Comparative Analysis of Atrial Electrophysiology Across Animal Species and Humans: Enhancing Translation in Atrial Arrhythmia Research.

Porcine atrial cardiomyocytes most closely resemble human atrial cells in depolarization characteristics among the animal species studied.

• Species studied included mice, rats, pigs, horses, and humans, all characterized using uniform protocols.
• Rodents exhibited marked differences from humans in depolarization characteristics.
• Tissue samples were obtained from patients undergoing open heart surgery and from the respective animal species.
• Both cellular electrophysiological and transcriptomic characterization were performed.

Human atrial action potentials showed pronounced early repolarization that was not reproduced in any other species studied.

• The pronounced early repolarization in humans corresponded to a greater contribution of the IKur gene group.
• IKur (ultrarapid delayed rectifier potassium current) gene group expression was higher in humans relative to other species.
• This finding was identified through both functional electrophysiological measurements and transcriptomic analysis.
• The absence of this feature in animal models represents a key translational limitation for early repolarization-related atrial arrhythmia research.

Late repolarization, reflected by action potential duration at 90% repolarization (APD90), scaled with species and cardiomyocyte size, with humans ranging between rodents and pigs.

• APD90 was used as the metric for late repolarization across species.
• Cardiomyocyte size was identified as a correlate of late repolarization duration.
• Humans were intermediate between rodents (shorter APD90) and pigs (longer APD90).
• This scaling relationship has implications for selecting appropriate animal models depending on which phase of the action potential is most relevant to the research question.

Sex-specific differences in repolarization observed in humans were represented in pigs but not in rodents.

• Sex-specific electrophysiological differences in atrial repolarization were characterized across species.
• Pigs recapitulated the sex-specific repolarization differences seen in humans.
• Rodents (mice and rats) did not reflect the human sex-specific repolarization differences.
• This finding further supports the superiority of porcine models over rodent models for studying sex-related atrial electrophysiology.

Chamber-specific differences between left and right atrial cardiomyocytes were reflected in in silico simulations based on ion channel expression profiles.

• Left and right atrial cardiomyocytes were characterized separately at both functional and transcriptomic levels.
• Ion channel expression profiles from transcriptomic data were used to simulate action potentials in silico.
• The in silico models successfully captured chamber-specific electrophysiological differences.
• This validates the use of transcriptomic data to infer functional electrophysiological properties across atrial chambers.

Relative changes in action potential parameters can be inferred from transcriptomic data using in silico simulations.

• Action potentials were simulated from ion channel expression profiles using computational models.
• The correlation between functional electrophysiological properties and transcriptomic features was assessed across species.
• In silico simulations were able to capture species- and chamber-specific differences in action potential characteristics.
• This approach provides a method to link gene expression data to functional cardiac electrophysiology without requiring direct electrophysiological measurements in every condition.

Electrophysiological disparities between animal models and humans are a systematic barrier to translation of experimental findings in atrial arrhythmia research.

• Atrial arrhythmias relevantly contribute to global morbidity and death and have been extensively studied in experimental models.
• The study was motivated by the recognition that species-specific electrophysiological differences hinder translation.
• A systematic, uniform-protocol characterization across multiple species was performed to quantify these disparities.
• The study provides a reference dataset for species-specific atrial action potential characteristics to support more accurate interpretation of animal experimental data.