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

Fig. 1. Grouping of participants according to the presence/absence of cardiovascular disease risk factors. Cardiovascular disease risk group criteria and sources: Obese (Amirabdollahian & Haghighatdoost, 2018; Yoo, 2016)—≥ 0.55 waist-to-height ratio; Physically inactive (Keating et al., 2019; World Health Organisation, 2022b)—< 600 METs for moderate and/or vigorous intensity physical activity; Smoking (Kim, 2016; Raja et al., 2016)—≥ 11 ng/mL cotinine & self-reported smoking; Excessive alcohol intake (Agarwal et al., 2016; Jastrzebska et al., 2016; Puukka et al., 2006)—≥ 49 U/L GGT & self-reported drinking; Masked hypertensive (Anstey et al., 2018)—normal clinic BP & 24 h/day/night BP classified as hypertensive; Hyperglycemic (Sherwani et al., 2016)—≥ 5.7% HbA1c; Dyslipidemic (Nelson, 2013; Pagana et al., 2020)—> 3.4 mmol/L LDL; Low socio-economic (Patro et al., 2012)—low SES. CVD cardiovascular disease

Fig. 2. Multi-variable adjusted regression analysis with central systolic blood pressure or pulse wave velocity as the dependent variable, with the metabolomics data in the control and cardiovascular disease risk group. Test used: Multiple linear regressions. β coefficients are presented—separate models. Central systolic BP, adjusted for age, sex, ethnicity; pulse wave velocity, adjusted for age, sex, ethnicity, mean arterial pressure. Cardiovascular disease risk group criteria: Obese—≥ 0.55 waist-to-height ratio; Physically inactive—< 600 METs for moderate and/or vigorous intensity physical activity; Smoking—≥ 11 ng/mL cotinine & self-reported smoking; Excessive alcohol intake—≥ 49 U/L GGT & self-reported drinking; Masked hypertensive—normal clinic BP & 24 h/day/night BP classified as hypertensive; Hyperglycemic—≥ 5.7% HbA1c; Dyslipidemic—> 3.4 mmol/L LDL; Low socio-economic—low SES. Metabolite concentration expressed as arbitrary units. BP blood pressure, CVD cardiovascular disease

Fig. 3. Markers of arterial stiffness relate to altered aromatic amino acid and branched chain amino acid metabolism within the cardiovascular disease risk group. Within the CVD risk group, central systolic BP and pulse wave velocity showed inverse associations with metabolites linked to AAA and BCAA metabolism. Phenylalanine and tyrosine feed into the catecholamine pathway, producing dopamine, norepinephrine and epinephrine which is implicated in vascular tone. Tryptophan is metabolised through the kynurenine pathway which is induced by inflammation and when nitric oxide is unable to inhibit this pathway. Kynurenine is implicated in vascular tone; the downstream metabolites is linked to oxidative stress and inflammation. The BCAAs, through mTOR activation, preserve cardiovascular integrity and enable cardiovascular adaptation; increased activation causes oxidative stress and inflammation. Metabolites associated with markers of arterial stiffness are indicated in bold and italic. IDO indoleamine-2,3-dioxygenase, KMO kynurenine 3-monooxygenase; NAD+ nicotinamide adenine dinucleotide, mTOR mammalian target of rapamycin

Fig. 4. Markers of arterial stiffness relate to altered energetics within the cardiovascular disease risk group. Within the CVD risk group, central systolic BP and pulse wave velocity showed inverse associations with metabolites linked to glycolysis and the citric acid cycle. Glycolysis is the primary energy-producing mechanism in the vasculature. This pathway uses amino acids as substrate to generate ATP. Metabolites associated with markers of arterial stiffness are indicated in bold and italic. ATP adenosine triphosphate, NAD+ nicotinamide adenine dinucleotide, FAD flavin adenine dinucleotide

Fig. 5. Markers of arterial stiffness relate to oxidative stress within the cardiovascular disease risk group. Within the CVD risk group, central systolic BP and pulse wave velocity showed inverse associations with metabolites linked to the methionine and y-glutamyl cycle. These pathways are important in producing the antioxidant glutathione to alleviate oxidative stress. Increased oxidative stress will in turn affect the NO bioavailability and cause vascular damage (fibrosis). Metabolites associated with markers of arterial stiffness are indicated in bold and italic