Cardiac Issues in Friedreich’s Ataxia

2nd 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

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

Hypertrophied Left Ventrcile

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

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

Echocardiogram

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

Cardiac MRI

Meyer C. Movement Disorders 2007

Idebenone

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

Neurology 2003

• 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

Kearney et al. Cochrane Rev 2009

• “No research on the clinical relevance of this heart change has been done.”

Kearney et al. Cochrane Rev 2009

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

• 28 children from 1974 through 2004

Pediatric Cardiology 2008

• High incidence of LVH

• Slow decrease in LV function over time

• No correlation of cardiac abnormalities with GAA repeats or ambulatory status

Therapy of HypertrophicCardiomyopathy 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

Dilated Cardiomyopathy

• Medications– Angiotensin converting enzyme (ACE) inhibitors– Beta-adrenergic receptor blockers (beta-blockers)– Aldosterone antagonists– Digoxin– Diuretics

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