CARDIOVASCULAR JOURNAL OF AFRICA • Volume 35, No 1, January – April 2024 58 AFRICA in concurrent cases of PE and HIV infection and concomitant initiation of ARVs.1 Pregnancy is usually associated with an upregulation of regulatory T cells (Treg) to maintain peripheral tolerance and promote normal placentation, however a downregulation of Treg cells was reported in PE.132,133 HIV infection is associated with an increase of Treg cells, however, with administration of ARVs, there was a decrease in Treg cells to levels similar to that of HIV-negative individuals.134,135 However, further studies are needed to investigate the Treg cell modulation in cases of concomitant HIV infection and PE. HIV and cardiovascular disease HIV has been clearly shown to be associated with cardiovascular disease. The correlation is determined by myriad molecular pathways and synergistic pathophysiological mechanisms involving an interaction between HIV itself, opportunistic infections and drug therapy, which lead to both systolic and diastolic dysfunction.7 Epidemiology Erqou et al. (2019) performed a systematic review and metaanalysis of cardiac dysfunction in persons with HIV (PHIV) and selected 54 studies done in various regions between the years 1988 and 2017.136,137 They analysed data from 125 382 PHIV, 82% men, and calculated a heart failure prevalence of 6.5%. This value was high considering the relatively low average age of the cohort (47 years). Among those studied, only 77% were on ARVs, and the majority were ARV naïve and had uncontrolled infection.136,137 Multiple studies across various regions demonstrate that heart failure outcomes are worse among PHIV versus non-HIVinfected individuals.136 Analysis of data from the predominantly male US Veterans Cohort suggests that among PHIV with heart failure, five-year mortality rates approached 50%.136,137 Through the Sub-Saharan Africa Survey of Heart Failure (THESUS HF) study, Sliwa et al. (2013) confirmed worse outcomes among PHIV with heart failure.136,138,139 The prospective multi-centre study recruited 1 006 people with acute heart failure (51% women) from nine countries in sub-Saharan Africa between 2007 and 2010. Within this cohort, the prevalence of hypertension was 56% while HIV prevalence was 7%. Sliwa et al. demonstrated that in this group, HIV status was associated with an increased risk of mortality and 60-day hospital re-admission.138-140 Pathogenesis HIV infection can cause a cardiomyopathy through various mechanisms: direct myocardial infiltration by HIV itself as well as infiltration and inflammation caused by opportunistic infections; immune dysregulation and an auto-immune response within the myocardium; HIV-related vasculopathy; and metabolic dysregulation secondary to HIV itself or the initiation of ARVs.136 HIVinfluences themetabolismthrough immunedysregulation, neurohormonal mechanisms and hormonal perturbations, leading to relative growth hormone deficiency.136,141-143 Early ARVs were associated with overt lipodystrophy, however even though newer regimens are better tolerated, ARVs can be associated with weight gain, excess adiposity, ectopic fat deposition and endothelial dysfunction.140,144,145 Inflammation and altered metabolomics lead to myocardial fibrosis and steatosis, respectively, resulting in diastolic dysfunction. Even though ARVs can mitigate the inflammatory response partially, inflammation persists and contributes to cardiovascular disease.146,147 Low-level viral replication, co-infection andmicrobial translocation create a pro-inflammatory state. Myocardial steatosis may lead to inflammation within the myocardial structural space. Inflammation leads to the generation of ROS, endothelial dysfunction, microvascular rarefaction, ischaemia and fibrosis (Harrison’s). In addition, traditional cardiovascular risk factors play a role and may have a synergistic effect with HIV-activated mechanisms.136 HIV has also been associated with an increase in circulating microparticles, which lead to endothelial dysfunction and have been shown to stimulate a pro-atherogenic phenotype.148,149 Microparticles are small (100–1 000 nm) membrane vesicles that are released by various cell types as a response to multiple stimuli that lead to cell activation, apoptosis.148,150 Circulating concentrations of endothelial-, platelet-, monocyte- and leucocyte-derived microparticles were found to be elevated in HIV-positive men treated with ARVs. These microparticles induced inflammation, oxidative stress, senescence and apoptotic susceptibility compared to microparticles obtained from HIV-negative men.148 Recently, a North American study focused on women with HIV (WHIV) and demonstrated diffuse myocardial fibrosis related to systemic inflammation as well as myocardial steatosis secondary to metabolic dysregulation.136,151 In this study, WHIV showed increased myocardial fibrosis [confirmed by magnetic resonance imaging (MRI)], and diastolic dysfunction, measured by the circumferential diastolic strain rate on MRI.136,151 In addition, novel immune markers of HIV-associated myocardial fibrosis have been identified. Increased levels of the monocyte activation marker sCD163 have been shown to correlate with myocardial fibrosis, and increased expression of the cell surface receptor CCR2 on inflammatory monocytes (CD14+ and CD16+) was found to correlate with both myocardial fibrosis and diastolic dysfunction.140,151 The CCR2 receptor promotes transmigration into target tissues among PHIV.140,152 This suggests that in WHIV, activated CD14+ and CD16+ monocytes transmigrate to the myocardium and stimulate fibrosis through the inflammatory response. Within the same cohort, Toribio et al. (2019) revealed that WHIV showed marked myocardial steatosis with a threefold increase in intramyocardial lipid content.136,140 Echocardiographic parameters and imaging modalities of cardiac function in HIV In the meta-analysis by Erqou et al. (2019) of cardiac dysfunction involving multiple studies at different locations and different times, there was found to be a lower prevalence of systolic dysfunction among PHIV in locations with increased accessibility to ARVs.137 It was found that the overall prevalence of left ventricular systolic dysfunction (EF < 50% or fractional shortening < 26%) was 12.3%.137,140 This meta-analysis suggests the population prevalence of diastolic dysfunction among PHIV was 29.3%.137,140
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