Correspondence Article Type Letter by Monfredi et al Regarding Article, “Physical Activity and Heart Rate Variability in Older Adults: The Cardiovascular Health Study” To the Editor: Circulation recently published the work of Soares-Miranda et al,1 in which physical activity and heart rate variability (HRV) in older adults were evaluated. The authors showed that greater leisure activity, walking distance, and walking pace are associated with higher HRV, which they interpreted as better autonomic function. We have reservations concerning this conclusion. First, physical activity lowers resting heart rate (HR).2 It is established that time- and frequency-domain measures of HRV are nonlinearly dependent on HR, with low HRV being intrinsically linked to a higher HR, and vice versa.3–5 We argue that HRV is a nonlinear surrogate of HR.3 Soares-Miranda et al recognized the dependence of HRV on HR, and stated that HR was evaluated as a “potential confounder or mediator” of HRV in a separate analysis by “adding a multiplicative interaction term and assessing the statistical significance of the Wald test”.1 They state: “Results were…not appreciably altered” by “further adjustment for baseline HR”.1 However, they do not give the mean HRs of the different groups at different time points. Furthermore, there are no details of how HRV was corrected for differences in HR; we assume they made a linear correction, which will be inadequate to correct for the nonlinear dependence of HRV on HR.3 The importance of HR on observed changes in HRV can be estimated: Zaza et al4 have independently shown that the natural log of standard deviation of normal-to-normal beats—logn(SDNN)—changes by 0.16 to 0.17 for every 10 beats per minute (bpm) change in HR; our own data yield a similar value.3 It follows that the ratio of SDNN in 2 different conditions is an exponential function of the difference in HR (ie, SDNN 2 = e − ( HR2 − HR1 )/ 58.8 ). This equation shows that the

SDNN1

modest increase in SDNN associated with activity in the study of Soares-Miranda et al (eg, from 104.8–115.5 ms in Figure 2) could be explained by a modest and plausible bradycardia (5.7 bpm decrease in the example given). Secondly, Soares-Miranda et al conclude that greater levels of physical activity lead to “more favorable indices of HRV” through reduction in sympathetic nerve activity and increased vagal activity. Previously, we have argued that there is no substantive evidence that resting bradycardia developing after physical activity is related to increased vagal tone (or decreased sympathetic tone),5 and recently we have shown that training-induced bradycardia is the result of remodeling of pacemaking mechanisms within sinus node cells (in particular a downregulation of the pacemaker channel, HCN4).2 In summary, although the article of Soares-Miranda et al demonstrates an increase in HRV in active older adults, this is likely to reflect the expected bradycardia rather than better autonomic function. The

majority of the >17 000 published works on HRV have failed to correct for HR differences between groups, potentially rendering their conclusions flawed—the readers of the article from Soares-Miranda et al should be afforded the opportunity to review the raw data to satisfy themselves that proper correction has been made.

Disclosures None. Oliver Monfredi, MD, PhD Institute of Cardiovascular Sciences University of Manchester Manchester, UK Henggui Zhang, PhD Biological Physics Group University of Manchester Manchester, UK Mark R. Boyett, PhD Institute of Cardiovascular Sciences University of Manchester Manchester, UK

References 1. Soares-Miranda L, Sattelmair J, Chaves P, Duncan GE, Siscovick DS, Stein PK, Mozaffarian D. Physical activity and heart rate variability in older adults: the Cardiovascular Health Study. Circulation. 2014;129:2100–2110. doi: 10.1161/CIRCULATIONAHA.113.005361. 2. D’Souza A, Bucchi A, Johnsen AB, Logantha SJ, Monfredi O, Yanni J, Prehar S, Hart G, Cartwright E, Wisloff U, Dobryznski H, DiFrancesco D, Morris GM, Boyett MR. Exercise training reduces resting heart rate via downregulation of the funny channel HCN4. Nat Commun. 2014;5:3775. doi: 10.1038/ncomms4775. 3. Monfredi O, Lyashkov AE, Johnsen AB, Inada S, Schneider H, Wang R, Nirmalan M, Wisloff U, Maltsev VA, Lakatta EG, Zhang H, Boyett MR. Biophysical characterization of the underappreciated and important relationship between heart rate variability and heart rate. Hypertension. 2014:64:1334–1343. doi: 10.1161/HYPERTENSIONAHA.114.03782. 4. Zaza A, Lombardi F. Autonomic indexes based on the analysis of heart rate variability: a view from the sinus node. Cardiovasc Res. 2001;50:434–442. 5. Boyett MR, D’Souza A, Zhang H, Morris GM, Dobrzynski H, Monfredi O. Viewpoint: is the resting bradycardia in athletes the result of remodeling of the sinoatrial node rather than high vagal tone? J Appl Physiol (1985). 2013;114:1351–1355. doi: 10.1152/ japplphysiol.01126.2012.

(Circulation. 2015;131:e348. DOI: 10.1161/CIRCULATIONAHA.114.011515.) © 2015 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.114.011515

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Letter by Monfredi et al Regarding Article, ''Physical Activity and Heart Rate Variability in Older Adults: The Cardiovascular Health Study'' Oliver Monfredi, Henggui Zhang and Mark R. Boyett Circulation. 2015;131:e348 doi: 10.1161/CIRCULATIONAHA.114.011515 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539

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