Understanding the impact of pulmonary vascular structure and function on exercise tolerance and dyspnea in health and chronic obstructive pulmonary disease

• Author / Creator

  Collins, Sophie É

• The purpose of this dissertation was to examine pulmonary vascular structure and function and its relationship with exercise capacity in individuals with and without chronic obstructive pulmonary disease (COPD). We hypothesized that pulmonary vascular structure and function play a key role in ventilation, dyspnea and exercise tolerance both in health and in COPD. This doctoral dissertation consists of three distinct studies. In the first and second study, we used multimodal research methods to evaluate the relationship between pulmonary vascular structure and function with exercise capacity and physical activity. These analyses used cross-sectional and longitudinal data from the Canadian Cohort Obstructive Lung Disease (CanCOLD) study. For the final study, we took an experimental approach to evaluate the therapeutic potential of pulmonary vascular targets in a prospective cohort of patients with COPD using a placebo controlled, double-blind, randomized control cross-over design.
  The first study aimed to test if baseline physical activity and V̇O2peak are related to baseline pulmonary diffusing capacity and quantitative computed tomography (CT) pulmonary vascular measurements. Participants from the CanCOLD study were categorized into three groups: 1) NS: never-smokers with normal spirometry; 2) ES: ever-smokers with normal spirometry; and 3) COPD: smokers with spirometric airflow obstruction. Total airway count (TAC), total vessel volume (TBV), the volume for all vessels with a cross-sectional area ≤5 mm2 (BV5), and between 5-10 mm2 (BV5-10) were calculated from CT scans, and pulmonary diffusing capacity for carbon monoxide (DLCO) was evaluated via the single breath DLCO technique. V̇O2peak was evaluated by symptom-limited incremental cycle cardiopulmonary exercise tests (CPET). A total of 1,004 participants (NS: 263; ES: 407; COPD: 334) met inclusion criteria. General linear regression models revealed that even after controlling for FEV1, emphysema severity and body morphology, V̇O2peak was independently associated with DLCO, TBV, BV5, BV5-10 but not TAC. Our results suggest that exercise capacity may be predictive of structural and functional differences in the pulmonary vasculature; and that these relationships are not limited to COPD.
  The second project evaluated if higher baseline V̇O2peak is protective of pulmonary vascular decline over three years and if higher baseline pulmonary vascular measures are protective of V̇O2peak decline over the same timeline. A tertiary aim was to determine whether potential associations between pulmonary vascular structure/function and V̇O2peak decline are mediated by exercise ventilatory inefficiency (V̇E/V̇CO2 nadir). Participants with baseline (visit 1) and 3 year follow-up data (visit 3) from the CanCOLD study were categorized into 2 groups: 1) ES; and 2) COPD. CT scan measurements at visits 1 and 3 were generated with identical methods as study #1. Separate random slope and intercept linear mixed effect models were built to evaluate the relationship between baseline V̇O2peak, longitudinal change in DLCO and CT-pulmonary vascular measures, while adjusting for baseline group and participant characteristics (e.g., height, FEV1, etc.,), and vice-versa (relationship between baseline DLCO and CT-pulmonary vascular measures and longitudinal change in V̇O2peak). For the tertiary aim, a mediation model was built to evaluate the relationship between baseline DLCO, LnLAA-950, and BV5/TVV (predictors), with change in V̇O2peak (outcome) through baseline V̇E/V̇CO2 nadir (mediator). Our findings were threefold: 1) Independent of emphysema and degree of airflow obstruction, higher baseline V̇O2peak was protective of small vessel volume decline in ES without COPD and in individuals with COPD; 2) Pulmonary vascular structure/function measures were not associated with longitudinal decline in V̇O2peak in ES or in individuals with COPD; 3) however, lower baseline BV5/TVV and higher DLCO was associated with lower V̇E/V̇CO2 nadir, which in turn was associated with V̇O2peak decline at 3-years follow-up, suggesting a mechanistic role of baseline pulmonary vascular structure and function in determining decline in exercise capacity through exercise ventilatory efficiency in people with and without COPD.
  In the third and final project of this dissertation, we conducted a randomized double-blind placebo-controlled cross-over trial to examine the effects of an acute inhaled selective pulmonary vasodilator (inhaled nitric oxide [iNO]) on V̇E/V̇CO2, dyspnea and V̇O2peak in patients with mild to severe COPD without pulmonary hypertension (NCT03679312). Fifty-two patients with mild to severe COPD were recruited. The first visit comprised of participant enrollment, pulmonary function test, and a symptom limited incremental CPET to determine V̇O2peak. At visit 2, participants completed a cardiac ultrasound to estimate right ventricular systolic pressure with and without iNO. At the next two visits, participants completed an incremental CPET breathing either room air (placebo) or iNO (room air with 40ppm iNO; order of intervention randomized). Finally, at the last visit, participants underwent a chest CT scan to quantify emphysema severity, total vessel count (TVC; a measure of vascular pruning), TBV, and BV5. Twenty nine of 52 patients demonstrated an increase in V̇O2peak with iNO, but in fully adjusted linear mixed models, iNO did not significantly improve V̇O2peak (fixed effect of condition: β= -7.93, 95%CIs= -18.41 to 2.56) or V̇E/V̇CO2nadir (fixed effect of condition: β=0.59, 95%CIs= -
  2.19 to 3.38); however, there was a significant effect of condition on dyspnea (β=-3.41, 95%CIs= -5.25 to -1.57). In secondary analyses, we found that there was no correlation between the change in V̇O2peak (%pred) with iNO and FEV1 (%pred) (condition by FEV1 interaction: p=0.97), DLCO (condition by DLCO interaction: p=0.73) or emphysema (condition by LAA-950% interaction: p=0.20). Exploratory analyses revealed that among CT variables, the measure most closely associated with change in V̇O2peak with iNO was TVC (Condition by TVC interaction: β= 0.001, 95%CIs= -4.74E-5 to 0.001), even after accounting for severity of airflow obstruction and emphysema.

  The results within this dissertation highlight the key role of pulmonary vascular structure and function in health and disease and demonstrates that pulmonary vascular function may be a potential therapeutic target to improve ventilation and exercise capacity in those with COPD.

• Subjects / Keywords

  • chronic obstructive pulmonary disease
  • inhaled nitric oxide
  • exercise capacity

• Graduation date

  Spring 2024

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-8bf6-5r10

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.