Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice with a large socioeconomic impact due to its associated morbidity, mortality, reduction in quality of life and health care costs. Currently, antiarrhythmic drug therapy is the first line of treatment for most symptomatic AF patients, despite its limited efficacy, the risk of inducing potentially life-threating ventricular tachyarrhythmias as well as other side effects. Alternative, in-hospital treatment modalities consisting of electrical cardioversion and invasive catheter ablation improve patients' symptoms, but often have to be repeated and are still associated with serious complications and only suitable for specific subgroups of AF patients. The development and progression of AF generally results from the interplay of multiple disease pathways and is accompanied by structural and functional (e.g., electrical) tissue remodeling. Rational development of novel treatment modalities for AF, with its many different etiologies, requires a comprehensive insight into the complex pathophysiological mechanisms. Monolayers of atrial cells represent a simplified surrogate of atrial tissue well-suited to investigate atrial arrhythmia mechanisms, since they can easily be used in a standardized, systematic and controllable manner to study the role of specific pathways and processes in the genesis, perpetuation and termination of atrial arrhythmias. In this review, we provide an overview of the currently available two- and three-dimensional multicellular in vitro systems for investigating the initiation, maintenance and termination of atrial arrhythmias and AF. This encompasses cultures of primary (animal-derived) atrial cardiomyocytes (CMs), pluripotent stem cell-derived atrial-like CMs and (conditionally) immortalized atrial CMs. The strengths and weaknesses of each of these model systems for studying atrial arrhythmias will be discussed as well as their implications for future studies.
Highlights
Atrial fibrillation (AF) is a rapidly growing global health problem mainly due to aging of the human population and adherence to unhealthy lifestyles
Especially due to the differences in cardiac ion channels and action potential (AP) characteristics between atrial myocytes (AMs) of humans and animals, cultures of animal-derived AMs may not always be representative for what happens in human AF patients
Use of AMs derived from human pluripotent stem cell (PSC) should potentially yield more relevant AF models than can be obtained with animal cells and Human iPSCs (hiPSCs) offer the possibility to generate patient-specific AMs, opening up the avenue for personalized disease modeling and drug screening
Summary
Atrial fibrillation (AF) is a rapidly growing global health problem mainly due to aging of the human population and adherence to unhealthy lifestyles. The multicellular modeling of atrial arrhythmias was based on computer simulations due to the lack of proper in vitro models [83] This changed when animal-derived atrial tissue was separated and used for CM isolation, resulting in studies that could use patch clamp as well as voltage- and Ca2+sensitive dyes to study the dynamics of specific ion currents in an atrial context [84,85,86]. A different and novel approach used to study the mechanisms involved in the termination of atrial arrhythmias was the optogenetic modification of NRAM monolayers, resulting in the expression in NRAMs of ion channels whose activity can be controlled with high precision in time and space by light [95, 96]. The high spatiotemporal control of electrical depolarization allowed Feola et al to demonstrate that the successful and local targeting of atrial rotors requires a line of conduction block that spans from the rotor core
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