Multicellular In vitro Models of Cardiac Arrhythmias: Focus on Atrial Fibrillation

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.

Electrophysiological Effects of Extracellular Vesicles Secreted by Cardiosphere-Derived Cells: Unraveling the Antiarrhythmic Properties of Cell Therapies

“…This study used HL-1 cardiomyocyte monolayers as models of arrhythmic substrate. Despite being an in vitro cell line capable of presenting a mature cardiac phenotype and being widely used to study cardiac electrophysiology and arrhythmias [39,40,[42][43][44][45][46][47][48][49], their use has several limitations that must be taken into account. HL-1 cells, although being mature, are of murine origin and present important electrophysiological differences with adult human cardiac tissue.…”

Ranolazine-Mediated Attenuation of Mechanoelectric Feedback in Atrial Myocyte Monolayers

“…The present study was performed using a specific experimental model of stretch based on HL-1 cells, which present a differentiated genotype and phenotype with characteristics of adult atrial myocytes ( Claycomb et al, 1998 ; White et al, 2004 ; Dias et al, 2014 ). HL-1 cells constitute a well-characterized atrial myocyte culture line, widely used to investigate cardiac electrophysiology and arrhythmias ( Climent et al, 2015 ; van Gorp et al, 2020 ). Nevertheless, extrapolation of the results obtained in the present study should consider the differences between HL-1 cell cultures and human atrial tissue, and the characteristics of the experimental preparation for inducing acute stretch, since the effects of stretch in chronic preparations (e.g., 24 h) and in situ atrium preparations can lead to different responses ( Chorro et al, 2015 ; Del Canto et al, 2018 ).…”

“…On the other hand, as mentioned above, the characteristics of this experimental model do not allow the study of activation patterns during programmed electrical stimulation, because the area of cultured monolayer facilitated the spontaneous fibrillatory activity (van Gorp et al, 2020;Climent et al, 2015;Agladze et al, 2017). However, it should be noted that, despite these disadvantages, HL-1 cultures have been previously used to study the effect of certain manipulations and drugs on the complexity of fibrillatory conduction (Climent et al, 2015;van Gorp et al, 2020).…”

“…Atrial murine immortalized cells (HL-1) exhibit spontaneous electromechanical activity whose characteristics have been shown to be sensitive to mechanical stimulation, and Na + currents in these cells are responsive to ranolazine (Strege et al, 2012). In addition, it has been reported that confluent monolayers of HL-1 cells exhibit re-entrant conduction, making it possible to analyze re-entrant activation at the cellular level in order to study fibrillatory patterns under basal conditions and under pharmacological interventions (Hong et al, 2008;Climent et al, 2015;Houston et al, 2018;van Gorp et al, 2020).…”

Integrative computational modeling of calcium handling and cardiac arrhythmias

“…In vitro experiments are widely used to study the arrhythmogenic consequences of calciumhandling abnormalities at the subcellular and cellular levels. Due to the limited availability of human cardiomyocytes, heterologous expression systems and, more recently, human induced pluripotent stem cells, have been widely used (618). However, these systems are not identical to human cardiomyocytes, and may present potentially different calcium-dependent effects.…”