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Disrupted calcium release as a mechanism for atrial alternans associated with human atrial fibrillation.

Chang KC, Bayer JD, Trayanova NA - PLoS Comput. Biol. (2014)

Bottom Line: As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown.The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest.Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope.

View Article: PubMed Central - PubMed

Affiliation: Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT
Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (kiCa) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope. Iterated map analysis revealed that because SR Ca2+ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in kiCa were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca2+ homeostasis which drives proarrhythmic APD alternans in patients with AF.

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Tissue preparation setup and comparisons of control, cAF, and cAFalt tissue during pacing.(A) Atrial tissue mesh with stimulus and recording electrodes. (B) APD restitution curves for control tissue (black), cAF-remodeled tissue [19] (red), and cAFalt tissue with APD alternans onset and amplitude matching clinical data [8] (dotted red line). The RyR inactivation rate constant (kiCa) was reduced 50% in the cAF model to create the cAFalt model. APs (C) and CaTs (D) recorded from the last two beats at 400-ms pacing CL. Alternans are present in the cAFalt tissue but not in control or cAF tissue.
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pcbi-1004011-g001: Tissue preparation setup and comparisons of control, cAF, and cAFalt tissue during pacing.(A) Atrial tissue mesh with stimulus and recording electrodes. (B) APD restitution curves for control tissue (black), cAF-remodeled tissue [19] (red), and cAFalt tissue with APD alternans onset and amplitude matching clinical data [8] (dotted red line). The RyR inactivation rate constant (kiCa) was reduced 50% in the cAF model to create the cAFalt model. APs (C) and CaTs (D) recorded from the last two beats at 400-ms pacing CL. Alternans are present in the cAFalt tissue but not in control or cAF tissue.

Mentions: In order to investigate ionic mechanisms in human AF that contribute to the generation of atrial APD alternans at the tissue level, we created a computer model of human atrial tissue incorporating ionic remodeling associated with chronic AF (cAF), as described in Methods. The sensitivity of APD alternans to ionic model parameters was evaluated by varying parameters one at a time and applying the clinical pacing protocol used by Narayan et al. to induce APD alternans in AF patients [8] (see Table 1 and Methods). For control, a model of normal human atrial tissue was also simulated. We then assessed the magnitude and onset pacing cycle length (CL) of APD alternans by analyzing voltage traces from the recording electrode (Fig. 1A), as outlined in Methods.


Disrupted calcium release as a mechanism for atrial alternans associated with human atrial fibrillation.

Chang KC, Bayer JD, Trayanova NA - PLoS Comput. Biol. (2014)

Tissue preparation setup and comparisons of control, cAF, and cAFalt tissue during pacing.(A) Atrial tissue mesh with stimulus and recording electrodes. (B) APD restitution curves for control tissue (black), cAF-remodeled tissue [19] (red), and cAFalt tissue with APD alternans onset and amplitude matching clinical data [8] (dotted red line). The RyR inactivation rate constant (kiCa) was reduced 50% in the cAF model to create the cAFalt model. APs (C) and CaTs (D) recorded from the last two beats at 400-ms pacing CL. Alternans are present in the cAFalt tissue but not in control or cAF tissue.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263367&req=5

pcbi-1004011-g001: Tissue preparation setup and comparisons of control, cAF, and cAFalt tissue during pacing.(A) Atrial tissue mesh with stimulus and recording electrodes. (B) APD restitution curves for control tissue (black), cAF-remodeled tissue [19] (red), and cAFalt tissue with APD alternans onset and amplitude matching clinical data [8] (dotted red line). The RyR inactivation rate constant (kiCa) was reduced 50% in the cAF model to create the cAFalt model. APs (C) and CaTs (D) recorded from the last two beats at 400-ms pacing CL. Alternans are present in the cAFalt tissue but not in control or cAF tissue.
Mentions: In order to investigate ionic mechanisms in human AF that contribute to the generation of atrial APD alternans at the tissue level, we created a computer model of human atrial tissue incorporating ionic remodeling associated with chronic AF (cAF), as described in Methods. The sensitivity of APD alternans to ionic model parameters was evaluated by varying parameters one at a time and applying the clinical pacing protocol used by Narayan et al. to induce APD alternans in AF patients [8] (see Table 1 and Methods). For control, a model of normal human atrial tissue was also simulated. We then assessed the magnitude and onset pacing cycle length (CL) of APD alternans by analyzing voltage traces from the recording electrode (Fig. 1A), as outlined in Methods.

Bottom Line: As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown.The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest.Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope.

View Article: PubMed Central - PubMed

Affiliation: Institute for Computational Medicine, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT
Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (kiCa) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope. Iterated map analysis revealed that because SR Ca2+ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in kiCa were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca2+ homeostasis which drives proarrhythmic APD alternans in patients with AF.

Show MeSH
Related in: MedlinePlus