Static Lung Hyperinflation and Sympathetic Nerve Activity-Associated Large Artery Stiffness in COPD Patients

The goal of this study is to evaluate the acute effects of a long-acting bronchodilator on pulmonary function, vascular function and muscle sympathetic nerve activity in individuals with COPD. Individuals will be recruited from previous pulmonary research cohorts at The University of Iowa hospitals and clinics. Individuals that are interested in the study and are deemed eligible to participate will have a total of 3 visits to the laboratory, which includes the screening and consent (visit 1) that will last approximately 1 hour. Visits 2 and 3 are experimental visits and will be more extensive (\~4 hours). Participants will be randomized to receive either a long-acting bronchodilator or a placebo inhaler at the first experimental visit, followed by either the placebo inhaler or the long-acting bronchodilator at the second experimental visit. Assessments of pulmonary function, vascular function (via non-invasive, well-established techniques), and muscle sympathetic nerve activity will be performed at both experimental visits.

COPD is a global health concern affecting more than 65 million people worldwide. In the U.S. alone, the estimated medical costs attributed to COPD surpassed $30 billion in 2010. A high percentage of this healthcare cost is attributed to the management of comorbidities associated with COPD, such as CVD. Although primarily a disease of the lungs, CVD accounts for up to 50% of all deaths among individuals with COPD. One likely mechanism contributing to the increased CVD risk observed in individuals with COPD is large central artery (i.e. carotid and aorta) stiffness. Elevated large artery stiffness is a robust predictor of CVD events and mortality in adults. Specifically, carotid-femoral pulse wave velocity (CFPWV), the reference standard measurement of aortic stiffness, is a robust, independent predictor of coronary heart events, and carotid artery stiffness, expressed as β-stiffness index, is strongly associated with incident stroke. Both CFPWV and carotid β-stiffness are markedly greater in individuals with COPD compared with age-matched controls suggesting that these mechanisms may contribute, at least in part, to the high CVD risk in this group. However, there is currently a gap in knowledge concerning the mechanisms that lead to increased large artery stiffness in individuals with COPD in part because assessing large artery stiffness among individuals with COPD has been limited to comparing aortic and carotid artery stiffness in all COPD patients with non-COPD controls, without differentiating between distinctive phenotypes of COPD. As a result of this overly simplistic approach, it has proven challenging to identify the mechanism(s) responsible for the accelerated large artery stiffness among COPD patients because different mechanisms may contribute to large artery stiffness in the various phenotypes of COPD. The two main computed tomography (CT)-quantifiable phenotypes that individuals with COPD can be subdivided into are emphysema-and airway-predominant phenotypes. COPD patients with an airway-predominant phenotype display characteristic signs of small airway disease including increased airway wall thickness, heightened airway inflammation and a greater concentration of mucus exudates in the small conducting airways. This structural remodeling leads to a greater amount of air to become trapped in the airways at residual volume and increases the resting volume of the lungs producing static lung hyperinflation. COPD patients with an airway-predominant phenotype have little or no emphysema and account for up to 60% of all mild-to-moderate COPD patients (i.e. Global Initiative for COPD; GOLD stage 1-2) and up to 25% of all severe-very severe COPD patients (GOLD 3-4). Although airway predominant patients are typically in the earlier stages of COPD progression, they are at greater CVD risk than emphysema-predominant COPD patients who make up the majority of severe-very severe (GOLD 3-4) COPD patients. However, the mechanisms responsible for the heighted CVD risk demonstrated in airway-predominant patients remain unclear. Our preliminary data demonstrate that static lung hyperinflation is strongly associated with carotid artery and aortic stiffness. These data suggest that static lung hyperinflation may be a mechanism contributing to the higher CVD risk in airway-predominant phenotypes of COPD in part from its effects on large artery stiffness. Bronchodilator therapy reduces static lung hyperinflation and improves respiratory symptoms in individuals with COPD, however the effects of bronchodilator therapy on CVD risk remain unclear. Combination long-acting muscarinic antagonist and long-acting beta2-agonist bronchodilator (LAMA/LABA) therapy reduces air-trapping and static lung hyperinflation to a greater extent than either monotherapy alone. This evidence suggests that a LAMA/LABA combination bronchodilator will elicit the greatest changes in large artery stiffness because of its superior effects on lung deflation compared with either medication alone.

Sympathetic nerve activity (SNA) is elevated in COPD patients compared with controls and is an independent predictor of morbidity and mortality in this group. However, the mechanisms underlying the hyperactivation of SNA in COPD remain incompletely understood. In healthy individuals, acute static lung hyperinflation, induced by Valsalva maneuver, is associated with a sustained increase in intrathoracic pressure and a subsequent decrease in central venous volume. This decrease in central venous volume in turn unloads the cardiopulmonary baroreceptors and results in sustained sympathetic activation. Importantly, in individuals with COPD, the positive pressure within hyperinflated lungs at the end of expiration from lung air-trapping raises intrathoracic pressure, reduces venous return and decreases ventricular filling theoretically unloading the cardiopulmonary baroreceptors. However, the effects of static lung hyperinflation on SNA and large artery stiffness in COPD patients remain unknown. Therefore, this novel study will provide important information regarding the underlying mechanisms that potentially contribute to the heightened CVD risk demonstrated in individuals with COPD.

Eligibility Criteria:
Inclusion Criteria:

* Age 30-80
* Ability to comfortably lie flat for 2 hours
* Normal/corrected hearing and vision
* English speaking
* Airway predominate phenotype of COPD

Exclusion Criteria:

* Other concomitant respiratory disorder (including asthma)
* Use of antibiotics or steroids for a COPD exacerbation within the past month
* Use of 24-hour oxygen
* Pregnancy or suspected pregnancy
* Uncontrolled cancer within the last 5 years
* Radiation therapy to the chest
* Lung surgery (LVRS, transplant, lobectomy)
* Lung cancer known or suspected
* Insulin-dependent diabetes
* Inability to use an inhaler bronchodilator
* Eye surgery in the last 5 weeks
* Chest or abdominal surgery in the past 3 months
* Heart attack in the last 3 months
* Hospitalization for any heart problem in the past month
* Renal failure
* Heart failure
* Substance use disorder
* Cystic fibrosis
* Glaucoma
* Prostate disorder
* Allergy to milk or milk products
* Cardiac arrhythmia
* Currently using a LAMA/LABA combination bronchodilator