Elsevier

Heart Rhythm

Volume 18, Issue 11, November 2021, Pages 1999-2008
Heart Rhythm

Experimental
Impacts of frailty on heart rate variability in aging mice: Roles of the autonomic nervous system and sinoatrial node

https://doi.org/10.1016/j.hrthm.2021.07.069Get rights and content

Background

Heart rate variability (HRV) is determined by intrinsic sinoatrial node (SAN) activity and the autonomic nervous system (ANS). HRV is reduced in aging; however, aging is heterogeneous. Frailty, which can be measured using a frailty index (FI), can quantify health status in aging separately from chronological age.

Objective

The purpose of this study was to investigate the impacts of age and frailty on HRV in mice.

Methods

Frailty was measured in aging mice between 10 and 130 weeks of age. HRV was assessed using time domain, frequency domain, and Poincaré plot analyses in anesthetized mice at baseline and after ANS blockade, as well as in isolated atrial preparations.

Results

HRV was reduced in aged mice (90–130 weeks and 50–80 weeks old) compared to younger mice (10–30 weeks old); however, there was substantial variability within age groups. In contrast, HRV was strongly correlated with FI score regardless of chronological age. ANS blockade resulted in reductions in heart rate that were largest in 90- to 130-week-old mice and were correlated with FI score. HRV after ANS blockade or in isolated atrial preparations was increased in aged mice but again showed high variability among age groups. HRV was correlated with FI score after ANS blockade and in isolated atrial preparations.

Conclusion

HRV is reduced in aging mice in association with a shift in sympathovagal balance and increased intrinsic SAN beating variability; however, HRV is highly variable within age groups. HRV was strongly correlated with frailty, which was able to detect differences in HRV separately from chronological age.

Introduction

Heart rate (HR) is a critical indicator of cardiac performance that is determined by the intrinsic properties of the sinoatrial node (SAN) and modulated by the sympathetic and parasympathetic divisions of the autonomic nervous system (ANS).1 The sympathetic nervous system (SNS) increases HR by enhancing intrinsic SAN function (via β-adrenergic receptors), whereas the parasympathetic nervous system (PNS) reduces HR by inhibiting the SAN (via muscarinic receptors).1 It is well recognized that HR exhibits a beat-to-beat variation denoted as heart rate variability (HRV).2,3 Reduced HRV is associated with increased risk for cardiovascular diseases and mortality, whereas a robust level of HRV is an indicator of a healthy cardiovascular system.2,4 HRV arises from changes in the activity of the ANS (ie, changes in sympathovagal balance), its effects on SAN activity, and alterations in the intrinsic properties of the SAN.2,5,6

The global population continues to experience increased longevity and longer lifespan. With this comes an increasing incidence of cardiac disease due to age-dependent changes in cardiac function.7,8 SAN dysfunction and impairments in HR regulation are highly prevalent in aging and can occur due to alterations in intrinsic SAN function as well as changes in the ANS and its regulation of the SAN.9, 10, 11, 12, 13 Although aging is a major risk factor for cardiac disease, including SAN dysfunction, it is essential to recognize that not all individuals age at the same rate. This has led to the concept of frailty, which describes an increased susceptibility to adverse health outcomes, including in individuals of similar chronological age.14 As the global population ages, there is an increasing need to accurately identify individuals who are frail and to distinguish them from those who exhibit healthy aging in order to ensure proper care based on the accurate assessment of health status.

Frailty can be quantified using a frailty index (FI), which measures health deficit accumulation over time in aging individuals.14,15 We developed the mouse clinical FI, which noninvasively quantifies frailty based on 31 established indicators of overall health status.16 With this approach, the FI score for an individual is measured by determining the ratio between the number of health deficits present and the total number of items assessed. This mouse clinical FI was developed based on similar approaches used in human patients, and it reliably reproduces the major features of deficit accumulation and frailty in aging humans.14,16 Previous studies demonstrated the ability of the mouse clinical FI to assess health status and heterogeneity in cardiac function in aging mice.10,17,18

Although frailty is a powerful approach for assessing overall health status independently of chronological age and HRV is a recognized indicator of cardiovascular health, few studies have investigated the links between frailty and HRV, and none have been conducted using the FI approach. Similarly, the links between intrinsic SAN function, sympathovagal balance, and HRV in aging are incompletely understood. Accordingly, the purpose of this study was to investigate HRV in aging and frail mice, using the mouse clinical FI, in vivo and in isolated atrial preparations lacking neural inputs.

Section snippets

Methods

An expanded methods section is available in the Supplemental Methods.

Statistical analysis

Summary data comparing distinct age groups are given as mean ± SEM. Sample sizes for all experimental groups were selected in accordance with previous studies demonstrating groups sizes used for frailty studies.10,17 Normality was tested using a Shapiro-Wilk test. Normally distributed data were analyzed using 1-way analysis of variance with a Holm-Sidak post hoc test. Nonparametric data were analyzed using a Kruskal-Wallis test with Dunn post hoc test. Specific statistical tests and n values

Frailty in aging mice

FI scores were measured in wild-type mice divided into 3 age groups: 10–30 weeks (10–30wk), 50–80 weeks (50–80wk), and 90–130 weeks (90–130wk). On average, FI scores increased progressively across these age groups (Figure 1A). There was also substantial variability within each age group (Figure 1A). As a result, FI scores exhibit overlap, indicating that mice in the different age groups can have similar “health status” regardless of chronological age differences. Thus, health status can be

Discussion

This study demonstrates that aging results in reduced HRV in vivo, as well as increased intrinsic SAN beating interval variability, and that each of these is strongly associated with frailty (ie, health status). Three distinct age groups were used in the present study and, although aging clearly led to reduced HRV, differences among all 3 discrete age groups were not always detected. This is likely related to the variability in frailty (ie, health status), as well as measures of HRV, within

Conclusion

This study provides a comprehensive assessment of the relationships between age, frailty, and multilevel HRV. The data presented highlight that age-dependent changes in HRV can exhibit substantial variability and that changes in HRV can be accurately discriminated based on frailty (ie, overall health status). Furthermore, we show that although HRV is reduced in a frailty-dependent manner during aging, SAN beating rate variability increases with both age and frailty status. Therefore,

Acknowledgment

We thank Sara Rafferty for outstanding technical assistance.

References (32)

  • E.G. Lakatta et al.

    Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease

    Circulation

    (2003)
  • H. Dobrzynski et al.

    New insights into pacemaker activity: promoting understanding of sick sinus syndrome

    Circulation

    (2007)
  • M. Moghtadaei et al.

    The impacts of age and frailty on heart rate and sinoatrial node function

    J Physiol

    (2016)
  • E.D. Larson et al.

    Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate

    Proc Natl Acad Sci U S A

    (2013)
  • Y. Yaniv et al.

    Deterioration of autonomic neuronal receptor signaling and mechanisms intrinsic to heart pacemaker cells contribute to age-associated alterations in heart rate variability in vivo

    Aging Cell

    (2016)
  • R. Parashar et al.

    Age related changes in autonomic functions

    J Clin Diagn Res

    (2016)
  • Cited by (0)

    Funding sources: This work was supported by the Heart and Stroke Foundation (G-18-0022148) and the Canadian Institutes of Health Research (MOP 142486 and PJT 166105) to Dr Rose. Tristan W. Dorey holds a Canadian Institutes of Health Research Doctoral Research Award. Dr Jansen holds a Libin Cardiovascular Institute Postdoctoral Fellowship. Dr Jamieson is supported by a Cumming School of Medicine/Libin Cardiovascular Institute Postdoctoral Fellowship.

    Disclosures: The authors have no conflicts of interest to disclose.

    View full text