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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.
Highlights
Atrial fibrillation (AF) is currently the most common cardiac rhythm disorder, posing a significant medical and economic challenge for the US health care system [1,2]
action potential duration (APD) alternans in the human AF tissue model 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, as described in Methods
These results suggest that altered ryanodine receptor (RyR) kinetics is the critical cellular component underlying the occurrence of APD alternans in AF patients at pacing rates near rest, and that kiCa plays a key role in this process
Summary
Atrial fibrillation (AF) is currently the most common cardiac rhythm disorder, posing a significant medical and economic challenge for the US health care system [1,2]. This burden is likely to increase as the population ages and AF prevalence rises [3]. Narayan et al found that APD alternans always preceded AF initiation, indicating that alternans may play an important role in establishing the arrhythmogenic substrate and creating vulnerability to AF. A better understanding of AF arrhythmogenesis will likely depend upon identification of the mechanism driving atrial alternans at heart rates near rest
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