Haemodynamics and biochemistry of a hypertensive response to exercise

A hypertensive response to exercise (HRE) at moderate intensity is associated with an increased cardiovascular (CV) risk, irrespective of a normal resting BP. This is an important observation, as moderate intensity exercise blood pressure (BP) is akin to the condition experienced during normal daily life activities and may better represent a chronic BP load that people experience on a daily basis when compared to resting office BP. However, the pathophysiological mechanisms of an HRE are unclear. Therefore, the overall aim of this thesis was to explore the haemodynamic and biochemical (haemostatic and metabolic) correlates of an HRE. In study 1 (Chapter 4), haemodynamic and haemostatic factors were examined in 64 participants (aged 57 ¬± 10 years, 71% male) with a clinical indication for exercise stress testing. This study showed for the first time that people with an HRE have higher blood levels of the von Willebrand factor (vWf; a haemostatic marker of endothelial dysfunction), as well as a significantly different response of vWf to exercise compared to people with normal exercise BP. Moreover, vWf was associated with moderate intensity exercise systolic BP, independent of resting office BP and other CV risk factors, whereas haemodynamic factors (including increased aortic stiffness) were not independently related to exercise systolic BP. This study suggests that haemostatic abnormalities reflecting endothelial dysfunction, rather than haemodynamic irregularities, may contribute to an HRE at moderate intensity. In study 2 (Chapter 5), retrospective metabolomics analysis of data collected in a clinical trial of people with an HRE was conducted in 115 participants (aged 55 ¬± 1 years, 58% male) in order to develop a metabolomics technique, as well as to investigate the underlying mechanisms of spironolactone's action on exercise BP and other haemodynamics. This study showed that spironolactone reduced exercise BP, as well as aortic stiffness, via BP-dependent effects of canrenoate, a downstream drug metabolite of spironolactone. Importantly, this study also showed that a reduction in exercise BP was not associated with the decrease in aortic stiffness, giving further support that aortic stiffness may not be as relevant to an HRE as is widely believed. In study 3 (Chapter 6), untargeted metabolomics analysis was used to explore possible metabolic factors related to an HRE in 39 participants with type 2 diabetes mellitus (T2DM; 62 ¬± 9 years; 51% male; a population with the high prevalence of an HRE) compared with 39 non-diabetic controls (52 ¬± 10 years; 46% male). Metabolomics analysis demonstrated that a metabolic pattern of disordered carbohydrate metabolism in T2DM may be a possible metabolic mechanism explaining central (but not peripheral) exercise hypertension. These findings have clinical relevance as central haemodynamics have shown a greater pathophysiological importance when compared with peripheral haemodynamics. Also, inosine levels (a metabolite with anti-inflammatory actions) were found to be decreased in people with T2DM and were also inversely associated with the peripheral moderate intensity exercise systolic BP. This indicates that inflammation may be a contributing factor to an HRE in people with T2DM. This research program also involved publication of a review article on the application of metabolomics analysis in hypertension research (Journal of Hypertension, 2014; Chapter 2- Review of Literature ‚- Part II), which will allow especially the non-experts in this field to better understand and interpret studies utilising metabolomics techniques. Importantly, the research program contained in this thesis demonstrates how metabolomics analysis could be used for exploring new insights into the underlying pathophysiological processes associated with high BP (which could be easily applied to different disease conditions). Also, the research projects included the development of methodology regarding metabolomics analysis (manuscript in submission - Appendix 2), as well as the development of a protocol for resting BP measurements (Journal of Human Hypertension, 2014; Appendix 1). Overall, the work contained in this thesis has found that people with an HRE have abnormal haemodynamics, but these do not explain exercise hypertension. However, people with an HRE have abnormal blood biochemistry (haemostasis and metabolic markers related to carbohydrate metabolism and inflammation in T2DM) and these explain exercise hypertension independent of resting BP and other CV risk factors. Taken altogether, this thesis provides novel information, and represents a significant advancement to the understanding of the pathophysiology of an HRE at moderate intensity.