Abstract
SummaryWe 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.
Highlights
It has been known since the 18th century that healthy heart beating intervals (BIs) are not strictly constant, but rather exhibit beat-to-beat variations, imparting complexity to the heart rhythm (Fye, 1995)
Two main mechanisms regulate the average Beating intervals (BIs) and beating interval variability (BIV): (i) stimulation of extrinsic autonomic receptors on pacemaker cells (i.e. b-adrenergic receptors (b-AR) or cholinergic receptors (CR)) within the sinoatrial node (SAN) (O’Brien et al, 1986; Sloan et al, 2008) controlled by the balance between sympathetic and parasympathetic neural impulses to the heart and (ii) constitutive signaling intrinsic to pacemaker cell via Ca2+calmodulin adenylyl cyclase (AC) types 1 and 8 (Papaioannou et al, 2013; Ben-Ari et al, 2014; Yaniv et al, 2014a,b), which, in the absence of autonomic receptor stimulation, drives many of the same cell mechanisms that are modulated by autonomic receptor stimulation (Mattick et al, 2007; Younes et al, 2008)
The average intrinsic BI in vivo began to be prolonged at 18 months, but prolongation reached a statistical significance at 30 months (Table S2)
Summary
It has been known since the 18th century that healthy heart beating intervals (BIs) are not strictly constant, but rather exhibit beat-to-beat variations, imparting complexity to the heart rhythm (Fye, 1995). Two main mechanisms regulate the average BI and BIV: (i) stimulation of extrinsic autonomic receptors on pacemaker cells (i.e. b-adrenergic receptors (b-AR) or cholinergic receptors (CR)) within the sinoatrial node (SAN) (O’Brien et al, 1986; Sloan et al, 2008) controlled by the balance between sympathetic and parasympathetic neural impulses to the heart and (ii) constitutive signaling intrinsic to pacemaker cell via Ca2+calmodulin adenylyl cyclase (AC) types 1 and 8 (Papaioannou et al, 2013; Ben-Ari et al, 2014; Yaniv et al, 2014a,b), which, in the absence of autonomic receptor stimulation, drives many of the same cell mechanisms that are modulated by autonomic receptor stimulation (Mattick et al, 2007; Younes et al, 2008)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
