1. Cardiac Issues in Friedreich’s Ataxia 2 nd Annual Friedreich’s Ataxia Symposium Robert E. Shaddy, MD Jennifer Terker Professor of Pediatrics Division Chief, Pediatric Cardiology Medical Director, Heart Transplant Program The Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine

2. Incidence Myocardial involvement is eventually evident in 95% of cases Typical findings are thickening of the walls of the heart, particularly the left ventricle Can progress to dilated LV Pathogenesis unclear –Mitochondrial respiratory chain dysfunction –Oxidative stress

3. Hypertrophied Left Ventrcile

4. Clinical Manifestations Cardiac signs and symptoms typically occur late in the course of the disease, but they may rarely precede the neurologic symptoms –Exertional dyspnea –Chest pain Some studies suggest that the frequency of cardiomyopathy increases with the size of the GAA repeat in the shorter allele Filla A et al. Am J Human Gen 1997

5. Diagnostic Testing ECG –Commonly abnormal usually left ventricular hypertrophy (LVH) Echocardiography –Most sensitive way to assess cardiac involvement –LVH –Can progress to dilated cardiomyopathy with decreased function Cardiac MRI Alizad A, Seward JB. J Am Soc Echocardiogr. 2000

7. Echocardiogram

8. Cardiac MRI 41 adults with FA (29% with atypical phenotype) 40% with LVH GAA repeat length had only minor influence on interventricular septal thickness Meyer C. Movement Disorders 2007

9. Cardiac MRI Meyer C. Movement Disorders 2007

10. Idebenone Rustin et al. Free Radical Res 2002 Hausse et al. Heart 2002

11. Neurology 2003

12. LVPW thickness reduction –6 months 4.3% idebenone group 0.8% placebo group p=0.43 –12 months 8.6% idebenone group 2.4% control group p=0.18

13. Kearney et al. Cochrane Rev 2009

14. “No research on the clinical relevance of this heart change has been done.” Kearney et al. Cochrane Rev 2009

15. Friedreich’s Ataxia: Idebenone Treatment in Early Stage Patients Open label trial, 9 patients, 11-19 years 5 mg/kg/day for 1 year No differences observed in echo measurements after the start of therapy Artuch et al. Neuropediatrics 2002

16. 28 children from 1974 through 2004 Pediatric Cardiology 2008

17. High incidence of LVH Slow decrease in LV function over time No correlation of cardiac abnormalities with GAA repeats or ambulatory status

18. Therapy of Hypertrophic Cardiomyopathy in Children Medications –Beta-adrenergic receptor blockers –Calcium channel blockers –Disopyramide –Amiodarone Implantable Cardioverters/Defibrillators –Can be used if there are significant concerns of arrhythmias

20. Dilated Cardiomyopathy Medications –Angiotensin converting enzyme (ACE) inhibitors –Beta-adrenergic receptor blockers (beta-blockers) –Aldosterone antagonists –Digoxin –Diuretics

21. Conclusions Ventricular hypertrophy is common in patients with Friederich’s Ataxia Echocardiography and MRI are the best methods to follow the progression of LVH It is uncommon to have symptoms from this during childhood Idebenone therapy appears to have some potential benefit