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Haemodynamics and biochemistry of a hypertensive response to exercise


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Nikolic, SB (2004) Haemodynamics and biochemistry of a hypertensive response to exercise. PhD thesis, University of Tasmania.

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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
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.

Item Type: Thesis (PhD)
Keywords: Blood pressure, exercise, metabolomics, haematology, haemodynamics
Copyright Holders: The Author
Copyright Information:

Copyright 2014 the author

Additional Information:

Chapter 2 Part II is the equivalent of a non-final version of an article published in final form as: Nikolic SB, Sharman JE, Adams MJ, Edwards LM. Metabolomics in hypertension.
J Hypertens. 2014; 32:1159-1169

Chapter 5 has been previously published as: Nikolic SB, Wilson R, Hare JL, Adams MJ, Edwards LM, Sharman JE. Spironolactone reduces aortic stiffness via blood pressure-dependent effects of canrenoate. Metabolomics. 2014;10:105-113 The final publication is available at Springer via

Appendix 1 was previously published as: Nikolic SB, Abhayaratna WP, Leano R, Stowasser M, Sharman JE. Waiting a few extra minutes before measuring blood pressure has potentially important clinical and research
ramifications. Journal of human hypertension. 2014;28:56-61

Chapter 4 later published as: Sonja B. Nikolic, Murray J. Adams, Petr Otahal, Lindsay M. Edwards, James E. Sharman, Association of von Willebrand factor blood levels with exercise hypertension, 2015;115,5:1057-1065

Chapter 6 was later published as: Sonja B. Nikolic, Lindsay M. Edwards, Yuliya V. Karpievitch, Richard Wilson, James Horne, Murray J. Adams, James E. Sharman, Serum metabolic profile predicts adverse central haemodynamics in patients with type 2 diabetes mellitus, Acta Diabetologica, online first 4/9/15. The final publication is available at Springer via​1007/​s00592-015-0802-4

Appendix 2 was later published as: Yuliya V. Karpievitch, Sonja B. Nikolic, Richard Wilson, James E. Sharman, Lindsay M. Edwards, Metabolomics data normalization with EigenMS, online 30/12/14

Date Deposited: 13 Oct 2015 22:31
Last Modified: 22 Mar 2016 00:29
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