Applying computational approaches to the understanding of the consequences and opportunities of ion channel properties in atrial fibrillation

Cardiac arrhythmias are disorders of the electrical system of the heart and an often clinically-challenging group of disorders. Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population; it is associated with significant morbidity and mortality. Available antiarrhythmic drugs (AADs) for the treatment of AF are older molecules with sub- optimal efficacy and safety profiles. Recent advances in basic electrophysiology and the development of sophisticated mathematical modeling approaches could help in expanding our understanding of the basic mechanisms of AF and assist in the development of novel AF- selective AADs. The purpose of this thesis was to utilize computational approaches to the understanding of the consequences and opportunities of ion channel properties, with a special emphasis on AF. The cardiac action potential is the basic functional unit of the electrical system of the heart and is the manifestation of coordinated current fluxes through specialized proteins known as ion channels. Antiarrhythmic drugs act through modulation of ion channel properties. We hypothesized that mathematical modeling could be used to study and optimize the pharmacodynamic properties of AADs for the treatment of AF. We demonstrated that the pharmacodynamic properties (binding/unbinding characteristics) of a state-dependent Na+- channel blocker modulate the drug’s anti-/proarrhythmic actions with inactivated-state blockers being optimally AF-selective. The optimized drug’s selectivity for AF was the result of its rate- selectivity (stronger effects at fast vs slow cardiomyocyte activation rates) with relatively mild atrial-selective (stronger effects in atrial vs ventricular cardiomyocytes) actions. We found that the optimally AF-selective Na+-channel blocker had sub-optimal anti-AF efficacy, but that slightly less selective drugs had favorable AF-termination rates. We then sought to explore potential current-block combinations with synergistic AF- selective properties. Using mathematical modeling and laboratory experiments, we demonstrated that the combination of optimized state-dependent Na+-channel block and K+- channel block had synergistic effects, significantly augmenting AF termination rates for any level of AF-selectivity vs pure Na+-channel block. The mechanisms of these synergistic effects were found to be mediated by the functional interaction between the action potential prolonging- v effects of K+-channel block, the Na+-channel blocker’s voltage-dependent binding/unbinding properties and the Na+ channel’s inactivation characteristics, highlighting the non-linear nature of the cardiac action potential’s dynamics. Traditional K+ currents targeted by AADs have significant ventricular proarrhythmic liabilities. Using recent experimental observations, we updated the mathematic formulation for the inactivation dynamics of the ultra-rapid delayed-rectifier K+ current (IKur), an atrial-specific current. Using this model, we showed that, contrary to what had been proposed in the published literature, IKur rate-dependent properties are mediated by its activation properties with minimal contribution from inactivation, under physiological conditions. We also demonstrated that the contribution of IKur to action potential repolarization is preserved, or even increased, in the setting of electrical remodeling-induced IKur downregulation. Finally, we described the mechanisms of the forward rate-dependent of IKur block, mediated by functional non-linear interactions with the rapid delayed inward-rectifier K+ current (IKr), the only K+ current with such properties. Until recently, fibroblasts were considered to be electrically inactive. More recently, experimental work demonstrated the presence of functional ionic current on the fibroblast and possible cardiomyocyte-fibroblast coupling. Here, we described a novel kind of heart failure- induced electrical remodeling involving the fibroblasts ion channels. This was characterized by downregulation of the fibroblast voltage-dependent K+ current (IKv,fb) and upregulation of the fibroblast inward-rectifier K+ current (IKir,fb). We then implemented our experimental findings into a mathematical model of cardiomyocyte-fibroblast coupling and found fibroblast electrical remodeling to have significant effects on the cardiomyocyte’s electrophysiological properties. In a 2-dimension model of simulated AF, downregulation of IKv,fb had an antiarrhythmic effect whereas IKir,fb upregulation was found to be proarrhythmic. The studies presented here utilized mathematical modeling to study non-linear systems in cardiac electrophysiology to tackle questions that would have been difficult to approach with traditional laboratory-based experimentation. They also showcased how theoretical results can help orient and receive confirmation with subsequent experimental work or, conversely, novel experimental findings results be implemented into a mathematical model to investigate potential consequences. Mathematical modeling is a promising tool to help in studying the complex and vi  non-linear effects of pharmacological modulation of ion channel properties and assist in the development of optimized antiarrhythmics for the treatment of AF, a major unmet need in clinical medicine. As models increase in sophistication to better represent the cardiomyocyte’s electrophysiology, they will almost certainly play an ever-growing role in expanding our understanding of the mechanisms of complex arrhythmias.

Keyphrases: cardiac electrophysiology, mathematical modeling, atrial fibrillation, antiarrhythmic drugs