Topic 4.3. The heart and cardiovascular system in Friedreich ataxia
This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.
Topic Contents
4.3 Management strategies for arrhythmias in Friedreich ataxia
4.3.1 Atrial tachyarrhythmias
4.3.2 Ventricular arrhythmias
Disclaimer / Intended Use / Funding
Disclaimer
The Clinical Management Guidelines for Friedreich ataxia (‘Guidelines’) are protected by copyright owned by the authors who contributed to their development or said authors’ assignees.
These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.
Guidelines users must seek out the most recent information that might supersede the diagnostic and treatment recommendations contained within these Guidelines and consider local variations in clinical settings, funding and resources that may impact on the implementation of the recommendations set out in these Guidelines.
The authors of these Guidelines disclaim all liability for the accuracy or completeness of the Guidelines, and disclaim all warranties, express or implied to their incorrect use.
Intended Use
These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.
These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
Guidelines users must not edit or modify the Guidelines in any way – including removing any branding, acknowledgement, authorship or copyright notice.
Funding
The authors of this document gratefully acknowledge the support of the Friedreich Ataxia Research Alliance (FARA). The views and opinions expressed in the Guidelines are solely those of the authors and do not necessarily reflect the official policy or position of FARA.
4.3 Management strategies for arrhythmias in Friedreich ataxia
Roger E. Peverill, Kimberly Y. Lin, Francoise Pousset, Aarti Patel and Konstantinos Savvatis
4.3.1 Atrial tachyarrhythmias
Rate controlling agents
No randomized controlled trial (RCT) has evaluated rate control of AF in FRDA, but there are no specific reasons why standard guidelines for rate control should not apply in FRDA. Recommendations for heart rate control in atrial fibrillation are provided in the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation (80).
In general, rate control is not the preferred option for long-term management in atrial arrhythmias in FRDA, as attaining and maintaining rate control, particularly during exercise in young people, can be difficult. Furthermore, young people tend to remain symptomatic when in AF even if reasonable rate control can be achieved. Nevertheless, in certain circumstances, rate control may still be a reasonable option. In such cases digoxin can be used irrespective of the left ventricular ejection fraction. A beta blocker will be the preferred option if there is a history of HF or reduced ejection fraction, but needs to be commenced slowly. If there is a reduced LVEF, verapamil and diltiazem are contraindicated because of their negative inotropic action.
Antiarrhythmic therapy
There are no RCTs which have examined the effectiveness or safety of antiarrhythmic drugs in FRDA for either reversion of atrial tachyarrhythmias or for maintenance of sinus rhythm following spontaneous, chemical or electrical cardioversion. However, the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation (80) can be used as a guide to antiarrhythmic treatment of AF in FRDA. There are important concerns raised in these guidelines about the safety of some of the antiarrhythmic medications in the setting of “organic heart disease” and it should be assumed that similar concerns apply to the abnormal heart in FRDA.
Antithrombotic therapy for prevention of thromboembolism related to atrial tachyarrhythmias
Based on data in subjects with AF and a dilated cardiomyopathy due to causes other than FRDA, a high risk of thromboembolism would be predicted for individuals with FRDA with AF and a reduced LVEF (80). Indeed, intracardiac thrombosis and systemic thromboembolism was described as a frequent finding in one post mortem study in FRDA (67). In the absence of a reduction in LVEF, where the risk of thromboembolism can be considered to be high, there are no specific reasons why the standard risk factors for thromboembolism in AF should not also apply to FRDA, and these may be a reasonable way to determine the need for anticoagulant therapy in FRDA. Anticoagulation with new oral anticoagulants, including dabigatran, rivoroxaban and apixaban, rather than a vitamin K antagonist, is recommended for individuals with FRDA and paroxysmal or permanent AF for the prevention of thromboembolism, unless there is a contraindication (81).
Ablation therapy
If the symptoms or ventricular response of atrial tachyarrhythmias are unable to be controlled with antiarrhythmic and/or ventricular rate control medications then there are electrophysiological options for management. Atrial flutter may be amenable to ablation therapy to prevent further episodes of atrial flutter. Atrial fibrillation can be treated with the percutaneous procedure of pulmonary vein isolation; however, the effectiveness of this technique in FRDA is currently unknown. There is also an option for atrioventricular (AV) node ablation or modification in combination with pacemaker insertion to prevent both a rapid ventricular response and bradycardia (80).
4.3.2 Ventricular arrhythmias
Antiarrhythmic therapy
There are no RCTs addressing the effectiveness or safety of antiarrhythmic drugs in FRDA for the treatment of ventricular arrhythmias. Furthermore, as there are few reports of symptomatic VT, syncope due to VT or resuscitated sudden death in FRDA, antiarrhythmic therapy to prevent recurrent ventricular arrhythmias will rarely be indicated. With the exception of beta blockers, no currently available antiarrhythmic drugs have been shown in RCTs to be effective in the primary management of people with life-threatening ventricular arrhythmias or in the prevention of sudden cardiac death (SCD) (82). On the other hand, beta blockers are effective in suppressing ventricular ectopic beats and arrhythmias as well as in reducing SCD in a spectrum of cardiac disorders in people with and without HF (82). As a general rule, antiarrhythmic agents may be effective as adjunctive therapy in the management of arrhythmia-prone individuals under special circumstances. Because of potential adverse side effects of the available antiarrhythmic drugs, these agents must be used with considerable caution.
If individuals with FRDA develop ventricular arrhythmias, then beta blockers should be considered first-line therapy for secondary prevention, but if not effective at full therapeutic doses, then amiodarone or sotalol can be tried, with careful monitoring for adverse effects during administration. Amiodarone is the only option if beta blockers are contraindicated. Both sotalol and amiodarone have also been shown to reduce the frequency of internal cardioverter-defibrillator (ICD) shock therapy. Sotalol should be used with caution in individuals with HF, severely reduced LVEF or renal dysfunction.
ICD for primary and secondary prevention of ventricular arrhythmias
There are no RCT data regarding ICD implantation for either primary or secondary prevention of ventricular arrhythmias in FRDA. Multiple clinical trials in other cardiac conditions have demonstrated a survival benefit of ICD use compared to antiarrhythmic therapy for secondary prevention of resuscitated SCD, sustained VT or sustained VF. It is recommended that the ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities be used to guide ICD placement for the secondary prevention of SCD or sustained VT/VF in FRDA (83). Importantly, these guidelines do not support ICD placement if the predicted lifespan from other causes is less than a year.
Primary prevention of SCD refers to the use of ICDs in individuals who are at risk for, but have not yet had an episode of sustained VT, VF, or resuscitated cardiac arrest. Clinical trials have evaluated the risks and benefits of ICD implantation in prevention of sudden death and have shown improved survival with ICD in multiple patient populations, including those with HF due to non-ischemic dilated cardiomyopathy (83). However, making a recommendation to use an ICD for primary prevention in FRDA is not possible at this time due to absence of evidence for ventricular arrhythmias as a common cause of death.
One series of five subjects with FRDA who received ICD implantation has been reported (ages from 14-26 years) (84). However, none of this cohort had syncope, near syncope, symptomatic VT or a dilated cardiomyopathy with reduced LVEF (i.e. there were no standard indications for an ICD).
Anticoagulation for atrial fibrillation
QUESTION: Should anticoagulation versus no anticoagulation be used for individuals with permanent, persistent or paroxysmal atrial fibrillation with Friedreich ataxia?
[sg_popup id=”587″ event=”click”]
[/sg_popup]STRENGTH OF RECOMMENDATION: ↑
[sg_popup id=”658″ event=”click”][/sg_popup]LEVEL OF EVIDENCE: ⨁◯◯◯
RECOMMENDATION: We conditionally recommend anticoagulation over no anticoagulation in individuals with Friedreich ataxia with permanent, persistent or paroxysmal atrial fibrillation.
JUSTIFICATION: There is no evidence to suggest treatment should be different for individuals with Friedreich ataxia versus individuals without Friedreich ataxia, where anticoagulation therapy would be appropriate for individuals with permanent, persistent or paroxysmal atrial fibrillation unless there is a contraindication. Shared decision-making should consider younger age of this cohort in the context of increased risk of falls, stroke, females with concomitant heavy menstrual bleeding and desire to maintain autonomy in decisions related to health.
SUBGROUP CONSIDERATION: The recommendation is for individuals with Friedreich ataxia with permanent, persistent or paroxysmal atrial fibrillation. Stroke happens across the age spectrum in Friedreich ataxia. The recommendation does need to encourage clinicians to think across all ages; however, be mindful of specific groups as specified in the justification above.
Evidence to Recommendation Table PDFRhythm control for atrial fibrillation
QUESTION: Should rhythm control versus rate control be used for atrial fibrillation/flutter with Friedreich ataxia?
[sg_popup id=”587″ event=”click”][/sg_popup]STRENGTH OF RECOMMENDATION: ↑
[sg_popup id=”658″ event=”click”][/sg_popup]LEVEL OF EVIDENCE: ⨁◯◯◯
RECOMMENDATION: We conditionally recommend attempts to maintain a normal cardiac rhythm over rate control in individuals with Friedreich ataxia and atrial tachyarrhythmias, and also recommend consideration of ablation for those who remain severely symptomatic due to a persistent atrial tachyarrhythmia or frequent paroxysms of an atrial tachyarrhythmia.
JUSTIFICATION: Highly symptomatic individuals who are younger in particular require careful consideration regarding intervention. Some consideration should be given for moderate risks of pharmacological intervention versus higher risks with ablation, including prolonged anesthesia.
SUBGROUP CONSIDERATION: This recommendation is for individuals with Friedreich ataxia with atrial fibrillation/flutter, with particular considerations as described in the justification above.
Evidence to Recommendation Table PDFLay summary of clinical recommendations for arrhythmias in Friedreich ataxia
Why these recommendations?
Individuals with Friedreich ataxia can experience arrhythmias (irregular heart rate), with symptoms including palpitations, dizziness, shortness of breath and chest discomfort.
These recommendations are about the use of medication or procedures to treat individuals with Friedreich ataxia who have permanent or episodic atrial fibrillation (an irregular and often rapid heart rate).
We suggest using anticoagulation medication for people with Friedreich ataxia with atrial fibrillation because the overall benefits (e.g., preventing a stroke) are likely to be greater than the risks (bleeding is the most common risk).
For individuals with Friedreich ataxia who have persistent or episodic atrial fibrillation, we also suggest that medication and possibly procedures (i.e. cardioversion) can be used to obtain a normal heart rhythm, as well as medication to maintain a normal heart rhythm. This is because maintaining a normal heart rhythm may lead to an improvement in symptoms. Even if there is no immediate improvement in symptoms, the treatment might help to look after heart function in the medium term. On the other hand, the risks of the use of cardioversion and medication for this purpose are small.
For those individuals who continue to have severe symptoms due to atrial fibrillation even after using medication, we suggest considering a procedure that can help break up the electrical signals that cause irregular heartbeats (called an ablation).
What does this mean for you as a person living with Friedreich ataxia or caring for someone living with Friedreich ataxia?
It may be important for you to speak with your healthcare professional about the investigation of palpitations you may be having. Making a diagnosis of atrial fibrillation has important management implications. If atrial fibrillation is confirmed, then it is important to discuss the management options with a cardiologist.
Who are these recommendations specifically for?
These recommendations are for individuals with Friedreich ataxia who have permanent or episodic atrial fibrillation.
Associate Professor, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Aarti Patel, MD
Associate Professor of Medicine, University of South Florida, Tampa, Florida, USA
Email: apatel15@usf.edu
Roger E. Peverill, MBBS, PhD
Cardiologist, MonashHeart, Monash Health, Clayton, Victoria, Australia
Email: roger.peverill@monash.edu
Francoise Pousset, MD
Sorbonne Université, Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Paris, France
Email: f.pousset@aphp.fr
Konstantinos Savvatis, MD, PhD
Consultant Cardiologist, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK
Email: k.savvatis@ucl.ac.uk
2. Lynch DR, Regner SR, Schadt KA, Friedman LS, Lin KY, St John Sutton MG. Management and therapy for cardiomyopathy in Friedreich’s ataxia. Expert Rev Cardiovasc Ther. 2012;10(6):767-77.
3. 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(6):1370-8.
4. Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996;335(16):1169-75.
5. Giunta A, Maione S, Biagini R, Filla A, De Michele G, Campanella G. Noninvasive assessment of systolic and diastolic function in 50 patients with Friedreich’s ataxia. Cardiology. 1988;75(5):321-7.
6. Gottdiener JS, Hawley RJ, Maron BJ, Bertorini TF, Engle WK. Characteristics of the cardiac hypertrophy in Friedreich’s ataxia. Am Heart J. 1982;103(4 Pt 1):525-31.
7. Maione S, Giunta A, Filla A, De Michele G, Spinelli L, Liucci GA, et al. May age onset be relevant in the occurrence of left ventricular hypertrophy in Friedreich’s ataxia? Clin Cardiol. 1997;20(2):141-5.
8. Peverill RE. Letter by Peverill regarding article, “The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms”. Circulation. 2012;126(17):e272.
9. Peverill RE, Romanelli G, Donelan L, Hassam R, Corben LA, Delatycki MB. Left ventricular structural and functional changes in Friedreich ataxia – Relationship with body size, sex, age and genetic severity. PLoS One. 2019;14(11):e0225147.
10. Pousset F, Legrand L, Monin ML, Ewenczyk C, Charles P, Komajda M, et al. A 22-year follow-up study of long-term cardiac outcome and predictors of survival in Friedreich ataxia. JAMA Neurol. 2015;72(11):1334-41.
11. Raman SV, Phatak K, Hoyle JC, Pennell ML, McCarthy B, Tran T, et al. Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome. Eur Heart J. 2011;32(5):561-7.
12. Ribaï P, Pousset F, Tanguy M, Rivaud-Pechoux S, Le Ber I, Gasparini F, et al. Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol. 2007;64:558-64.
13. Weidemann F, Rummey C, Bijnens B, Stork S, Jasaityte R, Dhooge J, et al. The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms. Circulation. 2012;125(13):1626-34.
14. Payne RM, Peverill RE. Cardiomyopathy of Friedreich’s ataxia (FRDA). Ir J Med Sci. 2012;181(4):569-70.
15. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287(10):1308-20.
16. Mottram PM, Delatycki MB, Donelan L, Gelman JS, Corben LA, Peverill RE. Early changes in left ventricular long axis function in Friedreich ataxia – relation with the FXN gene mutation and cardiac structural change. Journal of the American Society of Echocardiography 2011;24(7):782-9.
17. Schadt KA, Friedman LS, Regner SR, Mark GE, Lynch DR, Lin KY. Cross-sectional analysis of electrocardiograms in a large heterogeneous cohort of Friedreich ataxia subjects. J Child Neurol. 2012;27(9):1187-92.
18. Legrand L, Diallo A, Monin ML, Ewenczyk C, Charles P, Isnard R, et al. Predictors of left ventricular dysfunction in Friedreich’s ataxia in a 16-Year observational study. Am J Cardiovasc Drugs. 2020;20(2):209-16.
19. Weidemann F, Liu D, Hu K, Florescu C, Niemann M, Herrmann S, et al. The cardiomyopathy in Friedreich’s ataxia – New biomarker for staging cardiac involvement. Int J Cardiol. 2015;194:50-7.
20. De Michele G, Perrone F, Filla A, Mirante E, Giordano M, De Placido S, et al. Age of onset, sex, and cardiomyopathy as predictors of disability and survival in Friedreich’s disease: a retrospective study on 119 patients. Neurology. 1996;47(5):1260-4.
21. Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain. 1981;104(3):589-620.
22. Fang ZY, Leano R, Marwick TH. Relationship between longitudinal and radial contractility in subclinical diabetic heart disease. Clin Sci (Lond). 2004;106(1):53-60.
23. Fang ZY, Yuda S, Anderson V, Short L, Case C, Marwick TH. Echocardiographic detection of early diabetic myocardial disease. J Am Coll Cardiol. 2003;41(4):611-7.
24. Von Bibra H, Thrainsdottir IS, Hansen A, Dounis V, Malmberg K, Ryden L. Tissue Doppler imaging for the detection and quantitation of myocardial dysfunction in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2005;2(1):24-30.
25. Alchanatis M, Paradellis G, Pini H, Tourkohoriti G, Jordanoglou J. Left ventricular function in patients with obstructive sleep apnoea syndrome before and after treatment with nasal continuous positive airway pressure. Respiration. 2000;67(4):367-71.
26. Amin RS, Kimball TR, Kalra M, Jeffries JL, Carroll JL, Bean JA, et al. Left ventricular function in children with sleep-disordered breathing. Am J Cardiol. 2005;95(6):801-4.
27. Arias MA, Garcia-Rio F, Alonso-Fernandez A, Mediano O, Martinez I, Villamor J. Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation. 2005;112(3):375-83.
28. Reddy PL, Grewal RP. Friedreich’s ataxia: A clinical and genetic analysis. Clin Neurol Neurosurg. 2007;109:200-2.
29. Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 2000;102(4):470-9.
30. Albano LM, Zatz M, Kim CA, Bertola D, Sugayama SM, Marques-Dias MJ, et al. Friedreich’s ataxia: clinical and molecular study of 25 Brazilian cases. Revista do Hospital das Clinicas; Faculdade de Medicina Da Universidade de Sao Paulo. 2001;56(5):143-8.
31. Dutka DP, Donnelly JE, Nihoyannopoulos P, Oakley CM, Nunez DJ. Marked variation in the cardiomyopathy associated with Friedreich’s ataxia. Heart (British Cardiac Society). 1999;81(2):141-7.
32. Lamont PJ, Davis MB, Wood NW. Identification and sizing of the GAA trinucleotide repeat expansion of Friedreich’s ataxia in 56 patients. Clinical and genetic correlates. Brain. 1997;120(Pt 4):673-80.
33. Schöls L, Amoiridis G, Przuntek H, Frank G, Epplen JT, Epplen C. Friedreich’s ataxia. Revision of the phenotype according to molecular genetics. Brain. 1997;120(Pt 12):2131-40.
34. Bidichandani SI, Ashizawa T, Patel PI. Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. Am J Hum Genet. 1997;60(5):1251-6.
35. Cossée M, Dürr A, Schmitt M, Dahl N, Trouillas P, Allinson P, et al. Friedreich’s ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol. 1999;45(2):200-6.
36. Forrest SM, Knight M, Delatycki MB, Paris D, Williamson R, King J, et al. The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. Neurogenetics. 1998;1(4):253-7.
37. Harding AE, Hewer RL. The heart disease of Friedreich’s ataxia: a clinical and electrocardiographic study of 115 patients, with an analysis of serial electrocardiographic changes in 30 cases. Q J Med. 1983;52(208):489-502.
38. Hewer RL. Study of fatal cases of Friedreich’s ataxia. Br Med J. 1968;3(619):649-52.
39. Dedobbeleer C, Rai M, Donal E, Pandolfo M, Unger P. Normal left ventricular ejection fraction and mass but subclinical myocardial dysfunction in patients with Friedreich’s ataxia. Eur Heart J Cardiovasc Imaging. 2012;13(4):346-52.
40. Dutka DP, Donnelly JE, Palka P, Lange A, Nunez DJ, Nihoyannopoulos P. Echocardiographic characterization of cardiomyopathy in Friedreich’s ataxia with tissue Doppler echocardiographically derived myocardial velocity gradients. Circulation. 2000;102(11):1276-82.
41. Meyer C, Schmid G, Görlitz S, Ernst M, Wilkens C, Wilhelms I, et al. Cardiomyopathy in Friedreich ataxia: Assessment by cardiac MRI. Mov Disord. 2007;22(11):1615-22.
42. Regner SR, Lagedrost SJ, Plappert T, Paulsen EK, Friedman LS, Snyder ML, et al. Analysis of echocardiograms in a large heterogeneous cohort of patients with friedreich ataxia. Am J Cardiol. 2012;109(3):401-5.
43. Rajagopalan B, Francis JM, Cooke F, Korlipara LV, Blamire AM, Schapira AH, et al. Analysis of the factors influencing the cardiac phenotype in Friedreich’s ataxia. Mov Disord. 2010;25(7):846-52.
44. De Castro M, Cruz-Martinez A, Vilchez JJ, Sevilla T, Pineda M, Berciano J, et al. Early onset cerebellar ataxia and preservation of tendon reflexes: clinical phenotypes associated with GAA trinucleotide repeat expanded and non-expanded genotypes. J Peripher Nerv Syst. 1999;4(1):58-62.
45. de Simone G, Daniels SR, Kimball TR, Roman MJ, Romano C, Chinali M, et al. Evaluation of concentric left ventricular geometry in humans: evidence for age-related systematic underestimation. Hypertension. 2005;45(1):64-8.
46. Stoylen A, Molmen HE, Dalen H. Importance of length and external diameter in left ventricular geometry. Normal values from the HUNT Study. Open Heart. 2016;3(2):e000465.
47. Isnard R, Kalotka H, Durr A, Cossee M, Schmitt M, Pousset F, et al. Correlation between left ventricular hypertrophy and GAA trinucleotide repeat length in Friedreich’s ataxia. Circulation. 1997;95(9):2247-9.
48. Morvan D, Komajda M, Doan LD, Brice A, Isnard R, Seck A, et al. Cardiomyopathy in Friedreich’s ataxia: a Doppler-echocardiographic study. Eur Heart J. 1992;13(10):1393-8.
49. Benjamin EJ, Plehn JF, D’Agostino RB, Belanger AJ, Comai K, Fuller DL, et al. Mitral annular calcification and the risk of stroke in an elderly cohort. N Engl J Med. 1992;327(6):374-9.
50. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, 3rd, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277-314.
51. Filla A, De Michele G, Cavalcanti F, Pianese L, Monticelli A, Campanella G, et al. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet. 1996;59(3):554-60.
52. Bit-Avragim N, Perrot A, Schols L, Hardt C, Kreuz FR, Zuhlke C, et al. The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich’s ataxia. J Mol Med. 2001;78(11):626-32.
53. Kelly M, Bagnall RD, Peverill RE, Donelan L, Corben L, Delatycki MB, et al. A polymorphic miR-155 binding site in AGTR1 is associated with cardiac hypertrophy in Friedreich ataxia. J Mol Cell Cardiol. 2011;51(5):848-54.
54. de Simone G, Devereux RB, Daniels SR, Meyer RA. Gender differences in left ventricular growth. Hypertension. 1995;26(6 Pt 1):979-83.
55. Foster BJ, Gao T, Mackie AS, Zemel BS, Ali H, Platt RW, et al. Limitations of expressing left ventricular mass relative to height and to body surface area in children. J Am Soc Echocardiogr. 2013;26(4):410-8.
56. Peverill RE, Donelan L, Corben LA, Delatycki MB. Differences in the determinants of right ventricular and regional left ventricular long-axis dysfunction in Friedreich ataxia. PLoS One. 2018;13(12):e0209410.
57. Bunse M, Bit-Avragim N, Riefflin A, Perrot A, Schmidt O, Kreuz FR, et al. Cardiac energetics correlates to myocardial hypertrophy in Friedreich’s ataxia.[see comment]. Ann Neurol. 2003;53(1):121-3.
58. Lodi R, Rajagopalan B, Blamire AM, Cooper JM, Davies CH, Bradley JL, et al. Cardiac energetics are abnormal in Friedreich ataxia patients in the absence of cardiac dysfunction and hypertrophy: an in vivo 31P magnetic resonance spectroscopy study.[see comment]. Cardiovasc Res. 2001;52(1):111-9.
59. Mavrogeni S, Giannakopoulou A, Katsalouli M, Pons RM, Papavasiliou A, Kolovou G, et al. Friedreich’s Ataxia: Case series and the additive value of cardiovascular magnetic resonance. J Neuromuscul Dis. 2020;7(1):61-7.
60. Takazaki KAG, Quinaglia T, Venancio TD, Martinez ARM, Shah RV, Neilan TG, et al. Pre-clinical left ventricular myocardial remodeling in patients with Friedreich’s ataxia: A cardiac MRI study. PLoS One. 2021;16(3):e0246633.
61. Casazza F, Ferrari F, Piccone U, Maggiolini S, Capozi A, Morpurgo M. [Progression of cardiopathology in Friedreich ataxia: clinico-instrumental study]. Cardiologia. 1990;35(5):423-31.
62. Casazza F, Morpurgo M. The varying evolution of Friedreich’s ataxia cardiomyopathy. Am J Cardiol. 1996;77(10):895-8.
63. Hawley RJ, Gottdiener JS. Five-year follow-up of Friedreich’s ataxia cardiomyopathy. Arch Intern Med. 1986;146(3):483-8.
64. Kipps A, Alexander M, Colan SD, Gauvreau K, Smoot L, Crawford L, et al. The longitudinal course of cardiomyopathy in Friedreich’s ataxia during childhood. Pediatr Cardiol. 2009;30(3):306-10.
65. Leone M, Rocca WA, Rosso MG, Mantel N, Schoenberg BS, Schiffer D. Friedreich’s disease: survival analysis in an Italian population. Neurology. 1988;38(9):1433-8.
66. Legrand L, Heuze C, Diallo A, Monin ML, Ewenczyk C, Vicaut E, et al. Prognostic value of longitudinal strain and ejection fraction in Friedreich’s ataxia. Int J Cardiol. 2021;330:259-65.
67. Hewer R. The heart in Friedreich’s ataxia. Br Heart J. 1969;31(1):5-14.
68. James TN, Cobbs BW, Coghlan HC, McCoy WC, Fisch C. Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich’s ataxia. Br Heart J. 1987;57(5):446-57.
69. Michael S, Petrocine SV, Qian J, Lamarche JB, Knutson MD, Garrick MD, et al. Iron and iron-responsive proteins in the cardiomyopathy of Friedreich’s ataxia. Cerebellum. 2006;5(4):257-67.
70. Quercia N, Somers GR, Halliday W, Kantor PF, Banwell B, Yoon G. Friedreich ataxia presenting as sudden cardiac death in childhood: Clinical, genetic and pathological correlation, with implications for genetic testing and counselling. Neuromuscul Disord. 2010;20:340-2.
71. Ramirez RL, Qian J, Santambrogio P, Levi S, Koeppen AH. Relation of cytosolic iron excess to cardiomyopathy of Friedreich’s ataxia. Am J Cardiol. 2012;110(12):1820-7.
72. Bhidayasiri R, Perlman SL, Pulst SM, Geschwind DH. Late-onset Friedreich ataxia: phenotypic analysis, magnetic resonance imaging findings, and review of the literature. Arch Neurol. 2005;62(12):1865-9.
73. De Michele G, Filla A, Barbieri F, Perretti A, Santoro L, Trombetta L, et al. Late onset recessive ataxia with Friedreich’s disease phenotype. J Neurol Neurosurg Psychiatry. 1989;52(12):1398-401.
74. Montermini L, Richter A, Morgan K, Justice CM, Julien D, Castellotti B, et al. Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion. Ann Neurol. 1997;41(5):675-82.
75. Alboliras ET, Shub C, Gomez MR, Edwards WD, Hagler DJ, Reeder GS, et al. Spectrum of cardiac involvement in Friedreich’s ataxia: clinical, electrocardiographic and echocardiographic observations. Am J Cardiol. 1986;58(6):518-24.
76. Asaad N, El-Menyar A, Al Suwaidi J. Recurrent ventricular tachycardia in patient with Friedreich’s ataxia in the absence of clinical myocardial disease. Pacing Clin Electrophysiol. 2010;33(1):109-12.
77. Byard RW, Gilbert JD. Mechanisms of unexpected death and autopsy findings in Friedreich ataxia. Med Sci Law. 2017;57(4):192-6.
78. Fineschi V, Panarese F, Zeppa P, Riezzo I, Ricci P, Dotti MT, et al. Sudden cardiac death in a case of spinocerebellar ataxia (Friedreich-like phenotype). Int J Cardiol. 2006;106(3):424-5.
79. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-327.
80. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):e199-267.
81. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15(5):625-51.
82. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(10):e385-484.
83. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, 3rd, Freedman RA, Gettes LS, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation. 2008;117(21):e350-408.
84. Coskun KO, Popov AF, Schmitto JD, Coskun ST, Brandes I, Zenker D, et al. Feasibility of implantable cardioverter defibrillator treatment in five patients with familial Friedreich’s ataxia–a case series. Artif Organs. 2010;34(11):1061-5.
85. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Colvin MM, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e61.
86. Yoda M, El-Banayosy A, Arusoglu L, Tendrich G, Minami K, Korfer R. Permanent use of a ventricle assist device for dilated cardiomyopathy in Friedreich’s ataxia. J Heart Lung Transplant. 2006;25(2):251-2.
87. Leonard H, Forsyth R. Friedreich’s ataxia presenting after cardiac transplantation. Arch Dis Child. 2001;84(2):167-8.
88. Sedlak TL, Chandavimol M, Straatman L. Cardiac transplantation: a temporary solution for Friedreich’s ataxia-induced dilated cardiomyopathy. J Heart Lung Transplant. 2004;23(11):1304-6.
89. Segovia J, Alonso-Pulpon L, Burgos R, Silva L, Serrano S, Castedo E, et al. Heart transplantation in Friedreich’s ataxia and other neuromuscular diseases. J Heart Lung Transplant. 2001;20(2):169.
90. Yoon G, Soman T, Wilson J, George K, Mital S, Dipchand AI, et al. Cardiac transplantation in Friedreich ataxia. J Child Neurol. 2012;27(9):1193-6.
91. Ivak P, Zumrova A, Netuka I. Friedreich’s ataxia and advanced heart failure: An ethical conundrum in decision-making. J Heart Lung Transplant. 2016;35(9):1144-5.
These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.
This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.
It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.