Elsevier

The Lancet

Volume 361, Issue 9368, 3 May 2003, Pages 1511-1517
The Lancet

Mechanisms of Disease
Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia

https://doi.org/10.1016/S0140-6736(03)13177-7Get rights and content

Summary

Background

Maternal endothelial dysfunction is a feature of established pre-eclampsia but whether this is a cause or consequence of the disorder is not clear. We tested the hypothesis that endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine (ADMA), the endogenous inhibitor of endothelial nitric oxide synthase, precede and contribute to the development of pre-eclampsia.

Methods

We assessed uterine artery doppler waveforms in 86 women at 23–25 weeks' gestation. We tested endothelial function in all women using flow-mediated dilation of the brachial artery at 23–25 weeks' gestation. Plasma concentrations of ADMA were also measured.

Findings

43 women had normal uterine artery doppler waveforms and subsequently had a normal outcome. The second group of 43 had evidence of impaired placental perfusion and of these, 19 (44%) had normal outcome, 14 (33%) developed intrauterine growth restriction of the fetus (IUGR), and pre-eclampsia arose in ten (23%). Women who developed pre-eclampsia had significantly lower flow-mediated dilation than did women who had normal outcome (3·58% [SD 2·76] vs 8·59% [2·76]; p<0·0001). Irrespective of pregnancy outcome, women with evidence of impaired placental perfusion had significantly higher levels of ADMA than did women with normal doppler waveforms (2·4 μmol/L [IQR 1·97–3·14] vs 0·81 μmol/L [0·49–1·08]; p<0·0001). There was a strong inverse correlation between ADMA and flow-mediated dilation but only in the group of women who eventually developed pre-eclampsia (r=−0·8, p=0·005).

Interpretation

Maternal endothelial function is impaired in women who eventually develop pre-eclampsia and it occurs before the development of the clinical syndrome. Furthermore, women with high resistance placental circulation at risk of preeclampsia, IUGR, or both have raised concentrations of ADMA, which is a potential contributory factor for pre-eclampsia, and is associated with endothelial dysfunction in some women.

Introduction

During pregnancy there is an increase in maternal blood volume that is accommodated by vasodilatation, which results in a drop in maternal blood pressure in the first half of pregnancy before returning to prepregnancy values towards term.1 Several vasodilator mediators including prostaglandins, have been implicated, but there is good evidence to suggest that the increased generation of the potent vasodilator nitric oxide (NO) by the maternal endothelium plays an important part.2 A deficiency of maternal NO might be important in the development of pre-eclampsia,3 a disorder that affects 3–5% of pregnancies and accounts for 40% of non-spontaneous premature deliveries in the UK.4 Although some women might have high cardiac output5 and normal peripheral resistance before pre-eclampsia, by the time the condition is established a low-volume-high-resistance maternal circulation exists, blood pressure rises, and proteinuria and oedema are seen.

The stimulus for the development of pre-eclampsia is unclear. Initially, a failure of normal trophoblastic invasion and remodelling of the uterine spiral arteries is thought to lead to a high-resistance uteroplacental circulation that can be detected non-invasively by doppler ultrasonography of the uterine arteries at 23–25 weeks' gestation.6 Such abnormalities in uterine circulation are also associated with intrauterine growth restriction (IUGR) of the fetus. The underperfused placenta is then thought to release humoral, pre-eclamptic factors into the maternal circulation that cause endothelial dysfunction;7 oxidative stress8 and inflammatory cytokines9 might also contribute. Endothelial dysfunction could prevent normal maternal vasodilation and disrupt the endothelial cell layer leading to hypertension and proteinuria.

However, several issues remain unresolved. First, although women with established pre-eclampsia have endothelial dysfunction, whether this is a cause or a consequence of the pre-eclamptic state is not clear. Second, no pre-eclamptic factor has yet been unequivocally identified. If the current model of preeclampsia is correct, any causative factor should be produced in or liberated by the placenta, released into the maternal circulation, be in high concentrations in women with abnormal high-resistance placental circulation, and be able to cause maternal endothelial dysfunction.

We have compared the systemic endothelial function and pregnancy outcome of women with normal placental perfusion with those who have evidence of a high-resistance placental circulation on doppler ultrasonographs, and who are at risk of pre-eclampsia, IUGR, or both. We aimed to assess whether maternal endothelial dysfunction predates pre-eclampsia, and whether ASYMMETRIC DIMETHYLARGININE (ADMA), an endogenous inhibitor of endothelial NO synthase (NOS) that competes with the enzyme substrate L-arginine, could be a causative factor for pre-eclampsia.

Section snippets

Participants

We included 43 pregnant women with abnormal uterine artery doppler waveforms (that is, showing BILATERAL EARLY DIASTOLIC NOTCH), who were identified consecutively at the time of the doppler study,6 and 43 other women with normal uterine artery doppler waveforms matched for age, ethnic group, and smoking status. At study entry, all women had singleton pregnancies, were healthy, on no medications, had no personal or family history of premature cardiovascular disease, and had appropriately grown

Results

None of the women with normal uterine artery doppler waveforms developed pre-eclampsia and all of them delivered infants of appropriate size (mean 3326 g [SD 460]). 43 women with bilateral notches of the uterine arteries at 23–25 weeks' gestation were allocated to one of three groups in accordance with the outcome of pregnancy; those with no complications (19 [44%]), those with pregnancies complicated by IUGR (14 [33%]) and those who developed pre-eclampsia (10 [23%]), including four with IUGR.

Discussion

We noted two novel findings from our observational study. First, that women who later developed preeclampsia not only had bilateral uterine artery notches, but also had impaired brachial artery flow-mediated dilation at 23–25 weeks' gestation, suggesting that maternal endothelial dysfunction is an additional factor required for pre-eclampsia to manifest. Second, we noted that all women with bilateral notches had a striking elevation in the concentration of the NO synthase inhibitor, ADMA.

The

GLOSSARY

ASYMMETRIC DIMETHYLARGININE
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase that competes with binding of the natural substrate L-arginine. It is produced from methylated arginine residues in proteins by protein methyltransferases and is metabolised by the enzyme DDAH. ADMA causes impaired endothelium-dependent vasodilation and is an independent predictor of future vascular events.
BILATERAL EARLY DIASTOLIC NOTCH
Bilateral early diastolic notches can be

References (30)

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