Dataset Information

A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD.

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 (?-10.5 mm Hg; 95% CI, -19.9 to -1.1; P = .03) and serum ACE activity (?-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 (?0.5 s; 95% CI, -13.3-14.3; P = .94) or atrogin-1 messenger RNA expression (?-0.03 arbitrary units; 95% CI, -0.32-0.26; P = .84). QMVC improved in both groups (fosinopril: ?1.1 kg; 95% CI, 0.03-2.2; P = .045 vs placebo: ?3.6 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.

SUBMITTER: Shrikrishna D

PROVIDER: S-EPMC4188149 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Publications

A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD.

Shrikrishna Dinesh D Tanner Rebecca J RJ Lee Jen Y JY Natanek Amanda A Lewis Amy A Murphy Patrick B PB Hart Nicholas N Moxham John J Montgomery Hugh E HE Kemp Paul R PR Polkey Michael I MI Hopkinson Nicholas S NS

Chest 20141001 4

<h4>Background</h4>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.<h4>Methods</h4>This double-blind, randomized placebo-controlled trial investigated the effect of the ACE inhibitor, fosinopril, on quadriceps functi ...[more]

PMID: 24556825

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Project description:BACKGROUND:Transforming growth factor beta (TGF-?)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-?-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis. METHODS:Male C57BL/6?J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20?mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14?days postsurgery. RESULTS:Skeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14?days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14?days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-? and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1-7 postsurgery) and blood angiotensin II at 14?days postsurgery was increased in MI mice compared with sham mice. These impairments were improved in MI + Lis mice, without any effects on spontaneous physical activity, muscle strength, muscle weight, and blood pressure. CONCLUSIONS:ACE inhibitor administration prevents increased skeletal muscle fibrosis during the early phase after MI. Our findings indicate a new therapeutic target for ameliorating skeletal muscle abnormalities in heart diseases.

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Dataset Information

A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD.

Background

Methods

Results

Conclusions

Trial registry

Publications

A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD.

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