Cardiac Limitations in Chronic Obstructive Pulmonary Disease: Benefits of Bronchodilation

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.