title: Deterioration of autonomic neuronal receptor signaling and mechanisms intrinsic to heart pacemaker cells contribute to age-associated alterations in heart rate variability in vivo.
abstract: We aimed to determine how age-associated changes in mechanisms extrinsic and intrinsic to pacemaker cells relate to basal beating interval variability (BIV) reduction in vivo. Beating intervals (BIs) were measured in aged (23-25 months) and adult (3-4 months) C57BL/6 male mice (i) via ECG in vivo during light anesthesia in the basal state, or in the presence of 0.5 mg mL(-1) atropine + 1 mg mL(-1) propranolol (in vivo intrinsic conditions), and (ii) via a surface electrogram, in intact isolated pacemaker tissue. BIV was quantified in both time and frequency domains using linear and nonlinear indices. Although the average basal BI did not significantly change with age under intrinsic conditions in vivo and in the intact isolated pacemaker tissue, the average BI was prolonged in advanced age. In vivo basal BIV indices were found to be reduced with age, but this reduction diminished in the intrinsic state. However, in pacemaker tissue BIV indices increased in advanced age vs. adults. In the isolated pacemaker tissue, the sensitivity of the average BI and BIV in response to autonomic receptor stimulation or activation of mechanisms intrinsic to pacemaker cells by broad-spectrum phosphodiesterase inhibition declined in advanced age. Thus, changes in mechanisms intrinsic to pacemaker cells increase the average BIs and BIV in the mice of advanced age. Autonomic neural input to pacemaker tissue compensates for failure of molecular intrinsic mechanisms to preserve average BI. But this compensation reduces the BIV due to both the imbalance of autonomic neural input to the pacemaker cells and altered pacemaker cell responses to neural input.
authors.affiliation: Biomedical Engineering Faculty, Technion-IIT, Haifa, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Yaniv
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Ismayil
authors.initials: I
authors.lastname: Ahmet
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Kenta
authors.initials: K
authors.lastname: Tsutsui
authors.affiliation: Biomedical Engineering Faculty, Technion-IIT, Haifa, Israel.
authors.forename: Joachim
authors.initials: J
authors.lastname: Behar
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Jack M
authors.initials: JM
authors.lastname: Moen
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Toni-Rose
authors.initials: TR
authors.lastname: Guiriba
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Rostislav
authors.initials: R
authors.lastname: Bychkov
authors.affiliation: Laboratory of Cardiovascular Science, Biomedical Research Center, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008136:Longevity / Q000502:physiology; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010138:Pacemaker, Artificial; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012849:Sinoatrial Node / Q000187:drug effects / Q000502:physiology
chemical_list: D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D011956:Receptors, Cell Surface; D002217:Carbachol; D007545:Isoproterenol
keywords: autonomic neural impulses; chaotic systems; heart rate variability; intrinsic heart rate; pacemaker cells; sinoatrial nodal