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Chronotropic Modulation of the Source-Sink Relationship of Sinoatrial-Atrial Impulse Conduction and Its Significance to Initiation of AF: A One-Dimensional Model Study.

Cacciani F, Zaniboni M - Biomed Res Int (2015)

Bottom Line: Whereas antiarrhythmic-like interventions which involve downregulation of calcium channels or of calcium handling decrease SASF, the simulation of Ivabradine administration does so to a lesser extent.Particularly interesting is the increase of SASF observed when downregulation G Kr, which simulates the administration of class III antiarrhythmic agents and is likely sustained by an increase in I CaL.Also, the increase in SASF is accompanied by a decreased conduction delay and a better entrainment of repolarization, which is significant to anti-AF strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, University of Parma, Parco Area delle Scienze 11A, 43124 Parma, Italy.

ABSTRACT
Initiation and maintenance of atrial fibrillation (AF) is often associated with pharmacologically or pathologically induced bradycardic states. Even drugs specifically developed in order to counteract cardiac arrhythmias often combine their action with bradycardia and, in turn, with development of AF, via still largely unknown mechanisms. This study aims to simulate action potential (AP) conduction between sinoatrial node (SAN) and atrial cells, either arranged in cell pairs or in a one-dimensional strand, where the relative amount of SAN membrane is made varying, in turn, with junctional resistance. The source-sink relationship between the two membrane types is studied in control conditions and under different simulated chronotropic interventions, in order to define a safety factor for pacemaker-to-atrial AP conduction (SASF) for each treatment. Whereas antiarrhythmic-like interventions which involve downregulation of calcium channels or of calcium handling decrease SASF, the simulation of Ivabradine administration does so to a lesser extent. Particularly interesting is the increase of SASF observed when downregulation G Kr, which simulates the administration of class III antiarrhythmic agents and is likely sustained by an increase in I CaL. Also, the increase in SASF is accompanied by a decreased conduction delay and a better entrainment of repolarization, which is significant to anti-AF strategies.

No MeSH data available.


Related in: MedlinePlus

Passive and active properties of SAN source-atrial sink. RJ versus S plots, like that reported in Figure 1, were derived for each chronotropic intervention described in Figure 2. Iso corresponded to a 22% CL decrease, whereas all bradycardic maneuvers increased CL by 28%. Color code as in Figure 1. SASF values in MΩ were 8400 (NT), 11300 (Iso), 9550 (GKr), 4850 (Iva), 3400 (ACh), 2950 (Rya∗), and 2550 (GCaL).
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fig3: Passive and active properties of SAN source-atrial sink. RJ versus S plots, like that reported in Figure 1, were derived for each chronotropic intervention described in Figure 2. Iso corresponded to a 22% CL decrease, whereas all bradycardic maneuvers increased CL by 28%. Color code as in Figure 1. SASF values in MΩ were 8400 (NT), 11300 (Iso), 9550 (GKr), 4850 (Iva), 3400 (ACh), 2950 (Rya∗), and 2550 (GCaL).

Mentions: For each one of the simulated SAN APs which underwent the chronotropic interventions described in Figure 2, we simulated electrical coupling with a Lindblad et al. atrial cell model by solving the equation system (1) reported in Methods and varying, in turn, coupling resistance Rj and scaling factor S, as explained for Figure 1(d). Each simulation resulted, as shown above, in NP&ND, P&D, and P&ND configurations, all summarized in the color panels of Figure 3. In the case of downregulation of GKr and GCaL, we also report in Figure 4, superimposed to the surface profiles shown in Figure 3 (black dotted lines), the color contour plots of the corresponding CL values. Our hypothesis that the P&D area of each graphic (SASF) is a measure of the strength of the SAN source is confirmed by the simulated experiment reported in Figure 5. In each beating SAN cell, taken in steady state conditions (after 120 s, see Methods), we simulated a hyperpolarizing constant current injection of increasing amplitude in order to find the amount of current needed to stop pacemaking within an arbitrarily chosen interval of time (5 s). Longer intervals were also tried and gave qualitatively identical results (not shown). The correlation between the constant current value needed to switch off pacemaking and the corresponding SASF value derived from Figure 3 clearly appears in the histogram of Figure 5(b) and is statistically quantified by the correlation analysis in panel (c) of the same figure. Whether we consider, for each treatment in the uncoupled condition and for the corresponding coupled configuration, the hyperpolarizing current needed to turn off pacemaking and the SASF value, respectively, we find that both parameters significantly correlate with DDR and with no other AP parameter (see panel (d)).


Chronotropic Modulation of the Source-Sink Relationship of Sinoatrial-Atrial Impulse Conduction and Its Significance to Initiation of AF: A One-Dimensional Model Study.

Cacciani F, Zaniboni M - Biomed Res Int (2015)

Passive and active properties of SAN source-atrial sink. RJ versus S plots, like that reported in Figure 1, were derived for each chronotropic intervention described in Figure 2. Iso corresponded to a 22% CL decrease, whereas all bradycardic maneuvers increased CL by 28%. Color code as in Figure 1. SASF values in MΩ were 8400 (NT), 11300 (Iso), 9550 (GKr), 4850 (Iva), 3400 (ACh), 2950 (Rya∗), and 2550 (GCaL).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4502286&req=5

fig3: Passive and active properties of SAN source-atrial sink. RJ versus S plots, like that reported in Figure 1, were derived for each chronotropic intervention described in Figure 2. Iso corresponded to a 22% CL decrease, whereas all bradycardic maneuvers increased CL by 28%. Color code as in Figure 1. SASF values in MΩ were 8400 (NT), 11300 (Iso), 9550 (GKr), 4850 (Iva), 3400 (ACh), 2950 (Rya∗), and 2550 (GCaL).
Mentions: For each one of the simulated SAN APs which underwent the chronotropic interventions described in Figure 2, we simulated electrical coupling with a Lindblad et al. atrial cell model by solving the equation system (1) reported in Methods and varying, in turn, coupling resistance Rj and scaling factor S, as explained for Figure 1(d). Each simulation resulted, as shown above, in NP&ND, P&D, and P&ND configurations, all summarized in the color panels of Figure 3. In the case of downregulation of GKr and GCaL, we also report in Figure 4, superimposed to the surface profiles shown in Figure 3 (black dotted lines), the color contour plots of the corresponding CL values. Our hypothesis that the P&D area of each graphic (SASF) is a measure of the strength of the SAN source is confirmed by the simulated experiment reported in Figure 5. In each beating SAN cell, taken in steady state conditions (after 120 s, see Methods), we simulated a hyperpolarizing constant current injection of increasing amplitude in order to find the amount of current needed to stop pacemaking within an arbitrarily chosen interval of time (5 s). Longer intervals were also tried and gave qualitatively identical results (not shown). The correlation between the constant current value needed to switch off pacemaking and the corresponding SASF value derived from Figure 3 clearly appears in the histogram of Figure 5(b) and is statistically quantified by the correlation analysis in panel (c) of the same figure. Whether we consider, for each treatment in the uncoupled condition and for the corresponding coupled configuration, the hyperpolarizing current needed to turn off pacemaking and the SASF value, respectively, we find that both parameters significantly correlate with DDR and with no other AP parameter (see panel (d)).

Bottom Line: Whereas antiarrhythmic-like interventions which involve downregulation of calcium channels or of calcium handling decrease SASF, the simulation of Ivabradine administration does so to a lesser extent.Particularly interesting is the increase of SASF observed when downregulation G Kr, which simulates the administration of class III antiarrhythmic agents and is likely sustained by an increase in I CaL.Also, the increase in SASF is accompanied by a decreased conduction delay and a better entrainment of repolarization, which is significant to anti-AF strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Sciences, University of Parma, Parco Area delle Scienze 11A, 43124 Parma, Italy.

ABSTRACT
Initiation and maintenance of atrial fibrillation (AF) is often associated with pharmacologically or pathologically induced bradycardic states. Even drugs specifically developed in order to counteract cardiac arrhythmias often combine their action with bradycardia and, in turn, with development of AF, via still largely unknown mechanisms. This study aims to simulate action potential (AP) conduction between sinoatrial node (SAN) and atrial cells, either arranged in cell pairs or in a one-dimensional strand, where the relative amount of SAN membrane is made varying, in turn, with junctional resistance. The source-sink relationship between the two membrane types is studied in control conditions and under different simulated chronotropic interventions, in order to define a safety factor for pacemaker-to-atrial AP conduction (SASF) for each treatment. Whereas antiarrhythmic-like interventions which involve downregulation of calcium channels or of calcium handling decrease SASF, the simulation of Ivabradine administration does so to a lesser extent. Particularly interesting is the increase of SASF observed when downregulation G Kr, which simulates the administration of class III antiarrhythmic agents and is likely sustained by an increase in I CaL. Also, the increase in SASF is accompanied by a decreased conduction delay and a better entrainment of repolarization, which is significant to anti-AF strategies.

No MeSH data available.


Related in: MedlinePlus