Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals

Yaniv, Yael; Ahmet, Ismayil; Liu, Jie; Lyashkov, Alexey E.; Guiriba, Toni Rose; Okamoto, Y.; Ziman, Bruce D.; Lakatta, Edward G.

doi:10.1016/j.hrthm.2014.03.049

Cited by 67 publications

(85 citation statements)

References 24 publications

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“…Similar results have been documented previously [14]. Although the baseline beating rate is similar in isolated, intact rabbit sinoatial node tissue and isolated single SANC [25], the change in spontaneous AP firing rate in response to β-AR stimulation is lower in freshly isolated SANC than in intact sinoatial node tissue [26]. Therefore, it is possible that during the isolation procedure of single SANC some mechanisms that regulate the response to ISO become altered.…”

Section: Discussionsupporting

confidence: 85%

Real-time relationship between PKA biochemical signal network dynamics and increased action potential firing rate in heart pacemaker cells

Yaniv

Ganesan

Yang

et al. 2015

Journal of Molecular and Cellular Cardiology

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cAMP-PKA protein kinase is a key nodal signaling pathway that regulates a wide range of heart pacemaker cell functions. These functions are predicted to be involved in regulation of spontaneous action potential (AP) generation of these cells. Here we investigate if the kinetics and stoichiometry of increase in PKA activity match the increase in AP firing rate in response to β-adrenergic receptor (β-AR) stimulation or phosphodiesterase (PDE) inhibition, that alter the AP firing rate of heart sinoatrial pacemaker cells. In cultured adult rabbit pacemaker cells infected with an adenovirous expressing the FRET sensor AKAR3, the EC50 in response to graded increases in the intensity of β-AR stimulation (by Isoproterenol) the magnitude of the increases in PKA activity and the spontaneous AP firing rate were similar (0.4±0.1nM vs. 0.6±0.15nM, respectively). Moreover, the kinetics (t1/2) of the increases in PKA activity and spontaneous AP firing rate in response to β-AR stimulation or PDE inhibition were tightly linked. We characterized the system rate-limiting biochemical reactions by integrating these experimentally derived data into mechanistic-computational model. Model simulations predicted that phospholamban phosphorylation is a potent target of the increase in PKA activity that links to increase in spontaneous AP firing rate. In summary, the kinetics and stoichiometry of increases in PKA activity in response to a physiological (β-AR stimulation) or pharmacological (PDE inhibitor) stimuli match those of changes in the AP firing rate. Thus Ca2+-cAMP/PKA-dependent phosphorylation limits the rate and magnitude of increase in spontaneous AP firing rate.

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Section: Discussionsupporting

confidence: 85%

Real-time relationship between PKA biochemical signal network dynamics and increased action potential firing rate in heart pacemaker cells

Yaniv

Ganesan

Yang

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…1). A similar link between the increase in AP BI and AP BIV in response to acetylcholine has been previously documented [1, 2, 17]. Note, however, that in contrast to IVA or CPA, which has specific direct effects only on the M or the Ca 2+ clock, respectively, acetylcholine works directly on both [18].…”

Section: Discussionsupporting

confidence: 74%

Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells

Yaniv

Lyashkov

Sirenko

et al. 2014

Journal of Molecular and Cellular Cardiology

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Recent evidence indicates that the spontaneous action potential (AP) of isolated sinoatrial node cells (SANC) is regulated by a system of stochastic mechanisms embodied within two clocks: ryanodine receptors of the “Ca2+ clock” within the sarcoplasmic reticulum, spontaneously activate during diastole and discharge local Ca2+ releases (LCRs) beneath the cell surface membrane; clock crosstalk occurs as LCRs activate an inward Na+/Ca2+ exchanger current (INCX), which together with If and decay of K+ channels prompts the “M clock,” the ensemble of sarcolemmal-electrogenic molecules, to generate APs. Prolongation of the average LCR period accompanies prolongation of the average AP beating interval (BI). Moreover, prolongation of the average AP BI accompanies increased AP BI variability. We hypothesized that both the average AP BI and AP BI variability are dependent upon stochasticity of clock mechanisms reported by the variability of LCR period. We perturbed the coupled-clock system by directly inhibiting the M clock by ivabradine (IVA) or the Ca2+ clock by cyclopiazonic acid (CPA). When either clock is perturbed by IVA (3, 10 and 30μM), which has no direct effect on Ca2+ cycling, or CPA ( 0.5 and 5μM), which has no direct effect on the M clock ion channels, the clock system failed to achieve the basal AP BI and both AP BI and AP BI variability increased. The changes in average LCR period and its variability in response to perturbations of the coupled-clock system were correlated with changes in AP beating interval and AP beating interval variability. We conclude that the stochasticity within the coupled-clock system affects and is affected by the AP BI firing rate and rhythm via modulation of the effectiveness of clock coupling.

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“…From studies of healthy adult subjects during exercise and studies of heart-transplant recipients, we know that intrinsic components of cardiac rhythm contribute substantially to HRV. (11)(12)(13) The regulation of cardiac function is impaired during inflammation, as evidenced by a reduction in some HRV measures. Reduction of certain HRV measures during systemic inflammation is strongly correlated with an unfavourable prognosis.…”

Section: Discussionmentioning

confidence: 99%

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

Frasch

Herry

Niu

et al. 2018

Preprint

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Heart rate variability (HRV) is an important indicator of health and disease, yet its physiological origins are poorly understood. The contribution of intrinsic and extrinsic sources to HRV is not known. In a near-term fetal sheep model, we aimed to identify fetal HRV measures reflecting intrinsic contributions to HRV. Ex vivo Langendorff preparation was used to record intrinsic HRV in animals who were normoxic or hypoxic in vivo. We identify the intrinsic HRV in isolated hearts from fetal sheep in late gestation and how it is affected by chronic fetal hypoxia. Significance StatementHeart rate variability (HRV) is an important indicator of health and disease, yet its physiological origins are poorly understood. Both, the heart, intrinsically, and extrinsic systems, such as the brain, are hypothesized to contribute to HRV. In a near-term fetal sheep model of human development, we identified fetal HRV components reflecting intrinsic contributions to HRV. In addition, we show that these intrinsic HRV components carry memory of chronic oxygen deprivation the fetus experienced during the last third of gestation.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/242107 doi: bioRxiv preprint first posted online Jan. 22, 2018; 3 IntroductionFetal heart rate (FHR) monitoring is widely used clinically during labour, although its ability to identify fetuses at risk of severe metabolic acidosis is poor.(1) It is established that normal FHR variability (fHRV) represents a complex, nonlinear integration of the sympathetic and parasympathetic nervous system activities. Fetal body and breathing movements, baroreflex and circadian processes also influence HRV.(2,3,4-6) There is also some evidence that intrinsic pacemaker rhythms of the sino-atrial node affect HRV in critically ill adults. (7) However, whether intrinsic HRV (iHRV) exists in the fetal period and whether this is affected by chronic fetal hypoxia has never been tested. Here, we show iHRV in isolated hearts from fetal sheep in late gestation. We also show that chronic fetal hypoxia has significant effects on iHRV.

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Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals

Cited by 67 publications

References 24 publications

Real-time relationship between PKA biochemical signal network dynamics and increased action potential firing rate in heart pacemaker cells

Real-time relationship between PKA biochemical signal network dynamics and increased action potential firing rate in heart pacemaker cells

Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

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