Cardiac Manifestations of Friedreich Ataxia Presented by Hari Krishnan

1. Cardiac manifestations of Friedreich Ataxia
Hari Krishnan Nair
Cardiology
Boston Children’s Hospital

2. Introduction
•Most common inherited ataxia
•Autosomal recessive disease
•Incidence: 1 in 30,000
•Males=Females
•Carrier frequency: 1 in 60 to 1 in 120

3. Cardiac Manifestations
•Cardiomyopathy
–Hypertrophic, and later, dilated
•Progressive cardiac failure
•Tachycardias
•Heart block
•Myocarditis, myocardial fibrosis

4. Cardiomyopathy

5. Introduction
•Heart failure from cardiomyopathy is the primary mode of death in about 60% of patients with Friedreich ataxia.
•Initially hypertrophic, and later, dilated cardiomyopathy
•Heart typically maintains adequate systolic function until shortly before death (EF is in a low- normal range even though LV is markedly thickened)
•Death in the 3rd to 5th decade of life.

6. Pathophysiology
•GAA triplet expansion in the first intron of the human frataxin gene (FXN) on chromosome 9q21.11
•Frataxin is an iron-binding protein targeted to the mitochondrial matrix.
•In its absence, multiple iron-sulfur-dependent proteins in mitochondria and the cytosol lack proper assembly, destroying mitochondrial and nuclear function.
•Proliferation of mitochondria within the cardiomyocytes, and a marked loss of contractile fibers.
Payne RM, Wagner GR. Cardiomyopathy in Friedreich Ataxia: Clinical Findings and Research J Child Neurol. 2012 September ; 27(9): 1179–1186.

7. •Left ventricle (LV) mass correlates with the GAA repeat number and longer duration of disease
•LV hypertrophy is more asymmetric than concentric
•Later in the disease course, the cardiomyopathy may become dilated. Progressive systolic dysfunction is common and reduction in left ventricular wall thickness is often seen as disease progresses
Kipps A, Colan SD, Gauvreau K, Smoot L, Crawford L, Darras BT, Blume ED. The longitudinal course of cardiomyopathy in Friedreich's ataxia during childhood. Pediatr Cardiol. 2009;30:306–10.

8. Other cardiac pathologies

9. Impaired myocardial perfusion
•Impaired myocardial perfusion index
–Associated with microvascular disease and fibrosis of the heart
–Intimal proliferation of small intramural coronary arteries
–Occurs even prior to the onset of overt cardiomyopathy
–Patients experience chest pain and symptoms of decreased coronary reserve in the absence of epicardial coronary disease

10. Electrophysiological disturbances
•Dysrhythmias
–Atrial fibrillation
–Recurrent ventricular tachycardias
•EKG Changes
–ST-T wave abnormalities 79%
–Right axis deviation 40%
–Short P-R interval 24%
–Abnormal R waves in Lead I 20%
–Abnormal inferolateral Q waves 14%
–Left ventricular hypertrophy 16%
Child JS, Perloff JK, Bach PM, Wolfe AD, Perlman S, Kark RA. Cardiac involvement in Friedreich’s ataxia: a clinical study of 75 patients. J Am Coll Cardiol. 1986;7:1370–1378.

11. Echocardiography
•Concentric LV hypertrophy 11%
•Asymmetric septal hypertrophy 9%
•Globally decreased LV function 7%
Child JS, Perloff JK, Bach PM, Wolfe AD, Perlman S, Kark RA. Cardiac involvement in Friedreich’s ataxia: a clinical study of 75 patients. J Am Coll Cardiol. 1986;7:1370–1378.

12. Management
•The thickness of the ventricle impairs diastolic perfusion and coronary reserve
–Patients may not tolerate lowered blood pressures associated with certain surgeries
•Mitochondria have defects in electron transport chain and impaired ability to burn fats
–Maintain adequate glucose levels to avoid depressed cardiovascular function and injury
•Extensive myocardial scarring can limit the heart’s ability to alter stroke volume and cardiac output
–Patients may not tolerate large fluid shifts associated with major surgeries

13. Management
•Coenzyme Q
–Antioxidant that can buffer free radical formation that is induced by excess mitochondrial iron.
–A combined coenzyme Q (400 mg/d) and vitamin E (2100 IU/d) therapy has been used in a study of 10 patients with a significant improvement in cardiac function.

14. Management
•Idebenone
–Mitochondrially localized, lipid-soluble antioxidant related to coenzyme Q
–Idebenone did not decrease LV hypertrophy or improve cardiac function in subjects with FRDA over a 6-month treatment period
•Cardiac transplantation
Lagedrost et al. Idebenone in Friedreich ataxia cardiomyopathy—results
from a 6-month phase III study. American Heart Journal. Mar 2011

15. Gene Therapy
•Adeno-associated virus rh10 vector expressing human FXN injected intravenously in conditional mouse model with Frataxin gene deletion fully prevented the onset of cardiac disease.
•Moreover, later administration of the frataxin- expressing vector, after the onset of heart failure, was able to completely reverse the cardiomyopathy of these mice at the functional, cellular and molecular levels within a few days.
Perdomini et. al. Prevention and reversal of severe mitochondrialcardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia. Nature Medicine 2014.

16. Thank You