N–terminal prohormone B–type natriuretic peptide, inflammation and the vasculature : exploring the links in a bi–ethnic South African population
Cardiovascular disease states including hypertension and vascular stiffness are precursors of cardiac damage such as heart failure. The prevalence of cardiovascular disease among the African population in South Africa is also increasing dramatically. The N–terminal prohormone B–type natriuretic peptide (NT–proBNP) is a reliable biomarker and predictor of cardiovascular risk and heart failure. During the onset and development of heart failure, the heart undergoes structural and functional changes including hypertrophy and vascular remodelling. NT–proBNP levels are normally lower in men compared to women, but less is known about ethnic differences and also the associations between NT–proBNP and measures of cardiovascular function. Information on factors affecting vascular function and therefore the synergy between blood vessels and the heart leading to cardiac damage in a bi–ethnic South African population is also scant. Therefore, this study included markers of both atherosclerosis (C–reactive protein, soluble urokinase plasminogen activator receptor, fibulin–1) and arteriosclerosis (arterial compliance and alkaline phosphatase) to address the underlying vascular changes that augment cardiac load and damage. The lack of information in this regard, especially in South Africans, serves as motivation for this study. Aim The purpose of this study was to explore the possible associations of NT–proBNP with cardiovascular function and also biochemical components that may contribute to the development of cardiovascular disease in both African and Caucasian men and women. Methodology Data from the South African study regarding the role of Sex, Age and Ethnicity on Insulin sensitivity and Cardiovascular function (SAfrEIC) were used, and presented in the manuscript Chapters 3, 4, 5 and 6. This study included 756 Africans and Caucasians in total. Groups were stratified by ethnicity or gender, or both ethnicity and gender as specified by statistical interaction terms. Cardiovascular measurements were performed and NT–proBNP, fibulin–1, high sensitivity Creactive protein (CRP), soluble urokinase plasminogen activator receptor (suPAR) and also alkaline phosphatase (ALP) levels were determined. Means were compared with either T–tests or analysis of variance (ANOVA). Significant differences between groups were also tested with analysis of covariance (ANCOVA) with adjustments applied for age, body mass index (BMI) and systolic blood pressure (SBP). Partial correlations were performed to investigate associations between various variables with adjustments applied for age, BMI and SBP. Multiple regression analyses were performed to investigate independent associations between variables in the different groups. Results and conclusions of each manuscript The first paper in this thesis (Chapter 3) aimed to compare NT–proBNP as a marker of cardiac load and its possible associations with markers of cardiovascular function in Africans and Caucasians. The results indicated that the African population revealed higher NT–proBNP levels compared to Caucasians, however, these were partially confounded by SBP and completely by arterial compliance. NT–proBNP was positively associated with both SBP and pulse pressure in Africans, but not in Caucasians. Also, after adjustments were applied for significant covariates and confounders, the positive significant association remained in Africans only. These associations may suggest early vascular changes contributing to cardiac alterations in Africans. The aim in Chapter 4 was to explore the relationship between NT–proBNP and fibulin–1 (an extracellular matrix component and also expressed in atherosclerotic lesions) in African and Caucasian men and women. NT–proBNP was positively associated with fibulin–1 in African men only after adjustments were applied for age, BMI, SBP, heart rate and estimated creatinine clearance. No significant link existed between NT–proBNP and measures of arterial stiffness in any of the groups. However, after full adjustment, the positive significant association between NT–proBNP and fibulin–1 was confirmed in African men and also in younger African men and women after excluding participants older than 55 years. These associations were not present in the Caucasians. This suggests that vascular alterations also occur in young African men and women and that they may be prone to develop cardiovascular disease much earlier as opposed to Caucasian men and women. Due to earlier vascular changes present in the African population, we aimed to investigate the link between NT–proBNP and inflammatory markers (both CRP and suPAR) in African men and women (Chapter 5), independent of a hypertensive state. Although the levels of NT–proBNP and inflammatory markers were lower in men compared to women, the results showed that NTproBNP is positively and significantly associated with both CRP and suPAR in the normotensive African men only. No significant association was observed in normotensive African women. After full adjustments in multiple regression analyses, the positive significant association between NT–proBNP, CRP and suPAR was confirmed in African men. This suggests that in a low–grade inflammatory state, normotensive African men are more susceptible to developing vascular alterations that may result in cardiac overload and damage. In Chapter 6 we explored the possible association of NT–proBNP with a marker of osteoblastactivity, alkaline phosphatase (ALP). This sub–study was performed in a bi–ethnic male population. The results revealed a positive association between NT–proBNP and ALP in African men, but not in Caucasian men. African men also had higher NT–proBNP and ALP levels as opposed to Caucasian men. After adjusting for significant covariates, the link between cardiac strain and osteoblastic activity, and possible vascular calcification was confirmed in African men. This population seems to have a higher susceptibility to develop sclerosis in either the media or intima, which could contribute to cardiovascular damage due to a possible increased cardiac afterload. General conclusion NT–proBNP, a reliable marker of cardiac overload and damage, was positively associated with systolic blood pressure, pulse pressure, fibulin–1, C–reactive protein, soluble urokinase plasminogen activator receptor and alkaline phosphatase. Throughout this study, our findings were persistent in the black South African population, especially African men. These results indicate that the earlier burden of cardiovascular disease in young Africans may result from early vascular changes due to inflammation, extracellular matrix alterations and calcification which could cascade into cardiac strain and damage.
- Health Sciences