CARDIOVASCULAR JOURNAL OF AFRICA • Volume 35, No 1, January – April 2024 56 AFRICA angiogenesis following MI in miR-126-deficient mice.39,83 In addition, through upregulation of vascular endothelial growth factor (VEGF) and superoxide dismutase (SOD) expression through the PI3K/Akt pathway, it protects microvasculature against hypoxia and re-oxygenation injury.39,84 MiR-204 plays a role in regulation of autophagy. It may target cardiomyocyte microtubule-associated protein 1 light chain 3 (LC3-II) necessary for autophagosome formation in cardiac ischaemia–reperfusion injury in rats.39,85 MiR-15b was shown to inhibit several steps of the TGF-β pathway in cardiomyocytes, including p38 MAPK and TGF-β receptor 1 (TGF-βR-1), with antagonism promoting cardiomyocyte hypertrophy and fibrosis in pressure-overloaded mice.39,86 Novel markers have provided further insight into the cardiac pathophysiology of PE. Cardiovascular biomarkers such as atrial natriuretic peptide-converting enzyme, known as corin, and transcription factor storkhead box 1 (STOX 1) have been shown to be increased in PE.39,87 Corin is a serine protease of the trypsin superfamily, identified as an enzyme expressed mainly in the atrial and ventricular myocardium.88,89 The enzyme converts atrial natriuretic peptide (ANP) precursor (pro-ANP) to mature ANP. ANP regulates natriuresis, diuresis and vascular tone, and inhibits the neurohormonal axis of the RAAS system.88,90 Attenuated corin and ANP production have been shown to influence vascular and renal homeostasis. Recent animal studies demonstrated that Corin is able to activate ANP, allow for spiral artery remodelling in the pregnant uterus and prevent pregnancy-induced hypertension.87,88 Studies involving transgenic mouse models of corin and STOX1 have highlighted their role in cardiovascular complications related to PE.39,91 Corindeficient mice or aberrant expression of corin developed cardiac hypertrophy, which did not resolve postpartum.39,92 Recent studies have shown that maternal corin levels are higher in PE.88,93 The source of increased corin levels in PE has yet to be investigated. The heart is the main source of corin, however, the placenta may secrete the enzyme into the maternal circulation as well; the expression of corin was found in synctiotrophoblasts.88,94,95 Increased expression of A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), the main corin-shedding enzyme, was increased in synctiotrophoblasts in PE.88,96 The natriuretic peptide family has three types of transmembrane receptors: NPR-A, NPR-B and NPR-C that modulate activity of ANP. NPR-A and -B receptors are guanylyl cyclase receptors that convert GTP (guanylyl triphosphate) to cGMP (guanylyl monophosphate), which stimulates protein kinase G, leading to vasodilation. NPR-C is a non-guanylyl cyclase receptor and through inhibition of guanine nucleotide regulatory protein (Gi), it is coupled to adenylyl cyclase inhibition or phospholipase C activation.88,97 NPR-C clears circulating ANP and is the most prolifically expressed ANP receptor found in various tissues.88,98 NPR-C therefore likely influences cellular proliferation, migration and vascular remodelling.88,99 In the study by Gu et al. (2018), it was discovered that maternal pro ANP levels were also increased in patients who presented with severe PE.88 In addition, their results showed that NPR-A expression was decreased and NPR-C expression increased in maternal vascular endothelium in PE compared to normotensive controls.88 The mechanism describing the altered expression of ANP receptors remains to be elucidated, however as NPR-C is a clearance receptor for ANP, it can be extrapolated that increased NPR-C expression leads to increased clearance or degradation of circulating ANP and abnormal cardiovascular haemodynamics in PE. The study by Gu et al. (2018) found that corin levels were increased in PE. It remains to be investigated if the increased levels are a compensatory mechanism for systemic vasoconstriction in PE, or if corin gene mutations, noted in cases of PE, decreased enzymatic activity necessary for the processing of pro ANP.87,88,100 Interestingly, in the study, it was also noted that pro ANP, but not corin levels were increased in pregnancies complicated with chronic hypertension, in contrast to pregnancies complicated by PE.77 Although the sample size was small and further studies are needed to investigate the relationship between corin and cardiovascular disease, the difference in corin expression highlights the divergent pathophysiological mechanisms that underlie chronic hypertension and PE.77 Even though corin activity was not measured in the study, the aberrant expression of ANP receptors and an alteration in the downstream signalling provide evidence for the contribution of the pro ANP, corin, NPR-C axis to cardiovascular dysfunction in PE.77 As the source of corin may be both placenta and heart, the study further underscores the duality of disease: PE is likely a manifestation of a complex interplay between maternal cardiovascular function and placenta-mediated factors. Echocardiographic parameters in PE Several maternal echocardiographic studies conducted at the clinical onset of PE have shown abnormal structural cardiac changes and diastolic dysfunction.12,101,102 A study by Bhorat et al. (2016) showed that left ventricular hypertrophy is a frequent finding in patients presenting with severe PE, the prevalence increasing from 63% in patients without pulmonary oedema to 75% in patients with pulmonary oedema and preserved systolic function, in contrast to 6% in controls.58,103 The study used tissue Doppler imaging to assess haemodynamic changes in PE, using the ratio of the early transmitral flow velocity (Em) to the early tissue velocity at the mitral annulus (Ea) as an index of left ventricular filling. It was found that tissue Doppler Em and Ea were elevated in PE compared to controls.58,104 This reflected earlier studies where it was shown that PE was associatedwith diastolic dysfunction, left ventricular hypertrophy, increased left ventricular end-systolic and end-diastolic volumes, reduced cardiac output and increased filling pressures.58,105 A study by Dennis et al. in 2015 demonstrated that in patients with severe but stable PE, echocardiograms showed preserved systolic function and non-dilated ventricles, with evidence of diastolic dysfunction.106 HIV, angiogenesis and PE The HIV infection is characterised by systemic inflammation, endothelial injury, thrombosis and atherosclerosis. Immune dysregulation and abnormal angiogenesis could link the pathophysiology between PE and HIV infection. In pregnant HIV-positive patients, there is an increase in events such as miscarriages, PE, diabetes and preterm labour.1 However, various studies highlight the paradoxical and unpredictable
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