Using urinary metabolomics to identify metabolic pathways linked to cardiac structural alterations in young adults: The African-PREDICT study.

BACKGROUND AND AIMS: Risk factor exposure from young ages was shown to contribute to cardiovascular events - cardiac hypertrophy, which may be accompanied by an altered metabolism. To determine how early metabolic alterations associate with myocardial structural changes, we profiled urinary metabolites in young adults with cardiovascular disease (CVD) risk factor(s) and a control group without CVD risk factors. METHODS AND RESULTS: We included healthy adults (N = 1202), aged 20-30 years, stratified based on risk factors, i.e., obesity, physical inactivity, elevated blood pressure (BP), hyperglycemia, dyslipidemia, low socio-economic status, smoking and excessive alcohol use - forming the CVD risk group (N = 1036) and the control group (N = 166). Relative wall thickness (RWT) and left ventricular mass index (LVMi) were measured using echocardiography. Targeted metabolomics data were obtained using a liquid chromatography-tandem mass spectrometry method. Clinic systolic BP, 24 h BP and RWT were higher in the CVD risk group compared to the control group (all P ≤ 0.031). Exclusively in the CVD risk group, RWT associated with creatine and dodecanoylcarnitine; while LVMi associated with glycine, serine, glutamine, threonine, alanine, citrulline, creatine, proline, pyroglutamic acid and glutamic acid (all P ≤ 0.040). Exclusively in the control group, LVMi associated with propionylcarnitine and butyrylcarnitine (all P ≤ 0.009). CONCLUSION: In young adults without CVD, but with CVD risk factors, LVMi and RWT associated with metabolites linked energy metabolism (shifting from solely fatty acid oxidation to glycolysis, with impaired creatine kinase activity) and oxidative stress. Our findings support early onset metabolic changes accompanying cardiac structural alterations due to lifestyle and behavioural risk factors.

Markers of arterial stiffness 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 stiffness, we profiled 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 profile, reflecting 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 stiffness, 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 stiffness were negatively associated with metabolites related to AAA and BCAA as well as energy metabolism and oxidative stress. Our findings may suggest that metabolic adaptations may be at play in response to increased CVD risk to maintain cardiovascular integrity.

Urinary metabolomics profiling by cardiovascular risk factors in young adults: the African Prospective study on Early Detection and Identification of Cardiovascular disease and Hypertension study.

AIM: Risk factors contributes to a dysregulated metabolism and may ultimately increase the predisposition for cardiovascular disease (CVD) development. To increase our understanding of mechanistic pathways associated with CVD risk, we profiled the urinary metabolome according to individual and clusters of CVD risk factors in comparison with a control group without any risk factors. METHODS AND RESULTS: Healthy black and white women and men ( N  = 1202), aged 20-30 years with a detailed CVD risk factor profile were included. CVD risk groups: obese, physical inactive, smoking, excessive alcohol intake, masked hypertensive, hyperglycaemic, dyslipidemic and low socioeconomic status. CVD risk clusters were based on the presence of 1, 2 and 3 or more risk factors. Liquid chromatography-tandem mass spectrometry was used to obtain urinary metabolomics data (amino acids and acylcarnities). Compared with the control group, higher levels of metabolites associated with aromatic and branched chain amino acid metabolism including phenylalanine, tyrosine and leucine/isoleucine were found in the obese, masked hypertensive, hyperglycaemic, low socioeconomic groups (all q  ≤ 0.032) and 3+ CVD risk cluster (all P  ≤ 0.034). Metabolites associated with the y-glutamyl cycle including glycine, histidine, serine, glutamine, methionine, cystine and pyroglutamic acid were found in the hyperglycaemic, low socioeconomic groups (all q  ≤ 0.050), 2 and 3+ CVD risk clusters (all P  ≤ 0.041). Metabolites associated with energetics including acetylcarnitine (lower levels), hexanoylcarnitine and decanoylcarnitine were found in the low socioeconomic group, 1 and 3+ CVD risk clusters ( q / P  ≤ 0.050) ( ß -oxidation). In addition to the above-mentioned amino acids, alanine and threonine were found in the hyperglycaemic, low socioeconomic groups, 2 and 3+ CVD risk clusters (all q / P  ≤ 0.047) (glycolysis). Creatine in the obese, hyperglycaemic groups (all q  ≤ 0.049) and 3+ CVD risk cluster (all P  ≤ 0.041) (creatine pathway). CONCLUSION: Exposure to CVD risk factors is associated with a dysregulated metabolism in the above-mentioned pathways that may precede the development of CVD.

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 (ß= -0.168;  p = 0.017), Ang I (ß= -0.155; p = 0.028) and Ang II (ß= -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.

The relationship of blood pressure with uric acid and bilirubin in young lean and overweight/obese men and women: the African-PREDICT study.

Mounting evidence supports the central role of oxidative stress and inflammation in obesity and the development of hypertension. However, most studies focusing on the non-enzymatic antioxidants, such as uric acid and bilirubin, and their relationship with obesity and hypertension were done in older populations with overt cardiovascular disease. The aim of this study was therefore to compare measures of cardiovascular function (blood pressure and arterial stiffness) and non-enzymatic antioxidants (uric acid and bilirubin) between young healthy lean and overweight/obese men and women and to investigate the link between these variables. We grouped 967 men and women (aged 20-30 years) according to body mass index (BMI) categories (lean BMI < 25 kg/m2; overweight/obese BMI ≥ 25 kg/m2). Cardiovascular measurements included 24 h blood pressure and carotid-femoral pulse wave velocity. Serum samples were used to analyse uric acid and bilirubin. Women and men with a BMI ≥ 25 kg/m2 displayed higher 24 h blood pressure (P < 0.001) and uric acid (P ≤ 0.014) than their lean counterparts; lean women showed higher bilirubin (P < 0.001). In multi-variable adjusted regression analyses we found that 24 h systolic blood pressure was independently associated with uric acid (R2 = 0.10; ß = 0.19; P = 0.017) only in overweight/obese women. In lean women a negative association of 24 h systolic blood pressure with bilirubin (R2 = 0.03; ß = -0.14; P = 0.018) was found. No associations were found in men. In conclusion, we found adverse associations between blood pressure and uric acid in young healthy women with increased adiposity, but not in lean women or men.