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

Abstract

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.

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, societal considerations and the lack of genetically engineered models restrict their future use.

  • Pig models could close this translational gap because their use is more accepted in modern societies, pig cardiac anatomy and electrophysiology are similar to those of humans and pigs can be genetically modified.

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Acknowledgements

The authors received support from the German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK); 81Z4600241, 81X3600208 and 81X2600249), the Förderprogramm für Forschung und Lehre (FöFoLe; 962; 29/2017), the German Centre for Diabetes Research (Deutsches Zentrum für Diabetes-Forschung (DZD)) and the German Research Council (DFG; TRR127, SFB1123 and SFB914).

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Nature Reviews Cardiology thanks M. A. Vos and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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S.C., C.B., D.S. and P.T. researched data for the article and wrote the manuscript. All the authors discussed its content and reviewed and edited the manuscript before submission.

Correspondence to Sebastian Clauss.

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Fig. 1: Animal models for arrhythmia research.
Fig. 2: Cardiac action potentials in different species.
Fig. 3: A practical trio of animal models for translational research.
Fig. 4: Generation of genetically modified pigs by CRISPR–Cas.