Shani Botha

Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect?

Data from basic science experiments is overwhelmingly supportive of the causal role of immune‐inflammatory response(s) at the core of atherosclerosis, and therefore, the theoretical potential to manipulate the inflammatory response to prevent cardiovascular events. However, extrapolation to humans requires care and we still lack definitive evidence to show that interfering in immune‐inflammatory processes may safely lessen clinical atherosclerosis. In this review, we discuss key therapeutic targets in the treatment of vascular inflammation, placing basic research in a wider clinical perspective, as well as identifying outstanding questions.

Associations of suPAR with lifestyle and cardiometabolic risk factors

Soluble urokinase plasminogen activator receptor (suPAR), a novel indicator of low‐grade inflammation, is associated with cardiovascular disease and mortality in the general population, while an unhealthy lifestyle influences inflammatory status. We aimed to explore the relationship of suPAR with lifestyle and cardiometabolic risk factors in a black South African population.

The association of oxidative stress with arterial compliance and vascular resistance in a bi-ethnic population: the SABPA study.

Abstract A loss of arterial elasticity increases the risk for cardiovascular events. Oxidative injury to the vessel wall may be one of the underlying mechanisms influencing arterial elasticity. We compared markers of oxidative stress, antioxidant capacity, inflammation, windkessel compliance (Cwk), and total peripheral resistance (TPR) in black and white South Africans. Associations of arterial compliance and vascular resistance (as indicated by TPR) with oxidative stress, antioxidant capacity and inflammatory markers were also investigated. We included 146 black and 181 white men and women. Measurements from the Finometer device were used to calculate Cwk and TPR while thiobarbituric acids reactive substances (TBARS), glutathione peroxidase (GPx), C-reactive protein (CRP), and interleukin-6 (IL-6) were analyzed in serum or urine samples. Black participants had higher TPR, TBARS, GPx, CRP, and IL-6 levels (all p ≤ 0.018) and lower Cwk (both p ≤ 0.013) compared to white participants. Multiple regression analyses revealed independent associations of Cwk (β = −0.27, p = 0.015) and TPR (β = 0.18, p = 0.018) with TBARS in black participants, while Cwk (β = −0.10; p = 0.019) and TPR (β = 0.13, p = 0.047) were independently associated with GPx in white participants. Decreased arterial compliance and increased vascular resistance associated with increased oxidative damage independent of hypertensive status in black participants. These results suggest that oxidative stress plays a role in early vascular changes in a black population prone to the development of cardiovascular disease.

Recent advances in understanding hypertension development in sub-Saharan Africa

Consistent reports indicate that hypertension is a particularly common finding in black populations. Hypertension occurs at younger ages and is often more severe in terms of blood pressure levels and organ damage than in whites, resulting in a higher incidence of cardiovascular disease and mortality. This review provides an outline of recent advances in the pathophysiological understanding of blood pressure elevation and the consequences thereof in black populations in Africa. This is set against the backdrop of populations undergoing demanding and rapid demographic transition, where infection with the human immunodeficiency virus predominates, and where under and over-nutrition coexist. Collectively, recent findings from Africa illustrate an increased lifetime risk to hypertension from foetal life onwards. From young ages black populations display early endothelial dysfunction, increased vascular tone and reactivity, microvascular structural adaptions as well as increased aortic stiffness resulting in elevated central and brachial blood pressures during the day and night, when compared to whites. Together with knowledge on the contributions of sympathetic activation and abnormal renal sodium handling, these pathophysiological adaptations result in subclinical and clinical organ damage at younger ages. This overall enhanced understanding on the determinants of blood pressure elevation in blacks encourages (a) novel approaches to assess and manage hypertension in Africa better, (b) further scientific discovery to develop more effective prevention and treatment strategies and (c) policymakers and health advocates to collectively contribute in creating health-promoting environments in Africa.

Soluble urokinase plasminogen activator receptor and hypertension among black South Africans after 5 years

Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker that links inflammation with cardiovascular risk. However, studies linking suPAR and hypertension are scant. First, we determined whether baseline suPAR is elevated in normotensive black South Africans who developed hypertension over 5 years, compared with those who remained normotensive; and second, whether hypertension is associated with suPAR. This substudy is embedded in the South African leg of the Prospective Urban and Rural Epidemiology study, performed in the North West Province. We investigated 429 normotensive individuals, of which 191 developed hypertension and 238 remained normotensive over 5 years. We determined suPAR from plasma (ethylenediaminetetraacetic acid) samples with the suPARnostic ELISA Kit and blood pressure with an OMRON HEM-757 device. Despite similar mean baseline suPAR levels (P=0.43), suPAR increased more in the group that developed hypertension compared with those who remained normotensive (14.2% vs. 6.94%; P=0.007). Five-year percentage change in systolic blood pressure correlated positively (r=0.23; P=0.002) and associated independently with baseline suPAR (β=0.14; P=0.043), only in participants who developed hypertension. Participants were 1.41 times more likely (P=0.015) to develop hypertension with 1 s.d. increase in percentage change in suPAR levels over 5 years. Change in systolic blood pressure was associated with baseline suPAR in hypertensive participants and change in suPAR with hypertensive status. This study highlights the need for more research on the role of suPAR in hypertension and cardiovascular disease development in black South Africans.

Quantification of systemic renin-angiotensin system peptides of hypertensive black and white African men established from the RAS-Fingerprint®.

Objective: The objective of this study was to make use of a quantitative and qualitative approach comparing the systemic renin-angiotensin system (RAS) of hypertensive black and white African men by using RAS equilibrium analysis. Materials and methods: This sub-study involved 23 black (n = 15) and white (n = 8) hypertensive men aged 39.5–41 years, living in the North West Province of South Africa. The RAS-Fingerprinting was determined with LC-MS/MS quantification of angiotensin peptides. Blood pressure and other variables were determined with known methods. Results: The main finding of this study was the significant lower Ang I (<5.0 and 45.1 pg/ml; p = 0.005) and Ang II (15.6 and 123.9 pg/ml; p ⩽ 0.001) encountered in the hypertensive black African men compared to their white counterparts. Levels of Ang 1-5 (downstream metabolite of Ang 1-7) (1.8 and 3.0 pg/ml), were detected in black and white hypertensive men, respectively. Conclusions: The observed differences between circulating RAS components, which are reflected via equilibrium angiotensin levels, point to a distinctive molecular regulation of the RAAS in the two study cohorts. The increased peripheral resistance observed in hypertensive black individuals might take over a dominant role in control of blood pressure in this study population. A novel highly sensitive LC-MS/MS method resolved the issue of peptide recovery variations during sample preparation by using internal standards for each individual angiotensin metabolite.

Attenuated IGF-1 predicts all-cause and cardiovascular mortality in a Black population: a five-year prospective study

Background Inconsistent findings are reported on whether insulin-like growth factor-1 (IGF-1) is protective or harmful in predicting hypertension, carotid wall thickness and mortality. We determined the five-year prognostic value of IGF-1 for these outcomes in a large Black population prone to hypertension and cardiovascular disease. Design A longitudinal study as part of the PURE (Prospective Urban and Rural Epidemiology) study, North West Province, South Africa. Methods We measured IGF-1 and IGF binding protein-3 (IGFBP-3) in 1038 HIV-uninfected participants (age range 32–94 years) and assessed blood pressure, carotid intima-media thickness and mortality. Results Over five years 116 deaths occurred. Baseline IGF-1 was similar in survivors and non-survivors (p = 0.50), but tended to be higher in survivors upon adjustment for IGFBP-3 and covariates (p = 0.061). Normotensives and hypertensives (p = 0.072), and those with carotid intima-media thickness < 0.9 mm and ≥ 0.9 mm also displayed similar baseline IGF-1 (p = 0.55). Multivariable-adjusted Cox-regression indicated high IGF-1 predicting lower risk for all-cause mortality (hazard ratio 0.45; 0.23–0.88) and cardiovascular mortality (hazard ratio 0.26; 0.08–0.83) when also adjusting for IGFBP-3. When including normo- and hypertensives at baseline, high IGF-1 was related to normotension at follow-up (hazard ratio 0.68; 0.49–0.95). We found no association with carotid intima-media thickness (hazard ratio 0.59; 0.31–1.14). Conclusion In a Black South African population with low socio-economic status and harmful health behaviours, we found a protective independent association between IGF-1 and hypertension, cardiovascular and all-cause mortality, with no association with carotid wall thickness.

Effect of non‐surgical weight management on weight and glycaemic control in people with type 2 diabetes: a comparison of interventional and non‐interventional outcomes at 3 years

To examine the long‐term effectiveness of lifestyle weight management interventions, recommended in clinical guidelines for patients with type 2 diabetes mellitus (T2DM) and obesity.

1C.01: SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR AS A PROGNOSTIC MARKER OF ALL-CAUSE AND CARDIOVASCULAR MORTALITY IN A BLACK POPULATION.

Objective: Elevated inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are well-known risk factors for cardiovascular mortality. The less familiar marker, soluble urokinase plasminogen activator receptor (suPAR), is known to predict cancer, infections and all-cause mortality. We determined whether suPAR, CRP and IL-6 are predictive of both all-cause and cardiovascular mortality in a black population, highly burdened by cardiovascular disease and HIV infection. Design and method: We included 1 425 black South Africans, of which 208 died within five years after baseline data collection. EDTA plasma biomarker levels were determined, while all-cause and cardiovascular mortality were used as endpoints. Results: At baseline suPAR, CRP and IL-6 were higher in non-survivors than in survivors (P < 0.001). SuPAR (HR 1.27, 95% CI 1.09–1.48), IL-6 (HR 1.49, 95% CI 1.24–1.78) and CRP (HR 1.39, 95% CI 1.17–1.65) predicted all-cause mortality, while only suPAR (HR 1.40, 95% CI 1.04–1.87) and IL-6 (HR 1.61, 95% CI 1.10–2.35) predicted cardiovascular mortality. The prognostic value of suPAR was independent of IL-6 and CRP (P<=0.015). Figure. No caption available. Conclusions: SuPAR predicted both all-cause and cardiovascular mortality, independent of traditional risk factors, HIV and other inflammatory markers, underlining the prognostic value of suPAR in a black population.

Bioavailable IGF-1 is beneficially associated with biomarkers of endothelial function in young healthy adults: the African-PREDICT study

INTRODUCTION Low circulating levels of insulin-like growth factor-1 (IGF-1) are associated with endothelial dysfunction, subsequently leading to the development of cardiovascular disease. OBJECTIVE To better understand the early phases of vascular deterioration in a young, healthy population, we investigated, cross-sectionally, whether biomarkers of endothelial function (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand factor antigen (vWFag)) are associated with IGF-1 in a healthy study population forming part of the larger African Prospective study on the Early Detection and Identification of Cardiovascular diseases and Hypertension (African-PREDICT). METHOD We included 825 black and white men and women (aged 20-30 years) and determined IGF-1, IGF binding protein-3 (IGFBP-3), ICAM-1, VCAM-1 and vWFag from blood samples. We also measured 24-h blood pressure and health behaviours namely waist circumference, accelerometery, cotinine and gamma glutamyl transferase. We used the IGF-1/IGFBP-3 M ratio as an estimate of bioavailable IGF-1. RESULTS In multivariable-adjusted regression analyses performed in the total group, VCAM-1 associated positively with IGFBP-3 (β = 0.21; p < .001) and negatively with IGF-1/IGFBP-3 (β = -0.18; p < .001). ICAM-1 showed a borderline negative association with IGF-1 (β = -0.09; p = .054) and IGF-1/IGFBP-3 (β = -0.08; p = .057). vWFag was not associated with IGF-1, IGFBP-3 or bioavailable IGF-1. CONCLUSION VCAM-1 is beneficially associated with IGF-1 in a young healthy cohort, independent of sex, ethnicity, blood pressure and health behaviours - thereby confirming the potential importance of bioavailable IGF-1 in early vascular endothelial protection.