PO-01-126 SEXUAL DIMORPHISM AND CARDIAC ARRHYTHMIAS IN A MOUSE MODEL OF FRIEDREICH'S ATAXIA: WHAT DO WE KNOW?

Abstract

Friedreich ataxia (FA) is a monogenic recessive disorder caused by the reduction of the mitochondrial protein, frataxin (FXN). Despite neurological deficits place patients with FA in the wheelchairs, most patients die from lethal cardiomyopathy in their 40s. FA patients develop progressive cardiac disease with characteristics similar to primary hypertrophic cardiomyopathy but with more progressive cardiac fibrosis, both diastolic and systolic dysfunction, and arrhythmias. However, the mechanisms leading to cardiomyopathy and arrhythmias in FA patients are poorly understood. To characterize electrical signal propagation and cardiac function in a mouse model which imitates the late-stage cardiomyopathy in FA patients. Cardiac-specific McK-Cre FXN knockout (FXN cKO) mice were used as a model of severe cardiomyopathy which is characteristic for the late-stage of FA. Due to premature death, animals of either sex at 8-weeks of age were used to assess cardiac function in-vivo by echocardiography and surface electrocardiogram (ECG). We found that FXN cKO mice developed idiosyncratic arrhythmias with varying time durations for beat-to-beat (RR) intervals and heart rate variability (HRV) parameters such as root mean squared successive differences (RMSSD, p<0.0358), revealing increased vagal activity. Mice presented extended P-wave (p<0.0113) and QTc intervals (>150 ms, p<0.0015), suggesting impaired atrial and left-ventricular function, resembling human patients. HRV frequency parameters showed increased low-frequency (0.023), high-frequency (p<0.264) and total (p<0.0326) power. Non-linear parameters showed varying short-term variation (SD1, p<0.019), increased long-term variation (SD2, p<0.0017) and ellipse area values (S, p<0.0074). Poincare plots of FXN cKO males included multiple clustering of RR and RR+1 identities while females generally sustained a single clustered ellipse (area, p<0.028). Similarly, QTc intervals were increased mostly in FXN cKO males. Contractile dysfunction was also more severe in FXN cKO males as evident by reduction in left ventricular fractional shortening, ejection fraction, stroke volume and cardiac output. Our study revealed sexual dimorphism and significant impairment in electrical and contractile function in FXN cKO males compared to females. A detailed characterization of impaired electrical signals in FA hearts will build a platform for drug testing to treat lethal cardiomyopathy in FA.