Objective Explore the nature of postnatal cardiovascular morbidity following pregnancies complicated by preterm pre-eclampsia and identify associations between pregnancy characteristics and postnatal cardiovascular function. Design Observational sub-study of a single-centre feasibility randomised double-blind placebo-controlled trial. Setting Tertiary maternity hospital, UK. Population Women with preterm pre-eclampsia, delivering <37 weeks. Methods Eligible women underwent echocardiography, arteriography and blood pressure monitoring <3 days, 6 weeks and 6 months postpartum. Correlations between pregnancy and cardiovascular characteristics were assessed using Spearman’s correlation. Main Outcome Measure Prevalence of cardiovascular dysfunction and remodelling 6 months following preterm pre-eclampsia. Results Forty-four women completed the study. At 6 months, 27 (61%) had diastolic dysfunction, 33 (75%) had raised total vascular resistance (TVR) and 18 (41%) had left ventricular remodelling. Sixteen (46%) women had de novo hypertension by 6 months and only 2 (5%) women had a completely normal echocardiogram. Echocardiography did not change significantly from 6 weeks to 6 months. Earlier gestation at delivery and lower birthweight centile were associated with worse 6-month diastolic dysfunction (E/E’: rho=-0.39, p=0.001 & rho=-0.42, p=0.005) and TVR (rho=-0.34, p=0.02 & rho=-0.37, p=0.01). Conclusions Preterm pre-eclampsia is associated with persistent cardiovascular morbidity 6 months postpartum in the majority of women. These cardiovascular changes have significant implications to long-term cardiovascular health. The graded severity of diastolic dysfunction and TVR with worsening pre-eclampsia phenotype suggests a dose-effect. However, the mechanistic link remains uncertain. Funding Medical Research Council (MR/R001693/1). Registration https://www.clinicaltrials.gov; NCT03466333. Key words Pre-eclampsia: clinical research; radiological imaging: ultrasound; medical disorders in pregnancy.

Background and Purpose: We investigate mechanisms for potential pro-arrhythmic effects of hydroxychloroquine (HCQ) alone, or combined with azithromycin (AZM), in Covid-19 management supplementing the limited available experimental cardiac safety data. Experimental Approach: We integrated patch-clamp studies utilizing In Vitro ProArrhythmia Assay Schema IC50 paradigms, molecular modelling, cardiac multi-electrode array and voltage (RH237) mapping, ECG studies, and Ca2+ (Rhod-2 AM) mapping in isolated Langendorff-perfused guinea-pig hearts with human in-silico ion current modelling. Key Results: HCQ blocked IKr and IK1 with IC50s (10±0.6 and 34±5.0 µM) within clinical therapeutic ranges, INa and ICaL at higher IC50s, leaving Ito and IKs unaffected. AZM produced minor inhibition of INa, ICaL, IKs, and IKr,, sparing IK1 and Ito. HCQ+AZM combined inhibited IKr and IK1 with IC50s of 7.7±0.8 µM and 30.4±3.0 µM, sparing INa, ICaL and Ito. Molecular modelling confirmed potential HCQ binding to hERG. HCQ slowed heart rate and ventricular conduction. It prolonged PR, QRS and QT intervals, and caused prolonged, more heterogeneous, action potential durations and intracellular Ca2+ transients. These effects were accentuated with combined HCQ+AZM treatment, which then elicited electrical alternans, re-entrant circuits and wave break. Modelling studies attributed these to integrated HCQ and AZM actions reducing IKr and IK1, thence altering cell Ca2+ homeostasis. Conclusion and implications: Combined HCQ+AZM treatment exerts pro-arrhythmic ventricular events by synergetically inhibiting IKr, IKs with resulting effects on cellular Ca2+ signalling, and action potential propagation and duration. These findings provide an electrophysiological basis for recent FDA cardiac safety guidelines cautioning against combining HCQ/AZM when treating Covid-19.