Systemic blood flow in hypertension in a community of African ancestry
Date
2021
Authors
Mmopi, Keneilwe Nkgola
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Hypertension is a particularly important cause of death and disability in groups of African
descent, an effect thought to be consistent with the evolutionary theory of antagonistic pleiotropy.
In this regard, groups originating from equatorial countries are hypothesized to have evolved to
survive fluid losing states through a genetic predisposition to renal fluid retention. Although this
prevents fluid loss in hot climates, with aging and excess Na+
intake, fluid accumulation may result
in hypertension through an enhanced intravascular volume. However, because of the absence of
measurable increases in systemic blood flow in primary hypertension, this hypothesis is not
universally accepted. Nevertheless, studies to determine the hemodynamic basis of hypertension
in this ethnic group are markedly limited. In the present thesis, in a cross-sectional community based study conducted across the full adult lifespan (aged 16 years and above). I therefore
evaluated the hemodynamic basis of hypertension in a group of African descent living in South
Africa (SOWETO).
As renal fluid retention is thought to increase blood pressure (BP) in response to Na+
intake,
I first determined the relationship between 24-hour urinary Na+
and K+
excretion (an index of salt
intake) and systemic hemodynamics in 581 randomly selected community participants from
SOWETO. Using multivariate adjusted regression analysis, I showed that an abnormal salt intake
(indexed by a high Na+
/K+
) is independently associated with systolic BP (SBP) and pulse pressure
(PP) through an enhanced proximal aortic characteristic impedance (resistance to flow in a
pulsatile system in the absence of wave reflection [Zc]), but not through changes in peak aortic
flow (the product of maximum velocity and the largest diameter in the left ventricular outflow tract
in early systole) [Q]). The associations of salt intake with Zc were not accounted for by variations
in aortic root diameter and translated into elevated PP and SBP values through an enhanced early
central systolic (determined by PQxZc) and hence forward travelling pressure wave (the wave
generated from the interaction between maximal flow and impedance to flow in the proximal
aorta). These findings therefore suggest that the adverse effects of a high salt intake on BP in
groups of African ancestry are through chronic changes in the proximal aorta (aortic stiffness)
rather than through an impact of salt intake on renal fluid retention.
Although salt intake is not associated with systemic blood flow in groups of African
ancestry, this does not exclude a possible alteration in the pressure natriuresis relationship
produced by renal effects enhancing systemic blood flow. I therefore determined the age-related
iii
hemodynamic correlates of blood pressure (BP) across the adult lifespan in 824 participants from
the community sample of African ancestry in SOWETO. In multivariate linear regression analysis,
independent of confounders, a strong positive association between age and stroke volume (SV),
cardiac output (CO) and peak aortic Q, but not with systemic vascular resistance (SVR) was noted.
Age relations with pulse pressure were as strongly determined by aortic Q as by Zc or total arterial
compliance (TAC). SV, CO and Q accounted for a marked proportion of age-related increases in
BP as determined from both office and ambulatory (24-hour) measurements. Consistent with flow
effects on renin secretion, increases in systemic flow accounted for age-related decreases in plasma
renin concentrations and were correlated with age-related increases in plasma aldosterone
concentrations and the aldosterone-to-renin ratio. Thus, from young adulthood, strong age-related
increases in systemic flow account for increases in BP in Africa, and these effects explain low renin hypertension.
The extent to which increases in systemic flow across the adult age range account for most
forms of primary hypertension (systolic and diastolic as well as isolated systolic hypertension) in
Africa is unknown. I therefore subsequently aimed to determine the extent to which effects of
systemic blood flow contribute to untreated or inadequately controlled systolic and diastolic as
well as isolated systolic hypertension in 725 participants from the SOWETO community. Using
multivariate adjusted analysis of covariance, I showed that independent of confounders, compared
to those with a normotensive BP, uncontrolled systolic and diastolic hypertension was as strongly
associated with Q, SV or CO as with SVR, Zc and TAC. Moreover, independent of confounders,
as compared to normotensives, uncontrolled isolated systolic hypertension was more strongly
associated with Q, SV and CO than with SVR, but less than with TAC and similar to Zc. Thus, in
groups of African ancestry living in Africa, hypertension due to increases in either systolic or
diastolic BP is as strongly associated with increases in systemic flow (SV, CO and Q) as with
arterial and arteriolar effects (Zc, TAC, SVR).
In conclusion, in the present thesis I provide evidence published in the high impact journals
Hypertension (2 papers) and Journal of Hypertension (1 paper) to support the evolutionary theory
of antagonistic pleiotropy and a shifted pressure natriuresis relationship as a cause of primary
hypertension in groups of African descent living in Africa. In this regard, I show that although
habitual salt intake does not cause primary hypertension through alterations in systemic blood
flow, that age-related increases in systemic blood flow are pathognomonic of most low-renin forms
iv
of primary hypertension at a community level. These data therefore provide the missing evidence
(increases in systemic blood flow) to substantiate the importance of a shifted pressure natriuresis
relationship as a cause of primary hypertension proposed by Guyton and colleagues close to 50
years ago.
Description
A thesis submitted in
fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2021