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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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Iterated map analysis of Ca2+ cycling in cAF and control cells.For each panel, SR Ca2+ release slope () is plotted against SR Ca2+ uptake factor (), with cellular Ca2+ efflux factor () values indicated in the color bar. The boundaries between stable (no alternans) and unstable (alternans) regions in the - plane are denoted by dashed lines for different values of  (see Eq. 1). Circles and X's indicate the absence and presence of alternans, respectively. (A) Results for the cAF model. CL is varied, from 700 ms to 200 ms for the 100% kiCa model and from 700 ms to 300 ms for the 50% kiCa model (i.e., the cAFalt model), in 10-ms increments. At a CL of 390 ms, kiCa is scaled from 100% to 50% in 2% increments. (B) Same as in panel A, except that the control cell model is used, and kiCa is scaled from 100% to 16%. (C) Starting with the control cell parameter values, L-type Ca2+ current conductance (gCaL), maximal Na+/Ca2+ exchanger current (IbarNCX), and RyR activation rate constant (koCa) are sequentially scaled to cAF values, resulting in net decreases in  and . Finally, kiCa is scaled to 50% (as in the cAFalt model), and  increases sufficiently to reach the alternans boundary (red X). If only gCaL is decreased to the cAF value, then alternans threshold is achieved at a higher kiCa value (72%, green X).
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pcbi-1004011-g008: Iterated map analysis of Ca2+ cycling in cAF and control cells.For each panel, SR Ca2+ release slope () is plotted against SR Ca2+ uptake factor (), with cellular Ca2+ efflux factor () values indicated in the color bar. The boundaries between stable (no alternans) and unstable (alternans) regions in the - plane are denoted by dashed lines for different values of (see Eq. 1). Circles and X's indicate the absence and presence of alternans, respectively. (A) Results for the cAF model. CL is varied, from 700 ms to 200 ms for the 100% kiCa model and from 700 ms to 300 ms for the 50% kiCa model (i.e., the cAFalt model), in 10-ms increments. At a CL of 390 ms, kiCa is scaled from 100% to 50% in 2% increments. (B) Same as in panel A, except that the control cell model is used, and kiCa is scaled from 100% to 16%. (C) Starting with the control cell parameter values, L-type Ca2+ current conductance (gCaL), maximal Na+/Ca2+ exchanger current (IbarNCX), and RyR activation rate constant (koCa) are sequentially scaled to cAF values, resulting in net decreases in and . Finally, kiCa is scaled to 50% (as in the cAFalt model), and increases sufficiently to reach the alternans boundary (red X). If only gCaL is decreased to the cAF value, then alternans threshold is achieved at a higher kiCa value (72%, green X).

Mentions: For each version of the human atrial cell model (cAF and control), we calculated the SR Ca2+ release slope (), the SR Ca2+ uptake factor (), and the cellular Ca2+ efflux factor () [28], [29] for a range of kiCa values and pacing rates and compared the value of to the threshold for alternans. For a typical range of parameter values (, see S1 Text), the threshold value of required for alternans is given by the following equation:(1)Theoretical analysis predicts that the system is stable when . Eq. 1 is graphed for a range of values in Figs. 8A–C (dotted lines). Each curve represents the boundary between stable (no alternans) and unstable (alternans) Ca2+ cycling in the - plane for a particular value of . As increases (Fig. 8A–C, dark blue to dark red), the threshold curve steepens, indicating that increased Ca2+ extrusion from the cell has a protective effect, helping to restore Ca2+ content back to steady state following a perturbation. Thus, a higher value of is required to reach alternans threshold for higher values of . Note that in this theoretical approach, increased Ca2+ efflux (κ) has the opposite effect as in Qu et al.[29], suppressing rather than promoting Ca2+ alternans.


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

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

Iterated map analysis of Ca2+ cycling in cAF and control cells.For each panel, SR Ca2+ release slope () is plotted against SR Ca2+ uptake factor (), with cellular Ca2+ efflux factor () values indicated in the color bar. The boundaries between stable (no alternans) and unstable (alternans) regions in the - plane are denoted by dashed lines for different values of  (see Eq. 1). Circles and X's indicate the absence and presence of alternans, respectively. (A) Results for the cAF model. CL is varied, from 700 ms to 200 ms for the 100% kiCa model and from 700 ms to 300 ms for the 50% kiCa model (i.e., the cAFalt model), in 10-ms increments. At a CL of 390 ms, kiCa is scaled from 100% to 50% in 2% increments. (B) Same as in panel A, except that the control cell model is used, and kiCa is scaled from 100% to 16%. (C) Starting with the control cell parameter values, L-type Ca2+ current conductance (gCaL), maximal Na+/Ca2+ exchanger current (IbarNCX), and RyR activation rate constant (koCa) are sequentially scaled to cAF values, resulting in net decreases in  and . Finally, kiCa is scaled to 50% (as in the cAFalt model), and  increases sufficiently to reach the alternans boundary (red X). If only gCaL is decreased to the cAF value, then alternans threshold is achieved at a higher kiCa value (72%, green X).
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Related In: Results  -  Collection

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

pcbi-1004011-g008: Iterated map analysis of Ca2+ cycling in cAF and control cells.For each panel, SR Ca2+ release slope () is plotted against SR Ca2+ uptake factor (), with cellular Ca2+ efflux factor () values indicated in the color bar. The boundaries between stable (no alternans) and unstable (alternans) regions in the - plane are denoted by dashed lines for different values of (see Eq. 1). Circles and X's indicate the absence and presence of alternans, respectively. (A) Results for the cAF model. CL is varied, from 700 ms to 200 ms for the 100% kiCa model and from 700 ms to 300 ms for the 50% kiCa model (i.e., the cAFalt model), in 10-ms increments. At a CL of 390 ms, kiCa is scaled from 100% to 50% in 2% increments. (B) Same as in panel A, except that the control cell model is used, and kiCa is scaled from 100% to 16%. (C) Starting with the control cell parameter values, L-type Ca2+ current conductance (gCaL), maximal Na+/Ca2+ exchanger current (IbarNCX), and RyR activation rate constant (koCa) are sequentially scaled to cAF values, resulting in net decreases in and . Finally, kiCa is scaled to 50% (as in the cAFalt model), and increases sufficiently to reach the alternans boundary (red X). If only gCaL is decreased to the cAF value, then alternans threshold is achieved at a higher kiCa value (72%, green X).
Mentions: For each version of the human atrial cell model (cAF and control), we calculated the SR Ca2+ release slope (), the SR Ca2+ uptake factor (), and the cellular Ca2+ efflux factor () [28], [29] for a range of kiCa values and pacing rates and compared the value of to the threshold for alternans. For a typical range of parameter values (, see S1 Text), the threshold value of required for alternans is given by the following equation:(1)Theoretical analysis predicts that the system is stable when . Eq. 1 is graphed for a range of values in Figs. 8A–C (dotted lines). Each curve represents the boundary between stable (no alternans) and unstable (alternans) Ca2+ cycling in the - plane for a particular value of . As increases (Fig. 8A–C, dark blue to dark red), the threshold curve steepens, indicating that increased Ca2+ extrusion from the cell has a protective effect, helping to restore Ca2+ content back to steady state following a perturbation. Thus, a higher value of is required to reach alternans threshold for higher values of . Note that in this theoretical approach, increased Ca2+ efflux (κ) has the opposite effect as in Qu et al.[29], suppressing rather than promoting Ca2+ alternans.

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