The mechanisms of right ventricular dysfunction following lung resection

Lung cancer is the leading cause of cancer death in the UK and whilst lung resection, in appropriate cases, offers the best chance of cure it is associated with significant post-operative morbidity and mortality. Post-operative right ventricular dysfunction, secondary to an increase in afterload, has long been hypothesised to contribute to this morbidity although this has not been well demonstrated. Previous studies have used echocardiography and volumetric pulmonary artery catheters to assess changes in right ventricular function and afterload. These studies, however, are undermined by the reliability of the methods utilised and by their incomplete assessment of afterload. To better evaluate this our research group has undertaken a cardiac magnetic resonance study and demonstrated right ventricular dysfunction following lung resection. This thesis details investigation of right ventricular strain and afterload as potential mechanisms of this dysfunction. The introduction (Chapter 1) reviews the management of lung resection and the right ventricle, detailing its anatomy and physiology, with a particular focus on the pathophysiology and assessment of right ventricular failure secondary to increases in afterload. In Chapter 2, a literature review of studies investigating changes in right ventricular function and afterload following lung resection is presented. These studies have failed to demonstrate a significant change in afterload quantified by measurement of pulmonary artery pressure and/or pulmonary vascular resistance. These indices, however, only assess global impedance to steady flow and overlook impedance to pulsatile flow. Chapter 3 details the aims and the investigations performed in this thesis. The rationale, design, methodology and generic results of the first sequential cardiac magnetic resonance study to investigate right ventricular dysfunction are presented in Chapter 4. Additionally, the previous results from this study (reported prior to this thesis) are presented, the main finding of which is a post-operative reduction in right ventricular ejection fraction. All subsequent investigations presented in this thesis are performed on the cardiac magnetic resonance images collected within this study. The first investigation (Chapter 5) utilises CMR right ventricular strain analysis to assess changes in right ventricular function following lung resection. A review of strain analysis, measurement and changes in states of increased right ventricular afterload is presented followed by a review of three prior, but contradictory echocardiographic strain investigations in patients undergoing lung resection. This investigation demonstrates that there is no immediate change, but a delayed reduction in global and free wall right ventricular longitudinal strain evident at 2-months following lung resection. Chapters 6 and 7 investigate changes in right ventricular afterload, focusing on assessment of the pulsatile components of afterload. As lung resection is a unilateral insult to the pulmonary vasculature, indices that allow assessment of unilateral changes of afterload are described. Assessment is therefore performed in the main pulmonary artery and the branch (right or left) supplying the resected lung (termed the operative pulmonary artery) and the non-resected lung (non-operative pulmonary artery). Chapter 6 assesses pulmonary artery flow, acceleration time and distensibility following lung resection. It demonstrates, for the first time, an increase in right ventricular pulsatile afterload following lung resection. Post-operatively, pulsatile afterload is increased along with an altered distribution of cardiac output away from the operative pulmonary artery. On post-operative day two, indices of afterload in the non-operative pulmonary artery are associated with a reduction in right ventricular ejection fraction. The first use of wave intensity analysis in a lung resection cohort is presented in Chapter 7. Wave intensity analysis combines flow and area measurements in the time domain to calculate wave intensity, a measure of the rate of transport of wave energy, and assesses pulsatile afterload by calculation of wave reflection index. This investigation again demonstrates a post-operative increase in pulsatile afterload and the presence of early wave reflection in the operative pulmonary artery. Finally, Chapter 8 investigates the relationship between changes in right ventricular function (ejection fraction and strain) and changes observed in pulsatile afterload. This is the first evidence linking a reduction in right ventricular function to an increase in afterload following lung resection. At 2-months postoperatively, increased wave reflection is strongly associated with a reduction in right ventricular free wall strain. The increase in pulsatile afterload observed in the operative pulmonary artery is associated with an increase in the percentage of cardiac output travelling in the non-operative pulmonary artery which, in turn, is associated with the reduction in both right ventricular ejection fraction and strain at 2-months. The investigations presented in this thesis demonstrate, for the first time, the widely hypothesised increase in right ventricular afterload occurring following lung resection and its association with a decrease in right ventricular function. The thesis concludes with a discussion of future work describing the design and successful funding of two studies building on the results from this thesis; a pilot study investigating the right ventricular response to exercise following lung resection and a cardiac magnetic resonance investigation of right ventricular inflammation following lung resection