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Evaluation of Aldosterone Production/Salt Sensitivity in Early Pregnancy

English title Evaluation of Aldosterone Production/Salt Sensitivity in Early Pregnancy
Applicant Mohaupt Markus
Number 113902
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Gynaecology
Start/End 01.12.2006 - 30.11.2009
Approved amount 312'549.00
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All Disciplines (2)

Discipline
Gynaecology
Internal Medicine

Keywords (6)

pregnancy; hypertention in pregnancy; preeclampsia; aldosterone synthase; corticosterone methyl oxidation deficiency; mutation

Lay Summary (English)

Lead
Lay summary
1.SUMMARY
1.1.Summary
Hypertension in pregnancy can lead to preeclampsia (PE), thus presenting a major health threat for mother and child. The mechanism of elevated blood pressure in pregnant women is unknown in the great majority of these patients. One reason for the limited knowledge is the difficulty to perform clinical investigations in pregnant women. In the past, I have established collaborations with obstetricians from different universities allowing me to analyze groups of pregnant women including those with hypertensive and preeclamptic pregnancies. I propose now to extend these investigations in collaboration with Prof. Surbek, the head of obstetrics at our institution, with a main focus on reduced aldosterone (Aldo) production and the resulting need of salt in pregnancy. Increased Aldo levels and volume expansion are required in regular pregnancy. In contrast, Aldo levels are diminished in PE compared to healthy pregnancy, an observation made by several investigators including myself. The clinically observed sequence of intravascular volume depletion causing placental ischemia with subsequently increased maternal blood pressure clearly supports the concept that a high maternal cardiac output and sufficient placental perfusion is mandatory for fetal well-being.

The rate-limiting step of Aldo synthase (CYP11B2) is the 18-methyl oxidase (MO). Previously, I demonstrated a compromised Aldo synthesis at the level of the MO in the majority of preeclamptic women in our institutions. In a group of women with PE, but not in those with an uneventful pregnancy, the non-conservative mutation V386A, known to reduce the activity of CPY11B2 to produce Aldo, in exon 7 of the CYP11B2 was identified. The promoter polymorphism -344C/T and an intron 2 conversion are both associated with a high Aldo production. These changes were more common in our normal pregnancies when compared to PE. All these observations support the concept that high Aldo levels are required during an eventful pregnancy.

It is known from other clinical situations that Aldo deficiency can be counterbalanced by NaCl supplementation. Therefore, NaCl supplementation might be beneficial in pregnant women with impaired Aldo synthesis.Indeed, I recently observed in a woman with a low MO activity and low TH-Aldo excretion a fall in blood pressure in response to high amounts of NaCl prescribed in two pregnancies. Stimulated by these observations, I started to test salt sensitivity in women in early pregnancy. Initial results show a drop in blood pressure by 7 mm Hg within 1 week in response to salt supplementation.

I hypothesize now that inappropriately low Aldo availability and as a consequence a profound “reversed salt sensitivity” (i.e. a more pronounced reduction of blood pressure in response to salt) is one contributing factor to PE/hypertension in pregnancy. Therefore, I propose specifically
first, to assess salt sensitivity by supplementing NaCl up to a total intake of 20g/d for one week in 160 pregnant women early in pregnancy between the 7th and 20th week of gestation;
second, to assess the CYP11B2 and 18-MO activity by measuring the urinary ratio of DOC and total DOC to TH-Aldo and 18-OH-THA to TH-Aldo as well as total TH-Aldo by GC-MS;
third, to analyze the CYP11B2 including the promoter region for polymorphisms associated with an altered function in these women; and
fourth, to follow these women throughout gestation and up to 6 months after delivery in order to analyse the relationship between the above mentioned parameters and maternal/foetal outcome. I expect first, an increased incidence of hypertensive pregnancies/PE in subjects with inappropriate Aldo production and V386A mutation and a reduced incidence of hypertensive preeclampsia pregnancies in subjects with an increased Aldo synthesis due to 344C/T polymorphism and/or intron 2 conversion.Second, a more pronounced blood pressure reduction to NaCl supplementation in women with low Aldo production.

Rationale and future directions (not part of this proposal): If my hypothesis proofs to be correct in this larger cohort, I shall design a randomized placebo controlled prospective study in collaboration with my colleagues from obstetrics focusing on the prevention of arterial hypertension/PE by high NaCl intake in pregnant women with a reduced Aldo availability.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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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

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