Animal models of arrhythmia: classic electrophysiology to genetically modified large animals

Arrhythmias are common and contribute substantially to cardiovascular morbidity and mortality. The underlying pathophysiology of arrhythmias is complex and remains incompletely understood, which explains why mostly only symptomatic therapy is available. The evaluation of the complex interplay between various cell types in the heart, including cardiomyocytes from the conduction system and the working myocardium, fibroblasts and cardiac immune cells, remains a major challenge in arrhythmia research because it can be investigated only in vivo. Various animal species have been used, and several disease models have been developed to study arrhythmias. Although every species is useful and might be ideal to study a specific hypothesis, we suggest a practical trio of animal models for future use: mice for genetic investigations, mechanistic evaluations or early studies to identify potential drug targets; rabbits for studies on ion channel function, repolarization or re-entrant arrhythmias; and pigs for preclinical translational studies to validate previous findings. In this Review, we provide a comprehensive overview of different models and currently used species for arrhythmia research, discuss their advantages and disadvantages and provide guidance for researchers who are considering performing in vivo studies. Various models of cardiac arrhythmia have been developed in several different animal species to study the mechanisms of disease. In this Review, Clauss and colleagues summarize the advantages and disadvantages of the models and species used in arrhythmia research and provide guidance to investigators planning experiments in this field. Key points Millions of patients have arrhythmias and are at increased risk of morbidity and death, including atrial fibrillation and sudden cardiac death; however, insufficient therapies are currently available in clinical practice. Understanding the complexity of electrophysiology and arrhythmogenesis is necessary to develop innovative treatment options and requires disease modelling in animals. Despite marked differences in electrophysiology compared with humans, fundamental mechanisms can potentially be identified in rodents and translated into clinical practice; however, validation in larger animals is required. Rabbits should be considered to study ion channel function, repolarization and re-entrant ventricular tachycardia. Dogs have traditionally been widely used in arrhythmia research, but legal restrictions, societa