North-West University (South Africa) , Potchefstroom Campus
Abstract
PhD (Physiology), North-West University, Potchefstroom Campus, 2016Motivation - In South Africa, the process of rapid urbanisation has led to a high prevalence of noncommunicable diseases such as chronic respiratory and cardiovascular diseases which are
accompanied by a high cardiovascular mortality rate. The identification of possible risk factors for this disease burden is essential for prevention and the allocation of healthcare and treatment regimens. Lung function differs between different populations of the world and the use of appropriate reference data is important as inaccurate interpretation may lead to misdiagnosis. From international literature it is known that reduced lung function is associated with various cardiovascular variables such as blood pressure and arterial stiffness, and is also associated with an increased risk of cardiovascular-related mortality. The mechanism driving this
association remains largely unexplained. It has been hypothesised that the changes in lungand arterial function originate from the same pathophysiological process which could be mediated by systemic inflammation. However, whether lung function plays a role in the development of cardiovascular disease and whether reduced lung function could predict all-cause and cardiovascular mortality among the
understudied black South African population, remain to be established. In addition, the role of systemic inflammation in this regard needs to be explored. Aim -
The central aim of this study was to determine the potential role of lung function in the development of cardiovascular disease in a black South African population and to investigate whether inflammation is the mechanistic link between these two disease states. We therefore explored the associations between lung function and measures of cardiovascular function as
well as between lung function and inflammatory markers. Finally, we determined the value of lung function in predicting cardiovascular mortality over five years, whilst taking inflammatory markers into account. Methodology - This sub-study, which is embedded in the international Prospective Urban and Rural Epidemiology (PURE) study, included an apparently healthy cohort of black South African volunteers of ages older than 35 years from the North-West Province, South Africa. Baseline data collection took place in 2005 during which 2010 men and women from urban and rural
areas were included. The first follow-up took place in 2010 and a total of 218 participants had passed away over the five year follow-up period, with cardiovascular mortality contributing to 63 deaths and non-cardiovascular mortality to 155. Standardised methods were used to capture all data and included health questionnaires
(lifestyle factors, medication usage, disease status and history), cardiovascular and
anthropometric measurements, spirometry as well as biochemical analyses of inflammatory markers (C-reactive protein, interleukin-6), HIV status and relevant metabolic markers. Verbal autopsies were performed to establish mortality outcome.
In preparation for statistical analyses, non-Gaussian variables were logarithmically transformed. We compared means and proportions with independent t-tests, analysis of variance, analysis of covariance (for adjustments) and Chi-square tests. We determined relationships between variables with Pearson’s correlation coefficients. Independent relationships were determined
with logistic regression, forward stepwise multiple regression and proportional Cox-regression analyses. Mortality rates were calculated using Kaplan-Meier survival function estimates and log-rank tests. In all cases, p values ≤ 0.05 were regarded as statistically significant. Results and conclusions of each manuscript - Three manuscripts were written in order to achieve the main aim of this thesis. In the first
manuscript we compared respiratory prediction values from three different reference populations namely from Europe, the United States and South Africa and secondly explored whether lung function is associated with blood pressure in a large sample of black South Africans. We showed that South African reference values displayed the highest percentages of the predicted values for forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), (87.9 and 99.7%, respectively.) Blood pressure increased with a reduction in lung function for both FEV1 and FVC, (p for trend <0.001). After adjustment for potential confounders, the correlations remained significant (p<0.05). Our findings suggest that South African prediction equations may be more useful when investigating lung function in black South Africans. Furthermore, elevated blood pressure is related to reduced lung function, highlighting the importance in managing both respiratory- and cardiovascular disease. In the second manuscript the possible role of systemic inflammation as the mediator between
lung function and arterial stiffness in a sample of black South Africans was determined. An independent inverse association was found between interleukin-6 (IL-6) and FEV1 (β=-0.20, p<0.001) and FVC (β=-0.18, p<0.001). Similar results were found for C-reactive protein (CRP). Pulse wave velocity (PWV) was inversely associated with FEV1 (β=-0.06, p=0.037). No association was found between inflammatory markers, blood pressure or PWV, suggesting that
inflammation may not be the mediating link between lung- and vascular function in this
population. In the third manuscript the contribution of lung function in predicting all-cause and cardiovascular mortality in Africans was investigated, while taking inflammatory markers into account. The cardiovascular mortality group had the lowest FEV1 and FVC values when compared to the survivors and the non-cardiovascular mortality group. CRP did not significantly
predict all-cause or cardiovascular mortality in any of the Cox-regression models, however IL-6predicted all-cause mortality independent of potential confounders. Furthermore, FVC predicted cardiovascular mortality independent of several covariates (hazard ratio, 0.57 [0.35-0.94]), including C-reactive protein (CRP). When CRP was replaced by IL-6 in the model, the significance of FVC was lost (hazard ratio, 0.85 [0.55-1.30]). Our results suggest that FVC is a strong predictor of cardiovascular mortality in this population of black South Africans and that this association may be mediated by IL-6. However, further research is needed to establish the exact mechanism behind this association and this provides a strong motive for future research on the matter. General conclusion - We showed for the first time that reduced lung function is independently associated with arterial
stiffness and is prognostic of cardiovascular mortality in a large black population. In addition, elevated blood pressure is also related to reduced lung function. Although we further determined that reduced lung function is associated with increased inflammation in this population of black South Africans, the role of inflammation as the mediator for the relationship between lung function and CVD remains controversial. However, our findings showed that IL-6
seems to play a more significant role than CRP in this regard. This study underlines the
importance of preserving normal lung function, both in an occupational- and household environment. Ultimately, our findings lend support to the consideration of reduced lung function as a risk factor for the high prevalence of cardiovascular morbidity and mortality in black South Africans.Doctora
