Increased Excretion of C4-Carnitine Species after a Therapeutic Acetylsalicylic Acid Dose: Evidence for an Inhibitory Effect on Short-Chain Fatty Acid Metabolism

Acetylsalicylic acid and/or its metabolites are implicated to have various effects on metabolism and, especially, on mitochondrial function. These effects include both inhibitory and stimulatory effects. We investigated the effect of both combined and separate oral acetylsalicylic acid and acetaminophen administration at therapeutic doses on the urinary metabolite profile of human subjects. In this paper, we provided in vivo evidence, in human subjects, of a statistically significant increase in isobutyrylcarnitine after the administration of a therapeutic dose of acetylsalicylic acid. We, therefore, propose an inhibitory effect of acetylsalicylic acid on the short-chain fatty acid metabolism, possibly at the level of isobutyryl-CoA dehydrogenase

A urinary peptidomics approach for early stages of cardiovascular disease risk: the African-PREDICT study

Cardiovascular disease (CVD) affects individuals across the lifespan, with multiple cardiovascular (CV) risk factors increasingly present in young populations. The underlying mechanisms in early cardiovascular disease development are complex and still poorly understood. We therefore employed urinary proteomics as a novel approach to gain better insight into early CVD-related molecular pathways based on a CVD risk stratification approach. This study included 964 apparently healthy (no self-reported chronic illnesses, free from clinical symptoms of CVD) black and white men and women (aged 20–30 years old) from the African Prospective study on the Early Detection and Identification of Cardiovascular disease and Hypertension (African-PREDICT) study. Cardiovascular risk factors used for stratification included obesity, physical inactivity, tobacco use, high alcohol intake, hyperglycemia, dyslipidemia and hypertension. Participants were divided into low (0 risk factors), medium (1–2 risk factors) and high (≥3 risk factors) CV risk groups. We analyzed urinary peptidomics by capillary electrophoresis time-of-flight mass spectrometry. After adjusting for ethnicity, sex and age, 65 sequenced urinary peptides were differentially expressed between the CV risk groups (all q-values ≤ 0.01). These peptides included a lower abundance of collagen type I- and III-derived peptides in the high compared to the low CV risk group. With regard to noncollagen peptides, we found a lower abundance of alpha-1-antitrypsin fragments in the high compared to the low CV risk group (all q-values ≤ 0.01). Our findings indicate lower abundances of collagen types I and III in the high compared to the low CV risk group, suggesting potential early alterations in the CV extracellular matrix

Change in renin, cardiovascular and inflammatory markers over three years in a black and white population: the SABPA study

Abstract Background To investigate if percentage change (%∆) in renin over a 3 year follow-up is associated with %∆ in cardiovascular and inflammatory markers in a low renin bi-ethnic group. Methods Blood pressure, active renin, C-reactive protein and interleukin-6 levels of 73 black and 81 white teachers were measured at baseline and after 3 years. Results In the black group, %∆ renin was inversely associated with %∆ systolic blood pressure (β = −0.27; p = 0.011). In the white group %∆ renin was inversely associated with %∆interleukin-6 (β = −0.24; p = 0.005). Conclusions These prospective results indicate that a decrease in renin over time is associated with an increase in blood pressure in a low renin black South African cohort

Cardiovascular reactivity and oxidative stress in young and older adults: the African-PREDICT and SABPA studies

Background: Oxidative stress and increased cardiovascular reactivity are associated with endothelial dysfunction and cardiovascular disease development. These factors along with early vascular compromise are more pronounced in black populations. We aimed to compare cardiovascular reactivity and investigate associations thereof with oxidative stress in two bi-ethnic cohorts (younger: 25.0 ± 3.19yrs; older: 44.7 ± 9.61yrs). Methods: Cardiovascular reactivity using the color-word conflict test was measured with the Finometer device. Oxidative stress markers included superoxide dismutase (SOD), γ-glutamyl transferase (γ-GT) and reactive oxygen species (ROS). Results: Black groups displayed greater cardiovascular responses to stress than white groups. In younger white participants, diastolic blood pressure (DBP) (β = 0.31; p = 0.001) and mean arterial blood pressure (MAP) (β = 0.28; p = 0.002) associated with ROS. In older black participants, DBP (β = 0.23; p = 0.009), MAP (β = 0.18; p = 0.033), stroke volume (β = −0.20; p = 0.023) and arterial compliance (β = −0.25; p = 0.005) associated with γ-GT. In older white participants, systolic blood pressure (β = −0.20; p = 0.006) and MAP (β = −0.19; p = 0.009) associated with SOD. Conclusions: In the older black group, cardiovascular reactivity associated with markers of glutathione metabolism, suggesting a possible compensatory up-regulation thereof in order to correct their heightened responses to stress. Independent of age, findings in the white groups support a regulatory role of ROS to maintain vascular tone during stress. Trial registration: ClinicalTrials.gov identifier: NCT03292094

The renin-angiotensin-system and left ventricular mass in young adults: the African-PREDICT study

Purpose Raised blood pressure, with the renin-angiotensin system (RAS) as a central regulatory component, is one of the most important contributors to early development of left ventricular hypertrophy. Factors such as increased age, sex, black ethnicity and a low socio-economic status also contribute to left ventricular remodelling. To better understand early contributors to left ventricular mass, we investigated the relationship between left ventricular mass index (LVMi) and the components of the RAS in young healthy adults while considering ethnicity, sex and socio-economic status. Materials and methods Black and white women and men (N = 1186) between the ages of 20–30 years were included. By using standard echocardiography, we determined LVMi. Ultra-pressure-liquid chromatography tandem-mass spectrometry (LC-MS/MS) was used to measure the RAS-fingerprint®. Results Components of the RAS such as plasma renin activity (PRA-S), angiotensin I (Ang I), angiotensin II (Ang II) and aldosterone were suppressed in the black compared to the white group (all p < 0.001). No associations between LVMi and the RAS were evident in the total, black or white groups. With additional grouping according to sex and socio-economic status, inverse associations between LVMi and PRA-S (β= −0.168;  p = 0.017), Ang I (β= −0.155; p = 0.028) and Ang II (β= −0.172; p = 0.015) were found only in low socio-economic black women. Conclusion Despite a suppressed RAS in the black compared to the white group, components of the RAS were not associated with LVMi in this young cohort. The low socio-economic black women of this study population may be vulnerable to future RAS-related increases in left ventricular mass

Markers of arterial stifness and urinary metabolomics in young adults with early cardiovascular risk: the African‑PREDICT study

Introduction Increased exposure to risk factors in the young and healthy contributes to arterial changes, which may be accompanied by an altered metabolism. Objectives To increase our understanding of early metabolic alterations and how they associate with markers of arterial stifness, we profled urinary metabolites in young adults with cardiovascular disease (CVD) risk factor(s) and in a control group without CVD risk factors. Methods We included healthy black and white women and men (N=1202), aged 20–30 years with a detailed CVD risk factor profle, refecting obesity, physical inactivity, smoking, excessive alcohol intake, masked hypertension, hyperglycemia, dyslipidemia and low socio-economic status, forming the CVD risk group (N=1036) and the control group (N=166). Markers of arterial stifness, central systolic blood pressure (BP) and pulse wave velocity were measured. A targeted metabolomics approach was followed by measuring amino acids and acylcarnitines using a liquid chromatography-tandem mass spectrometry method. Results In the CVD risk group, central systolic BP (adjusted for age, sex, ethnicity) was negatively associated with histidine, arginine, asparagine, serine, glutamine, dimethylglycine, threonine, GABA, proline, methionine, pyroglutamic acid, aspartic acid, glutamic acid, branched chain amino acids (BCAAs) and butyrylcarnitine (all P≤0.048). In the same group, pulse wave velocity (adjusted for age, sex, ethnicity, mean arterial pressure) was negatively associated with histidine, lysine, threonine, 2-aminoadipic acid, BCAAs and aromatic amino acids (AAAs) (all P≤0.044). In the control group, central systolic BP was negatively associated with pyroglutamic acid, glutamic acid and dodecanoylcarnitine (all P≤0.033). Conclusion In a group with increased CVD risk, markers of arterial stifness were negatively associated with metabolites related to AAA and BCAA as well as energy metabolism and oxidative stress. Our fndings may suggest that metabolic adaptations may be at play in response to increased CVD risk to maintain cardiovascular integrit

Iron loading, alcohol and mortality: a prospective study

Background and 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