with significant inverse correlation between the respective mRNAs/miRNAs. Conclusion: These preliminary results suggest that miRNAs in placenta could be more important in the dysregulation of mRNAs in early-onset PE than in late-onset of the disease. [Copyright &y& Elsevier]