Poincaré plot analysis of ECG uncovers beneficial effects of omaveloxolone in a mouse model of Friedreich's ataxia.

Abstract

Background: Friedreich's ataxia (FA) is a rare inherited neuromuscular disorder, where most patients die from lethal cardiomyopathy and arrhythmias. Mechanisms leading to arrhythmic events in FA patients are poorly understood.

Objective: This study aims to examine cardiac electrical signal propagation in mouse model of FA with severe cardiomyopathy and evaluate effects of omaveloxolone (OMAV), the first FDA-approved therapy.

Methods: Cardiac-specific MCK-Cre frataxin knockout (FXN-cKO) mice were used to mimic FA cardiomyopathy. In vivo surface ECG recordings, western blotting, qPCR, and histochemistry were performed.

Results: Characteristics like long QT syndrome, interatrial block, and ST-segment abnormalities in FA patients 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, while 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, ANS 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 ANS 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.