Modulation of cardiac pacemaker inter beat intervals by sinoatrial fibroblasts — A numerical study

Greisas, Ariel; Zlochiver, Sharon

doi:10.1109/embc.2016.7590666

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…At the same time, multicellular models of coupled SAN cells have demonstrated dynamic changes in the location of the primary pacemaker site in response to β-adrenergic stimulation [20]. Other studies have coupled heterogeneous cell types in multicellular preparations to examine the influence of inexcitable cells (e.g., fibroblasts) on pacemaking [21,22].…”

Section: Introductionmentioning

confidence: 99%

Synchronization of Pacemaking in the Sinoatrial Node: A Mathematical Modeling Study

et al. 2018

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Computational studies using mathematical models of the sinoatrial node (SAN) cardiac action potential (AP) have provided important insight into the fundamental nature of cell excitability, cardiac arrhythmias, and potential therapies. While the impact of ion channel dynamics on SAN pacemaking has been studied, the governing dynamics responsible for regulating spatial and temporal control of SAN synchrony remain elusive. Here, we attempt to develop methods to explore cohesion in a network of coupled spontaneously active SAN cells. We present the updated version of a previously published graphical user interface LongQt: a cross-platform, threaded application for advanced cardiac electrophysiology studies that does not require advanced programming skills. We incorporated additional features to the existing LongQt platform that allows users to (1) specify heterogeneous gap junction conductivity across a multicellular grid, and (2) set heterogeneous ion channel conductance across a multicellular grid. We developed two methods of characterizing the synchrony of SAN tissue based on alignment of activation in time and similarity of voltage peaks among clusters of functionally related cells. In pairs and two-dimensional grids of coupled cells, we observed a range of conductivities (0.00014-0.00033 1/ -cm) in which the tissue was more susceptible to developing asynchronous spontaneous pro-arrhythmic behavior (e.g., spiral wave formation). We performed parameter sensitivity analysis to determine the relative impact of ion channel conductances on cycle length (CL), diastolic and peak voltage, and synchrony measurements in isolated and coupled cell pairs. We also defined measurements of evaluating synchrony based on peak AP voltage and the rate of wave propagation. Cell-to-cell coupling had a non-linear effect on the relationship between ion channel conductances, AP properties, and synchrony measurements. Our simulations demonstrate that conductivity plays an important role in regulating synchronous firing of heterogeneous SAN tissue, and demonstrate how to evaluate the role of coupling and ion channel conductance in pairs and grids of SAN cells. We anticipate that the approach outlined here will facilitate identification of key cell-and tissue-level factors responsible for cardiac disease.

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Section: Introductionmentioning

confidence: 99%

Synchronization of Pacemaking in the Sinoatrial Node: A Mathematical Modeling Study

et al. 2018

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“…Simulations of fibroblasts coupled with a single myocyte have been reported by Greisas and Zlochiver . They show that the CL of a myocite depends nonmonotonically on number of fibroblasts attached to it: A small number of fibroblasts shorten (the effect also reported in Tolstokorov et al), while large number of fibroblasts may prolong the CL.…”

Section: Discussionmentioning

confidence: 99%

Effects of fibroblast‐myocyte coupling on the sinoatrial node activity: A computational study

Karpaev

Syunyaev

Алиев

2018

Numer Methods Biomed Eng

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While the sinoatrial node (SAN) is structurally heterogeneous, most computer simulations of electrical activity take into account SAN pacemaker cells only. Our aim was to investigate how fibroblasts affect the SAN activity. We simulated the rabbit sinoatrial node accounting for differences between central and peripheral pacemaker cells, and for fibroblast-myocyte electrical coupling. We have observed that only if fibroblast-myocyte coupling is taken into account, (1) action potential is initiated in the central part of the SAN (within 1.2 mm of the center of simulated tissue); otherwise, leading centers are located on the periphery; (2) few (1 to 6) leading centers initiate action potential in the SAN; otherwise, we observed more than 8 leading centers; (3) acetylcholine superfusion results in a shift of leading centers toward the SAN periphery; and (4) sinus pauses up to 1.9 second follow acetylcholine superfusion. We observed negligible effect of fibroblast-myocyte coupling on the period of SAN activation. We conclude that fibroblast-myocyte coupling may explain action potential initiation and propagation from the center of the SAN observed in experimental studies, while atrial load on the peripheral SAN fails to explain this fact.

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“…Shox2 is a member of the homeobox family of transcription factors [22][23][24] , and recent studies suggest it is important for development and maintenance of rhythmic activity in adult heart. Cells in the sinoatrial node of the heart generate spontaneous, rhythmic action potentials and lead other working myocytes to beat at a stable firing rate, thus these cells are known as pacemaker cells 25 . The rhythmic action potential generation in the pacemaker cells is mediated by the prominent expression of HCN channels and T-type calcium channels 26,27 .…”

Section: Introductionmentioning

confidence: 99%

The transcription factor Shox2 shapes thalamocortical neuron firing and synaptic properties

Maroteaux

Song

et al. 2019

Preprint

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Thalamocortical neurons (TCNs) transmit information about sensory stimuli from the thalamus to the cortex. In response to different physiological states and demands TCNs can fire in tonic and/or phasic burst modes. These firing properties of TCNs are supported by precisely timed inhibitory synaptic inputs from the thalamic reticular nucleus and intrinsic currents, including T-type Ca 2+ and HCN currents. These intrinsic currents are mediated by Cav3.1 and HCN channel subunits, and alterations in expression or modulation of these channels can have dramatic implications on thalamus function. The factors that regulate these currents controlling the firing patterns important for integration of the sensory stimuli and the consequences resulting from the disruption of these firing patterns are not well understood. Shox2 is a transcription factor known to be important for pacemaker activity in the heart. We show here that Shox2 is also expressed in adult mouse thalamus. We hypothesized that genes regulated by Shox2's transcriptional activity may be important for physiological properties of TCNs. In this study, we used RNA sequencing on control and Shox2 knockout mice to determine Shox2-affected genes and revealed a network of ion channel genes important for neuronal firing properties. Quantitative PCR confirmed that expression of Hcn2, 4 and Cav3.1 genes were affected by Shox2 KO. Western blotting showed expression of the proteins for these channels was decreased in the thalamus, and electrophysiological recordings showed that Shox2 KO impacted the firing and synaptic properties of TCNs. Finally, behavioral studies revealed that Shox2 expression in TCNs play a role in somatosensory function and object recognition memory. Overall, these results reveal Shox2 as a transcription factor important for TCN firing properties and thalamic function. 1 Processing of sensory information is mediated by precise circuitry that senses stimuli in 2 the periphery and transforms the information through a network of synaptic connections to 3 ultimately allow perception and cognitive processing of the surrounding world. Rhythmic 4 oscillations of brain activity crucial to cognitive function emerge from neuronal network 5 interactions that consist of reciprocal connections between the thalamus, the inhibitory 6 thalamic reticular nucleus and the cortex 1 . Dysfunction of these oscillations caused by 7 aberrant activity in the thalamic circuit is thought to play a role in many neuropathological 8 conditions, including epilepsy 2-4 , autism 5-7 , and schizophrenia [8][9][10][11] . Furthermore, damage to 9 thalamic nuclei, especially medial and anterior nuclei, causes severe memory deficits known 10 as diencephalic amnesia 12-17 . 11 The intrinsic properties that shape action potential firing and contribute to rhythmic 12 oscillations of the thalamocortical neurons (TCNs) are important for efficient transfer of 13 information from the thalamus to the cortex. Notably, TCNs switch their firing states between 14 2 modes, burst and tonic fi...

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Modulation of cardiac pacemaker inter beat intervals by sinoatrial fibroblasts — A numerical study

Cited by 3 publications

References 20 publications

Synchronization of Pacemaking in the Sinoatrial Node: A Mathematical Modeling Study

Synchronization of Pacemaking in the Sinoatrial Node: A Mathematical Modeling Study

Effects of fibroblast‐myocyte coupling on the sinoatrial node activity: A computational study

The transcription factor Shox2 shapes thalamocortical neuron firing and synaptic properties

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