Inflammatory mediators
Outside of pregnancy, increased serum IL-6 and TNF-α has been reported in patients with CH. In one study, the prevalence of hypertension was double in those in the upper quartile of IL-6 and TNF-α when compared to those in the lower quartile.18 Two smaller studies further support a role for TNF-α in the pathophysiology of hypertension by reporting elevated TNF-α in those with CH compared to those without.19, 20 TNF-α has been shown to induce structural as well as functional alterations in endothelial cells, enhances the production of endothelin and other inflammatory mediators, including IL-6 and VCAM, that ultimately lead to atherosclerotic plaque formation and progression.12, 21 In addition, the increases in serum IL-6, TNF-α, endothelin and VCAM have been correlated to the degree of cardiovascular risk in patients with CH and, thus, have emerged as predictors of cardiovascular morbidity.22
During pregnancy, there is extensive literature to support a 2-3 fold increase in the production of IL-6, TNF-α, endothelin and VCAM in pregnancies already complicated with PE.23, 24 It has been proposed that, similar to outside of pregnancy, these inflammatory mediators lead to the development of atherosclerotic-like lesions.25 Within the feto-placental circulation, these lesions result in placental hypoxia and, within the systemic circulation, result in endothelial dysfunction and the maternal syndrome of PE.26 However, it remains to be clarified as to whether this inflammatory process predates the placental impairment or whether it is a consequence of it.
Our work has demonstrated that, in women with CH, first trimester alterations in IL-6 and endothelin exist. We have shown that women with CH who are hypertensive have elevated first trimester serum endothelin when compared to normotensive controls. Women in group 4 who are taking antihypertensive medications are likely to have had a longer duration of disease than those in group 1 who are previously undiagnosed. Along with our findings, this supports the existing literature where a positive correlation between levels of endothelin and mean arterial pressure but not duration of disease has been demonstrated.23, 27
Endothelin is also known to increase the expression of other inflammatory cytokines such as IL-6, another biomarker of endothelial disease.13 The finding of lower first trimester serum IL-6 for group 4 only when compared to normotensive controls was unexpected. In normal pregnancy, current literature has demonstrated a doubling in the maternal serum concentration of IL-6 when compared to non-pregnant controls due to trophoblastic production in the early first trimester.28 It has been suggested that IL-6 may have a major role in the normal paracrine regulation of placental development and hormone production.28 We propose that in women with CH, particularly those with more severe disease as in group 4, there is less capacity of the impaired placenta to up-regulate its production of IL-6, as with sFLT-1. In contrast, first trimester maternal serum concentration of endothelin is approximately halved when compared to non-pregnant controls and is considered to be a protective mechanism against its vasoconstrictive properties.29Thus, the endothelin levels measured are a reflection of maternal systemic production rather than a trophoblastic contribution, as with IL-6.