Abstract 2954: Short-term Effects of High Dose Idebenone on Left Ventricular Mass and Function in a Pediatric Cohort with Friedreich’s Ataxia

Abstract

Background: Early mortality in Friedreich’s Ataxia (FA) is believed to commonly result from an underlying hypertrophic cardiomyopathy which may be caused by increases in reactive oxygen species. Antioxidant therapy could result in slowing of disease progression or regression of left ventricular mass (LVM). Methods: We tested the hypothesis that high dose idebenone could lead to regression of LVM and LV functional improvement in 48 pediatric subjects with genetically-confirmed FA (23 females, 25 males, mean age=13.4 years) randomly assigned to weight-stratified low (4 – 8 mg/kg), medium (10–20 mg/kg) or high (30–50 mg/kg) doses of idebenone or placebo. Cardiac magnetic resonance imaging (MRI) and echocardiographic (echo) two-dimensional and Doppler analysis blinded to treatment assignment were performed at baseline and after 6 months of therapy. Results: At baseline, increased LVM indexed by height 2.7 was observed in 44%, LV concentric remodeling (relative wall thickness &gt;0.39) in 83% and impaired early relaxation by Doppler tissue velocity (E’) in 88% of subjects as determined by age-adjusted, normative echo data. MRI-determined LVM (n=45 subjects) was inversely related to measures of LV relaxation including E’ (p&lt;0.0001), color Doppler flow propagation (p&lt;0.007) and isovolumic relaxation time (p&lt;0.005) but not mitral deceleration time. LVM also correlated with peak lateral systolic tissue velocity (p=0.002) but not LV ejection fraction. At 6 months combined, idebenone-assigned subjects demonstrated a 1.3 ± 1.6 % reduction of LVM vs. baseline which compared to an 8.9 ± 4.0% LVM increase in placebo subjects (p=.007). By Fisher’s test, LVM regression was observed only in the high and intermediate dose groups (p≤0.05 and p≤0.01) with a trend toward regression in the low dose group (p=0.056). No effects on diastolic relaxation or systolic functional parameters were observed after 6 months of idebenone treatment. Conclusions: Hypertrophic cardiomyopathy and associated diastolic functional impairment is highly prevalent in pediatric FA patients with moderate neurologic impairment. Short term treatment with high dose idebenone appears to result primarily in blunting of LV mass progression but not to detectable improvements in LV function. </jats:p