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

Context-dependent effects of the renin-angiotensin-aldosterone system on blood pressure in a group of African ancestry

Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011In groups of African ancestry, who have a high prevalence of “salt-sensitive, low-renin” hypertension, there is considerable uncertainty as to relevance of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of primary hypertension. In the present thesis I explored the possibility that the RAAS, through interactions with environmental effects, contributes to blood pressure (BP) in this ethnic group. After excluding participants with aldosterone-to-renin ratios (ARR) above the threshold for primary aldosteronism, in 575 participants of African ancestry, I demonstrated that with adjustments for confounders, an interaction between ARR and urinary Na+/K+ (and index of salt intake obtained from 24-hour urine samples) was independently associated with BP (p<0.0001). This effect was accounted for by interactions between serum aldosterone concentrations and urinary Na+/K+ (p<0.0001), but not between plasma renin concentrations and urinary Na+/K+ (p=0.52). The interaction between ARR and urinary Na+/K+ translated into a marked difference in the relationship between urinary Na+/K+ and BP in participants above and below the median for ARR (p<0.0001 for a comparison of the relationships). Having demonstrated that circulating aldosterone concentrations may account for a substantial proportion of the relationship between salt intake and BP in this community sample, I subsequently assessed whether genetic factors contribute toward serum aldosterone concentrations. In 153 randomly selected nuclear families of African ancestry consisting of 448 participants without primary aldosteronism, with, but not without adjustments for plasma renin concentrations, independent correlations were noted for iii serum aldosterone concentrations between parents and children (p<0.05), with parent-child partial correlation coefficients being greater than those for father-mother relationships (p<0.05). Furthermore, after, but not before adjustments for plasma renin concentrations, serum aldosterone concentrations showed significant heritability (h2=0.25±0.12, p<0.02). No independent relationships between RAAS gene polymorphisms and serum aldosterone concentrations were observed. I also aimed to assess whether RAAS genes modify the relationship between cigarette smoking and BP in groups of African descent. However, as the impact of mild smoking on BP is uncertain, and in the community studied only 14.5% smoked and the majority of smokers were mild smokers (mean=7.4±4.6 cigarettes per day) in 689 randomly participants I initially assessed the relationship between smoking habits and out-of-office BP. In this regard, current smokers had higher unadjusted and multivariate adjusted 24-hour systolic/diastolic BP (SBP/DBP in mm Hg) (p<0.005-p<0.0005) than non-smokers, effects that were replicated in sex-specific groups, non-drinkers, and in the overweight and obese. Current smoking was second only to age and at least equivalent to body mass index in the quantitative impact on out-of-office BP and the risk of uncontrolled out-of-office BP was increased in smokers as compared to non-smokers. Thus, despite minimal effects on in-office BP, predominantly mild current smoking was independently associated with an appreciable proportion of out-of-office BP in a community of African ancestry. In 652 participants I subsequently assessed whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism accounts for the strong relationships between predominantly mild smoking and out-of-office BP. After iv appropriate adjustments, an interaction between ACE DD genotype and current cigarette smoking, or the number of cigarettes smoked per day was independently associated with 24-hour and day diastolic BP (DBP) (p<0.05-0.005). This effect translated into a relationship between smoking and out-of-office BP or the risk for uncontrolled out-of-office BP only in participants with the DD as compared to the ID + II genotypes. In conclusion therefore, I afford evidence to suggest that in groups of African ancestry, aldosterone, within ranges that cannot be accounted for by the presence of primary aldosteronism, modifies the relationship between salt intake and BP, and that genetic factors account for the variation in serum aldosterone concentrations in this group. Furthermore, I show that the ACE gene modifies the relationship between smoking and out-of-office BP and hence accounts for even predominantly mild smoking producing a marked and clinically important effect on out-of-office BP. The present thesis therefore provides further evidence in favour of an important pathophysiological role for the RAAS in contributing toward BP in groups of African ancestry