Cardiovascular disease and reduced pulmonary function in black South Africans : investigating the interplay with markers of systemic inflammation

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