title: Exercise pathophysiology and exercise therapy in Pulmonary Arterial Hypertension
Creators: name: MacKenzie, Alison
Publisher: name: University of Glasgow
Year: 2020
Subjects: subject: Pulmonary Hypertension, exercise, physiology, pehabilitation.

description: Pulmonary hypertension (PH) is an incurable disorder of the pulmonary circulation, characterised by progressive vascular remodelling, vasoconstriction and increased right ventricular afterload. The direct consequence of this is impaired cardiac output, initially in response to exercise and in later stages of the disease at rest. Progressive exercise limitation is the cardinal clinical feature and ultimately premature death from right heart failure ensues. Available disease targeted treatments slow progression, however, PAH remains incurable with a high symptom burden and prognosis remains poor. Lung transplantation provides the only hope of cure. A small proportion of patients are eligible and fit enough for transplantation, notwithstanding the availability of suitable donor lungs and associated post-transplant morbidity in those who survive. Current drug therapy is expensive and is limited to three classes of pulmonary arterial vasodilator. The most effective form of treatment, epoprostenol, is invasive, requiring central venous access and significantly impacts on quality of life despite the associated improvements in exercise capacity. The abnormalities in the right ventricle and pulmonary circulation are well established in PH. More recent evidence has highlighted multi-system abnormalities in PH patients, with muscle dysfunction from a clinical to cellular level, systemic inflammation and insulin resistance. It is unclear whether these changes are a result of the atrophying effects of low cardiac output, or a systemic process associated with PH but independent from cardiac function. Historically exercise had been avoided in PAH, however recent evidence suggests it provides significant benefit in terms of exercise capacity and quality of life. Exercise is an attractive therapeutic option for many reasons. With established infrastructure, it is cost effective, sustainable and provides wide-ranging benefits out with the pulmonary circulation, such as reduced risk of diabetes, cardiovascular disease and improved mental health. The exercise programmes studied in PAH have been wide ranging in terms of the approach used and have shown variable degrees of success. The most successful programmes have employed fairly intensive exercise regimens and many countries do not have the resource or infrastructure to adopt this approach. The role of exercise therapy in PAH and the mechanisms by which it exerts a beneficial effect remain poorly understood. It is also unclear what the best outcome measure is to determine the efficacy of exercise-based interventions in PAH. The feasibility of intensive exercise therapy in countries where residential exercise programmes are not robustly established remains untested. The aims of this thesis are • To establish the population demand, feasibility and safety of PH specific exercise therapy in a UK pre-capillary PH population. • To explore potential physiological and biological mechanisms behind the improvements seen in exercise capacity in order to gain a greater understanding of the disease process. • Identify key components of the exercise programme to allow recommendations for effective PAH exercise prescriptions moving forwards. To address the aims of the thesis, three studies were performed. The first two studies were precursors to the main study discussed in chapters 5 to 9: 1. “Assessing the demand for exercise therapy in a Scottish PAH population” (Chapter 2): 2. “The ventilatory, gas exchange and haemodynamic response to upright and supine exercise”, (Chapter 3), 3. “The effect of adding exercise training to optimal drug therapy in Pulmonary Arterial Hypertension”. Chapter 1 provides an introduction to exercise physiology in PAH and describes the current state of knowledge regarding exercise therapy in PAH Chapter 2 describes the current standard of care for patients with PAH in Scotland and the demand for exercise therapy in the Scottish PAH population. From this data, it is clear that there is significant enthusiasm for exercise rehabilitation in PAH. Potential barriers to its uptake or implementation were explored and these included employment, carers commitments and proximity to the exercise venue. In Chapter 3, the ventilatory, gas exchange and haemodyanamic responses to upright and supine exercise are discussed in order to determine the degree to which exercise capacity is reduced in the supine position and the physiological changes that accompany this. This information was used to help design the protocol used for supine endurance exercise with invasive haemodynamic measurements, discussed in Chapter 7. From this data, it is clear that exercise capacity is significantly reduced in the supine position, this appeared to be due to changes in ventilatory efficiency and was associated with significant alterations in the stroke volume – heart rate response to exercise. Chapter 4 outlines the study protocol and exercise intervention for the main study in this thesis “The effect of adding exercise training to optimal drug therapy in Pulmonary Arterial Hypertension”. Chapter 5 describes the overall efficacy of exercise therapy in PAH in relation to the primary outcome measures of the study “The effect of adding exercise training to optimal drug therapy in Pulmonary Arterial Hypertension”; specifically, 6 minute walk distance (6MWD), quality of life and right ventricular ejection fraction. Analysis of potential “responders” and “non-responders” and factors associated with poorer prognosis are discussed in an exploratory post-hoc analysis. Chapters 6 to 9 adopt a systems-based approach to describe the physiological and pathobiological changes that are present in the studied PAH cohort and the factors that change with exercise therapy. Each chapter discusses the specific relationship with responders and non-responders to exercise therapy in more detail. The specific methods used to assess each system are discussed in the individual chapters and the overall protocol for the exercise therapy is discussed in Chapter 2. Chapter 6 discusses the impact of exercise therapy on lung function, looking at cardiopulmonary exercise testing (CPET), pulmonary function tests and mouth pressures. The sensitivity of different exercise outcome measures are also explored including cycling endurance time, 6MWD, and incremental CPET. Chapter 7 investigates invasive haemodynamic responses to exercise therapy using both resting and exercise right heart catheterisation. A steady state exercise protocol is used to assess serial measurements of haemodyamics and oxygen extraction throughout exercise. In Chapter 8, a non-invasive approach to assessing cardiac status before, during and after exercise therapy is investigated using cardiac magnetic resonance imaging and N-terminal pro brain natriuretic peptide (NTproBNP). These changes are correlated with invasive haemodynamic markers. Chapter 9 discusses the impact of exercise therapy on muscle function, metabolism and levels of systemic inflammation. Serum and muscle biomarkers are explored to provide pilot data on potential mechanisms for PAH myopathy and how it may be reversed. Collectively these chapters demonstrate improved exercise capacity and quality of life in response to exercise therapy in PAH. This is associated with improved ventilatory efficiency and cardiovascular function, with changes being linked to prognosis. Potential mechanisms behind these improvements are explored and include the reversal of deconditioning, lung recruitment, improved vascular endothelial health, reduced atrial stretch and reduced hyperventilation. Chapter 10 outlines the major findings and conclusions of this research and future research avenues to be explored.