Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Sep;596(17):3977-3991.
doi: 10.1113/JP276396. Epub 2018 Aug 3.

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

Samantha D Francis Stuart  1 , Lianguo Wang  1 , William R Woodard  2 , G Andre Ng  3 , Beth A Habecker  2 , Crystal M Ripplinger  1
Affiliations

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

Samantha D Francis Stuart et al. J Physiol. 2018 Sep.

Abstract

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 (Vm ,)- 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.

Keywords: adrenergic; aging; arrhythmia; sympathetic.

PubMed Disclaimer

Figures

Figure 1
Figure 1. SAN recovery time, AVN recovery time, and HR changes in young and aged hearts
A, an example ECG following rapid pacing; red arrow denotes termination of pacing and black arrows denote when return of P‐waves and QRS complexes were noted. B and C, cSAN and cAVN recovery times. D, differences in stimulation thresholds for SNS in each group. E, increases in heart rate with SNS and ISO infusion compared to baseline. F, a normalized time course of heart rate increase and return to baseline with SNSL. Data are means ± SEM, n = 7–11, * P < 0.05, ** P < 0.01, **** P < 0.0001 compared within groups. † P < 0.05, compared to matching conditions between groups. YWT, young hearts; AGED, aged hearts; SNS, sympathetic nerve stimulation; cSAN, corrected sinoatrial node return; cAVN, corrected atrioventricular node return; SNSL, SNS low; SNSH; SNS high; ISO, isoproterenol.
Figure 2
Figure 2. APD responses to SNS and ISO in young and aged hearts
A and B, representative contour maps show how SNS and ISO infusion alter action potential duration (APD80) in YWT (A) and AGED (B) hearts. C, example optical action potentials at baseline (red), SNSH (yellow), and with ISO (green). D, APD80 with SNS and ISO infusion. E, APD50 with SNS and ISO infusion. Data are means ± SEM, n = 7–11, * P < 0.05, ** P < 0.01, *** P < 0.001 compared within groups. YWT, young hearts; AGED, aged hearts; SNS, sympathetic nerve stimulation; SNSL, SNS low; SNSH, SNS high; ISO, isoproterenol.
Figure 3
Figure 3. Changes in the direction of repolarization with SNS and ISO in young and aged hearts
A, percentage of hearts in which the direction of repolarization changed following either SNSH or ISO. Direction changes were scored based on the degree of directional change – either no change, ∼90°, or ∼180°. B, representative repolarization maps demonstrate directional changes in a YWT and AGED heart with SNSH or ISO. n = 8–11; YWT, young hearts; AGED, aged hearts; SNSH, SNS high; ISO, isoproterenol.
Figure 4
Figure 4. CaT properties and alternans magnitude with SNS and ISO in young and aged hearts
A, representative optical CaTs at baseline (red) with SNSH (yellow) and ISO infusion (green). B, CaT rise times (Trise) with SNS and ISO. C, CaT decay time constants (tau) with SNS and ISO. D and E, representative contour maps and CaT traces show changes in calcium alternans magnitude with SNS and ISO (D, YWT; E, AGED). White/black boxes denote corresponding 9 × 9 pixel regions where example CaT traces were derived. F, CaT alternans magnitude. Values are an average of the entire epicardial field of view. Data are means ± SEM, n = 4–11, * P < 0.05, ** P < 0.01, **** P < 0.0001 compared within groups. † P < 0.05, †† P < 0.01 compared to matching conditions between groups. YWT, young hearts; AGED, aged hearts; SNS, sympathetic nerve stimulation; SNSL, SNS low; SNSH, SNS high; ISO, isoproterenol.
Figure 5
Figure 5. Arrhythmia susceptibility in young and aged hearts
ECG recordings demonstrate arrhythmias following rapid ventricular pacing. A, example of PVC; B, example of ventricular fibrillation. Red arrows denote when pacing was terminated. C, average arrhythmia scores per group. Data are means ± SEM, n = 10–11, * P < 0.05. YWT, young hearts; AGED, aged hearts.
Figure 6
Figure 6. Fibrosis in young and aged hearts
A, average fibrosis density (presented as % area, red lines are means, black error bars are SEM). B and C, representative images of Masson's Trichrome staining; fibrosis is blue and myocardial tissue is dark red. n = 3 hearts/group, * P < 0.05. YWT, young hearts; AGED, aged hearts.
Figure 7
Figure 7. Sympathetic nerve fibre density and noradrenaline content in young and aged hearts
A and B, ventricular sympathetic nerve fibre density (A, average LV fibre density; B, LV fibre density stratified by location, red lines are means, black error bars are SEM). Left ventricular (C) and right atrium (D) noradrenaline content. E, representative immunofluorescence images of tyrosine hydroxylase (TH) labelling (white fibres and puncta), n = 3–5, * P < 0.05, ** P < 0.01, *** P < 0.001 compared between groups. YWT, young hearts; AGED, aged hearts; RV, right ventricle; LV, left ventricle; RA, right atrium; NA, noradrenaline.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Al Shawi R, Hafner A, Chun S, Raza S, Crutcher K, Thrasivoulou C, Simons P & Cowen T (2007). ProNGF, sortilin, and age‐related neurodegeneration. Ann NYAcad Sci 1119, 208–215. - PubMed
    1. Al‐Shawi R, Hafner A, Olson J, Chun S, Raza S, Thrasivoulou C, Lovestone S, Killick R, Simons P & Cowen T (2008). Neurotoxic and neurotrophic roles of proNGF and the receptor sortilin in the adult and ageing nervous system. Eur J Neurosci 27, 2103–2114. - PubMed
    1. Chow LT, Chow SS, Anderson RH & Gosling JA (2001). Autonomic innervation of the human cardiac conduction system: changes from infancy to senility – an immunohistochemical and histochemical analysis. Anat Rec 264, 169–182. - PubMed
    1. Curtis MJ & Walker MJ (1988). Quantification of arrhythmias using scoring systems: an examination of seven scores in an in vivo model of regional myocardial ischaemia. Cardiovasc Res 22, 656–665. - PubMed
    1. De Jesus NM, Wang L , Lai J, Rigor RR, Francis Stuart SD, Bers DM, Lindsey ML & Ripplinger CM (2017). Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. Heart Rhythm 14, 727–736. - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources

-