Abstract Body: Background: Friedreich’s ataxia (FA) is an inherited disorder caused by GAA repeat expansion in the FXN gene, leading to reduced expression of the mitochondrial protein frataxin. Although FA is primarily recognized as a neurodegenerative disease, cardiomyopathy represents the leading cause of mortality in affected patients. Mitochondrial dysfunction and oxidative stress have been implicated in FA. However, the mechanisms linking frataxin deficiency to cardiac excitation-contraction coupling defects and arrhythmogenesis remain incompletely understood.

Objective: To determine whether frataxin deficiency disrupts cardiac calcium signaling and excitation-contraction coupling, contributing to myocardial dysfunction and arrhythmia susceptibility.

Methods: Cardiac function was evaluated in frataxin knockout (FXN-KO) mice using transthoracic echocardiography, including myocardial strain analysis. Electrophysiological remodeling was assessed using surface ECG and programmed electrical stimulation to determine effective refractory period (ERP) and ventricular tachycardia (VT) inducibility. Single-cell contractility, sarcomere shortening, cytosolic Ca2+ transients, and sarcoplasmic reticulum (SR) Ca2+ content were measured in isolated ventricular myocytes.

Results: FXN-KO mice exhibited impaired myocardial mechanics characterized by abnormal strain and reduced contractility. Electrophysiological studies demonstrated increased susceptibility to ventricular arrhythmias, including increased ERP and increased duration of inducible VT episodes compared with wild-type controls. At the cellular level, FXN-KO myocytes showed significantly reduced contractility and sarcomere shortening. These functional defects were accompanied by decreased cytosolic Ca2+ transient amplitude, reduced caffeine-induced Ca2+ release, indicating decreased SR Ca2+ content, and prolonged Ca2+ decay kinetics consistent with impaired Ca2+ reuptake.

Conclusions: Frataxin deficiency induces remodeling of cardiac calcium signaling, leading to impaired excitation-contraction coupling, reduced contractility, and increased arrhythmia susceptibility. These findings provide new insights into the mechanisms underlying cardiac dysfunction in Friedreich’s ataxia.

Keywords: Friedreich’s ataxia, Contractility, Ca2+ transient, Arrhythmia.