The black population in South Africa has a high prevalence of hypertension and atherosclerosis. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been implicated as an important biomarker in the development of vascular dysfunction and cardiovascular disease, including arteriosclerosis, atherosclerosis and hypertension. Resting ET-1 levels are higher in black Americans than in whites, and higher in men than in women under normal physiological conditions. Under pathophysiological conditions, the biosynthesis of ET-1 is stimulated by cardiovascular risk factors such as elevated levels of oxidised low-density lipoprotein cholesterol, hypertension and aging. Prolonged exposure to cardiovascular risk factors seems to disrupt the balance between vasodilation and vasoconstriction, leading to conditions such as increased blood pressure, increased inflammation, arterial stiffness, oxidative stress and vascular remodeling. In this regard it is important to determine the potential impact of ET-1 levels on the cardiovascular system over time, especially in the black population of South Africa. This study included markers of cardiovascular function (systolic blood pressure, pulse pressure and mean arterial pressure), inflammation (interleukin-6 and C-reactive protein), oxidative stress (reactive oxygen species (ROS)), anti-oxidant capacity (total glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione reductase-to-glutathione peroxidase ratio (GR-to-GPx ratio)), and vascular remodeling (carotid intima media thickness (CIMT), carotid cross-sectional wall area (CSWA), and arterial compliance) to address the vascular changes that augment vascular damage. The study was motivated by the awareness of limited data in this regard, especially in South Africans. Aim
The general aim of this study is to explore the possible associations of ET-1 levels with cardiometabolic and vascular function. Furthermore, to determine whether ET-1 levels differ among sex and race and if there is an association between ET-1 levels with markers of cardiovascular function, inflammation, oxidative stress, anti-oxidant capacity, and vascular remodeling in black and white South Africans. Methodology
This study was embedded in the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. The study was a prospective cohort study that included 409 black and white schoolteachers working in the Kenneth Kuanda Education District of the North West Province at baseline (2008/09). At follow-up (2011/12) the cohort totalled 359 participants. The total group was stratified by race and sex and in the third manuscript by an increase or a decrease in ET levels after three years. Cardiovascular measurements were performed and ET-1, interleukin-6, C-reactive protein, ROS, GSH, GPx, and GR levels were determined. T-tests were done to compare means between groups. Chi-square and crosstabs were used to compare proportions between baseline values or baseline and follow-up values, respectively. Pearson and partial correlations were performed to investigate the associations between various variables with adjustments for age, body mass index, C-reactive protein, total energy expenditure, anti-hypertension medication, gamma glutamyl transferase, race and sex in the relevant manuscripts. Multiple regression analyses were performed to investigate associations of ET-1 with cardiovascular and biochemical markers according to the specific focus of each research manuscript. Results and conclusions of each manuscript
The objectives of the first manuscript (Chapter 3) were to compare ET-1 levels among sex and race and to explore the association of ET-1 with cardiovascular function and inflammation. The black men and white women had significantly higher ET-1 levels when compared to their counterparts after adjusting for C-reactive protein (p<0.001). Furthermore, partial and multivariate regression analyses showed an independent association of ET-1 with interleukin-6, systolic blood pressure and pulse pressure in black women only (p<0.01). These associations suggest that ET-1 and its link with subclinical arteriosclerosis are potentially driven by low-grade inflammation in the black female cohort.
The second manuscript (Chapter 4) investigated the associations of ET-1 with markers of oxidative stress and anti-oxidant capacity in black and white South Africans. Multiple regression analyses showed that ET-1 associated positively with GR activity (β=0.232; p=0.020) and tended to associate with GR-to-GPx ratio (β=0.190; p=0.057) in black men, while there was an inverse association between ET-1 and GSH (β=–0.214; p=0.026) in black women. There was a positive association with ROS (β=0.260; p=0.010) and negative association with GPx activity (β=–0.233; p=0.020) in white men. The results suggest that ET-1 may contribute to GR up-regulation through increased ROS production in black men, while higher GSH levels may act as a counter-regulatory mechanism to protect against oxidative vascular damage attributed to ET-1 in black women. In white men, the negative association observed between ET-1 and GPx and positive association with ROS may describe the expected physiological relationship between ET-1 and ROS. The third manuscript (Chapter 5) investigated the association of change in ET-1 levels and the change of markers implicated in vascular remodeling after three years in a black and white South African population. Multiple regression analysis, after splitting for race, indicated that the increase in ET-1 levels associated positively with the change in pulse pressure (β=0.278; p=0.036), while a borderline association exist between the extent of decrease in ET-1 levels and a lesser change in CSWA (β=–0.201; p=0.054) in the black population only. Anti-hypertension medication also played an important role in this study. After excluding patients using anti-hypertension medication the borderline inverse association between the decrease in ET-1 levels and a change in CSWA disappeared in the black participant, but became significant in the white participants (β=–0.127; p=0.046). The results suggest that in the black participants with increased ET-1 levels after three years, the positive association between ET-1 levels and pulse pressure suggest subclinical haemodynamic changes with potential premature onset of cardiovascular disease, while anti-hypertension treatment and statin usage seem to slow down adverse vascular remodeling caused by elevated ET-1 levels in the white population only. General conclusion
Our study is the first to indicate a link between a marker of vascular function (ET-1) and inflammation, oxidative stress, anti-oxidant capacity and vascular remodeling in a bi-ethnic South African population. Our results persistently found that ET-1 contributed to a higher risk of early vascular deterioration (arteriosclerosis) and future comorbidities, potentially driven by low-grade inflammation (black women), ROS production (black men), decreased anti-oxidant capacity (black men) and vascular remodeling in the black population, whereas a decrease in ET-1 slow down adverse vascular remodeling in the white population.||en_US