Cardiac Limitations in Chronic Obstructive Pulmonary Disease: Benefits of Bronchodilation

This study is being done to examine the influence of Tiotropium (good or bad) on heart function at rest and during exercise in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

Patients who develop chronic obstructive pulmonary disease (COPD) have a loss of elastic recoil of the lungs, have remodeling in the airways and pulmonary vasculature, develop inhomogeneities in ventilation (VA) and perfusion (Qc) and gradually lose their reserves for producing expiratory flow, particularly over the mid to lower lung volumes. As a result, they develop air trapping, have slowed expiration, and gradually hyperinflate with a large residual volume, an exaggerated total lung capacity, reduced vital capacity, and markedly reduced maximal expiratory flows. With exercise, patients with moderate to severe COPD are further challenged by the need for increased ventilation. Expiring against the narrowed airways results in breathing at higher and higher lung volumes until the elastic load on inspiration increases the work and cost of breathing to the point where exercise discontinues. It remains controversial if this scenario leads to primarily dyspnea from the weak and heavily recruited inspiratory muscles, inspiratory muscle fatigue or if a primary limitation might be related to the relatively large cardiac output required for the respiratory muscles, at the expense of the locomotor muscles, resulting in leg fatigue. The expiratory load also increases intrathoracic pressure and reduces the gradient for venous return, thus having the potential to reduce cardiac output. Pulmonary hypertension develops and may influence blood flow to the left side of the heart further inhibiting cardiac output. The ineffective inspiratory pressure generation by the diaphragm may also reduce the typical benefits of the respiratory muscle pump on venous return and the marked hyperinflation may influence left ventricular filling due to competition for intrathoracic space. Thus, although COPD primarily influences the respiratory system, we believe it has profound effects on cardiac function, and during exercise this may play a particular limitation. Use of a long-acting anticholinergic agent such as Tiotropium partially reverses airway obstruction (expiratory load) and hyperinflation, both potentially improving cardiovascular function. The focus of this research will be to determine influence of Tiotropium on cardiac parameters measured both at rest and during exercise.

The focus of this study was to determine the influence of Tiotropium (Spiriva) on cardiac parameters measured both at rest and during exercise. More specifically, we first examined cardiac function in a group of COPD patients and healthy age and gender matched controls. Our hypothesis was that at rest cardiac function would be similar between groups; however, with light and heavier exercise, there would be evidence for a blunted stroke volume and perhaps cardiac output in the COPD patients. Second, we compared in a placebo-controlled double blinded manner cardiac function with and without chronic use of tiotropium in age, gender, and disease matched COPD patients. Our hypothesis was that in the Tiotropium (Spiriva) group at a matched workload, the reduced obstruction would allow for improved cardiac function, specifically an increase in stroke volume and reduction in heart rate. The interactions in this population between metabolic demand, fitness, lung mechanics, and cardiovascular function are complicated and thus studies were pursued at matched workloads and heart rate as well as with heavier exercise in an attempt to discriminate a primary influence of altered obstruction on cardiovascular function.

The participants will be asked to come to the Cardiopulmonary Research Laboratory on 4 occasions (separate visits) for exercise testing (typically over the course of 2 to 4 weeks). Each session will take approximately 1-4 hours to complete and in the COPD population, visits will be repeated after receiving placebo or Tiotropium for 4 weeks.

All of the exercise testing will be performed on an exercise bicycle either in the upright or semi-supine (recumbent) position and the participant will wear a SCUBA-type mouthpiece and a nose clip to analyze expired air. In addition, an EKG will be used to monitor heart rate and rhythm.

Visit 1 (Screening Visit): During the first visit, participants will have a brief exam by a pulmonary physician. The exam will include a complete blood count (CBC) to rule out anemia, baseline spirometry to assess lung volumes and flow rates to meet entry criteria, and in women of childbearing potential a pregnancy test. They will also be taken off theophylline and inhaled anticholinergics, but allowed to continue long acting inhaled beta agonists (LABA) or short acting beta agonist (SABA) for a rescue medication. Subjects on long acting inhaled beta agonists will be asked to discontinue this medication temporarily, 48 hr. prior to each study visit, but restarted upon completion of the visit.

Visit 2: A minimum of 48 hours after the first visit, participants will return for complete measures of lung volumes, flow rates, and diffusing capacity of the lung for carbon monoxide (DLCO), a baseline echocardiogram and a maximal exercise test on a cycle ergometer. Before the exercise begins, participants will have one or two small balloon(s) (2 inches long, deflated) attached to a small plastic tube (the width of a pencil tip) inserted through the nasal cavity and into the esophagus. This is done to measure respiratory muscle work. Participants will receive a numbing gel (2% lidocaine) to numb the nasal passage and upper esophagus prior to insertion of the balloon(s). During the insertion of the esophageal balloons, participants will also be asked to swallow water to minimize gagging and assure correct balloon placement in the esophagus. Participants will also be asked to breathe a mixture of gases containing acetylene (0.6%), dimethyl ether (1.8%), oxygen (21%, same as room air), helium (9%) and nitrogen (69.4%). The mixture of gases will be inhaled at various time points over the course of the exercise session for 8 to 10 breaths at a time. This is done to non-invasively measure cardiac output.

Visit 3: Visit 3 will involve steady-state semi-recumbent cycling exercise at two steady-state exercise intensities; 40 percent of peak work and (after a brief rest) an intensity eliciting a heart rate of 110 beats per minute (to standardize diastolic duration). Before the exercise begins, participants will have one or two small balloon(s) (2 inches long, deflated) attached to a small plastic tube (the width of a pencil tip) inserted through the nasal cavity and into the esophagus. This is done to measure respiratory muscles at work. Participants will receive a numbing gel (2% lidocaine) to numb the nasal passage and upper esophagus prior to insertion of the balloon(s). During the insertion of the esophageal balloons, participants will also be asked to swallow water to minimize gagging and assure correct balloon placement in the esophagus. Participants will also be asked to breathe a mixture of gases containing acetylene (0.6%), dimethyl ether (1.8%), oxygen (21%, same as room air), helium (9%) and nitrogen (69.4%). The mixture of gases will be inhaled at various time points over the course of the exercise session for 8 to 10 breaths at a time. This is done to non-invasively measure cardiac output. Also during the session, a sonographer will use ultrasound to measure cardiac pressures and volumes.

Visit 4: Visit 4 will involve steady-state exercise at 70% of peak work. Before the exercise begins, participants will have one or two small balloon(s) (2 inches long, deflated) attached to a small plastic tube (the width of a pencil tip) inserted through the nasal cavity and into the esophagus. This is done to measure respiratory muscles at work. Participants will receive a numbing gel (2% lidocaine) to numb the nasal passage and upper esophagus prior to insertion of the balloon(s). During the insertion of the esophageal balloons, participants will also be asked to swallow water to minimize gagging and assure correct balloon placement in the esophagus. Participants will also be asked to breathe a mixture of gases containing acetylene (0.6%), dimethyl ether (1.8%)oxygen (21%, same as room air), helium (9%) and nitrogen (69.4%). The mixture of gases will be inhaled at various time points over the course of the exercise session for 8 to 10 breaths at a time. This is done to non-invasively measure cardiac output.

Upon completion of these baseline visits, the COPD patients will be randomly assigned to a standard dose of Tiotropium once-daily (18 µg) or placebo for 4 weeks (or until study completion as visits 2-4 may require 1-2 wks to complete). Patients otherwise will receive usual care, except (as noted) for discontinuing other anticholinergic bronchodilators and theophylline. They will also discontinue long acting beta agonists for 48 hours prior to performing each of the designated visits. At the end of this intervention period, the procedures outlined in Visits 2-4 will be repeated (on the COPD patients only). All post intervention visits will be timed so that the primary measures will be made 1.5 to 2 hrs post dose of Tiotropium.

Eligibility Criteria:
Chronic obstructive pulmonary disease (COPD) participants-

Inclusion criteria:

* Body Mass Index (BMI) \<36
* Moderate to severe COPD patient, (similar to or slightly better than Gold Guidelines Stage 2-3, forced expiratory volume in one second \[FEV_1\] \<60% of age predicted)
* Smoking history of 10 pack years or more
* Clinical diagnosis of COPD
* Not on daytime oxygen

Exclusion criteria:

* Clinical diagnosis of asthma
* Myocardial infarction within the last 6 months, or known ischemia
* Serious uncontrolled cardiac arrhythmia (i.e., atrial fibrillation or ventricular tachycardia) or hospitalization for heart failure within the previous year
* Known moderate to severe renal impairment
* Known moderate to severe symptomatic prostatic hypertrophy or bladder neck obstruction
* Known narrow angle glaucoma
* Current radiation or chemotherapy for a malignant condition
* Inability to give informed consent
* On systemic corticosteroids at unstable doses or on regular daily doses of 20 mg or more of prednisone (or equivalent)
* Not fully recovered from an exacerbation of COPD for at least 30 days
* Inability to perform light to moderate activity for orthopedic reasons or who significantly desaturated with exercise (percentage of available hemoglobin that is saturated with oxygen \[SaO_2\] \< 85% on screening test

Healthy controls -

Inclusion:

- Age and gender matched to COPD participants

Exclusion:

- Subjects who are unable to engage in exercise testing due to existing comorbidities