CARDIOVASCULAR JOURNAL OF AFRICA • Volume 35, No 1, January – April 2024 54 AFRICA endothelial dysfunction.10,21 STBM particles contain vesicles ranging from 20 to 3 000 nm in size, which are secreted from the placenta into the maternal circulation.10,22 Exosomes are the main components of STBM. They are formed as part of the lysosomal pathway, contain myriad signalling molecules, growth factors, as well as miRNA and mRNA involved in immunity.10,23,24 Exosomes play a role in maintaining immune tolerance at the foeto– maternal interface and they regulate cell function, proliferation, metabolism and apoptosis.10,25,26 In addition, exosomes may cluster with matrix metalloprotease 14 (MMP14), resulting in increased release of soluble endoglin (sEng) from the placenta, the upregulation of which impairs normal vasculogenesis in PE.16,27 Ultimately, exosomes may contribute to endothelial dysfunction.27 Endothelial dysfunction in PE may be extrapolated to involve the maternal vasculature and cardiac function, and is postulated to predispose to cardiovascular disease. There is growing evidence to suggest that impairedplacentation may be the consequence of pre-existing cardiovascular disease and altered maternal haemodynamics, thereby inferring a duality in causality: pre-existing abnormal maternal vasculature can lead to poor placentation and clinical manifestations of PE.12 PE and cardiovascular disease There may be additional factors other than trophoblast invasion that determine normal transformation of uterine spiral arterioles.12,28 This is demonstrated in a case report that demonstrated a low uterine artery resistance index in an extra-uterine pregnancy (advanced abdominal pregnancy): indices found in a normal pregnancy despite lack of adequate trophoblastic invasion. Further evidence is described by Binder et al. (2018) in a study describing a longitudinal uterine Doppler assessment into the third trimester of pregnancy. It was discovered that one-third of patients, who were shown to have had normal indices previously, developed a high resistance artery Doppler in the third trimester. These patients had a 30%higher prevalence of PE.12,29 This finding of dynamic changes is counter-intuitive as it in essence implies reversal of initial spiral artery transformation. This therefore challenges the accepted hypothesis of impaired trophoblastic invasion being the key contributing factor in the maelstrom of abnormal vasculogenesis, and rather suggests a significant impact of inherent maternal cardiovascular function.12,30,31 Systematic reviews have found concordance in resistance artery indices of vessels of the systemic vasculature. Doppler assessment of radial and ophthalmic arteries has shown a corresponding decrease in resistance with progress in gestation as well as persistently high resistance in first-trimester pregnancies of patients at high risk for PE.12,32,33 This measured uniformity demonstrates a common origin of disease and supports the understanding that abnormal placentation can be a result of pre-existing systemic disease. In corroboration, a prospective study that assessed pre-pregnancy haemodynamics in 530 women found that patients who had developed PE had lower cardiac output and higher systemic vascular resistance indices before placentation.12,34 To investigate for evidence of pre-pregnancy cardiovascular dysfunction, Foo et al. (2018) conducted a longitudinal assessment of cardiovascular function in 356 spontaneously conceived pregnancies in healthy women before conception.34 It was noted that 15 (4.2%) women who developed PE had lower cardiac output and higher total peripheral resistance pre-conceptually compared to uncomplicated pregnancies.12,34 In a Scottish data-linkage cohort study, the risk of ischaemic heart disease was highest among women who had PE with an infant both preterm and small for gestational age.35,36 In Norway, among 3 225 women who underwent a metabolic screening of blood pressure, serum lipids and body mass index pre and post pregnancy, the association between PE and postpartum cardiovascular risk was partly related to pre-existing risk factors.35,37 These findings suggest that similar risk factors that predispose to placental vascular disease predispose to cardiovascular disease and its premature development.35,38 This provides further evidence that the relationship between PE and cardiovascular disease is complex and interrelated. It is a clinical problem where causality is bidirectional, multifactorial, dynamic with temporal evolution, and the clinical manifestations are perpetuated by this auto-amplification loop. PE and pathogenesis of cardiovascular disease Pregnancy represents a fluid clinical paradigm, which exquisitely maintains functionality at a new physiological equilibrium in order to support both foetal development and maternal health. In order to achieve this balance, natural changes to the cardiovascular system occur.39 Blood flow increases to accommodate an increase in metabolic demand.39,40 Blood volume increases about 45% above pre-pregnancy levels. Stoke volume, heart rate and end-diastolic volume increase, leading to an increase in cardiac output, which rises to about 50% above pre-pregnancy levels at approximately 16–20 weeks’ gestation.28,41,42 Systolic and diastolic blood pressures decrease in the first and second trimesters, however blood pressures rise in the third trimester, returning to baseline at the end of gestation.28,43 The heart undergoes physiological changes in order to adapt to alterations in fluid volume and cardiac preload.39,40 Physiological pregnancy-induced cardiac hypertrophy involves the proportional increase in cardiomyocyte size, resultant increase in LV wall thickness and normal myocardial capillary density.39,44 It is not associated with increased oxidative stress, metabolic dysfunction, fibrosis, apoptosis, myocardial fibre disarray or genomic foetal reprogramming characteristic of pathological hypertrophy.39,44 Importantly, the structural cardiac changes reverse postpartum.39,45 The underlying molecular mechanisms that determine the divergent phenotypic pathways require further elucidation. Animalmodels have demonstrated that pregnancy is associated with a decrease in cardiac glucose metabolism and increased utilisation of fatty acids, which contrasts with heart failure where there is a switch from myocardial fatty acid oxidation, glucose metabolism and oxidative phosphorylation.39,46-48 However, a decrease in cardiac fatty oxidation has been reported as well.39,49 Insulin signalling and mitochondrial bio-energenetics are preserved in pregnancy but are depressed in pathological hypertrophy and cardiac failure.39,46,50 Intracellular signalling and miRNA-omics determine the cardioprotective phenotype of pregnancy-induced hypertrophy. The pathways include the phosphoinositide-3-kinase/protein kinase B/glycogen synthase kinase 3-beta signalling, mitogen-activated protein kinase
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