Cardiovascular Effects of                   Pre-eclampsia

Pre-eclampsia affects 2 to 5% of pregnant women worldwide and is associated with considerable morbidity and mortality for both the mother and the foetus. The condition is characterised by high blood pressure and excretion of protein in the urine. Pre-eclampsia can only be treated by delivery of the baby, which is again associated with risks to mother and the newborn. Early detection of women at risk for pre-eclampsia would allow better monitoring and preventative therapy, but currently no routinely applicable and reliable markers exist that predict development of the condition. In our research we aim to detect novel biomarkers of pre-eclampsia and study the effect of pre-eclampsia on future cardiovascular risk.

Proteomic studies

We designed the PIP (Proteomics in Pre-eclampsia) Study and collected blood and urine samples from more than 5,000 women in the first trimester of pregnancy. We examined whether the number and kinds of proteins and protein fragment in urine are different between women who subsequently develop pre-eclampsia and those with uncomplicated pregnancy. We employed a proteomic strategy to generate typical signatures normal and pre-eclamptic pregnancies and demonstrated a significant difference between these patterns at gestational week 28 (Figure 1). Pre-eclampsia-specific urinary biomarkers included fragments of collagen, fibrinogen alpha chain and uromodulin [1].

Urine samples from gestational week 28 from women who had normotensive pregnancies (n=17; panels A and C) and who subsequently developed pre-eclampsia (n=18; panels B and D) were analysed. A urinary polypeptide signature of 50 pregnancy specific biomarkers was defined (bottom panels C and D). From [1].

Circulating biomarkers

We also used the PIP Study to examine whether circulating biomarkers in plasma can predict the development of pre-eclampsia [2]. We found that as early as in gestational week 14 the plasma levels of soluble E-selectin are increased in pregnant women who subsequently develop pre-eclampsia compared to those who went on to have normotensive pregnancies (Figure 2). This finding demonstrates that well before the development of clinical symptoms there is already endothelial cell activation that may be causally involved in the development of pre-eclampsia [3].

Boxplots indicate median, interquartile range and range. From [2].

Vascular function

We studied microcirculatory function in pregnant women using a novel non-invasive device that assessed peripheral arterial tone. Whilst these studies appear not to predict the development of pre-eclampsia we made important observations about vascular regulation during pregnancy. Interestingly, we fund that women who had recent history of pre-eclampsia are characterized by relative peripheral vasoconstriction (Figure 3). This finding indicates that pre-eclampsia is associated with vascular dysregulation beyond pregnancy [4].

Data were obtained 6 to 9 months post-natally using the Endo-=PAT2000 device.

Effect of pre-eclampsia on future cardiovascular risk

The above observation on vasoconstriction and also findings from our proteomic and biomarker studies are in line with the concept that pre-eclampsia and other cardiovascular diseases share common pathophysiological mechanisms (Figure 4). This not only puts women with cardiovascular disease such as hypertension at higher risk for pre-eclampsia but also leads to increased risk of future cardiovascular disease in women who had pre-eclampsia [5]. We also study microRNA profiles as  predictors of preeclampsia.

We currently study the effects of pre-eclampsia on vascular function and structure and biomarkers of cardiovascular risk as a follow-up to the PIP Study.

A number of risk factors and pathophysiological mechanisms are common to both preeclampsia and cardiovascular disease. It remains uncertain whether risk factors, preeclampsia itself, or a combination contribute to increased future cardiovascular risk. From [5].

Publications:

1. Carty DM, Siwy J, Brennand JE, Zürbig P, Mullen W, Franke J, McCulloch JW, North RA, Chappell LC, Mischak H, Poston L, Dominiczak AF, Delles C. Urinary proteomics for prediction of preeclampsia. Hypertension 2011;57:561-9.
2. Delles C, Carty DM, Brennand JE, McCulloch JW, Johnstone J, Welsh P, Dominiczak AF. Prediction of Pre-Eclampsia by First Trimester E-Selectin. Presented at ISH 2010, Vancouver, Canada.
3. Carty DM, Delles C, Dominiczak AF. Novel biomarkers for predicting preeclampsia. Trends Cardiovasc Med. 2008;18:186-94.
4. Carty DM, Anderson LA, Nicolson Duncan C, Baird DP, Rooney LK, Dominiczak AF, Delles C. Peripheral arterial tone: assessment of microcirculatory function in pregnancy. J Hypertens 2012;30:117-23.
5. Carty DM, Delles C, Dominiczak AF. Preeclampsia and future maternal health. J Hypertens. 2010 Jul;28:1349-55.