S48 The Effect of Angiotensin-Converting Enzyme Inhibition on Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease: A Randomised Controlled Trial

Abstract

Introduction: Skeletal muscle impairment is a recognised complication of COPD, predicting mortality in severe disease1. Increasing evidence from animal models, genetic data and observational studies implicates the renin-angiotensin system in control of muscle phenotype2. We hypothesised that angiotensin-converting enzyme (ACE)-inhibition would improve quadriceps function, atrophy signalling and exercise performance in patients with COPD. Methods: A single-centre, double-blind, randomized controlled parallel-group trial investigating the effect of 3 months treatment with fosinopril versus placebo on quadriceps muscle dysfunction in COPD patients with quadriceps weakness. Muscle weakness was defined as a quadriceps maximum voluntary contraction (QMVC) less than 120% of the body mass index1. Measurements: Primary outcomes were change in quadriceps endurance, measured non-volitionally using repetitive magnetic stimulation, and atrogene expression following vastus lateralis muscle biopsy. Quadriceps maximum voluntary contraction (QMVC), mid-thigh CT cross-sectional area (MTCSA) and incremental shuttle walk distance (ISWD) were secondary outcomes. Results: Eighty patients were enrolled (mean(SD), 65(8)years, FEV1 43(21)% predicted, 53% male). Sixty-seven patients (31 fosinopril and 36 placebo) completed the trial. The treatment group demonstrated a significant reduction in systolic blood pressure (DELTA-10.5mmHg, 95%CI -19.9 to -1.1, p=0.03) and serum ACE activity (DELTA-20.4units/L, 95%CI -31.0 to -9.8, p<0.001) compared to placebo. No significant differences were observed between groups in quadriceps endurance half-time (DELTA0.5s, 95%CI -13.3 to 14.3, p=0.94) or atrogin-1 mRNA expression (DELTA-0.03AU, 95%CI -0.32 to 0.26, p=0.84). QMVC improved in both groups (fosinopril DELTA1.1kg, 95%CI 0.03-2.2, p=0.045 vs. placebo DELTA3.6kg, 95%CI 2.1-5.0, p<0.0001) with a greater increase in the placebo arm (between group difference, p=0.009). There was no significant change in MTCSA (p=0.09), or ISWD (p=0.51) between groups. Stratification based on ACE genotype did not influence study outcomes. Conclusion: This randomised controlled trial found that 3 months treatment with the ACE-inhibitor, fosinopril, did not improve quadriceps phenotype in COPD patients with evidence of quadriceps weakness.