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Title: Skeletal muscle, exercise and activity in pulmonary hypertension
Authors: Sithamparanathan, Sasiharan
Issue Date: 2018
Publisher: Newcastle University
Abstract: Pulmonary Arterial hypertension (PAH) is a rare and progressive condition presenting with exercise intolerance, leading to right ventricle (RV) failure and death. There has been significant progress in understanding the basic pathophysiology leading to the development of a number of targeted therapies, resulting in improved prognosis. Despite this, patients remain limited in performing exertional activities with a poorer quality of life. Recent research has focused on PAH being a multi-systemic disease with skeletal muscle dysfunction contributing to exercise intolerance. There needs to be greater understanding of the physiological and behavioural mechanisms that limit daily functional capabilities in PAH patients. The aims of the thesis were to study the role of skeletal muscle mitochondrial function, the limitations in central and peripheral haemodynamics on maximum exercise, and develop a greater understanding of whether habitual daily physical activity levels are improved by current pharmaceutical treatments. Using 31Phosphorous-magnetic resonance spectroscopy (31P-MRS), oxygen delivery as opposed to impaired mitochondrial function would explain the abnormal skeletal muscle bioenergetics observed. This is further supported by analysing skeletal muscle biopsy samples demonstrating that mitochondrial protein expression and function was normal, therefore not contributing to impaired exercise capacity. Using continuous non-invasive cardiac output, chronotropic incompetence and reduced peripheral oxygen extraction are the predominant mechanisms leading to impaired peak oxygen consumption. Finally, in a pilot study targeted-therapies failed to change habitual daily physical activity and fatigue levels in PAH patients despite a significant observed change in submaximal exercise capacity. In conclusion, a number of physiological mechanisms that impair exercise capacity and habitual physical activity in PAH are beyond the currently available targeted therapies. Further research is needed into how best to improve exercise capacity, fatigue and activity levels that will directly lead to improvement in quality of life for PAH patients.
Description: MD Thesis
Appears in Collections:Institute of Cellular Medicine

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