Activation of the Renin-Angiotensin-Aldosterone System Is Attenuated in Hypertensive Compared with Normotensive Pregnancy

Abstract

Hypertension during pregnancy increases the risk of adverse maternal and fetal outcomes, but the mechanisms of pregnancy hypertension are not precisely understood. Elevated plasma renin activity and aldosterone concentrations play an important role in the normal physiologic adaptation to pregnancy. These effectors are reduced in patients with pregnancy hypertension, creating an opportunity to define the features of the renin-angiotensin-aldosterone system (RAAS) that are characteristic of this disorder. In the current study, we used a novel LC-MS/MS-based methodology to develop comprehensive profiles of RAAS peptides and effectors over gestation in a cohort of 74 pregnant women followed prospectively for the development of gestational hypertension and pre-eclampsia (HYP, 27 patients) versus those remaining normotensive (NT, 47 patients). In NT pregnancy, the plasma renin activity surrogate, (PRA-S, calculated from the sum of Angiotensin I + Angiotensin II) and aldosterone concentrations significantly increased from the first to the third trimester, accompanied by a modest increase in the concentrations of angiotensin peptide metabolites. In contrast, in HYP pregnancies, PRA-S and angiotensin peptides were largely unchanged over gestation, and third-trimester aldosterone concentrations were significantly lower compared with those in NT pregnancies. The results indicated that the predominant features of pregnancies that develop HYP are stalled or waning activation of the RAAS in the second half of pregnancy (accompanied by unchanging levels of angiotensin peptides) and the attenuated secretion of aldosterone.

Keywords: aldosterone; angiotensin; biomarkers; mass spectrometry; maternal; pregnancy hypertension.

Figure 1

RAS Fingerprint-generated biomarkers of the activation of the classical RAAS in normotensive versus hypertensive pregnancies. (A) PRA-S, a surrogate for plasma activity calculated from the sum of the equilibrium concentrations of Ang I and Ang II, and (B) concentrations of aldosterone in the first and third trimesters of pregnancies that developed hypertension after 20 weeks of gestation (HYP, n = 27) and those that remained normotensive (NT, n = 47). PRA-S and aldosterone levels were not different among the NT and HYP groups in the first trimester, but increased over gestation only in the group that remained NT. Data are the median and 95th confidence intervals (CI). ***, p < 0.001 and ****, p < 0.0001 for within-group increases from the first to third trimester analyzed by Wilcoxon’s matched-pairs signed rank tests. ##, p < 0.01 compared with NT using the Mann–Whitney test. The percentage of change in (C) PRA-S and (D) concentrations of aldosterone from the first to third trimester in NT and HYP patients. The percentage of increase over gestation in PRA-S and aldosterone was significantly lower in pregnancies that developed HYP compared with the NT group. Data are the median and 95th CI of the percentage of change for each biomarker over pregnancy in the NT and HYP groups. #, p < 0.05 compared with NT using the Mann–Whitney test.

Figure 2

Equilibrium concentrations of Ang II, and upstream and downstream angiotensin metabolites in normotensive and hypertensive pregnancy. (A) Ang II and (B) Ang I concentrations in the first and third trimesters in the NT (n = 47) and HYP (n = 27) groups. Data are the median and 95th confidence intervals (CI). *, p < 0.01, ****, p < 0.01 for within-group increases from the first to third trimester analyzed by Wilcoxon’s matched-pairs signed rank tests; p = 0.052 for the increase across gestation in HYP patients. (C) The concentration of N-terminal metabolites of Ang II, calculated from the sum of the concentrations of Ang III and Ang IV, and (D) the concentration of C-terminal metabolites of Ang II, calculated from the sum of the concentrations of Ang-1-5 and Ang-1-7. Data are the median and 95th CI. p = 0.053 for the between-group analysis at the third trimester analyzed via the Mann–Whitney test . **, p < 0.01 for within-group increases from the first to third trimester analyzed by Wilcoxon’s matched-pairs signed rank tests.