Cardiac alternans have been observed to precede atrial fibrillation (AF) episodes in clinical studies with patients, and thus have been hypothesized to be correlated with arrhythmogenic propensity. Computational models of cellular electrophysiology have been used to gain insight into the mechanisms that drive this dynamic behavior preceding cardiac arrhythmias. However, the complexity of dynamic phenomena that give rise to arrhythmias makes elucidation of the mechanisms underlying arrhythmogenicity difficult. Furthermore, the nonlinear nature of the models of cardiac electrophysiology poses additional challenges to uncovering the mechanisms of cellular instability. Therefore, single cell studies of cardiac alternans can help bring insight into the the ionic and molecular mechanisms that drive alternans, and ultimately, arrhythmogenic behavior in the heart.
Recently, a ‘populations of models’ approach has been proposed to incorporate the effects of experimental and clinical variability on simulations of cardiac models. This approach has been combined with sensitivity analysis (SA) to uncover ionic mechanisms that drive cellular arrhythmogenic behaviors.
In this study, we built two populations of single cells using the Koivumäki model, one in normal Sinus Rhythm and the other in AF, by varying model parameters within ±30% of the baseline. We extracted 13 biomarkers from each model, and the two populations were constrained to experimental values of action potential markers. The calibrated populations were subject to SA to quantify correlations between model parameters and pro-arrhythmia markers.
The normal and AF populations showed distinct steady state and dynamical behaviors. The normal population revealed greater variability and dynamic instability as compared to the AF population, indicating that ionic remodeling in AF rendered these cells’ dynamical behavior more stable to parameter variation and rate adaptation. SA revealed that the biomarkers depended on five major ionic currents, with different sensitivities in normal and AF. These results highlight that arrhythmia maintenance in AF may not be due to instability in cell membrane excitability, but rather due to tissue-level effects which promote reentrant arrhythmia.