Physical inactivity is a primary risk factor for most chronic diseases and accounts for many deaths worldwide. Physical inactivity predisposes towards exercise intolerance, which is the strongest predictor of mortality in health and disease. The ability to sustain exercise is predominantly determined by the ability of the body to transport and utilize oxygen, however the pathophysiology of exercise intolerance remains poorly understood. The current thesis described four experimental studies to investigate the plasticity of oxygen uptake (\/02) and skeletal muscle microvascular oxygenation dynamics under the conditions of health, disease, prior exercise, and hypoxia, in an attempt to better understand the control and limitation of aerobic energy transfer during exercise and its association with exercise intolerance. The initial study developed the first clinical assessment of chronic heart failure (CHF) patients that was able to delineate between attainment of the peak and maximum \/02, The nature of the test design, incorporating prior high-intensity exercise, further revealed that a large subset of patients were able to increase peak \/02 acutely, and this may represent a novel therapeutic target in CHF. To better understand the aetiology of this effect, a moderate-intensity warm- up exercise intervention was used, and revealed two subsets of CHF patients: those in whom \/02 kinetics were limited by a microvascular oxygen delivery and those in whom an intramuscular pathology of oxygen utilization was implicated: the latter being associated with greater disease severity. In vi addition, this study revealed a transient dynamic overshoot in microvascular deoxygenation during exercise - common to CHF - was ameliorated by prior activity, and this was associated with speeded \/02 kinetics. These findings were mirrored in healthy humans, where progressive reductions in oxygen delivery were associated with a lower microvascular oxygenation. These studies confirmed for the first time in humans that the transient microvascular deoxygenation can limit \/02 kinetics. Impairments to skeletal muscle oxygenation therefore likely contribute to the pathophysiology of exercise intolerance demonstrated in health and disease. The final study focused on intramuscular mechanisms that slow \/02 kinetics in health. This study confirmed \/02 kinetics were slowed when exercise was initiated from a raised moderate-intensity work rate, but this was consequent to the raised metabolic rate per se. A reduced intracellular energetic state in the active muscle fibres was implicated to be the mechanism slowing \/02 kinetics during the transient. Overall, the in vivo and in silico evidence collected here has provided new insight into the physiology and pathophysiology underpinning the dynamics of aerobic energy transfer during exercise and its association with exercise intolerance in health and disease. The experiments presented are expected to form the basis of novel therapeutic strategies that may help ameliorate pathological symptoms in CHF and other disease states characterized by exercise intolerance.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:589383 |
| Date | January 2012 |
| Creators | Bowen, Thomas Edward Scott |
| Publisher | University of Leeds |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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