ACE-inhibition and skeletal muscle dysfunction in chronic obstructive pulmonary disease

Abstract

This thesis addresses the impact of quadriceps wasting and physical inactivity across disease severity (GOLD stages I-IV) in Chronic Obstructive Pulmonary Disease (COPD) and assesses the influence of angiotensin-converting enzyme (ACE)-inhibition on quadriceps dysfunction in these patients. In a cross-sectional study of 161 COPD patients, ultrasound measurement of rectus femoris cross-sectional area was reduced in mild as well as advanced disease when compared to controls. Daily physical activity, measured using an armband accelerometer, was reduced in COPD subjects across all GOLD stages compared to controls. Physical activity was independently associated with quadriceps wasting in GOLD stage I, but not stage II-IV disease where residual volume to total lung capacity ratio was the only independent predictor of activity level. This data suggests that quadriceps wasting is not an end-stage phenomenon in COPD and highlights the need for early identification of these patients to guide lifestyle and therapeutic interventions. The effect of the ACE-inhibitor, fosinopril on quadriceps dysfunction in COPD was then investigated in a double-blind randomised controlled trial of 80 COPD patients with quadriceps weakness. Despite a significant reduction in systolic blood pressure and serum ACE activity in the treatment group compared to placebo, no significant differences were observed at 3 months in the primary outcome of non-volitional quadriceps endurance. Quadriceps strength improved in both groups, but there was a greater increase in the placebo arm. No significant changes were observed in mid-thigh cross-sectional area or incremental shuttle walk distance. The trial also assessed the effect of ACE-inhibition on vastus lateralis atrogene expression in COPD, with no significant differences observed between groups. In conclusion, although evidence from observational cohorts suggest a role for the renin-angiotensin system in the control of muscle phenotype, data from this thesis found that ACE-inhibition did not improve quadriceps function in a COPD population with quadriceps weakness.