Metabolomic Insights on Potassium Excretion, Blood Pressure, and Glucose Homeostasis: The African-PREDICT Study.

BACKGROUND: Low-potassium intake is associated with a higher risk of type 2 diabetes and hypertension. Both conditions occur more frequently in Black populations, who also consume less potassium-rich foods. OBJECTIVES: Using metabolomics to identify dysregulated metabolic pathways associated with low-potassium excretion may procure more accurate entry points for nutritional prevention and intervention for type 2 diabetes and hypertension. METHODS: A total of 440 White and 350 Black adults from the African-PREDICT study (aged 20-30 y) were included. Twenty-four-hour blood pressure (BP) was measured. Potassium, sodium, and fasting glucose concentrations were analyzed in 24-h urine and plasma samples. Liquid chromatography-tandem mass spectrometry-based metabolomics included the analyses of amino acids and acylcarnitines in spot urine samples. RESULTS: Black participants had lower urinary potassium concentrations than Whites (36.6 compared with 51.1 mmol/d; P < 0.001). In White but not Black adults, urinary potassium correlated positively with 2-aminoadipic acid (2-AAA) (r = 0.176), C3-[propionyl]carnitine (r = 0.137), C4-[butyryl]carnitine (r = 0.169) and C5-[isovaleryl]carnitine (r = 0.167) in unadjusted and 2-AAA (r = 0.158) and C4-carnitine (r = 0.160) in adjusted analyses (all P < 0.05 and q < 0.05). Elevated C0-, C3-, and C5-carnitine in turn were positively associated with systolic BP (Black and White groups), diastolic BP (Black group), and glucose (White group) (all P < 0.05). CONCLUSIONS: Racial differences are an important consideration when investigating nutrient-metabolite relationships and the role thereof in cardiovascular disease. Only in White adults did urinary potassium associate with 2-AAA and short-chain acylcarnitines. These metabolites were positively related to BP and fasting plasma glucose concentrations. In White adults, the metabolomic profiles related to potassium excretion may contribute to BP regulation and glucose homeostasis. This trial was registered at clinicaltrials.gov as NCT03292094.

Urinary Peptidomics and Pulse Wave Velocity: The African-PREDICT Study.

Increased arterial stiffness is related to early vascular aging and is an independent predictor for cardiovascular disease and mortality. Molecular mechanisms underlying increased arterial stiffness are largely unexplored, especially at the proteome level. We aimed to explore the relationship between pulse wave velocity and urinary proteomics. We included 919 apparently healthy (no chronic illnesses) Black and White men and women (equally distributed) between 20 and 30 years from the African-PREDICT study. Capillary electrophoresis time-of-flight mass spectrometry was used to analyze the urinary proteome. We measured the carotid-femoral pulse wave velocity to estimate arterial stiffness. In the total group, pulse wave velocity correlated positively with collagen-derived peptides including collagen types I, II, III, IV, V, and IX and inversely with collagen type XI (adjusted for mean arterial pressure). Regarding noncollagen-derived peptides, pulse wave velocity positively correlated with polymeric immunoglobulin receptor peptides (n = 2) (all q-value ≤0.05). In multivariable adjusted analyses, pulse wave velocity associated positively and independently with seven urinary peptides (collagen type I, n = 5) (all p-value ≤0.05). We found significant positive and independent associations between pulse wave velocity and the collagen type I-derived peptides, suggesting that dysregulation of collagen type I in the extracellular matrix scaffold could lead to early onset of increased arterial stiffness.

Left ventricular mass and urinary metabolomics in young black and white adults: The African-PREDICT study.

BACKGROUND AND AIMS: Increased left ventricular mass is an independent predictor for cardiovascular events, and shown to be higher in black than white populations. To gain a better understanding of early factors contributing to increased left ventricular mass in young black adults, we investigated metabolomic profiles, identified and compared metabolites that associated with left ventricular mass index in healthy black and white adults. METHODS AND RESULTS: We included normotensive black and white participants from the African-PREDICT study, with data on urinary metabolomics and echocardiography. Urinary metabolites were measured using three different analytical platforms. Univariate statistical analyses, including independent t-test (adjusted for multiple comparisons), effect size (d ≥ 0.3) and single regression analyses were used to identify metabolites. When comparing the black and white groups, the black group had higher central systolic blood pressure (p > 0.005), whereas left ventricular mass index was similar between the groups (p = 0.97). Three from a total of 192 metabolites were identified to be more abundant (p < 0.046) and inversely associated with left ventricular mass index in the black group only: hydroxyproline (ß = -0.22; p = 0.045), glycine (ß = -0.20; p = 0.049) and trimethylamine (ß = -0.21; p = 0.037). CONCLUSION: Higher urinary levels of hydroxyproline, glycine and trimethylamine were inversely associated with left ventricular mass index in the black adults only. Hydroxyproline and glycine are important in maintaining healthy collagen turnover and stability in the heart. Our results may reflect an increase in collagen biosynthesis and collagen deposition in the left ventricle due to higher central systolic blood pressure in the black population.

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.

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.