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Pathophysiology of pulmonary hypertension in chronic obstructive pulmonary disease

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thesis
posted on 27.02.2017, 03:52 authored by Wrobel, Jeremy
Chronic obstructive pulmonary disease (COPD) is a major international health burden. Moderate and severe COPD is often complicated by the development of pulmonary hypertension (PHT) which is associated with a worse prognosis. As targeted therapies for PHT in COPD patients are lacking, there is renewed interest in understanding the underlying pathophysiology of this complication. An extensive literature review reveals that the aetiology of PHT in COPD is complex, multifaceted and due to both pre- and post capillary mechanisms. Furthermore, the strength of evidence implicating the various postulated mechanisms is highly variable. This thesis contributes to our understanding of PHT in COPD by investigating clinical, pathological and physiological aspects of this condition. PHT in COPD is associated with a poor prognosis and there is evidence to suggest that it may also be associated with inferior outcomes following lung transplantation. We retrospectively studied a single institution’s transplant experience over a 10 year period. Amongst 46 patients that underwent lung transplantation for COPD, patients with moderate-severe PHT on echocardiographic criteria, had inferior short-term outcomes following lung transplantation. The potential pathophysiological mechanisms underlying this are discussed with a focus on cardiopulmonary interactions. Pulmonary arterial remodelling is a pathological hallmark of pulmonary arterial hypertension. Although pulmonary arterial remodelling has also been demonstrated in patients with COPD, the significance of this is unclear. We performed prospective pathological assessment on stored explanted lung specimens from 42 COPD lung transplant patients and demonstrated significant pulmonary arterial remodelling compared with non-smoking, age-matched controls. There was significant heterogeneity of remodelling in the COPD patients. Although remodelling was not significantly increased amongst COPD patients with moderate-severe PHT compared with no PHT or mild PHT, complex interactions were identified between pulmonary arterial pressure, lung lobe and pulmonary arterial size. Furthermore, there was a positive relationship between pulmonary arterial remodelling and regional perfusion which suggests that cardiopulmonary interactions likely contribute to the remodelling process. Functional factors have also been postulated to contribute to PHT in COPD. In particular, it has been suggested that dynamic hyperinflation is associated with increased pulmonary arterial pressures in patients with COPD. We prospectively investigated the haemodynamic effects of intermittent positive pressure ventilation on 22 subjects with severe, stable COPD. We demonstrate that increased airway pressure was associated with a small but consistent increase in the diastolic pulmonary arterial pressure. Whilst this study provides “in principle” support for the notion that dynamic hyperinflation is associated with increased pulmonary arterial pressures, the magnitude of change is of marginal clinical significance for patients during spontaneous ventilation. Nevertheless, the cardiovascular consequences of intermittent positive pressure ventilation demonstrated in this study suggest that cardiopulmonary interactions are clinically relevant in patients receiving positive pressure ventilation. This thesis demonstrates that cardiopulmonary interactions contribute to the pathophysiology and clinical outcomes in COPD patients with PHT. Further research is required to better understand the full extent of these interactions and to explore avenues to translate this information into improved clinical outcomes.

History

Principal supervisor

Trevor Williams

Year of Award

2014

Department, School or Centre

Medicine

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences