CARDIOVASCULAR JOURNAL OF AFRICA • Volume 35, No 1, January – April 2024 AFRICA 53 Heart failure is pervasive globally and is associated with a high mortality rate; it is estimated that 37.7 million globally are afflicted by the condition.7 There is a paucity of published data describing the epidemiology of heart failure in SA.7 Almost all studies are hospital based. The largest recent study of confirmed cases of heart failure in SA, the Heart of Soweto study (n = 4 162), included 1 593 newly diagnosed and 2 569 previously diagnosed cases who attended the cardiology unit at a tertiary hospital in Soweto, SA. It was noted that 59% of those affected were women, with females being slightly younger than males (mean age 53 vs 55 years, respectively); 25% of those studied were less than 40 years old and 85% were of African ancestry.7 Heart failure Heart failure is defined as three subtypes: heart failure with preserved ejection fraction (HFpEF: left ventricular ejection fraction of ≥ 50%), heart failure with reduced ejection (HFrEF: left ventricular ejection fraction ≤ 40%) and heart failure with mid-range ejection fraction (HFmrEF: left ventricular ejection fraction 40–49%).7 Pathophysiology of heart failure Heart failure is the clinical end-point of cardiac maladaptation; the structural and functional abnormalities leading either to HFrEF: decreased left ventricular (LV) contractility and LV dilation; or HFpEF: impaired myocardial relaxation and decreasedLVcompliance.However, even though ejection function is normal in HFpEF, contractility is abnormal: longitudinal fibre contractility is impaired as well as abnormal contractile reserve.8 Neuro-hormonal factors and altered fluid balance results in LV modelling, macroscopically seen as a change in LV geometry, volume and mass. In HFrEF, activation of the renin– angiotensin–aldosterone system (RAAS), increased sympathetic innervation and systemic vasoconstriction, lead to cellular and molecular aberrations within the myocardium. Microscopically, there is slippage and increased apoptosis of cardiac myocytes, disruption of ion channels, downregulation of receptors, altered cardiac metabolism and calcium homeostasis, electromechanical uncoupling, ischaemia, increased extracellular matrix deposition and myocardial fibrosis. The aetiology of HFpEF is heterogeneous and characterised by a pro-inflammatory phenotype, endothelial dysfunction, microvascular ischaemia and interstitial fibrosis. Studies have illustrated the role of macrophages in promotion and resolution of inflammation within the myocardium.7,8 Echocardiographic parameters and biomarkers Both PE and HIV affect the cardiovascular system and manifest as systolic or diastolic dysfunction. Echocardiographically, patients who present with HFrEF have LVEF < 40%. In HFmrEF, patients have a LVEF of 40–49% and at least one additional criterion on echo: relevant structural heart disease [left ventricular hypertrophy (LVH) and/or left atrial enlargement (LAE)] or diastolic dysfunction. Patients with HFpEF have a LVEF > 50% as well as structural cardiac changes, as mentioned above, or diastolic dysfunction. In the latter case, these patients have elevated levels of natriuretic peptide (NT-proBNP > 125 pg/ml or BNP > 35 pg/ml).7 Definition of PE PE is defined as new-onset, repeatedly high blood pressure levels (systolic ≥ 140 mmHg and/or diastolic ≥ 90 mmHg) accompanied by proteinuria or evidence of organ dysfunction occurring after 20 weeks of gestation with involvement of one or more organ systems.9 Proteinuria is not mandatory for the diagnosis of PE. Severe PE is defined as systolic blood pressure ≥ 160 mmHg and diastolic pressure ≥ 100 mmHg. PE is divided into early- and late-onset types, early onset presenting prior to 33 weeks plus five days and late onset occurring after 34 weeks and zero days. The early-onset type is much more likely to have underlying cardiac dysfunction. Pathogenesis of PE The pathophysiology of PE is hypothesised to be a two-stage disease process that is placenta mediated. The first stage is hypothesised to involve impaired trophoblastic invasion of the uterine spiral arterioles and abnormal vascular remodelling.10,11 These changes are measured objectively in early pregnancy as persistence of high resistance in uterine artery Doppler indices.12,13 The abnormal vascular transformation results in the second stage: a hypoxic, inflammatory milieu that leads to an imbalance of pro- and anti-angiogenic factors and subsequent endothelial dysfunction: increased generation of reactive oxygen species (ROS), apoptosis, microvascular rarefaction, molecular alterations in gene expression that influence cellular interactions and cell migration.10,12,14 The exact aetiology of PE is an area of ongoing research, however, angiogenic, cell-free foetal DNA, vasoactive mediators, immunological synapses as well as synctiotrophoblast microparticles play a role in the pathogenesis of the disease.10,15 The anti-angiogenic factors involved in the pathogenesis of PE include soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin. Soluble Flt1 is a spliced variant of the vascular endothelial growth factor receptor 1 and lacks the cytoplasmic binding domains of membrane-bound Flt1 and antagonises the effects of vascular endothelial growth factor and placental growth factor, thereby inhibiting normal angiogenesis.16,17 Maynard showed in 2003 that sFlt1 levels were substantially higher in patients with established PE, and the decline in levels following delivery correlated with improvement in clinical symptoms.18 A study by Govender et al. (2013) noted that syncytial knots of the synctiotrophoblast contain large amounts of sFlt1. Syncytial knots separate from placental villi through fission, leading to multinucleated syncytial aggregates loaded with sFlt1 and able to synthesise additional sFlt1 from intrinsic mRNA.16 Endoglin is a co-receptor for the transformation growth receptor family (TGF), which influences vascular transformation. Transformation growth factor stimulation activates the nitric oxide synthase pathway and induces cellular proliferation, migration and vascular remodelling.16,17 However, soluble endoglin, a truncated variant of endoglin, antagonises the binding of TGF beta (TGF-β), preventing the downstream vasodilatory effect.16,19 The interaction between the immune system and angiogenic factors is significant in PE. Toll-like receptor 9 (TLR9) inhibits angiogenesis and stimulates tumour necrosis factor alpha (TNF-α) expression, which increases the release of sFlt1.16,20 Recent studies have elucidated the role of synctiotrophoblast microparticles (STBM) as factors in the pathogenesis of PE: immune regulation, angiogenesis, hypercoagulability and
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