Changes of blood biomarkers following pre-eclampsia and predictors of future cardiovascular risk

Abstract

Background: Pre-eclampsia (P-EC) is a major cause of maternal and neonatal mortality and morbidity. Alterations in the maternal vasculature and coagulation profile may predispose women with P-EC to subsequent deleterious cardiovascular consequences. Indeed women with a history of P-EC are known to have heightened risks of future cardiovascular disease and thromboembolic complications.Aims: To assess the relationship between circulating haemostatic factors and inflammatory cytokines in women with a previous history of P-EC.To investigate the relationship between haemostatic, angiogenic and anti-angiogenic factors in women with a past history of P-EC.To assess the plasma levels of Annexins A2 and A5 in pre-eclamptic women postpartum at different time intervals.To identify clusters of differentially expressed plasma proteins in P-EC associated with the susceptibility to developing future cardiovascular diseases.To examine miRNAs expression in P-EC post-delivery at different intervals time points.Study-I: 26 pre-eclamptic women and 14 age-matched to healthy women. Women were included within six months to 3 years post-delivery. Plasma TF, IL-6, IL-8 and IL-10 levels increased in the P-EC group, whereas plasma TFPI and TNF-α levels were reduced. Plasma TF/TFPI ratios and IL-10 values were significantly increased in the P-EC group (p<0.05, p<0.01, respectively). There were positive and significant correlations between TFPI(r= 0.5; p<0.01) and IL-10 and TF/TFPI ratio and IL-10 (r= 0.31; p<0.041).Study-II: 21 primiparous women after a pregnancy affected by P-EC and 21 women with a previously unaffected pregnancy. Blood samples were obtained at 6-12 months postpartum. Significant differences were not observed for VEGF, PlGF, sFlt-1, sEng, TF or TFPI between two groups.Study-III: 66 women who had P-EC at interval years starting from 2007, and then from 2012 till 2016 and five as a control group. Findings revealed that the level of ANXA5 was reduced in P-EC cohort, and there was an increase in levels of annexin A2, particularly in late post-delivery pre-eclamptic women, although these changes were statistically insignificant. The lack of statistical significance may be due to the small number of control compare to P-EC group.Study-IV: 5 women aged-matched with five women with normal pregnancy, results show that inflammation, immune response, blood coagulation and metabolism are dysregulated processes one-year post-delivery in women with a history of pre-eclampsia.Study-Study-V: Next-Generation Sequencing (NGS) technique was used during the discovery stage to identify miRNAs differentially expressed in P-EC postpartum (n=30) in comparison to five healthy control, then quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay used for confirmation and validation. 14 miRNAs that were significantly differentially expressed at a significance level of 0.05 (FDR) in the discovery experiment. The plasma miR-103a-3p were significantly differentially expressed in the validating experiment, which was downregulated in entire pre-eclamptic women with FC= -1.3; BH-adj P-value =0.033.Conclusions: Results suggest the presence of elevated inflammatory cytokines and an imbalance of the haemostatic system in women with a past-history of P-EC, which may contribute to the known increased risk of cardiovascular disease later in life. The proteomics findings provide insight into the dysregulated cardiometabolic profile in the P-EC group. The miRNAs novel marker pave the way for the importance of miR-103a-3p in monitoring P-EC women in the future and could be a useful tool in predicting the development of cardiovascular disease in P-EC.

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ORCID for Bashir Lwaleed: orcid.org/0000-0001-5748-4892

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