Multiscale analysis of atrial fibrillation mechanisms

Atrial fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia, particularly in developed countries. AF is mainly initiated and sustained by reentrant circuits (rotors) and ectopic foci in different parts of the atria, which entail a chaotic electrical activation pattern in the muscular tissue. However, the ionic mechanisms underlying the generation and maintenance of AF are not fully understood, thus leading to a limited efficacy of current pharmacological AF therapies, which often require concomitant surgical ablation of atrial tissue. In this thesis we provide mechanistic descriptions of the physiological and pathophysiological behavior of atrial cells and tissues by means of modeling and simulation of human atrial electrical activity. During the course of this thesis, a number of models have been used to simulate the electrical activity of human atrial cardiomyocytes and investigate properties related with arrhythmic risk. The models used in this thesis provide a full description of all the ionic currents and intracellular dynamics of sodium, potassium and calcium ions that underlie differences between the potentials in the intracellular and the extracellular spaces during each cardiac cycle. The time course of this transmembrane potential when an external stimulus is applied to the cell is known as action potential (AP). The first part of this thesis consisted of the analysis of the adaptation of the AP duration (APD), in both individual cells and unidimensional fibers, to changes in heart rate. Simulations showed that APD adaptation occurred in two phases, fast and slow, with different underlying ionic mechanisms. The maximal conductance of ICaL and the activity of the NaCa exchanger were the main drivers of the fast adaptation phase, while the activity of the NaK pump was the major determinant of the slow phase. In the second part of the present thesis, the investigations were extended to study additional cell and tissue electrophysiological properties related to the risk of suffering atrial arrhythmias, including APD and resting membrane potential at steady-state after periodic stimulation, APD restitution curves with S1S2 and dynamic restitution protocols, conduction velocity in unidimensional fibers, and effective refractory period, dominant frequency and phase singularities in bidimensional tissue. The ionic mechanisms modulating these electrophysiological properties were investigated in sinus rhythm (SR) and AF conditions. The results from the conducted simulations allowed to conclude that the activity of the NaK pump and the IK1 current are the most important ionic mechanisms modulating properties at cell level, both in SR and AF conditions, whereas the role of INa was proved to be key in the modulation of tissue properties, particularly in AF. Interestingly, simulations showed that temporal adaptation of atrial electrophysiological properties to alterations in ionic currents was monotonic, except for alterations in the NaK pump where adaptation was biphasic (initial increase followed by progressive decrease, or viceversa). The third part of this thesis dealt with the study of the large variability that exists between cells from different patients and different regions of the atria. Particularly, the ionic mechanisms involved in the variability in atrial cell repolarization and AP morphology were investigated. Populations of models were built to mimic the variability of experimental data from patients diagnosed with SR and with chronic AF by generating combinations of the most important ionic mechanisms in AP modulation. Only AP models within experimentally determined physiological ranges were selected. Using the developed populations of models, the ionic mechanisms underlying variability in the APD measured at different stages of repolarization were ascertained. IK1 and the NaK pump were identified as the most relevant mechanisms determining variability in APD90, whereas ICaL, Ito and IKur were key in modulating inter-subject differences in APD20 and APD50, both in SR and AF conditions. The unraveled ionic mechanisms underlying variability in AP morphology were IK1, INaK and INaCa. Results obtained with different AP models were consistent with each other, except for some differences such as the relevance of ICaL in modulating variability in APD90, the importance of IK1 and the NaK pump in modulating variability in APD20 and the likelihood of presenting AP alternans within the population at fast pacing rates. In the fourth part of this thesis, AF dynamics at whole atria level were investigated using a three-dimensional (3D) virtual human atrial model developed at the Karlsruhe Institute of Technology. From the analysis of 49 pseudo-electrogram signals mapping the atria, we observed the dominant frequency of the signals was strongly reduced when either inhibition INa or, to a lesser extent, IK1 and the NaK pump. The temporal regularity of the arrhythmia was increased by both INa and IK1 inhibition in left atrium, but the effects were reduced in the right atrium, whereas NaK pump inhibition acted to reduce the regularity in both atria. The effects on AF dynamics of introducing variability in APD90, APD50 and APD20 were studied by calculating sub-populations of models (extracting them from the total population of models previously described) and assigning each cell in the 3D model with a model of the sub-population. The results of the simulations showed that human atria presenting long APDs could be associated with slow but very regular fibrillatory patterns, whereas those with short APDs may have high frequency reentrant rotors and high organization. To summarize, the results presented in this thesis have improved the understanding of the ionic mechanisms underlying electrophysiological properties related to arrhythmic risk in human atria through the use of cardiac computational modeling techniques.