BACKGROUND

Friedreich's ataxia (FA) is a rare inherited neuromuscular disorder whereby most patients die of lethal cardiomyopathy and arrhythmias. Mechanisms leading to arrhythmic events in patients with FA are poorly understood.

OBJECTIVE

This study aimed to examine cardiac electrical signal propagation in a mouse model of FA with severe cardiomyopathy and to evaluate effects of omaveloxolone (OMAV), the first Food and Drug Administration-approved therapy.

METHODS

Cardiac-specific MCK-Cre frataxin knockout (FXN-cKO) mice were used to mimic FA cardiomyopathy. In vivo surface electrocardiogram (ECG) recordings, Western blotting, quantitative real-time polymerase chain reaction analysis, and histochemistry were performed.

RESULTS

Characteristics like long QT syndrome, interatrial block, and ST-segment abnormalities in patients with FA were identified in FXN-cKO mice. FXN-cKO mice exhibited sexual dimorphism in electrical signal propagation and cardiac structural integrity. Untreated FA males showed increased ventricular propagation intervals, whereas females exhibited delayed atrial propagation. OMAV showed no significant therapeutic effect on average ECG time intervals but improved chamber-specific waveforms when aggregated frequency distributions were analyzed. The J wave was absent in FXN-cKO male mice but reappeared with OMAV treatment. Poincaré plots revealed disparate idiopathic arrhythmias with multi-clustering events in individual mice with high incidence in FXN-cKO males. OMAV treatment reduced multi-clustering events to a single cluster; however, autonomic nervous system dysfunction still remained.

CONCLUSION

Our study revealed significant electrical propagation disturbances and sexual dimorphism in FXN-cKO mice with severe cardiomyopathy. Poincaré plots identified irregularities in heart rhythm and autonomic nervous system dysfunction. OMAV improved heart function by stabilizing early repolarization and reducing disparate arrhythmias. This work stresses sex-specific ECG interpretations and alternative mathematical approaches for drug testing in FA models.