Static Lung Hyperinflation and Sympathetic Nerve Activity-Associated Large Artery Stiffness in COPD Patients
Condition: COPD
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Umeclidinium / Vilanterol Dry Powder Inhaler; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): umeclidinium/vilanterol dry powder inhaler; Placebo inhaler
Other intervention name(s): Anora Ellipta
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science