Cystic Fibrosis (CF) is the most common, deadly, genetic disease in North America and is diagnosed in approximately 1,200 individuals each year. Over 20 years ago, exercise intolerance was shown to predict mortality in patients with CF, independent of lung function. In addition, lower exercise capacity is associated with greater mortality, steeper decline in pulmonary function, and more pulmonary infections. A critical barrier to improving exercise tolerance in patients with CF is our lack of knowledge regarding the different physiological mechanisms which contribute to their lower exercise capacity. Clinical manifestations of CF not only include lung dysfunction, but many additional systemic consequences as well. In fact, our group has recently published the first evidence of systemic endothelial dysfunction in young patients with CF and now we have compelling preliminary data to support that patient's with CF exhibit an impairment in blood flow regulation during exercise. Accordingly, the overall goals of this proposal are to 1) provide proof of concept for using PDE5 inhibition to improve exercise capacity in patients with CF and 2) investigate blood flow per se and endothelial dysfunction as potential mechanisms that contribute to exercise intolerance in CF. Our central hypothesis is that PDE5 inhibition will improve blood flow (acute treatment) and endothelial function (chronic treatment) leading to an increase in exercise capacity. We are proposing a randomized, placebo controlled, acute experiment (aim 1) followed by an open label 4 week treatment trial (aim 2). Findings from aim 1 will isolate the transient increase in blood flow delivery as a mechanism to improve exercise capacity in CF, whereas findings from aim 2 will target an improvement in endothelial function and therefore, the improvement in exercise capacity will likely be greater in magnitude and sustainable The impact of this proof of concept investigation will test PDE5 inhibitors as a potential therapy in CF and will explore blood flow and endothelial function as potential mechanisms which contribute to exercise intolerance in CF. This proposal, through the integration of exercise physiology, vascular biology, and pharmacology, represents a major breakthrough in the approach to begin understanding the mechanisms which contribute to exercise intolerance in CF.
The most disturbing aspect of Cystic Fibrosis (CF) is the associated premature death. Low exercise capacity predicts death in patients with CF and is also associated with a steeper decline in lung function and more lung infections. A critical barrie to improving exercise tolerance in patients with CF is our lack of knowledge regarding the different physiological mechanisms which contribute to their lower exercise capacity. We have compelling data to indicate that the blood vessels may contribute to the low exercise capacity in CF. The impact of this proof of concept investigation will test PDE5 inhibitors as a potential therapy in CF and will explore blood flow and endothelial function as potential mechanisms which contribute to exercise intolerance in CF. Improvements in exercise capacity will not only contribute to a better quality of live for patients with CF, it will also increase longevity in thee patients.