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Salt Supplementation in Pregnancies at High Risk to Develop Preeclampsia - Clinical Outcome and Molecular Prediction of Response

English title Salt Supplementation in Pregnancies at High Risk to Develop Preeclampsia - Clinical Outcome and Molecular Prediction of Response
Applicant Mohaupt Markus
Number 156830
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Internal Medicine
Start/End 01.02.2015 - 31.01.2018
Approved amount 499'000.00
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All Disciplines (2)

Discipline
Internal Medicine
Clinical Pathophysiology

Keywords (13)

PlGF; placenta; VEGF; outcome; TGF-beta; salt; interleukin-10; preeclampsia; sFlt-1; blood pressure; interleukin-17; pregnancy; hypertension

Lay Summary (German)

Lead
Hypertensive Schwangerschaftserkrankungen beeinträchtigen Mutter und Kind häufig lebenslang. Dieses Projekt untersucht den Einfluss von Kochsalz, welches in der Schwangerschaft im Gegensatz zu sonstigen Lebensabschnitten einen günstigen Effekt zu haben scheint, bezüglich molekularer Effekte, im Tiermodell sowie in Risikoschwangerschaften.
Lay summary

Oft tritt hoher Blutdruck während einer Schwangerschaft auf. Nach einer solchen Schwangerschaft erkranken und sterben Mütter und Kinder lebenslang häufiger an Herz-, Kreislauf- und Nierenerkrankungen. Wir haben gezeigt, dass Kochsalz und das „Salzhormon“ Aldosteron in Schwangerschaften günstig auf den Blutdruck, die Plazenta und das Kind wirken. Salz kann vielfältige molekulare Signale auslösen, darunter auch für das Endothel günstige. Falls diese bei Schwangeren vorrangig wirken, wäre eine einfache nutritive Intervention möglich. Generell wird eine kochsalzarme Ernährung durch die Gesundheitsbehörden gefördert. Die komplexe Situation während einer Schwangerschaft wird unzureichend berücksichtigt oder ein simplifizierter Transfer der Empfehlung salzarmer Diät aus dem nicht-schwangeren Zustand durchgeführt, der das Vorgehen vielerorts (u.a. Schweiz) prägt.

Wir möchten zeigen, dass Kochsalz bei Schwangeren mit einem hohen Risiko für eine schwere Bluthochdruckerkrankung mit Organbeteiligung (Präeklampsie) den Blutdruck und die Erkrankungshäufigkeit senkt, und dass dieser Effekt durch Blutuntersuchungen vorhergesagt werden kann. Wir beabsichtigen, zunächst in Tiermodellen die optimale Salzzufuhr zu charakterisieren und dann eine klinische Studie mit einer Änderung der Salzzufuhr durchführen.

Da eine gesunde Schwangerschaft ausserordentlich und langfristig den Gesundheitszustand einer Bevölkerung bestimmt, sind präventive Massnahmen in diesem entscheidenden Lebenszeitraum bedeutsam. Kochsalz könnte in der Schwangerschaft paradoxerweise Hochdruckerkrankungen vorbeugen. Da diese auch dann einen erheblichen Schaden bei Mutter und Kind hinterlassen können, wenn sie nach der Schwangerschaft zunächst geheilt scheinen, wäre es gut, Schwangere zu identifizieren, die besonders, und falls ja, von wie viel Kochsalz profitieren. Damit könnten staatliche Steuerungsmassnahmen von evidenz-basierten Empfehlungen profitieren und so zu einer Verbesserung der Volksgesundheit beitragen.

Direct link to Lay Summary Last update: 30.12.2014

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
Dr. Pecks, University of Aachen, Department of Obstetrics Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Dr. Hiten Mistry, University of Nottingham, Department of Obstetrics Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. Broughton-Pipkin + Dr. Kurlak, University of Nottingham, Department of Obstetrics Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Schlembach, University of Jena, Department of Obstetrics Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Delles, Glasgow Cardiovascular Research Centre University of Glasgow Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Franziska Theilig, University of Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Awards

Title Year
Best oral presentation, DACH ISSHP 2017
Best poster Award, DGfN 2017
Best abstract, IFPA 2016

Associated projects

Number Title Start Funding scheme
135596 Is Fetal and Placental Size, Blood Pressure and Overall Pregnancy Outcome Determined by Aldosterone Production and Salt Intake? 01.09.2011 Project funding
135596 Is Fetal and Placental Size, Blood Pressure and Overall Pregnancy Outcome Determined by Aldosterone Production and Salt Intake? 01.09.2011 Project funding

Abstract

High blood pressure (BP) in pregnancy is progressively affecting pregnancies. In this placental disease mediators released into the circulating confer systemic endothelial dysfunction. While organ predominance determines the clinical syndrome, renal affection resembles “classical” preeclampsia (PE). Inherited and environmental factors contribute to the disease. Our recent data has significantly added to the understanding of the critical regulation and important role of aldosterone (Aldo) in normal and preeclamptic pregnancy. Aldo not only enhances salt and water retention, but also contributes to placental growth and fetal well-being. In contrast to non-pregnant women, BP does not rise with high Aldo levels. Still responsive to renin and angiotensin II, we identified angiogenic signaling via vascular endothelial growth factor (VEGF) as major and specific regulator of Aldo. If low either genetically or due to VEGF trapping by a soluble VEGF receptor (sFlt-1) such as in PE, elevated BP and even PE is observed. In addition, Aldo was notably insensitive to salt exposure in pregnant women, while renin still responded. If appropriate plasma volume expansion and placental perfusion are critical, enhanced environmental salt availability might be beneficial. Aldo synthase (CYP11B2)-/- in mice resulted in intrauterine growth restriction and placental ischemia which was reduced while the fetal phenotype was rescued upon high salt diet. Likewise, in human genetic hypoaldosteronism and in healthy women we could lower BP in pregnancy upon adding salt. This is in line with earlier studies where reducing salt intake did not improve the clinical outcome. An old, not optimally randomized study using high salt intake to reduce pregnancy-related cramps revealed a reduction in maternal rate of PE and fetal mortality. Only recently has salt intake been attributed to increased molecular signals, transforming growth factor-ß (TGF-ß) and interleukin-17 (IL-17) via T helper-17 lymphocytes (TH17-L). TGF-ß enhances endothelial production of nitric oxide in pregnancy, and a loss of TGF-ß signaling is related to liver involvement of PE and an upregulation of TGF-ß is wanted; whereas TH17-L increases IL-17 which has been linked to enhanced expression of agonistic angiotensin II receptor subtype 1 autoantibodies. IL-17 responses are counterbalanced by IL-10, a mechanism disclosed in tolerant renal transplant recipients related to an appropriate expression of transitional B-cells. Low IL-17 and high IL-10 levels are found in normal pregnancies. Thus, a pattern of either high Aldo, TGF-ß as well as IL-10, and low IL-17 can be expected to favor normotensive pregnancies. Likewise, in those with low Aldo and TGF-ß levels, salt supplementation should be most beneficial. An already established collaborative effort with Prof. Surbek, the Head of obstetrics at our institution, and international partners gives me access to existing data and biosamples of pregnant women in health and disease. The impact of salt is currently tested in a pregnant animal model providing a whole array of organ target responses. Our local and further obstetric departments have agreed to participate in the interventional trial testing salt supplementation in patients at high risk of developing PE. I hypothesize that salt supplementation reduces hypertension in pregnancy or PE if at high risk and that molecular characteristics will be developed to predict the effect of salt. Therefore, I specifically propose first, to assess the BP phenotype and pregnancy outcome (placental size, fetal development) related to salt intake via urinary Na+ excretion, Aldo, IL-10/-17, TGF-ß, VEGF, sFlt-1 and placental growth factor (PlGF) longitudinally in pregnancy (from the Bernese pregnancy registry); second, to assess in a pregnant rat model in different salt intake conditions the parameters indicated in specific aim 1; and third, to perform a randomized placebo-controlled study on salt supplementation in patients at high risk to develop high BP in pregnancy or PE, to analyze the parameters as in specific aim 1 before and on salt, and to perform lymphocytes FACS analysis, and to in vitro perfuse placentas after birth to characterize the cytokine profile of treatment with and without PE. Rationale and future directions (not part of this proposal): If my hypothesis proofs to be correct these data will provide information on salt as easy preventive intervention and help to identify patients most likely to respond beneficial to salt. Given the huge impact on future maternal and fetal health any effort should be taken to reduce hypertensive diseases in pregnancy. This also will support governmental health authorities to provide recommendations on salt intake in pregnancy.
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