Prospective study on biomarkers of endothelial dysfunction in hypertensive disorders of pregnancy

Abstract

Hypertension is the leading chronic cardiovascular disease (CVD) affecting 5.8 million Malaysians. The prevalence of hypertensive disorders of pregnancy (HDP) in Malaysia is approximately 23.3 per 1000 live births. HDP can cause both maternal and foetal morbidity and mortality. It is also an independent risk factor of CVD with endothelial dysfunction postulated as the main pathophysiology. Endothelin-1 (ET-1), a potent vasoconstrictor, has been identified as a pivotal mediator in HDP. Prolonged disturbances in nitric oxide (NO) bioavailability and imbalance of angiogenic factors such as soluble FMS like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) found in endothelial dysfunction may increase susceptibility to CVD and other major adverse cardiac events (MACEs). This study aims to determine serial ET-1, NO and other angiogenic factors in patients with HDP and its association in persistent endothelial dysfunction. Thirty-six pregnant women from the following categories (i) normal pregnant women (Control) (ii) chronic hypertension during pregnancy (CH) and (iii) gestational hypertension (GH) participated in this study. Blood pressure indices measurements and sample collection was done at antepartum (32 weeks) and postpartum (8 weeks and 12 weeks). ET-1 and serum NO was measured using the Human ET-1 (Endothelin-1) ELISA Kit and Nitric Oxide (total) detection kit respectively. sFlt-1, PlGF and VEGF were measured using commercially available kits. A competitive NO antagonist, asymmetric dimethylarginine (ADMA), was measured using high performance liquid chromatography (HPLC). Serum ET-1 was significantly higher in patients with CH (55.3 pg/ml) and GH (35.6 pg/ml) compared to control (11.8 pg/ml) during antenatal until 12 weeks postpartum (CH 38.3 pg/ml, GH 29.5 pg/ml, Control 1.9 pg/ml); accompanied by significantly high levels of sFlt-1 in HDP subjects. Conversely, subjects with CH and GH had lower levels of serum NO, PlGF and VEGF. Persistently higher levels of ET-1 and lower levels of NO up to 12 weeks postpartum in patients with history of HDP results in unmitigated vasoconstrictive effects of ET-1 despite BP normalisation in GH subjects. Long term NO/ET-1 imbalance and non-physiological levels of angiogenic factors in persistent endothelial dysfunction may account for the increased CVD risk.