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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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Alternans in cAFalt tissue at the onset CL.The odd (blue) and even (red) beats at the alternans onset CL (400 ms) are shown superimposed. Large Ca2+ release occurred during the long beat (blue traces). Top (left to right): transmembrane potential (Vm), intracellular Ca2+ ([Ca2+]i), and SR Ca2+concentration ([Ca2+]SR). Bottom (left to right): RyR open probability (RyRo), L-type Ca2+ current (ICa), Na+/Ca2+ exchanger current (INCX).
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pcbi-1004011-g004: Alternans in cAFalt tissue at the onset CL.The odd (blue) and even (red) beats at the alternans onset CL (400 ms) are shown superimposed. Large Ca2+ release occurred during the long beat (blue traces). Top (left to right): transmembrane potential (Vm), intracellular Ca2+ ([Ca2+]i), and SR Ca2+concentration ([Ca2+]SR). Bottom (left to right): RyR open probability (RyRo), L-type Ca2+ current (ICa), Na+/Ca2+ exchanger current (INCX).

Mentions: When kiCa was decreased by 50% in the cAF model (we refer to this as the cAFalt ionic model), APD alternans onset data from the human AF tissue model agreed well with data from persistent AF patients. Significant APD alternans began at 400-ms CL (Fig. 1B, dotted red line), mean APD at onset was 229 ms, and APD alternans magnitude at onset was 27 ms (Fig. 1C, dotted red line). These metrics were each within one standard deviation (SD) of clinical observations [8] (Fig. 3). The cAFalt model also displayed noticeable alternans in intracellular Ca2+ ([Ca2+]i) at the onset CL (Fig. 1D). For both the cAF and cAFalt models, mean APDs were shorter than in the control model (Fig. 1B–C), and diastolic and systolic [Ca2+]i were lower than in control (Fig. 1D). At 400-ms CL in the cAFalt model, on the odd (long) vs. the even (short) beat (Fig. 4, blue vs. red), there was higher sarcoplasmic reticulum (SR) Ca2+ load before release (0.288 vs. 0.273 mM), higher peak RyR open probability (RyRo) (9.0e-4 vs. 4.7e-4), a larger intracellular Ca2+ transient (CaT) amplitude (Δ[Ca2+]i = 0.13 vs. 0.067 µM), similar L-type Ca2+ (LCC) current (integrated over one beat: 144 vs. 140 mC/F), and increased Na+/Ca2+ exchanger (NCX) current (INCX, integrated over one beat: 98.4 vs. 74.5 mC/F). The positive coupling between transmembrane potential (Vm) and Ca2+, with INCX as the primary electrogenic current, is consistent with experimental findings [20]. Since the magnitude and onset of APD alternans in the cAFalt model provided the best agreement with clinical APD alternans data (Fig. 3), we chose to use this model for subsequent investigations into the underlying causes of alternans occurrence.


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

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

Alternans in cAFalt tissue at the onset CL.The odd (blue) and even (red) beats at the alternans onset CL (400 ms) are shown superimposed. Large Ca2+ release occurred during the long beat (blue traces). Top (left to right): transmembrane potential (Vm), intracellular Ca2+ ([Ca2+]i), and SR Ca2+concentration ([Ca2+]SR). Bottom (left to right): RyR open probability (RyRo), L-type Ca2+ current (ICa), Na+/Ca2+ exchanger current (INCX).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1004011-g004: Alternans in cAFalt tissue at the onset CL.The odd (blue) and even (red) beats at the alternans onset CL (400 ms) are shown superimposed. Large Ca2+ release occurred during the long beat (blue traces). Top (left to right): transmembrane potential (Vm), intracellular Ca2+ ([Ca2+]i), and SR Ca2+concentration ([Ca2+]SR). Bottom (left to right): RyR open probability (RyRo), L-type Ca2+ current (ICa), Na+/Ca2+ exchanger current (INCX).
Mentions: When kiCa was decreased by 50% in the cAF model (we refer to this as the cAFalt ionic model), APD alternans onset data from the human AF tissue model agreed well with data from persistent AF patients. Significant APD alternans began at 400-ms CL (Fig. 1B, dotted red line), mean APD at onset was 229 ms, and APD alternans magnitude at onset was 27 ms (Fig. 1C, dotted red line). These metrics were each within one standard deviation (SD) of clinical observations [8] (Fig. 3). The cAFalt model also displayed noticeable alternans in intracellular Ca2+ ([Ca2+]i) at the onset CL (Fig. 1D). For both the cAF and cAFalt models, mean APDs were shorter than in the control model (Fig. 1B–C), and diastolic and systolic [Ca2+]i were lower than in control (Fig. 1D). At 400-ms CL in the cAFalt model, on the odd (long) vs. the even (short) beat (Fig. 4, blue vs. red), there was higher sarcoplasmic reticulum (SR) Ca2+ load before release (0.288 vs. 0.273 mM), higher peak RyR open probability (RyRo) (9.0e-4 vs. 4.7e-4), a larger intracellular Ca2+ transient (CaT) amplitude (Δ[Ca2+]i = 0.13 vs. 0.067 µM), similar L-type Ca2+ (LCC) current (integrated over one beat: 144 vs. 140 mC/F), and increased Na+/Ca2+ exchanger (NCX) current (INCX, integrated over one beat: 98.4 vs. 74.5 mC/F). The positive coupling between transmembrane potential (Vm) and Ca2+, with INCX as the primary electrogenic current, is consistent with experimental findings [20]. Since the magnitude and onset of APD alternans in the cAFalt model provided the best agreement with clinical APD alternans data (Fig. 3), we chose to use this model for subsequent investigations into the underlying causes of alternans occurrence.

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