Complexity of the clinical condition

Range of clinical presentations and underlying mechanisms

Variation in features over the life-course

Complexity of human condition, often involving multiple pathologies and conditions

Limitations of experimental paradigms

Limitations imposed by species differences in cardiac electrophysiology, heart size, availability etc.

Lack of models manifesting spontaneous AF

Complications due to anaesthesia, need for chronic instrumentation or acute surgery for arrhythmia susceptibility testing

Technical challenges and patient variability for human atrial-biopsy studies

Often immature and incompletely controlled IPSC-CM phenotype

Problems extrapolating from animal models to humans

Animal models lack complexity of human condition

Differences in ion-channel properties, anatomy, structure etc.

Intrinsic limitations of the model systems studied

Each experimental system extrapolates with restrictions to specific human scenarios and AF phenotypes

Inference to clinical pathophysiology must be careful and guarded