The cardiovascular profile of the low renin phenotype in a black South African population

Abstract

Motivation Blood pressure is decreasing globally, however, the prevalence of hypertension continues to increase in Sub-Saharan African countries such as South Africa. Populations of African ancestry are more likely to suffer from cardiovascular outcomes such as cerebrovascular accidents and heart disease due to hypertension, as compared to whites. The mechanisms involved are not clear, particularly the role of the renin-angiotensin-aldosterone system (RAAS). The RAAS is the master regulator of water, electrolyte and blood pressure balance. The rate-limiting enzyme of this cascade, namely renin, is usually suppressed in Africans and as a result low-renin hypertension is common in this population group. Low-renin hypertension is not a diagnosis, but rather a description. A lower renin level indicates that renin secretion in the kidney is inhibited by increasing blood pressure, possibly due to volume-overload. Features of low-renin hypertension include blood pressure sensitivity to increased salt intake; a poor response to angiotensin blockade; and a positive response to calcium channel blockers, aldosterone blockade or diuretics. It is therefore questionable whether the activation of the RAAS has a causal role in the development of hypertension and its associated complications in Africans. Relationships between the components of the RAAS and cardiovascular disease are well established in other populations, however such information in Africans is scant, particularly a detailed physiological description of the low renin phenotype. Aim: The overarching aim of this study was to examine the cardiovascular profile of a black South African population, and the associations of renin, aldosterone, and their ratio with cardiovascular haemodynamics. In addition, the study aimed to determine if the low renin phenotype is associated with an increased risk for cardiovascular- and all-cause mortality. Firstly, the frequency of low renin levels in a black and white population was determined as well as the associations between renin and cardiovascular responses to a laboratory stressor, the cold pressor test (CPT). It was then explored whether aldosterone and renin relate to surrogate measures of sympathetic activity. Lastly, the prognostic value of renin and its interactions with systolic blood pressure (SBP) for all-cause and cardiovascular mortality was investigated. Methodology: This thesis used data collected from the Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) and Prospective Urban and Rural Epidemiology (PURE) studies. For the first objective, our study population consisted of 153 black and 188 white men and women (age range, 20 to 65 years) from the SABPA study. Haemodynamic measurements included blood pressure (BP), heart rate (HR), stroke volume, total peripheral resistance (TPR) and Windkessel arterial compliance. Active plasma renin levels were determined at rest and when a stressor (CPT) was applied. Reactivity was calculated for each participant as the percentage change from the resting value. For the second objective, black (N=162) and white (N=206) participants (also from the SABPA study) with similar age range as aforementioned were included. The study population was stratified by low and high renin status and the focus was on the low renin groups. Ambulatory BP and HR were measured and night-time dipping calculated. Biochemical analyses were done for plasma renin and aldosterone, and then the aldosterone-to-renin ratio (ARR) was calculated. Noradrenaline and creatinine were determined in urine and the noradrenaline:creatinine ratio was calculated. Lastly, from the PURE study, plasma renin was determined in 1502 black men and women from urban and rural areas in South Africa (age ≥ 35 years), and mortality was assessed over five years. The population was divided into low and high renin groups based on the cut-off from the Renin III CISBIO kit. Results: Lower renin and elevated BP were apparent in blacks compared to whites at rest and during stress (both, P<0.001). When a stressor was applied, HR increased more in blacks (P<0.001), whereas stroke volume (P<0.001) and arterial compliance (P=0.013) decreased more in blacks compared to their white counterparts. There was a positive association between TPR reactivity and renin reactivity in blacks only (β=0.17; P=0.041), while in whites diastolic BP reactivity was positively associated with renin reactivity (β=0.21; P=0.005). Furthermore, a high percentage of blacks exhibited a low renin status (80.9%) compared to whites (57.8%) (P<0.001). In univariate and after multivariate analyses the following significant associations were evident only in low-renin blacks: noradrenaline:creatinine ratio associated positively with aldosterone (β=0.32, P=0.001), 24-hour HR associated positively with renin (β=0.17, P=0.041), while HR dipping associated negatively with aldosterone (β=-0.30, P=0.001) and ARR (β=-0.23, P=0.010). No significant findings were obtained in whites in the low renin group. Lastly, multivariable-adjusted Cox-regression analyses were performed. In the low renin group, SBP and renin*SBP interaction, but not renin, predicted both all-cause [(HR, 1.41; 95% CI, 1.07- 1.87; P=0.014), (HR, 1.72, 95% CI, 1.05-2.83, P= 0.031)] and cardiovascular mortality [(HR, 1.87; 95% CI, 1.16-3.01; P=0.010), (HR, 2.40; 95% CI, 1.06-5.46; P=0.037)]. In the total group, renin and SBP*renin predicted all-cause, but not cardiovascular mortality [(HR, 1.33; 95% CI, 1.07- 1.65; P=0.011), (HR, 1.30; 95% CI, 1.06-1.60; P=0.012)]. In the high renin group, neither renin, SBP nor the renin*SBP predicted all-cause or cardiovascular mortality. Conclusion: The low renin phenotype (volume-loading hypertension) is eminent in the black South African population, and may be suggestive of an increased cardiovascular risk. Although blacks had supressed renin levels at rest and during acute stress, vascular resistance reactivity associated positively with renin reactivity only in the black population. These results suggest that even at low renin levels a sympathetic response evoked by stress is linked to increased peripheral vascular responses, which may contribute to elevated BP in blacks. Furthermore, in a black low-renin population, the observed associations of surrogate indices of sympathetic nerve activity with components of the RAAS suggest that higher aldosterone levels relative to renin may have detrimental effects on the heart, and that the effects of aldosterone may be coupled to sympathetic dominance. Lastly, the interaction of renin with SBP is predictive of all-cause and cardiovascular mortality only in Africans with low renin levels