Age-related changes in cardiac electrophysiology and calcium handling in response to sympathetic nerve stimulation

Key points: Ageing results in changes to cardiac electrophysiology, Ca²⁺ handling, and β-adrenergic responsiveness. Sympathetic neurodegeneration also occurs with age, yet detailed action potential and Ca²⁺ handling responses to physiological sympathetic nerve stimulation (SNS) in the aged heart have not been assessed. Optical mapping in mouse hearts with intact sympathetic innervation revealed reduced responsiveness to SNS in the aged atria (assessed by heart rate) and aged ventricles (assessed by action potentials and Ca²⁺ transients). Sympathetic nerve density and noradrenaline content were reduced in aged ventricles, but noradrenaline content was preserved in aged atria. These results demonstrate that reduced responsiveness to SNS in the atria may be primarily due to decreased β-adrenergic receptor responsiveness, whereas reduced responsiveness to SNS in the ventricles may be primarily due to neurodegeneration. Abstract: The objective of this study was to determine how age-related changes in sympathetic structure and function impact cardiac electrophysiology and intracellular Ca²⁺ handling. Innervated hearts from young (3-4 months, YWT, n = 10) and aged (20-24 months, AGED, n = 11) female mice (C57Bl6) were optically mapped using the voltage (V_m,)- and calcium (Ca²⁺)-sensitive indicators Rh237 and Rhod2-AM. Sympathetic nerve stimulation (SNS) was performed at the spinal cord (T1-T3). β-Adrenergic responsiveness was assessed with isoproterenol (1 μM, ISO). Sympathetic nerve density and noradrenaline content were also quantified. Stimulation thresholds necessary to produce a defined increase in heart rate (HR) with SNS were higher in AGED vs. YWT hearts (5.4 ± 0.4 vs. 3.8 ± 0.4 Hz, P < 0.05). Maximal HR with SNS was lower in AGED vs. YWT (20.5 ± 3.41% vs. 73.0 ± 7.63% increase, P < 0.05). β-Adrenergic responsiveness of the atria (measured as percentage increase in HR with ISO) was decreased in AGED vs. YWT hearts (75.3 ± 22.5% vs. 148.5 ± 19.8%, P < 0.05). SNS significantly increased action potential duration (APD) in YWT but not AGED. Ca²⁺ transient durations and rise times were unchanged by SNS, yet AGED hearts had an increased susceptibility to Ca²⁺ alternans and ventricular arrhythmias. β-Adrenergic responsiveness of all ventricular parameters were similar between AGED and YWT. Sympathetic nerve density and noradrenaline content were decreased in the AGED ventricle, but not atria, compared to YWT. These data suggest that decreased responsiveness to SNS in the aged atria may be primarily due to decreased β-adrenergic responsiveness, whereas decreased responsiveness to SNS in the aged ventricles may be primarily due to nerve degeneration.