Session S23.6

Cardiac Memory in Human Atria and Relation to Arrhythmogenesis

C Sánchez*, E Pueyo, P Laguna, B Rodríguez

Universidad de Zaragoza
Zaragoza, Spain

Abnormal adaptation of action potential duration (APD) to changes in heart rate (HR) has been suggested as an indicator of increased arrhythmic risk. In this study, we investigate the mechanisms underlying APD rate adaptation in human atrial cells and its relationship to arrhythmogenesis. Simulations are performed using action potential (AP) computational models and results are compared with experimental data from the literature.
APD rate adaptation in response to sudden sustained HR changes, from 1 Hz to 1.67 Hz and back to 1 Hz, is shown to take some minutes to be completed and two adaptation phases are identified: a fast initial one (with a time constant tfast of 7 s), related to the L-type calcium current (ICaL) and the Na+/Ca2+ exchanger; and a subsequent slow phase (with a time constant tslow of 6 min) determined by intracellular Na dynamics. APD adaptation dynamics and its underlying mechanisms are found to be independent on the human atrial AP model used, and they are also found to be consistent in different species (human, dog). Our simulation results are in qualitative and quantitative agreement with experimental canine data.
Alterations in ionic mechanisms leading to delayed APD adaptation are shown to be associated with increased proarrhythmic risk, as quantified by electrophysiological biomarkers describing probability of calcium reactivation (?), AP triangulation (d) and APD restitution slopes (Ss1s2 and Sdyn). Simulations show that protracted fast adaptation (increased tfast) occurs when ICaL and/or Na+/Ca2+ exchanger are inhibited, with ICaL having larger impact on adaptation. Specifically, 30% ICaL inhibition leads to increased values of ? and d (?=0.46 and d=2.99 versus ?=0.39 and d=2.33 in control) and shallower restitution slopes (Ss1s2=0.24 and Sdyn=0.23 versus Ss1s2=0.52 and Sdyn=0.29 in control). Regarding the slow adaptation phase, Na+/K+ pump inhibition, which slows Na dynamics and APD accommodation (increased tslow), is found to be associated with slightly higher probability of calcium reactivation (?=0.40), strongly triangulated APs (d=4.70), and flatter restitution slopes (Ss1s2=0.29 and Sdyn=0.20).
In this study APD adaptation in human atrial cells has been characterized, and mechanisms underlying it have been unravelled. Delayed APD accommodation has been associated with slow sodium dynamics, which are related to increased proarrhythmic risk, mostly due to increased likelihood of developing early afterdepolarizations.

(Abstract Control Number: 101)