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

Dorey, Tristan W.; Jansen, Hailey J.; Moghtadaei, Motahareh; Jamieson, K. Lockhart; Rose, Robert A.

doi:10.1016/j.hrthm.2021.07.069

Cited by 11 publications

(17 citation statements)

References 30 publications

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“…The aging mouse manifests HR and heartbeat interval variability abnormalities that recapitulate many of those described in humans [8,[12][13][14][15]. Cross-sectional studies that compare average data in different mice that have survived to different ages indicate that the intrinsic heartbeat interval variability and mean intrinsic HR are relatively constant between young adulthood and middle age but become substantially altered later in life [8].…”

Section: Introductionmentioning

confidence: 99%

“…The increased sympathetic input to the SAN of older mice helps to reduce intrinsic heartbeat interval variability towards that of mice at younger ages. Other cross-sectional studies have associated changes in SAN automaticity in older mice with whole-body frailty [14,16]. However, because these cross-sectional studies lack mouse-specific, longitudinal perspectives, they are plagued by marked heterogeneity of results in mice of older ages when whole-body frailty becomes manifest [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…Other cross-sectional studies have associated changes in SAN automaticity in older mice with whole-body frailty [14,16]. However, because these cross-sectional studies lack mouse-specific, longitudinal perspectives, they are plagued by marked heterogeneity of results in mice of older ages when whole-body frailty becomes manifest [17][18][19]. Longitudinal data on heart rhythm frailty in mice (or in humans) are mainly lacking because the longitudinal study design requires repeated measures of HRV that are implemented over a large part of the life course.…”

Section: Introductionmentioning

confidence: 99%

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Emergence of heartbeat frailty in advanced age I: perspectives from life-long EKG recordings in adult mice

et al. 2022

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The combined influences of sinoatrial nodal (SAN) pacemaker cell automaticity and its response to autonomic input determine the heart’s beating interval variability and mean beating rate. To determine the intrinsic SAN and autonomic signatures buried within EKG RR interval time series change in advanced age, we measured RR interval variability before and during double autonomic blockade at 3-month intervals from 6 months of age until the end of life in long-lived (those that achieved the total cohort median life span of 24 months and beyond) C57/BL6 mice. Prior to 21 months of age, time-dependent changes in intrinsic RR interval variability and mean RR interval were relatively minor. Between 21 and 30 months of age, however, marked changes emerged in intrinsic SAN RR interval variability signatures, pointing to a reduction in the kinetics of pacemaker clock mechanisms, leading to reduced synchronization of molecular functions within and among SAN cells. This loss of high-frequency signal processing within intrinsic SAN signatures resulted in a marked increase in the mean intrinsic RR interval. The impact of autonomic signatures on RR interval variability were net sympathetic and partially compensated for the reduced kinetics of the intrinsic SAN RR interval variability signatures, and partially, but not completely, shifted the EKG RR time series intervals to a more youthful pattern. Cross-sectional analyses of other subsets of C57/BL6 ages indicated that at or beyond the median life span of our longitudinal cohort, noncardiac, constitutional, whole-body frailty was increased, energetic efficiency was reduced, and the respiratory exchange ratio increased. We interpret the progressive reduction in kinetics in intrinsic SAN RR interval variability signatures in this context of whole-body frailty beyond 21 months of age to be a manifestation of “heartbeat frailty.”

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Emergence of heartbeat frailty in advanced age I: perspectives from life-long EKG recordings in adult mice

et al. 2022

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“…The increased sympathetic input to the SAN of older mice helps to reduce intrinsic heartbeat interval variability towards that of mice at younger ages. Other cross-sectional studies have associated changes in SAN automaticity in older mice with whole-body frailty [8, 10]. However, these cross-sectional studies lack mouse-specific, longitudinal perspectives on when and how changes in heartbeat interval variability leads to marked SAN dysfunction in individual long-lived mice, at an age when whole body frailty becomes manifest at older ages [11].…”

Section: Introductionmentioning

confidence: 99%

“…The aging mouse manifests abnormalities in HR and heartbeat interval variability that recapitulate many of those described in humans [5][6][7][8][9]. Cross-sectional studies that compare average data in different mice that have survived to different ages indicate that the intrinsic heartbeat interval variability and mean intrinsic HR are relatively constant between young adulthood and middle age but become substantially altered later in life [7].…”

Section: Introduction (834 Words)mentioning

confidence: 99%

Emergence of Heartbeat Frailty in Advanced Age: Perspectives from Life-Long EKG Recordings in Mice

Moen

Morrell

Ahmet

et al. 2022

Preprint

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SAN failure, aka sick-sinus syndrome, which features sinus bradycardia, SAN impulse pauses, and irregularity of RR interval rhythms are manifestations of SAN cell dysfunction that increases exponentially with advanced age, i.e., SAN frailty. Abnormalities in intrinsic RR interval variability may be the earliest signatures of SAN cell dysfunction leading to SAN frailty in late life. We measured RR interval variability within EKG time-series prior to and during double autonomic blockade in long-lived C57/BL6 mice at 3 month intervals from 6 months of age until the end of life. Long-lived mice (those that achieved the median cohort lifespan of 24 months and beyond) displayed relatively minor changes in intrinsic RR interval variability prior to 21 months of age. Between 21 and 30 months of age, marked changes in intrinsic RR interval variability signatures in time, frequency, non-linear, and fragmentation domains result in a marked increase in the mean intrinsic RR interval. The effects of autonomic input partially compensated for the prolongation of the mean RR interval by impacting the age-associated deterioration in the RR interval variability signatures toward a youthful pattern. Cross-sectional analyses of other subsets of mice at ages at or beyond the median life span of our longitudinal cohort demonstrated increased non-cardiac, constitutional, whole body frailty, a decrease in energetic efficiency, and an increase in respiratory exchange ratio. In this context, we interpret the progressive increase in intrinsic RR interval variability beyond 21 months of age to be an indication of heartbeat frailty.

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What to consider for ECG in mice—with special emphasis on telemetry

Calvet

Seebeck

2023

Mamm Genome

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Genetically or surgically altered mice are commonly used as models of human cardiovascular diseases. Electrocardiography (ECG) is the gold standard to assess cardiac electrophysiology as well as to identify cardiac phenotypes and responses to pharmacological and surgical interventions. A variety of methods are used for mouse ECG acquisition under diverse conditions, making it difficult to compare different results. Non-invasive techniques allow only short-term data acquisition and are prone to stress or anesthesia related changes in cardiac activity. Telemetry offers continuous long-term acquisition of ECG data in conscious freely moving mice in their home cage environment. Additionally, it allows acquiring data 24/7 during different activities, can be combined with different challenges and most telemetry systems collect additional physiological parameters simultaneously. However, telemetry transmitters require surgical implantation, the equipment for data acquisition is relatively expensive and analysis of the vast number of ECG data is challenging and time-consuming. This review highlights the limits of non-invasive methods with respect to telemetry. In particular, primary screening using non-invasive methods can give a first hint; however, subtle cardiac phenotypes might be masked or compensated due to anesthesia and stress during these procedures. In addition, we detail the key differences between the mouse and human ECG. It is crucial to consider these differences when analyzing ECG data in order to properly translate the insights gained from murine models to human conditions.

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

Cited by 11 publications

References 30 publications

Emergence of heartbeat frailty in advanced age I: perspectives from life-long EKG recordings in adult mice

Emergence of heartbeat frailty in advanced age I: perspectives from life-long EKG recordings in adult mice

Emergence of Heartbeat Frailty in Advanced Age: Perspectives from Life-Long EKG Recordings in Mice

What to consider for ECG in mice—with special emphasis on telemetry

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