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