The African Prospective study on the Early Detection and Identification of Cardiovascular disease and Hypertension (African-PREDICT): Design, recruitment and initial examination.

BACKGROUND: Globally hypertension is stabilising, but in sub-Saharan Africa the incidence of hypertension remains on an increase. Although this might be attributed to poor healthcare and ineffective antihypertensive treatment, there is a limited understanding of population and individual-specific cardiovascular pathophysiology - necessary for effective prevention and treatment strategies in Africa. As there is a lack of longitudinal studies tracking the early pathophysiological development of hypertension in black populations, the African-PREDICT study was initiated. The purpose of this paper is to describe the detailed methodology and baseline cohort profile of the study. METHODS AND RESULTS: From 2013 to 2017, the study included 1202 black ( N = 606) and white ( N = 596) men and women (aged 20-30 years) from South Africa - screened to be healthy and clinic normotensive. At baseline, and each 5-year follow-up examination, detailed measures of health behaviours, cardiovascular profile and organ damage are taken. Also, comprehensive biological sampling for the 'omics' and biomarkers is performed. Overall, the baseline black and white cohort presented with similar ages, clinic and 24-hour blood pressures, but black adults had lower socioeconomic status and higher central systolic blood pressure than white individuals. CONCLUSIONS: The prospective African-PREDICT study in young black and white adults will contribute to a clear understanding of early cardiovascular disease development.

Iron loading, alcohol and mortality: A prospective study.

BACKGROUND & AIMS: The relationship between total body iron and cardiovascular disease remains controversial and information absent in black sub-Saharan Africans in whom alcohol consumption tends to be high. The level of total body iron is tightly regulated, however this regulation is compromised by high alcohol intake causing iron loading. The aim of this study is to investigate total body iron, as represented by serum ferritin, and its interaction with measures of alcohol intake in predicting all-cause and cardiovascular mortality. METHODS: We followed health outcomes for a median of 9.22 years in 877 randomly selected HIV negative African women (mean age: 50.4 years). RESULTS: One hundred and five deaths occurred of which 40 were cardiovascular related. Ferritin averaged 84.0 (5th to 95th percentile interval, 7.5-533.3) ng/ml and due to the augmenting effect of inflammation, lowered to 75.3 (6.9-523.2) ng/ml after excluding 271 participants with high-sensitivity C-reactive protein (CRP) levels (above 8 mg/l). CRP increased by quartiles of ferritin in the total group (P trend = 0.002), but this relationship was absent after excluding the 271 participants with high CRP values (P trend = 0.10). Ferritin, gamma-glutamyl transferase and carbohydrate deficient transferrin (all P < 0.0001) were higher in drinkers compared to non-drinkers, but CRP was similar (P = 0.77). In multivariable-adjusted analyses, ferritin predicted both all-cause (hazard ratio, 2.08; 95% confidence interval, 1.62-2.68; P < 0.0001) and cardiovascular (1.94; 1.29-2.92; P = 0.002) mortality. In participants with CRP levels below or equal to 8 mg/l, the significant relationship remained between ferritin and all-cause (2.51; 1.81-3.49; P < 0.0001) and cardiovascular mortality (2.34; 1.45-3.76; P = 0.0005). In fully adjusted models, interactions existed between ferritin and gamma-glutamyl transferase, self-reported alcohol use and carbohydrate deficient transferrin in predicting all-cause (P ≤ 0.012) and cardiovascular mortality (P ≤ 0.003). CONCLUSIONS: Iron loading in African women predicted all-cause and cardiovascular mortality and the intake of alcohol seems mechanistically implicated.

Assessing tobacco use in an African population: Serum and urine cotinine cut-offs from South Africa.

BACKGROUND: Cotinine, a nicotine metabolite, is used to measure tobacco use and exposure, but recommended cut-offs to differentiate tobacco users from those exposed through the environment range from 3 to 58 ng/ml in serum, and 2.5 to 550 ng/ml in urine. Cut-offs may differ by ethnicity, sex and age. As data from adults in Africa are scarce, our aim was to evaluate cut-offs for serum and urine cotinine that best predict self-reported tobacco use in South African adults. METHODS: Two datasets were explored: African-PREDICT (n = 941 black and white healthy young adults, 20-30 years, serum cotinine); and WHO SAGE Wave 2 (n = 604 adults, 18-102 years, urine cotinine). Population specific cut-offs (ROC analyses) were compared with published cut-offs and self-reported tobacco use. RESULTS: Overall, 19% (293 of 1545) reported current tobacco use. The following cotinine cut-offs showed the highest sensitivity and specificity: serum ≥15 ng/ml in black and white men, and white women; serum ≥10 ng/ml in black women; urine ≥300 ng/ml for black, mixed ancestry, and older adults (50-plus years); urine ≥500 ng/ml for younger adults (18-49 years). Specificity was lower for urine than for serum cotinine. CONCLUSION: Our study suggests that a serum cotinine level of ≥15 ng/ml and a urine cotinine level of ≥300 ng/ml best distinguish current tobacco users from non-users generally in the South African adult 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 (ß = 0.21; p < .001) and negatively with IGF-1/IGFBP-3 (ß = -0.18; p < .001). ICAM-1 showed a borderline negative association with IGF-1 (ß = -0.09; p = .054) and IGF-1/IGFBP-3 (ß = -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.

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.

AIMS: 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. MATERIALS AND METHODS: Electronic health records were used to follow 23 208 patients with T2DM and obesity in Glasgow, UK, for up to 3 years between 2005 and 2014. Patients were stratified by referral to and attendance at a lifestyle weight management intervention, and by attainment of a target weight loss of ≥5 kg over 7 to 9 sessions ("successful completers"). Outcomes were change in weight, glycated haemoglobin (HbA1c) and diabetes medications. RESULTS: A total of 3471 potentially eligible patients were referred to the service, and fewer than half of these attended (n = 1537). Of those who attended 7 to 9 sessions, >40% successfully completed and achieved 5-kg weight loss (334/808). Successful completers maintained greater weight loss (change at 3 years -8.03 kg; 95% confidence interval [CI] -9.44 to -6.62) than the non-completers (-3.26 kg; 95% CI -4.01 to -2.51; P < .001) and those not referred to the service (-1.00 kg; 95% CI -1.15 to -0.85; P < .001). Successful completers were the only patient group who did not increase their use of diabetes medication and insulin over 3 years. In adjusted models, successful completers had a clinically significant reduction in HbA1c (-3.7 mmol/mol; 95% CI -5.82 to -1.51) after 3 years; P ≤ .001) compared with non-completers and unsuccessful completers. CONCLUSIONS: A real-life structured weight management intervention in patients with diabetes can reduce weight in the medium term, result in improved glycaemic control with fewer medications, and may be more effective than pharmacological alternatives. Challenges include getting a higher proportion of patients referred to and engaged with interventions.

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. LINKED ARTICLES: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

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.

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

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 (ß = -0.27, p = 0.015) and TPR (ß = 0.18, p = 0.018) with TBARS in black participants, while Cwk (ß = -0.10; p = 0.019) and TPR (ß = 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.

Soluble urokinase plasminogen activator receptor as a prognostic marker of all-cause and cardiovascular mortality in a black population.

BACKGROUND: 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. METHODS: We included 1425 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). CONCLUSION: 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.

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 (ß=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.

Cornell product relates to albuminuria in hypertensive black adults independently of blood pressure: the SABPA study.

Evidence of the relationship between left ventricular hypertrophy and urinary albumin excretion is contradictory and limited in black adults in whom hypertensive heart disease is common. We aimed to investigate the relationship between subclinical left ventricular hypertrophy and albuminuria in non-diabetic hypertensive blacks. Urinary albumin-to-creatinine ratio (UACR) was determined from 8-hour overnight urine collection. We recorded ambulatory blood pressure and 12-lead electrocardiogram during a typical working day. Cornell product (P = .002), UACR (P = .042), 24-hour systolic pressure (P < .0001), and 24-hour pulse pressure (P < .0001) were higher in the hypertensive group. Cornell product was associated with UACR in single (r = 0.25; P = .012), partial (P trend = .002), and multiple regression (ß = 0.326; P = .0005) analyses in the hypertensive group only, even below the threshold for microalbuminuria and independent of 24-hour systolic pressure. Urinary albumin excretion is associated with subclinical left ventricular hypertrophy in non-diabetic hypertensive blacks and may be a useful marker of early cardiovascular disease in blacks.

Associations of suPAR with lifestyle and cardiometabolic risk factors.

BACKGROUND: 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. DESIGN: This cross-sectional study includes 1068 men and women (56·4 ± 10·1 years) from the North West province who took part in the South African leg of the Prospective Urban and Rural Epidemiology (PURE) study in 2010. Captured data included a detailed lifestyle profile (tobacco use, alcohol consumption, physical activity, psychological and dietary intake status), biochemical analyses (suPAR, C-reactive protein (CRP), glucose and lipids), as well as cardiovascular and anthropometric measurements. RESULTS: In exploratory analyses, we observed positive relationships between suPAR and lifestyle factors, such as tobacco use (P-trend < 0·001), both alcohol consumption (P-trend = 0·001) and γ-glutamyl transferase (GGT) (P-trend < 0·001) and unemployment (P-trend = 0·002). suPAR and CRP correlated significantly (r = 0·23; P < 0·001). These relationships were confirmed in multiple regression analyses as suPAR independently associated with tobacco use (ß = 0·13; P < 0·001), GGT (ß = 0·24; P < 0·001) and unemployment (ß = 0·07; P = 0·039). suPAR did not associate with the cardiometabolic factors glucose, lipids, blood pressure or measures of adiposity. CONCLUSION: suPAR was independently associated with unhealthy lifestyle behaviours, but not with cardiometabolic risk factors suggesting that suPAR, as known predictor of cardiovascular disease and mortality, is augmented by modifiable cardiovascular risk factors. These findings emphasise the need for a healthy lifestyle to decrease the burden of cardiovascular disease in Africans.

Cardiometabolic changes in treated versus never treated HIV-infected black South Africans: the PURE study.

BACKGROUND: The use of antiretroviral treatment is known to be accompanied by several negative health outcomes and may negatively affect a country such as South Africa, which is the most burdened by the human immunodeficiency virus (HIV) in the world. We aimed to determine whether receiving antiretroviral treatment changes the cardiometabolic profile of HIV-infected South Africans. METHODS: In this sub-study, embedded in the Prospective Urban and Rural Epidemiology (PURE) study, we compared the cardiometabolic profile in a cohort of 66 treated and 71 never treated HIV-infected participants from the North-West province, South Africa. By using standard techniques, these participants' cardiometabolic, biochemical and lifestyle variables were assessed in 2005 and 2010, respectively. RESULTS: The treated group showed a higher percentage change in pulse pressure (13.3%; p = 0.004), systolic blood pressure (4.5%; p = 0.029) and CD4 cell count (9.2%; p = 0.009) levels over five years. During follow-up (2010), lipid variables were worse in the treated group. Further, antiretroviral treatment was associated with the percentage change in pulse pressure (R(2) = 0.24; ß = 0.19; p = 0.020). CONCLUSIONS: We concluded that Africans receiving antiretroviral treatment had a greater increase in pulse pressure and systolic blood pressure, as well as an unfavourable lipid profile when compared to never treated participants. Whether, in the long term, antiretroviral treatment will lead to increased arterial stiffness and/or accelerated atherosclerosis among this HIV-infected African population remains to be seen.