Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD: A Secondary Analysis of the BLOCK COPD Trial

David M MacDonald; Takudzwa Mkorombindo; Sharon X. Ling; Selcuk Adabag; Richard Casaburi; John E Connett; Erika S. Helgeson; Janos Porszasz; Harry B. Rossiter; William W. Stringer; Helen T Voelker; Dongxing Zhao; Mark T. Dransfield; Ken M. Kunisaki

doi:10.15326/jcopdf.2021.0264

Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD: A Secondary Analysis of the BLOCK COPD Trial

David M MacDonald, Takudzwa Mkorombindo, Sharon X. Ling, Selcuk Adabag, Richard Casaburi, John E Connett, Erika S. Helgeson, Janos Porszasz, Harry B. Rossiter, William W. Stringer, Helen T Voelker, Dongxing Zhao, Mark T. Dransfield, Ken M. Kunisaki

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	226-236
Number of pages	11
Journal	Chronic Obstructive Pulmonary Diseases
Volume	9
Issue number	2
DOIs	https://doi.org/10.15326/jcopdf.2021.0264
State	Published - 2022

Bibliographical note

Funding Information:
Abbreviations: chronic obstructive pulmonary disease, COPD; acute exacerbation of COPD, AECOPD; heart rate variability, HRV; standard deviation of normal RR intervals, SDNN; root mean square of successive RR interval differences, RMSSD; electrocardiograms, ECGs; Beta Blockers for the Prevention of Acute Exacerbations of COPD trial, BLOCK COPD; forced expiratory volume in 1 second,FEV1; confidence interval, CI; forced vital capacity, FVC; long-acting muscarinic antagonists, LAMAs; St George’s Respiratory Questionnaire, SGRQ; locally estimated scatterplot smoothing line, LOESS; standard deviation, SD; interquartile range, IQR; adjusted hazard ratio, aHR Funding Support: The Beta-Blockers for the Prevention of Acute Exacerbations of COPD trial (BLOCK COPD) was supported by a grant from the Department of Defense (W81XWH-15-1-0705). DMM was supported by the University of Minnesota T32 Training in Lung Science training grant (2T32HL007741-26A1). This material is also the result of work supported with resources and the use of facilities at the Minneapolis VA Medical Center, Minneapolis. The views expressed in this article are those of the authors and do not reflect the views of the United States Government, the Department of Defense, the Department of Veterans Affairs, or any of the authors’ affiliated academic institutions.

Funding Information:
SA has received research grants from Medtronic. RC has received grant support, advisory board fees, or lecture fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, consulting fees from Regeneron and Genentech, and reports owning stock in Inogen. HBR is supported by grants from National Institutes of Health (R01HL151452, R01HL153460, P50HD098593, R01DK122767, P2CHD086851), the Tobacco-Related Disease Research Program (T31IP1666), and the University of California, Office of the President. He reports consulting fees from Omniox Inc., and is involved in contracted clinical research with Boehringer Ingelheim, GlaxoSmithKline, Novartis, AstraZeneca, Astellas, United Therapeutics, Genentech and Regeneron. He is a visiting Professor at the University of Leeds, United Kingdom. WWS has received grant support from AstraZeneca and Boehringer Ingelheim, consulting fees and fees for serving on a data and safety monitoring board from Allergan, and fees for serving on a data and safety monitoring board from Syneos Health. MTD has received grant support from the National Institutes of Health, the Department of Defense, and the American Lung Association; consulting from AstraZeneca, GlaxoSmithKline, Pulmonx, and Teva; and contracted clinical trial support from Boehringer Ingelheim, Boston Scientific, Gala, Nuvaira, and Pulmonx. KMK has received consulting fees from Nuvaria and Allergan. The remaining authors have nothing to declare.

Publisher Copyright:
© 2022 COPD Foundation. All rights reserved.

Keywords

BLOCK-COPD
acute exacerbation of COPD
autonomic nervous system
electrocardiogram
heart rate variability

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Journal Article

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10.15326/jcopdf.2021.0264

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MacDonald, D. M., Mkorombindo, T., Ling, S. X., Adabag, S., Casaburi, R., Connett, J. E., Helgeson, E. S., Porszasz, J., Rossiter, H. B., Stringer, W. W., Voelker, H. T., Zhao, D., Dransfield, M. T., & Kunisaki, K. M. (2022). Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD: A Secondary Analysis of the BLOCK COPD Trial. Chronic Obstructive Pulmonary Diseases, 9(2), 226-236. https://doi.org/10.15326/jcopdf.2021.0264

MacDonald, DM, Mkorombindo, T, Ling, SX, Adabag, S, Casaburi, R, Connett, JE , Helgeson, ES, Porszasz, J, Rossiter, HB, Stringer, WW, Voelker, HT, Zhao, D, Dransfield, MT & Kunisaki, KM 2022, 'Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD: A Secondary Analysis of the BLOCK COPD Trial', Chronic Obstructive Pulmonary Diseases, vol. 9, no. 2, pp. 226-236. https://doi.org/10.15326/jcopdf.2021.0264

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title = "Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD: A Secondary Analysis of the BLOCK COPD Trial",

abstract = "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.",

keywords = "BLOCK-COPD, acute exacerbation of COPD, autonomic nervous system, electrocardiogram, heart rate variability",

author = "MacDonald, {David M} and Takudzwa Mkorombindo and Ling, {Sharon X.} and Selcuk Adabag and Richard Casaburi and Connett, {John E} and Helgeson, {Erika S.} and Janos Porszasz and Rossiter, {Harry B.} and Stringer, {William W.} and Voelker, {Helen T} and Dongxing Zhao and Dransfield, {Mark T.} and Kunisaki, {Ken M.}",

note = "Funding Information: Abbreviations: chronic obstructive pulmonary disease, COPD; acute exacerbation of COPD, AECOPD; heart rate variability, HRV; standard deviation of normal RR intervals, SDNN; root mean square of successive RR interval differences, RMSSD; electrocardiograms, ECGs; Beta Blockers for the Prevention of Acute Exacerbations of COPD trial, BLOCK COPD; forced expiratory volume in 1 second,FEV1; confidence interval, CI; forced vital capacity, FVC; long-acting muscarinic antagonists, LAMAs; St George{\textquoteright}s Respiratory Questionnaire, SGRQ; locally estimated scatterplot smoothing line, LOESS; standard deviation, SD; interquartile range, IQR; adjusted hazard ratio, aHR Funding Support: The Beta-Blockers for the Prevention of Acute Exacerbations of COPD trial (BLOCK COPD) was supported by a grant from the Department of Defense (W81XWH-15-1-0705). DMM was supported by the University of Minnesota T32 Training in Lung Science training grant (2T32HL007741-26A1). This material is also the result of work supported with resources and the use of facilities at the Minneapolis VA Medical Center, Minneapolis. The views expressed in this article are those of the authors and do not reflect the views of the United States Government, the Department of Defense, the Department of Veterans Affairs, or any of the authors{\textquoteright} affiliated academic institutions. Funding Information: SA has received research grants from Medtronic. RC has received grant support, advisory board fees, or lecture fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, consulting fees from Regeneron and Genentech, and reports owning stock in Inogen. HBR is supported by grants from National Institutes of Health (R01HL151452, R01HL153460, P50HD098593, R01DK122767, P2CHD086851), the Tobacco-Related Disease Research Program (T31IP1666), and the University of California, Office of the President. He reports consulting fees from Omniox Inc., and is involved in contracted clinical research with Boehringer Ingelheim, GlaxoSmithKline, Novartis, AstraZeneca, Astellas, United Therapeutics, Genentech and Regeneron. He is a visiting Professor at the University of Leeds, United Kingdom. WWS has received grant support from AstraZeneca and Boehringer Ingelheim, consulting fees and fees for serving on a data and safety monitoring board from Allergan, and fees for serving on a data and safety monitoring board from Syneos Health. MTD has received grant support from the National Institutes of Health, the Department of Defense, and the American Lung Association; consulting from AstraZeneca, GlaxoSmithKline, Pulmonx, and Teva; and contracted clinical trial support from Boehringer Ingelheim, Boston Scientific, Gala, Nuvaira, and Pulmonx. KMK has received consulting fees from Nuvaria and Allergan. The remaining authors have nothing to declare. Publisher Copyright: {\textcopyright} 2022 COPD Foundation. All rights reserved.",

year = "2022",

doi = "10.15326/jcopdf.2021.0264",

language = "English (US)",

volume = "9",

pages = "226--236",

journal = "Chronic Obstructive Pulmonary Diseases",

issn = "2372-952X",

publisher = "COPD Foundation",

number = "2",

}

TY - JOUR

T1 - Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD

T2 - A Secondary Analysis of the BLOCK COPD Trial

AU - MacDonald, David M

AU - Mkorombindo, Takudzwa

AU - Ling, Sharon X.

AU - Adabag, Selcuk

AU - Casaburi, Richard

AU - Connett, John E

AU - Helgeson, Erika S.

AU - Porszasz, Janos

AU - Rossiter, Harry B.

AU - Stringer, William W.

AU - Voelker, Helen T

AU - Zhao, Dongxing

AU - Dransfield, Mark T.

AU - Kunisaki, Ken M.

N1 - Funding Information: Abbreviations: chronic obstructive pulmonary disease, COPD; acute exacerbation of COPD, AECOPD; heart rate variability, HRV; standard deviation of normal RR intervals, SDNN; root mean square of successive RR interval differences, RMSSD; electrocardiograms, ECGs; Beta Blockers for the Prevention of Acute Exacerbations of COPD trial, BLOCK COPD; forced expiratory volume in 1 second,FEV1; confidence interval, CI; forced vital capacity, FVC; long-acting muscarinic antagonists, LAMAs; St George’s Respiratory Questionnaire, SGRQ; locally estimated scatterplot smoothing line, LOESS; standard deviation, SD; interquartile range, IQR; adjusted hazard ratio, aHR Funding Support: The Beta-Blockers for the Prevention of Acute Exacerbations of COPD trial (BLOCK COPD) was supported by a grant from the Department of Defense (W81XWH-15-1-0705). DMM was supported by the University of Minnesota T32 Training in Lung Science training grant (2T32HL007741-26A1). This material is also the result of work supported with resources and the use of facilities at the Minneapolis VA Medical Center, Minneapolis. The views expressed in this article are those of the authors and do not reflect the views of the United States Government, the Department of Defense, the Department of Veterans Affairs, or any of the authors’ affiliated academic institutions. Funding Information: SA has received research grants from Medtronic. RC has received grant support, advisory board fees, or lecture fees from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, consulting fees from Regeneron and Genentech, and reports owning stock in Inogen. HBR is supported by grants from National Institutes of Health (R01HL151452, R01HL153460, P50HD098593, R01DK122767, P2CHD086851), the Tobacco-Related Disease Research Program (T31IP1666), and the University of California, Office of the President. He reports consulting fees from Omniox Inc., and is involved in contracted clinical research with Boehringer Ingelheim, GlaxoSmithKline, Novartis, AstraZeneca, Astellas, United Therapeutics, Genentech and Regeneron. He is a visiting Professor at the University of Leeds, United Kingdom. WWS has received grant support from AstraZeneca and Boehringer Ingelheim, consulting fees and fees for serving on a data and safety monitoring board from Allergan, and fees for serving on a data and safety monitoring board from Syneos Health. MTD has received grant support from the National Institutes of Health, the Department of Defense, and the American Lung Association; consulting from AstraZeneca, GlaxoSmithKline, Pulmonx, and Teva; and contracted clinical trial support from Boehringer Ingelheim, Boston Scientific, Gala, Nuvaira, and Pulmonx. KMK has received consulting fees from Nuvaria and Allergan. The remaining authors have nothing to declare. Publisher Copyright: © 2022 COPD Foundation. All rights reserved.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - BLOCK-COPD

KW - acute exacerbation of COPD

KW - autonomic nervous system

KW - electrocardiogram

KW - heart rate variability

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UR - http://www.scopus.com/inward/citedby.url?scp=85130760376&partnerID=8YFLogxK

U2 - 10.15326/jcopdf.2021.0264

DO - 10.15326/jcopdf.2021.0264

M3 - Article

C2 - 35403415

AN - SCOPUS:85130760376

SN - 2372-952X

VL - 9

SP - 226

EP - 236

JO - Chronic Obstructive Pulmonary Diseases

JF - Chronic Obstructive Pulmonary Diseases

IS - 2

ER -

Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD: A Secondary Analysis of the BLOCK COPD Trial

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