Marinobufagenin and its relationship with systolic blood pressure in a young black and white population : the African-PREDICT study

Abstract

Motivation: Hypertension remains one of the foremost causes of cardiovascular morbidity and mortality in sub-Saharan Africa. Importantly, the prevalence of hypertension within black and white populations has been ascribed to distinct pathophysiological mechanisms. Numerous studies have shown that black individuals are predisposed to hypertension in part due to their genetic susceptibility to be salt-sensitive. Hence, the scope of research investigating possible underlying mechanisms of saltsensitivity remains a subject of growing interest. There is emerging evidence indicating an association between salt-sensitivity and the novel biomarker, MBG. This endogenous sodium-pump ligand’s role in blood pressure regulation is attributed to its ability to inhibit both renal as well as cardiovascular α1-Na+/K+-ATPase subunits. Studies have demonstrated a vasoconstrictive response to MBG in Dahl salt-sensitive rats — with attenuated pressure-natriuresis — as opposed to the expected homeostatic natriuretic response. Accordingly, black populations portray a similar salt-sensitive phenotype with an impaired pressure-natriuresis profile. Thus, we calculated the 24hr urinary MBG/Na+ excretion ratio as a proposed estimate of Na+ excretion resistance to higher levels of urinary MBG. A better understanding with regards to both ethnic and sex differences in MBG/Na+ and its association with measures of cardiovascular function, could provide new insight into the possible role of MBG in the salt-sensitive hypertension phenotype. Aim: The aim of this study was to compare the MBG and 24hr urinary sodium profiles between black and white, men and women. Furthermore, we aimed to investigate the association of the MBG/Na+ excretion ratio with systolic blood pressure (SBP) and hemodynamic parameters in this young bi-ethnic population. Methods: This cross-sectional study is affiliated with the African Prospective study on the Early Detection and Identification of Cardiovascular Disease and Hypertension (African- PREDICT), and was reviewed and approved by the Health Research Ethics Committee (HREC) of the North-West University (NWU-00022-16-A1). The overarching aim of the African-PREDICT study partly entails the early identification of novel biomarkers involved in the development of CVD especially in young black South Africans. We investigated the data of the first consecutive 331 participants (42.9% black, 43.8% men) with complete 24hr urinary data. We obtained basic anthropometric measurements including height, weight and waist circumference, after which the body mass index (kg/m2) as well as the waist:height ratio were calculated. Cardiovascular measurements included central systolic blood pressure (cSBP), 24hr SBP and beat-to-beat hemodynamic measurements including heart rate, stroke volume and total peripheral resistance (TPR). Participants were asked to collect 24hr urine samples in which the 24hr urinary sodium, potassium and MBG concentrations were determined. Furthermore, we used blood samples to determine the high density lipoprotein cholesterol (HDL-C), total cholesterol, and γ- glutamyltransferase (GGT), glycated haemoglobin (HbA1c) and aldosterone levels. After performing interaction testing participants were stratified by sex and ethnicity. Accordingly we used T-tests and Chi-square tests to compare means and proportions between groups. Subsequent single, partial and multiple regression analyses were performed to explore the relationship between MBG and the MBG/Na+ excretion ratio with SBP and other hemodynamic variables. P-values ≤0.05 were considered significant. Results: Interaction testing performed in the entire cohort, indicated an interaction of sex on the relationship between cSBP and MBG/Na+ excretion ratio (p=0.027), while there was an interaction of ethnicity on the associations between cSBP and 24hr SBP with MBG/Na+ in women (p=0.010 and p=0.012). Black men and women displayed a higher cSBP and TPR with a lower stroke volume compared to whites, whereas white men had higher 24hr SBP measures. We observed no apparent ethnic differences in either MBG excretion or MBG/Na+ in men or women, although men had a significantly higher salt intake of 8.58 g/day and MBG excretion when compared to women. Black women portrayed a significant positive trend in cSBP (p=0.003) as well as nighttime systolic ABPM (p=0.013) across increasing MBG/Na+ quartiles. Furthermore, in black women only single and multiple regression analyses indicated a positive association of central SBP (R2=0.26; ß=0.28; p=0.039), 24hr SBP (R2=0.46; ß=0.30; p=0.011) and stroke volume (R2=0.26; ß=0.29; p=0.036) with MBG/Na+, whereas a negative association was found between MBG/Na+ and TPR (R2=0.21; ß=−0.33; p=0.018). Conversely, in white women a negative association existed between MBG/Na+ and nighttime SBP (r=−0.20; p=0.038), which became non-significant after adjusting for multiple covariates (R2=0.36; ß=−0.13; p=0.12). There were no significant trends or associations in young black and white men with regards to the MBG/Na+ excretion ratio. Conclusion: Compared with white women, black women might be more vulnerable to early cardiovascular risk brought on by an apparent resistance to sodium excretion, based on MBG/Na+ and its association with an increase in cSBP, 24hr SBP and stroke volume. Yet, clear contrasting associations in young white women supports the normal physiological natriuretic effect of MBG. Our results suggest that the interregulation of MBG and Na+ may partially contribute to the prevalence of a saltsensitive hypertension phenotype. The absence of any associations with the MBG/Na+ excretion ratio in men requires further investigation