A Randomized Controlled Trial of Angiotensin-Converting Enzyme Inhibition for Skeletal Muscle Dysfunction in COPD

Dinesh Shrikrishna,Rebecca J Tanner,Jen Y Lee,Amanda Natanek,Amy Lewis,Patrick B Murphy,Nicholas Hart,John Moxham,Hugh E Montgomery,Paul R Kemp,Michael I Polkey,Nicholas S Hopkinson

doi:10.1378/chest.13-2483

Abstract

BACKGROUND:Skeletal muscle impairment is a recognized complication of COPD, predicting mortality in severe disease. Increasing evidence implicates the renin-angiotensin system in control of muscle phenotype. We hypothesized that angiotensin-converting enzyme (ACE) inhibition would improve quadriceps function and exercise performance in COPD.METHODS:This double-blind, randomized placebo-controlled trial investigated the effect of the ACE inhibitor, fosinopril, on quadriceps function in patients with COPD with quadriceps weakness. Primary outcomes were change in quadriceps endurance and atrophy signaling at 3 months. Quadriceps maximum voluntary contraction (QMVC), mid-thigh CT scan of the 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% men). Sixty-seven patients (31 fosinopril, 36 placebo) completed the trial. The treatment group demonstrated a significant reduction in systolic BP (Δ−10.5 mm Hg; 95% CI, −19.9 to −1.1; P = .03) and serum ACE activity (Δ−20.4 IU/L; 95% CI, −31.0 to −9.8; P < .001) compared with placebo. No significant between-group differences were observed in the primary end points of quadriceps endurance half-time (Δ0.5 s; 95% CI, −13.3-14.3; P = .94) or atrogin-1 messenger RNA expression (Δ−0.03 arbitrary units; 95% CI, −0.32-0.26; P = .84). QMVC improved in both groups (fosinopril: Δ1.1 kg; 95% CI, 0.03-2.2; P = .045 vs placebo: Δ3.6 kg; 95% CI, 2.1-5.0; P < .0001) with a greater increase in the placebo arm (between-group, P = .009). No change was shown in the MTCSA (P = .09) or ISWD (P = .51).CONCLUSIONS:This randomized controlled trial found that ACE inhibition, using fosinopril for 3 months, did not improve quadriceps function or exercise performance in patients with COPD with quadriceps weakness.TRIAL REGISTRY:Current Controlled Trials; No.: ISRCTN05581879; URL: www.controlled-trials.com

Highlights

Skeletal muscle impairment is a recognized complication of COPD, predicting mortality in severe disease
No significant between-group differences were observed in the primary end points of quadriceps endurance half-time (⌬0.5 s; 95% CI, 213.3-14.3; P 5 .94) or atrogin-1 messenger RNA expression (⌬20.03 arbitrary units; 95% CI, 20.32-0.26; P 5 .84)
Quadriceps maximum voluntary contraction (QMVC) improved in both groups with a greater increase in the placebo arm

Summary

Methods

This double-blind, randomized placebo-controlled trial investigated the effect of the ACE inhibitor, fosinopril, on quadriceps function in patients with COPD with quadriceps weakness. Quadriceps maximum voluntary contraction (QMVC), mid-thigh CT scan of the cross-sectional area (MTCSA), and incremental shuttle walk distance (ISWD) were secondary outcomes. Study inclusion criteria were patients diagnosed with COPD based on GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria[23] and the presence of quadriceps weakness defined as a quadriceps maximum voluntary contraction (QMVC) in kilograms , 120% of the patient’s BMI.[5] Exclusion criteria were patients within 3 months of pulmonary rehabilitation or 1 month of an exacerbation, and those with a comorbidity including cardiac failure, diabetes, renal disease, or rheumatoid arthritis. Patients receiving ACE inhibitors, angiotensin II receptor blockers, or warfarin (because the study entailed a vastus lateralis biopsy) were excluded

Results

Discussion

Conclusion