CHronic hypERtension and L-citRulline studY (CHERRY): an Early-Phase Randomised Controlled Trial in Pregnancy.

Oral supplementation with L-citrulline, which is sequentially converted to L-arginine then nitric oxide, improves vascular biomarkers and reduces blood pressure in non-pregnant, hypertensive human cohorts and pregnant mice with a pre-eclampsia-like syndrome. This early-phase randomised feasibility trial assessed the acceptability of L-citrulline supplementation to pregnant women with chronic hypertension and its effects on maternal BP and other vascular outcomes. Pregnant women with chronic hypertension were randomised at 12-16 weeks to receive 3-g L-citrulline twice daily (n = 24) or placebo (n = 12) for 8 weeks. Pregnant women reported high acceptability of oral L-citrulline. Treatment increased maternal plasma levels of citrulline, arginine and the arginine:asymmetric dimethylarginine ratio, particularly in women reporting good compliance. L-citrulline had no effect on diastolic BP (L-citrulline: - 1.82 95% CI (- 5.86, 2.22) vs placebo: - 5.00 95% CI (- 12.76, 2.76)), uterine artery Doppler or angiogenic biomarkers. Although there was no effect on BP, retrospectively, this study was underpowered to detect BP changes < 9 mmHg, limiting the conclusions about biological effects. The increase in arginine:asymmetric dimethylarginine ratio was less than in non-pregnant populations, which likely reflects altered pharmacokinetics of pregnancy, and further pharmacokinetic assessment of L-citrulline in pregnancy is advised.Trial Registration EudraCT 2015-005792-25 (2017-12-22) and ISRCTN12695929 (2018-09-20).

Kynurenine Relaxes Arteries of Normotensive Women and Those With Preeclampsia.

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The kynurenine pathway; A new target for treating maternal features of preeclampsia?

In preeclampsia, vasospasm, oxidative stress, endothelial dysfunction, and immune dysregulation are key mediators of maternal disease. A new time-of-disease treatment is needed with the potential to treat these areas of pathophysiology. A review of the literature has indicated that metabolites of the kynurenine pathway have the potential to; (i) induce vasorelaxation of resistance arteries and reduce blood pressure; (ii) exert antioxidant effects and reduce the effects of poly-ADP ribose polymerase activation (iii) prevent endothelial dysfunction and promote endothelial nitric oxide production; (iv) cause T cell differentiation into tolerogenic regulatory T cells and induce apoptosis of pro-inflammatory Th1 cells. This has led to the hypothesis that increasing Kynurenine pathway activity may offer a new treatment strategy for preeclampsia.

Antenatal glucocorticoid exposure and long-term alterations in aortic function and glucose metabolism.

OBJECTIVE: Animal studies have demonstrated long-term effects of in utero glucocortcoid exposure on vascular development and glucose metabolism. We hypothesized that there would be a similar impact in humans. METHODS: One hundred and two young adults born preterm aged 23 to 28 years, with prospective data collection from birth, and 95 adults born term after uncomplicated pregnancies underwent cardiovascular MRI. We compared cardiac and aortic structure and function, as well as cardiovascular risk profile, in a nested case-control study of 16 participants exposed to antenatal steroids and 32 who were not, but with otherwise similar perinatal care. Outcomes were compared with normal ranges in those born term. RESULTS: Adults whose mothers had received antenatal steroids had decreased ascending aortic distensibility (9.88 ± 3.21 vs 13.62 ± 3.88 mm Hg(-1) × 10(3), P = .002) and increased aortic arch pulse wave velocity (5.45 ± 1.41 vs 4.47 ± 0.91 m/s, P = .006). The increase in stiffness was equivalent to that of term adults a decade older. Those who had in utero exposure to antenatal steroids also had significant differences in homeostatic model assessments for ß-cell function (P = .010), but in multiple regression analysis this did not explain the impact of steroids on aortic function. CONCLUSIONS: Antenatal glucocorticoid exposure in preterm infants is associated with increased aortic arch stiffness and altered glucose metabolism in early adulthood.

Prevention of vascular dysfunction after preeclampsia: a potential long-term outcome measure and an emerging goal for treatment.

Preeclampsia is increasingly being recognised as more than an isolated disease of pregnancy. In particular, preeclampsia has emerged as an independent risk factor for maternal cardiovascular disease and has recently been recognised as a risk factor for cardiovascular disease in children exposed in utero. Preeclampsia and cardiovascular disease may share important pathophysiological and molecular mechanisms and further investigation into these is likely to offer insight into the origins of both conditions. This paper considers the links between cardiovascular disease and preeclampsia and the implication of these findings for refinement of the management of patients whose care is complicated by preeclampsia.