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

Sinoatrial node (SAN) function declines with age; however, not all individuals age at the same rate and health status can vary from fit to frail. Frailty was quantified in young and aged mice using a non-invasive frailty index so that the impacts of age and frailty on heart rate and SAN function could be assessed. SAN function was impaired in aged mice due to alterations in electrical conduction, changes in SAN action potential morphology and fibrosis in the SAN. Changes in SAN function, electrical conduction, action potential morphology and fibrosis were correlated with, and graded by, frailty. This study shows that mice of the same chronological age have quantifiable differences in health status that impact heart rate and SAN function and that these differences in health status can be identified using our frailty index. Sinoatrial node (SAN) dysfunction increases with age, although not all older adults are affected in the same way. This is because people age at different rates and individuals of the same chronological age vary in health status from very fit to very frail. Our objective was to determine the impacts of age and frailty on heart rate (HR) and SAN function using a new model of frailty in ageing mice. Frailty, which was quantified in young and aged mice using a frailty index (FI), was greater in aged vs. young mice. Intracardiac electrophysiology demonstrated that HR was reduced whereas SAN recovery time (SNRT) was prolonged in aged mice; however, both parameters showed heteroscedasticity suggesting differences in health status among mice of similar chronological age. Consistent with this, HR and corrected SNRT were correlated with, and graded by, FI score. Optical mapping of the SAN demonstrated that conduction velocity (CV) was reduced in aged hearts in association with reductions in diastolic depolarization (DD) slope and action potential (AP) duration. In agreement with in vivo results, SAN CV, DD slope and AP durations all correlated with FI score. Finally, SAN dysfunction in aged mice was associated with increased interstitial fibrosis and alterations in expression of matrix metalloproteinases, which also correlated with frailty. These findings demonstrate that age-related SAN dysfunction occurs in association with electrical and structural remodelling and that frailty is a critical determinant of health status of similarly aged animals that correlates with changes in HR and SAN function.

Moghtadaei M ，Jansen HJ ，Mackasey M ，Rafferty SA ，Bogachev O ，Sapp JL ，Howlett SE ，Rose RA ... -  《-》

Loss of Natriuretic Peptide Receptor C Enhances Sinoatrial Node Dysfunction in Aging and Frail Mice.

Heart rate (HR) is controlled by the sinoatrial node (SAN). SAN dysfunction is highly prevalent in aging; however, not all individuals age at the same rate. Rather, health status during aging is affected by frailty. Natriuretic peptides regulate SAN function in part by activating natriuretic peptide receptor C (NPR-C). The impacts of NPR-C on HR and SAN function in aging and as a function of frailty are unknown. Frailty was measured in aging wild-type and NPR-C knockout (NPR-C-/-) mice using a mouse clinical frailty index (FI). HR and SAN structure and function were investigated using intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, histology, and molecular biology. NPR-C-/- mice rapidly became frail leading to shortened life span. HR was reduced and SAN recovery time was increased in older versus younger mice, and these changes were exacerbated in NPR-C-/- mice; however, there was substantial variability among age groups and genotypes. HR and SAN recovery time were correlated with FI score and fell along a continuum regardless of age or genotype. Optical mapping demonstrates impairments in SAN function that were also correlated with FI score. SAN fibrosis was increased in aged and NPR-C-/- mice and was graded by FI score. Loss of NPR-C results in accelerated aging and rapid decline in health status in association with impairments in HR and SAN function. Frailty assessment was effective and better able to distinguish aging-dependent changes in SAN function in the setting of shortened life span due to loss of NPR-C.

Jansen HJ ，Moghtadaei M ，Rafferty SA ，Belke DD ，Rose RA ... -  《-》

Atrial structure, function and arrhythmogenesis in aged and frail mice.

Jansen HJ ，Moghtadaei M ，Mackasey M ，Rafferty SA ，Bogachev O ，Sapp JL ，Howlett SE ，Rose RA ... -  《Scientific Reports》

The impact of age and frailty on ventricular structure and function in C57BL/6J mice.

Heart size increases with age (called hypertrophy), and its ability to contract declines. However, these reflect average changes that may not be present, or present to the same extent, in all older individuals. That aging happens at different rates is well accepted clinically. People who are aging rapidly are frail and frailty is measured with a 'frailty index'. We quantified frailty with a validated mouse frailty index tool and evaluated the impacts of age and frailty on cardiac hypertrophy and contractile dysfunction. Hypertrophy increased with age, while contractions, calcium currents and calcium transients declined; these changes were graded by frailty scores. Overall health status, quantified as frailty, may promote maladaptive changes associated with cardiac aging and facilitate the development of diseases such as heart failure. To understand age-related changes in heart structure and function, it is essential to know both chronological age and the health status of the animal. On average, cardiac hypertrophy and contractile dysfunction increase with age. Still, individuals age at different rates and their health status varies from fit to frail. We investigated the influence of frailty on age-dependent ventricular remodelling. Frailty was quantified as deficit accumulation in adult (≈7 months) and aged (≈27 months) C57BL/6J mice by adapting a validated frailty index (FI) tool. Hypertrophy and contractile function were evaluated in Langendorff-perfused hearts; cellular correlates/mechanisms were investigated in ventricular myocytes. FI scores increased with age. Mean cardiac hypertrophy increased with age, but values in the adult and aged groups overlapped. When plotted as a function of frailty, hypertrophy was graded by FI score (r = 0.67-0.55, P < 0.0003). Myocyte area also correlated positively with FI (r = 0.34, P = 0.03). Left ventricular developed pressure (LVDP) plus rates of pressure development (+dP/dt) and decay (-dP/dt) declined with age and this was graded by frailty (r = -0.51, P = 0.0007; r = -0.48, P = 0.002; r = -0.56, P = 0.0002 for LVDP, +dP/dt and -dP/dt). Smaller, slower contractions graded by FI score were also seen in ventricular myocytes. Contractile dysfunction in cardiomyocytes isolated from frail mice was attributable to parallel changes in underlying Ca2+ transients. These changes were not due to reduced sarcoplasmic reticulum stores, but were graded by smaller Ca2+ currents (r = -0.40, P = 0.008), lower gain (r = -0.37, P = 0.02) and reduced expression of Cav1.2 protein (r = -0.68, P = 0.003). These results show that cardiac hypertrophy and contractile dysfunction in naturally aging mice are graded by overall health and suggest that frailty, in addition to chronological age, can help explain heterogeneity in cardiac aging.

Feridooni HA ，Kane AE ，Ayaz O ，Boroumandi A ，Polidovitch N ，Tsushima RG ，Rose RA ，Howlett SE ... -  《-》

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

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

Dorey TW ，Jansen HJ ，Moghtadaei M ，Jamieson KL ，Rose RA ... -  《-》