Age‐related changes in sympathetic responsiveness and cardiac electrophysiology

Abstract

IntroductionAging is associated with chronic increases in sympathetic activity, yet neurodegeneration also occurs, leading to a loss of functional sympathetic fibers in the heart. How these age‐related changes in sympathetic structure and function directly impact cardiac electrophysiology and intracellular Ca2+ handling have not been systematically characterized.ObjectiveTo determine how aging affects electrophysiological responses to sympathetic stimulation in intact mouse hearts.MethodsYoung (3 – 4 months, YWT, n=10) and aged (20 – 24 months, AGED, n=11) C57Bl6 female mice were studied. Optical mapping was performed on fully innervated hearts loaded with voltage‐ (Vm, Rh237) and calcium‐sensitive (Ca2+, Rhod2‐AM) indicators. Two stimulation electrodes were used – one on the apex of the heart for ventricular pacing and one inserted into the spinal canal (T1‐T3) for sympathetic nerve stimulation (SNS). SNS thresholds were determined as the lowest stimulation frequency (SNSL) necessary to elicit a 5% increase in heart rate (HR); the high SNS stimulation frequency (SNSH) was set at SNSL + 5 Hz. After SNS, hearts were perfused with isoproterenol (1 μM, ISO) to assess β‐adrenergic responsiveness. Hearts were then preserved for immunohistochemistry for tyrosine hydroxylase (TH: sympathetic fibers) and neurotransmitter content with HPLC analysis.ResultsBaseline HRs trended higher in AGED vs. YWT hearts (225.14±26.24 bpm vs. 166.50±13.11 bpm; p=NS). The SNSL threshold was increased in AGED vs. YWT hearts (5.36±0.34 Hz vs. 3.81±0.44 Hz, p<0.05). A time course of HR increase and return to baseline in response to SNSL showed significant increases at 5 and 10s of SNS in YWT compared baseline (5 sec: 73±23% increase, p=<0.0001 vs. time 0; 10 sec: 53±19% increase, p<0.05 vs. time 0). There were no statistically significant changes in HR at any time point in AGED compared to baseline. However, both AGED and YWT hearts had similarly increased HRs in response to ISO. Despite an increased susceptibility to pacing‐induced arrhythmias in AGED, there were no significant differences in action potential duration compared to YWT. Ca2+ transient decay constants (tau) were decreased in YWT with SNS, but AGED tau were unaffected by SNS. AGED had significantly lower nerve fiber density than YWT (0.99±0.14% vs. 2.50±0.09% TH+, p<0.01) and trended toward lower norepinephrine (NE) content (2.61±0.214 vs. 3.61±0.184 pmol/mg, p=NS).ConclusionsInterestingly, baseline HRs tended to be higher in AGED vs. YWT hearts, suggesting an increase in basal sympathetic tone, even in a de‐centralized innervated heart preparation. Stimulation thresholds for SNS‐induced changes in HR were increased in AGED and stimulation with supra‐threshold frequencies resulted in minimal changes in HR, action potential, or Ca2+ handling properties compared to YWT responses. With ISO, however, HR and action potential responses were similar in AGED and YWT hearts, suggesting that altered nerve density and function, and not necessarily β‐adrenergic responsiveness, are responsible for these differences.Support or Funding InformationThis project was funded by the NIH (NIH R01 HL111600; to C.M. Ripplinger), the Training Program in Pharmacology at UC Davis (T32GM099608; to S.D. Francis Stuart) and an Achievement Rewards for College Scientists scholarship (to S.D. Francis Stuart).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.