The Effect of Oral Sildenafil on Exercise Capacity, Dyspnea and Cardiopulmonary Function in Chronic Obstructive Pulmonary Disease (COPD)

COPD is a condition characterized by airway obstruction and is currently the 4th leading cause of death in Canada. Patients with COPD experience significant exertional dyspnea, which has been shown to reduce quality of life and physical activity, and increase risk of mortality. Much work has examined the mechanisms for dyspnea in moderate and severe COPD, but the mechanisms for dyspnea in patients with mild COPD, in whom symptoms are often disproportionate to the degree of airway obstruction, are not well understood. Mild COPD patients show an exaggerated ventilatory response to exercise, determined by the ventilatory response to carbon dioxide production (V̇E/V̇CO2), which is a key contributor to dyspnea and is predictive of mortality. Recent work suggests that the increased V̇E/V̇CO2 during exercise in mild COPD is secondary to increased deadspace (i.e. ventilation with no perfusion) and/or ventilation/perfusion (V̇ A/Q) inequality (i.e. poor matching of ventilation to perfusion). Researchers have proposed that the increased deadspace or V̇A/Q inequality is secondary to pulmonary vascular dysfunction and hypoperfusion of the pulmonary capillaries. Recently we have shown that iNO reduces dyspnea, and V̇E/V̇CO2, and improves exercise capacity in mild COPD, suggesting that pulmonary vascular dysfunction is an important contributor to exercise intolerance in mild COPD. Importantly, this work demonstrated that pulmonary NO mediated vasodilation pathways are intact, and are a viable target for improving exercise tolerance in mild COPD. Therefore, we hypothesize that sildenafil, which potentiates intrinsic NO mediated vasodilation mechanisms, will improve exercise tolerance in mild COPD.

Compared to disease free controls, mild COPD patients have a blunted diffusion capacity and pulmonary capillary blood volume response to exercise. In the supine position, which minimizes flow heterogeneity through removal of the coronal gravity-induced pressure gradient, diffusion capacity and pulmonary capillary blood volume responses to exercise were not corrected. The implication of this finding is that even mild COPD, there is a degree of permanent vascular destruction, in addition to reversible pulmonary vascular dysfunction. It is presently unknown when or if in the COPD severity continuum there is a transition from treatable pulmonary vascular dysfunction to irreversible pulmonary vascular destruction.

Sildenafil was previously tested in moderate to severe COPD with mixed success. Blanco et al. tested the effect of sildenafil (20 or 40 mg dose) on hemodynamics and gas exchange in a sample of patients with moderate to severe COPD. Eighty-five percent of the sample had pulmonary hypertension defined as mean pulmonary artery pressure >20 mmHg. Sildenafil significantly reduced pulmonary artery pressure at rest and during exercise (-6 and -11 mmHg respectively), and improved VA/Q inequality. Rietema et al. found no benefit of sildenafil (3x50mg daily for 3 months) on stroke volume (supine, rest/exercise) or exercise capacity in moderate to severe COPD. In a randomized, placebo controlled trial, sildenafil (3x20 mg daily, 3 months) did not improve pulmonary rehabilitation outcomes including cycle endurance time, 6 minute walk distance, or quality of life. It is not known why the promising reduction in pulmonary artery pressure and improved V̇A/Q matching did not translate to increased stroke volume or exercise capacity with chronic sildenafil dosing. Results may partially be explained by supine body positioning during measurement of stroke volume, and the generally late disease state of COPD patients. Pulmonary vascular dysfunction observed early in disease progression may transition to irrevocable vascular/pulmonary structural changes, for which iNO or sildenafil have limited utility. Accordingly, a secondary objective of the present study is to gain understanding of pathological vascular progression in COPD to identify the therapeutic window for pulmonary vascular intervention. We hypothesize that sildenafil will have greater cardiopulmonary benefit (increased diffusion capacity at rest and during exercise, greater decrease in pulmonary artery pressure) in early, mild COPD as compared to moderate-severe COPD, indicative of vascular dysfunction in mild COPD transitioning to vascular destruction in later disease states.

Trial Objectives

1. To examine the effect of acute oral sildenafil on maximal oxygen consumption (peak V̇O2) during exercise in the continuum of COPD
2. To examine whether acute oral sildenafil improves exertional dyspnea in COPD.
3. To examine the cardio-pulmonary effects and mechanisms of oral sildenafil.