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Introduction: Autonomic dysfunction is common in chronic obstructive pulmonary disease (COPD), and worse autonomic function may be a marker of risk for acute exacerbations of COPD (AECOPD). Heart rate variability (HRV) is a measure of autonomic function. Our objective was to test whether lower (worse) HRV is a risk factor for AECOPD. Methods: We measured standard deviation of normal RR intervals (SDNN) and root mean square of successive RR interval differences (RMSSD) on 10-second electrocardiograms (ECGs) performed at screening and day 42 in participants in the Beta Blockers for the Prevention of Acute Exacerbations of COPD trial ( BLOCK-COPD), a placebo-controlled trial of metoprolol for prevention of AECOPD. We used Cox-proportional hazards models to test if these HRV measures were associated with risk of any AECOPD, and separately, hospitalized AECOPD. We tested associations using baseline HRV measures and incorporating HRV measures from day 42 as a time-varying covariate. We also tested for interactions with metoprolol assignment. Results: Of 532 trial participants, 529 (forced expiratory volume in 1 second [FEV(1) ]41 ± 16.3 % predicted) were included in this analysis. We did not find a significant association between HRV measures and risk of AECOPD when all participants were analyzed together. There was a significant interaction between RMSSD and assignment to metoprolol on time to first hospitalized AECOPD; in the placebo group greater RMSSD was associated with a lower risk of hospitalized AECOPD (adjusted hazard ratio0.71, 95% confidence interval: 0.52 to 0.96, per 10 ms increase) but there was no association in the metoprolol group. Conclusions: Autonomic dysfunction as measured by HRV may be a risk factor for AECOPD. Future studies should analyze longer HRV recordings and their performance in broader samples of people with COPD, including those on beta-blockers.

RATIONALE: The chronotropic index quantifies the proportion of the expected heart rate increase that is attained during exercise. The relationship between the chronotropic index and acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) has not been evaluated. OBJECTIVES: To determine whether a higher chronotropic index during a 6-minute walk (CI-6MW) is associated with lower risk of AECOPD and whether the CI-6MW is a marker of susceptibility to adverse effects of metoprolol in chronic obstructive pulmonary disease (COPD). METHODS: We analyzed data from the BLOCK COPD (Beta-Blockers for the Prevention of AECOPDs) trial. We used Cox proportional hazards models to investigate the relationship between the CI-6MW and the time to AECOPDs. We also tested for interactions between study group assignment (metoprolol vs. placebo) and the CI-6MW on the time to AECOPDs. RESULTS: Four hundred seventy-seven participants with exacerbation-prone COPD (mean forced expiratory volume in 1 second, 41% of predicted) were included in this analysis. A higher CI-6MW was independently associated with a decreased risk of AECOPDs of any severity (adjusted hazard ratio per 0.1 increase in CI-6MW of 0.88; 95% confidence interval, 0.80–0.96) but was not independently associated with AECOPDs requiring hospitalization (adjusted hazard ratio, 0.94; 95% confidence interval, 0.81–1.05). There was a significant interaction by treatment assignment, and in a stratified analysis, the protective effects of a higher CI-6MW on AECOPDs were negated by metoprolol use. CONCLUSIONS: A higher CI-6MW is associated with a decreased risk of AECOPDs and may be an indicator of susceptibility to the adverse effects of metoprolol.