The Impact of CFTR Modulator Therapy on Exercise Intolerance and Oxygen Transport Metabolism in Cystic Fibrosis

Cystic fibrosis (CF) is a fatal autosomal-recessive genetic disorder with multiorgan effects. Exercise intolerance is a common symptom, and exercise capacity is an important prognostic indicator in CF. Some CF patients now have access to novel pharmacological “modulator therapies” that improve pulmonary function by directly targeting the cystic fibrosis transmembrane regulator (CFTR) protein defect. However, the impact of these therapies on other organ systems and exercise tolerance remains unknown. This is compounded by the ongoing debate related to the pathophysiological impact of CF on central and peripheral contributors to oxygen transport metabolism that determine exercise tolerance. The purpose of this research was therefore to explore central and peripheral contributors to exercise tolerance in healthy controls, patients with CF, and CF patients treated with modulator therapy using non-invasive magnetic resonance-based assessments. Thirty-two participants were included in the study: 10 healthy non-CF controls, 10 CF controls naïve to modulator therapy, and 12 CF patients on long-term CFTR modulator therapy. Participants completed resting and exercise MRI testing to quantify quadriceps blood flow, mitochondrial metabolism, and oxygen extraction. Results showed that there were no differences in pulmonary function and central cardiac limitations at rest. However, there were differences in peripheral factors of the oxygen transport chain in patients taking modulator therapies. Peripheral arterial blood flow in participants on modulator therapy was significantly increased at rest versus healthy controls (healthy control: 120.4±24.8 mL•kg-1•min-1; CF Control: 135.5±45.3 mL•kg-1•min-1; CF Orkambi: 171.2±45.3 mL•kg-1•min-1, p=0.016). CF controls naïve to modulator therapy had a significantly slower recovery of muscle metabolism post-exercise measured by tau of phosphocreatine recovery (healthy control: 28.5±9.2s; CF Control: 41.0±9.4s; CF Orkambi: 36.0 ±9.7, p=0.025). Aerobic muscle metabolism measured using MR spectroscopy was correlated with resting arterial flow in modulator-naïve CF participants (r=0.78, p=0.013), but was not correlated in healthy controls or patients on modulator therapy. Results suggest that there are peripheral limitations to exercise capacity in patients with CF that may be alleviated by CFTR modulator therapy. These include a) blood flow delivery of substrates to tissues, and b) improvements in muscle metabolism.Ph.D.2020-12-22 00:00:0