This short-term study aims to prove the potential cardio-protective physiological effect of inhaled aclidinium bromide/formoterol fumarate on inspiratory pleural pressures.

Smoking is associated with gas-trapping (hyperinflation), even in the absence of chronic obstructive pulmonary disease. Breathing in the presence of gas-trapping requires large negative inspiratory pleural pressures, which are transmitted to the surface of the heart and increase cardiac wall stress.

Inhaled aclidinium bromide and formoterol fumarate has been shown to reduce gas-trapping, but the impact on inspiratory pleural pressures and biomarkers of cardiac stress in smokers is unknown.

Inclusion Criteria:

• Current and former smokers with ≥20 pack-years of smoking history
• Gas-trapping (residual volume >110% predicted)

Exclusion Criteria:

Physician-diagnosis of chronic obstructive pulmonary disease in the past 1 year and regular use of long-acting antimuscarinic (LAMA) and/or long-acting beta-agonist (LABA) (i.e., at least 30 consecutive days)

• Physician-diagnosis of asthma in the past 5 years
• Regular inhaled corticosteroid (ICS) use in the past 5 years (i.e., at least 30 consecutive days)
• Physician-diagnosis of other lung diseases (sarcoidosis, tuberculosis, cystic fibrosis, pulmonary fibrosis, lung cancer), or long-term oxygen therapy
• Respiratory tract infection within 4-weeks
• Physician-diagnosis of arrhythmia, or significant valvular disease.
• Physician-diagnosis of myocardial infarction, unstable angina or heart failure requiring unscheduled outpatient or emergency department visit within 6-months.
• Arrhythmia or prolonged corrected QT (QTc) on electrocardiogram.
• Inability to use study inhaler
• Glaucoma
• Benign prostatic hypertrophy
• Pregnancy
• Allergy to the study treatment, salbutamol, lidocaine, or severe milk protein allergy (note: lactose intolerance is not an exclusion criteria)
• Contraindications to anti-cholinergic, beta-agonist, or cardiopulmonary exercise testing with manometry
• Inability to provide written informed consent

Self-reported gender

Matched placebo.