Table 1.

Summary of the main findings, advantages, and disadvantages of the experimental models used for studying Brugada syndrome.

Model	Major Findings	Advantages	Disadvantages
Murine	SCN5A +/− mouse: ~50% reduction in INa, slowed conduction, conduction block, re-entrant arrhythmias and ventricular tachycardia [22]. Age and sex-related factors in disease progression [24,25,26,27,28]. Reduced Nav1.5 protein expression [33,34]. Fibrosis-related to decreased Nav1.5 expression [34]. Scn5a 1798insD mouse: Bradycardia, QT prolongation and right ventricular conduction slowing [39]. Strain dependence of conduction defect caused by the Scn5a1798insD/+ [41].	Allows integral studies from the whole animal, organ, tissue, and single cells. Ion channels can be knock out or modified.	Size and electrophysiological differences with the human heart. Profile of ion channel expression different to the human heart.
Canine	Correlation between epicardial notch AP amplitude and J wave amplitude [43]. Transmural dispersion of repolarization leading to ST-segment elevation [16,43]. Repolarization abnormalities associated with ST-segment elevation are located in the right ventricular outflow tract [49]. Male/female differences in susceptibility to Brugada syndrome are related to gender differences in Ito [53]. Focused application of RFA to the epicardium might be more efficient in eradicating ventricular tachycardia in Brugada syndrome patients [56].	Allows investigation of cells in epicardium and endocardium preserving their structural organization in the heart. Electrophysiological similarities with the human heart. Profile of ion channel expression similar to the human heart.	Brugada Syndrome phenotype has to be pharmacologically induced.
Porcine	Conduction slowing and increased susceptibility to ventricular arrhythmias [91] Lack of a clear Brugada Syndrome [91].	Allows investigation of cells in epicardium and endocardium preserving their structural organization in the heart. Electrophysiological similarities with the human heart.	Expensive. Long reproductive cycles.
Heterologous expression	See Supplementary Table	Relatively easy to perform. Allows detailed studies of the intrinsic biophysical properties of ion channels affected by mutations.	Lack of many specific cardiac proteins. Absence of patient-specific genetic background. Results may vary according to the cell model (e.g.,: HEK cells vs. Xenopus oocytes).
iPS-CM	Reduced sodium current, increased triggered AP activity, and abnormal Ca2+ transients. Genome editing reversed the effects of the mutation, indicating causality [78]. Patients with no mutation identified do not present current abnormalities [79,80]. Decrease in current correlated with a reduction of the maximum upstroke velocity and AP amplitude [82]. Mutation-induced changes, other than current density may appear in patient-specific iPS-CM, but not in heterologous expression recordings [83]. No changes in sodium current were observed in iPS-CM from patients without SCN5A mutation [79].	Patient-specific iPS-CM carry the patient’s exact genetic background. iPS-CM expression profile closely resembles that of cardiomyocytes. iPS cells are suitable for genome editing.	Immature phenotype. Depolarized membrane potential compared with adult cardiomyocytes. Negligible levels of IK1. Poor ultrastructural organization regarding sarcomere and t-tubule development.