Central blood pressure in an urban developing community in South Africa

Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011Contemporary notions of the adverse effects of blood pressure (BP) incorporate the increasingly recognised damaging effects of not only distending pressure (indexed by mean arterial pressure-MAP) but also pulse pressure (PP) (the difference between systolic and diastolic BP) on the cardiovascular system. Although the factors which determine brachial artery PP are similar to those affecting central (aortic) PP (PPc), some factors may affect central PP preferentially, and thus PP calculated from brachial artery BP measurement may not closely reflect the PP that accounts for cardiovascular damage. In order that therapeutic strategies are developed that modify PPc independent of distending pressures, there is considerable interest in the pathophysiological mechanisms that explain increases in PPc. In this regard, aortic PP is comprised of the forward or incident pressure component (P1), which is largely determined by stroke volume, aortic compliance or stiffness and aortic diameter; and the augmented pressure component (AP), which is determined by wave reflection. Whilst currently employed antihypertensive agents may modify AP independent of distending pressures, there is little evidence to indicate a similar effect on the structural aortic changes responsible for P1. Although changes in AP as opposed to P1 largely account for age-related increases in PPc across the adult lifespan in normotensives, the relative contribution of AP and P1 to PPc in communities with a high prevalence of uncontrolled BP is unknown. In 1015 randomly recruited participants (range 16-88 years) from a community sample, 37.7% of whom had uncontrolled BP, I demonstrated that independent of MAP and other confounders, P1 contributes as much as AP to age-related increases in PPc and to variations in PPc across the adult lifespan. As no previous studies have assessed the relationship between P1 and cardiovascular damage, in 503 randomly recruited participants from a community with a high prevalence of uncontrolled BP, the relative contribution of P1 and AP to increases in left ventricular mass index (LVMI) was subsequently evaluated. In this regard, independent of distending pressures, P1 was associated with LVMI, highlighting the need to understand the iii potential mechanisms which contribute to P1. Could the pathophysiological mechanisms that determine hypertension account for the contribution of P1 to PPc? In this regard, I evaluated the potential role of three mechanisms. First, in 635 randomly selected participants with 24-hour urine samples that met with pre-specified quality control criteria, I provide the first data to demonstrate that urinary sodium-to-potassium ratio (an index of Na+ and K+ intake) is independently associated with PPc, but not brachial PP independent of distending pressures, a relationship that could be accounted for by changes in both AP and P1, but not aortic pulse wave velocity. Second, I explored the possibility that low grade inflammation as indexed by circulating high-sensitivity C-reactive protein concentrations (hs-CRP) may contribute toward PPc and the component pressures. In this regard, although hs-CRP has been associated with changes in central haemodynamics in small study samples, in a large community sample of participants these findings could not be reproduced. However, in that study the community had a low prevalence of risk-related hs-CRP concentrations. In 836 randomly recruited participants from a population sample with a high prevalence of risk-related hs-CRP concentrations (~57%), although on univariate analysis I showed that hs-CRP was strongly associated with PPc and the component pressures, this relationship did not persist with adjustments for confounders. Last I evaluated the potential contribution of genetic factors toward PPc and the component pressures. Although three prior studies had demonstrated heritability of PPc, AP and P1, two studies failed to adjust for MAP and a third assessed the heritability in females only. In none of these studies was the contribution of aortic PWV to the heritability estimates of PPc, AP and P1 assessed. In 568 participants from 183 nuclear families, I showed that independent of MAP, multivariable adjusted PPc, AP, P1 and PWV aggregated in families and were inherited. However, adjustments for aortic PWV failed to modify the extent of intrafamilial aggregation and heritability of PPc, AP, or P1. In conclusion, in the present thesis I have advanced our understanding of the mechanisms responsible for increases in PPc. In this regard, I provide evidence to suggest that independent of distending pressures and stroke volume, P1 accounts for a significant iv proportion of the age-related increases in PPc and the variability of PPc across the adult lifespan in communities with a high prevalence of uncontrolled hypertension; that P1 contributes substantially to the relationship between PPc and LVMI; and that PPc and both the AP and P1 component pressures are associated with a urinary index of salt intake as well as genetic factors, but not to an index of low-grade inflammation. These findings suggest that to achieve optimal cardiovascular risk reduction in hypertension, therapeutic strategies that target the aortic structural changes responsible for P1 are likely to be required across the adult lifespan, and that this therapy must in-part address the impact of salt intake and genetic factors, but not necessarily low-grade inflammation on PPc