Rate-Dependent Role of I^sub Kur^ in Human Atrial Repolarization and Atrial Fibrillation Maintenance
The atrial-specific ultrarapid delayed rectifier K+ current (I^sub Kur^) inactivates slowly but completely at depolarized voltages. The consequences for I^sub Kur^ rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed I^sub Kur^ inactivation dynamics. Here, we developed an updated formulation of I^sub Kur^ inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation. We then modified the human atrial cardiomyocyte Courtemanche AP model to incorporate realistic I^sub Kur^ inactivation properties. Despite markedly different inactivation dynamics, there was no difference in AP parameters across a wide range of stimulation frequencies between the original and updated models. Using the updated model, we showed that, under physiological stimulation conditions, I^sub Kur^ does not inactivate significantly even at high atrial rates because the transmembrane potential spends little time at voltages associated with inactivation. Thus, channel dynamics are determined principally by activation kinetics. I^sub Kur^ magnitude decreases at higher rates because of AP changes that reduce I^sub Kur^ activation. Nevertheless, the relative contribution of I^sub Kur^ to AP repolarization increases at higher frequencies because of reduced activation of the rapid delayed-rectifier current I^sub Kr^. Consequently, I^sub Kur^ block produces dose-dependent termination of simulated atrial fibrillation (AF) in the absence of AF-induced electrical remodeling. The inclusion of AF-related ionic remodeling stabilizes simulated AF and greatly reduces the predicted antiarrhythmic efficacy of I^sub Kur^ block. Our results explain a range of experimental observations, including recently reported positive rate-dependent I^sub Kur^-blocking effects on human atrial APs, and provide insights relevant to the potential value of I^sub Kur^ as an antiarrhythmic target for the treatment of AF..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:112 |
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| Enthalten in: |
Biophysical journal - 112(2017), 9, Seite 1997 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Martin Aguilar [VerfasserIn] |
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| Links: |
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| Förderinstitution / Projekttitel: |
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OLC199605984X |
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| 520 | |a The atrial-specific ultrarapid delayed rectifier K+ current (I^sub Kur^) inactivates slowly but completely at depolarized voltages. The consequences for I^sub Kur^ rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed I^sub Kur^ inactivation dynamics. Here, we developed an updated formulation of I^sub Kur^ inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation. We then modified the human atrial cardiomyocyte Courtemanche AP model to incorporate realistic I^sub Kur^ inactivation properties. Despite markedly different inactivation dynamics, there was no difference in AP parameters across a wide range of stimulation frequencies between the original and updated models. Using the updated model, we showed that, under physiological stimulation conditions, I^sub Kur^ does not inactivate significantly even at high atrial rates because the transmembrane potential spends little time at voltages associated with inactivation. Thus, channel dynamics are determined principally by activation kinetics. I^sub Kur^ magnitude decreases at higher rates because of AP changes that reduce I^sub Kur^ activation. Nevertheless, the relative contribution of I^sub Kur^ to AP repolarization increases at higher frequencies because of reduced activation of the rapid delayed-rectifier current I^sub Kr^. Consequently, I^sub Kur^ block produces dose-dependent termination of simulated atrial fibrillation (AF) in the absence of AF-induced electrical remodeling. The inclusion of AF-related ionic remodeling stabilizes simulated AF and greatly reduces the predicted antiarrhythmic efficacy of I^sub Kur^ block. Our results explain a range of experimental observations, including recently reported positive rate-dependent I^sub Kur^-blocking effects on human atrial APs, and provide insights relevant to the potential value of I^sub Kur^ as an antiarrhythmic target for the treatment of AF. | ||
| 650 | 4 | |a Activation | |
| 650 | 4 | |a Cardiac arrhythmia | |
| 650 | 4 | |a Mathematical models | |
| 650 | 4 | |a Stimulation | |
| 650 | 4 | |a Physiology | |
| 650 | 4 | |a Frequency dependence | |
| 650 | 4 | |a Dynamic mechanical properties | |
| 650 | 4 | |a Inactivation | |
| 650 | 4 | |a Blocking | |
| 650 | 4 | |a Cardiomyocytes | |
| 650 | 4 | |a Computer simulation | |
| 650 | 4 | |a Remodeling | |
| 650 | 4 | |a Fibrillation | |
| 650 | 4 | |a Kinetics | |
| 650 | 4 | |a Potassium channels (delayed-rectifying) | |
| 650 | 4 | |a Audio frequencies | |
| 650 | 4 | |a Deactivation | |
| 650 | 4 | |a Frequencies | |
| 650 | 4 | |a Membrane potential | |
| 650 | 4 | |a Depolarization | |
| 700 | 0 | |a Jianlin Feng |4 oth | |
| 700 | 0 | |a Edward Vigmond |4 oth | |
| 700 | 0 | |a Philippe Comtois |4 oth | |
| 700 | 0 | |a Stanley Nattel |4 oth | |
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