Clinical Management Guidelines for Friedreich Ataxia (FRDA)

Topic 4.4. Management strategies for heart failure

Return to Chapter Overview
 

Full Chapter PDF

Full TextRecommendationsBest Practice StatementsLay SummaryAuthorsReferencesMethodology & Date

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

4.4 Management strategies for heart failure
4.4.1 Pharmacologic treatment of heart failure with reduced left ventricular ejection fraction
4.4.2 Lifestyle factors and cautions to aid in management of heart failure
4.4.3 Device therapy and heart transplantation for heart failure
4.4.4 Fluid and operative management of individuals with and without heart failure

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.


4.4 Management strategies for heart failure

Roger E. Peverill, Kimberly Y. Lin, Francoise Pousset, Aarti Patel and Konstantinos Savvatis

There is currently no evidence to support any cardiac treatment for individuals with FRDA with normal LV ejection fraction and without cardiac symptoms or signs. A number of studies have investigated the effects of idebenone on LV wall thickness and/or LV mass but most of these studies have been small and the findings have not been consistent (2). Furthermore, a reduction of wall thickness or LV mass cannot be assumed to be a beneficial outcome of treatment in FRDA.

Spontaneous onset of HF symptoms is rarely seen in individuals with FRDA with increased LV wall thickness in the setting of a normal LVEF and normal sinus rhythm, and so regular HF medication therapy is unlikely to be indicated in such individuals. However, individuals with FRDA with such patterns of LV remodeling are more likely to develop symptoms and signs of acute HF in circumstances of stress, such as surgery and serious infections, particularly when accompanied by changes in intravascular volume. Careful fluid management to avoid depletion or overload is recommended in such situations and diuretic therapy could be required if symptoms or signs develop due to fluid overload.

4.4.1 Pharmacologic treatment of heart failure with reduced left ventricular ejection fraction

Adults

There are no RCT data regarding the treatment of either asymptomatic people with FRDA with reduced LVEF or of individuals with FRDA and with HF associated with reduced LVEF (HFREF). However, in the absence of any evidence for any FRDA disease-specific harmful effects of standard HF treatments it is reasonable to use standard HF guidelines as a guide to therapy in FRDA, recognizing that there could be differences in the pathophysiology of FRDA heart disease. The fundamentals of medication management for symptomatic HFREF are provided in the 2013 ACCF/AHA guideline for the management of HF (79) and in the 2017 ACC/AHA/HFSA update on the 2013 ACCF/AHA guideline (85).

Children

There are no RCTs investigating the treatment of reduced LVEF with or without HF in children with FRDA. Neither is there even much data available from trials in children with HF due to a cardiomyopathy with reduced LVEF and causes other than FRDA. This is due in part to the difficulty of performing RCTs in children given the low prevalence of pediatric HFREF. Treatment of HFREF in children has been based on the results from adult studies.

4.4.2 Lifestyle factors and cautions to aid in management of heart failure

Lack of physical activity, poor diet, excessive consumption of salt and fluids and being overweight can exacerbate HF. Exercise-based rehabilitation can lead to reductions in hospitalizations for HF and improved quality of life and does not increase mortality in people with stable HF. Individuals who are requiring diuretics should generally be on a fluid restriction of less than 2L/day and more strict fluid restrictions may be necessary depending on the severity of the HF, the sodium level and the required doses of diuretics.

4.4.3 Device therapy and heart transplantation for heart failure

Prolongation of the QRS interval occurs in a proportion of people with advanced HF and has been associated with ventricular electromechanical delay (“dyssynchrony”) (83). QRS duration, dyssynchrony of contraction, and left bundle branch block (LBBB) in particular, have been identified as predictors of worsening HF, SCD, and total mortality. Modification of ventricular electromechanical delay with multisite ventricular pacing (biventricular pacing and cardiac resynchronization therapy (CRT)) can improve ventricular systolic function, ameliorate functional mitral regurgitation, and, in some individuals, induce favorable remodeling with reduction of cardiac chamber dimensions. Individuals with FRDA can develop HF due to severe systolic LV systolic dysfunction and can have a LBBB so CRT should be considered in such circumstances. There is a single case report of the successful use of a ventricular assist device in a patient with FRDA and heart failure due reduced LVEF (86).

Guidelines for CRT in patients with severe systolic HF are included in the 2013 ACCF/AHA guideline for the management of HF (79).

Transplantation of the heart in FRDA is not common but has been reported (87-91). Individuals with FRDA appear to do well after transplantation.

4.4.4 Fluid and operative management of individuals with and without heart failure

The increased thickness of the left ventricle in FRDA results in a reduction in coronary flow reserve and less tolerance to tachycardia. The reduced size of the LV cavity in FRDA means a greater reliance on heart rate to maintain cardiac output and a reduction in stroke volume reserve. Hearts of individuals with FRDA will therefore have less tolerance for changes in hemodynamics such as bradycardia, tachycardia, low blood pressure, and increases or decreases in LV filling. Careful monitoring of fluid balance is essential in individuals with FRDA undergoing stressful events, such as scoliosis surgery or hydration therapy in the emergency room setting. In addition, rapid access to advanced technologies for supporting cardiac output following major surgery, such as dialysis and left ventricular assist devices, may be required.

Although significant advances have been made in understanding the molecular biology of FRDA, there remain substantial and fundamental gaps in our understanding of the clinical disease and natural history of FRDA. Furthermore, there are no RCTs of the treatment or prevention of arrhythmias or the treatment of HF and no trials showing any benefit of treatment to delay the onset of or prevent the development of left ventricular dysfunction in FRDA.

Jump to Recommendations

Jump to Best practice statements

Jump to Lay summary

Please note: Recommendations 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. Best Practice Statements are commonly accepted practices, as such formal rating of the quality of evidence by the GRADE process is not indicated. In addition if recommendations from the 2014 guidelines were deemed still relevant, although unable to undergo the scrutiny from a GRADE framework, they were also included as best practice statements.
Heart failure medication/devices (preserved left ventricular ejection fraction)

QUESTION: Should heart failure medication and/or devices vs. no medication and/or devices be used for individuals with Friedreich ataxia and a preserved left ventricular ejection fraction (i.e. >55%)?

STRENGTH OF RECOMMENDATION:
LEVEL OF EVIDENCE: ⨁◯◯◯

RECOMMENDATION: We do not suggest using heart failure medication and/or devices for individuals with Friedreich ataxia with a preserved left ventricular ejection fraction.

JUSTIFICATION: There is no evidence that the use of medication and/or devices has any benefit in reducing the occurrence of cardiac dysfunction in individuals with Friedreich ataxia with preserved ejection fraction and there are risks of side effects and over-medication if such treatments are used.

SUBGROUP CONSIDERATION: This recommendation is for individuals with Friedreich ataxia and a preserved left ventricular ejection fraction (i.e. >55%).

Evidence to Recommendation Table PDF
Heart failure medication (reduced ejection fraction)

QUESTION: Should heart failure medication versus no medication be used for individuals with reduced ejection fraction with Friedreich ataxia?

STRENGTH OF RECOMMENDATION:
LEVEL OF EVIDENCE: ⨁◯◯◯

RECOMMENDATION: We conditionally recommend treating individuals with Friedreich ataxia with a reduced left ventricular ejection fraction with medications according to current American Heart Association/American College of Cardiology heart failure guidelines (2013 & 2017 update).

JUSTIFICATION: Medical treatment of an individual with Friedreich ataxia with reduced ejection fraction should include those with a LVEF <50%, but could also be considered for those with a significant downward trend in ejection fraction over time. This is based on current recommendations of the AHA/ACC (79, 85) for treatment of heart failure as there is no evidence to suggest that individuals with Friedreich ataxia should be treated differently to other people with heart failure and reduced ejection fraction.

SUBGROUP CONSIDERATION: This recommendation is for individuals with Friedreich ataxia and a reduced ejection fraction, and as indicated in the justification above.

Evidence to Recommendation Table PDF
Advanced heart failure treatments (reduced left ventricular ejection fraction)

QUESTION: Should advanced heart failure treatments (e.g., biventricular pacemaker, internal cardioverter-defibrillator, left ventricular assist device, heart transplantation) versus supportive care be used for individuals with Friedreich ataxia in the advanced stages of heart failure due to a reduced left ventricular ejection fraction?

STRENGTH OF RECOMMENDATION:
LEVEL OF EVIDENCE: ⨁◯◯◯

RECOMMENDATION: Advanced heart failure therapies such as a left ventricular assist device, implantable cardioverter-defibrillator, biventricular pacemaker and heart transplantation should be considered for individuals with Friedreich ataxia and heart failure due to a reduced left ventricular ejection fraction, based on consideration of both their cardiac and overall health status.

JUSTIFICATION: Based on the current evidence, advanced heart failure therapies should be considered based on individual circumstances. A diagnosis of Friedreich ataxia alone should not preclude such consideration. Evidence from case reports indicates positive outcomes (86-91).

SUBGROUP CONSIDERATION: This recommendation is for individuals with Friedreich ataxia with a reduced left ventricular ejection fraction (i.e. <55%).

Evidence to Recommendation Table PDF
Please note: Recommendations 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. Best Practice Statements are commonly accepted practices, as such formal rating of the quality of evidence by the GRADE process is not indicated. In addition if recommendations from the 2014 guidelines were deemed still relevant, although unable to undergo the scrutiny from a GRADE framework, they were also included as best practice statements.
There is no therapy with proven cardiac benefits for asymptomatic people with Friedreich ataxia with echocardiographic or cardiac magnetic resonance findings of either a normal heart or increased left ventricular wall thickness but normal ejection fraction.


In adults with Friedreich ataxia and a reduction in left ventricular ejection fraction there is a case for treating according to standard heart failure guidelines.


In individuals with Friedreich ataxia and symptomatic heart failure there is a case for treating according to standard heart failure guidelines.


Women with Friedreich ataxia and a reduction in left ventricular ejection fraction should be advised that pregnancy could result in cardiac decompensation and a greater maternal and fetal risk.


Treatment options such as an ICD and heart transplantation are not contraindicated in Friedreich ataxia, but the appropriateness of such therapy requires careful consideration of the individual’s functional status and their prognosis from non-cardiac morbidities.

Lay summary of clinical recommendations for heart failure in Friedreich ataxia

Why these recommendations?

Heart failure is a condition where your heart function is impaired and it can result in loss of exercise tolerance, breathlessness and leg swelling. Heart failure can also result in abnormal heart rhythms.

These recommendations did not find that any specific heart failure medication or devices had evidence of benefit in individuals with Friedreich ataxia with a normal left ventricular ejection fraction (a commonly used measure of the percentage of blood pumped by the left ventricle with each heart beat). On the other hand, if an individual has a reduced left ventricular ejection fraction, we suggest that treatment should follow the same guidelines as for individuals with a reduced left ventricular ejection fraction who do not have Friedreich ataxia.

In the case of advanced heart failure, and after considering both the heart and general health of the individual concerned, we suggest that devices that can help to maintain heart output or heart transplantation could be considered.

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 Friedreich ataxia and heart failure and what it means for you.

Who are these recommendations specifically for?
These recommendations are for individuals with Friedreich ataxia who have been diagnosed with heart failure.

Kimberly Y. Lin, MD
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

1. Tsou AY, Paulsen EK, Lagedrost SJ, Perlman SL, Mathews KD, Wilmot GR, et al. Mortality in Friedreich ataxia. J Neurol Sci. 2011;307:46-9.

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.

For the rating of the strength of the recommendation, in addition to evidence from studies in FRDA, evidence from like conditions, clinical experience and expert consensus are taken into account when published evidence is not available.

The level of evidence is based on published evidence from studies in FRDA. If there is no published evidence in FRDA, evidence from other like conditions or clinical expertise may have been used to make the recommendation – this is graded as ‘very low’ or in some cases ‘low’ level evidence. See the table below for an explanation of the symbols used to grade recommendations.

Strength of recommendation Symbol Level of evidence Symbol
Strong for intervention ↑↑ High ⨁⨁⨁⨁
Conditional for intervention Moderate ⨁⨁⨁◯
Neither intervention nor comparison Low ⨁⨁◯◯
Conditional against intervention Very low ⨁◯◯◯
Strong against intervention ↓↓
Close