Skip to main content
SpringerLink
Log in

Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study

  • Original Research Article
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 25 July 2020

A Letter to the Editor to this article was published on 25 July 2020

Abstract

Background

Friedreich’s ataxia (FRDA) is a cerebellar ataxia due to GAA repeat expansions in the FXN gene, and in affected patients, lower left ventricular ejection fraction (LVEF) leads to poorer prognosis. We aimed to identify patients likely to develop worsening LVEF at an early stage.

Methods

We included 115 FRDA patients aged 30 ± 10 years with 620 ± 238 GAA repeats on the shorter allele and disease onset of 15 ± 7 years.

Results

At baseline, left ventricular (LV) hypertrophy was present in 53%, with LVEF 65 ± 7%, LV end diastolic diameter (LVEDD) 43 ± 5 mm, septal wall thickness (SWT) 11.8 ± 2.7 mm, and posterior wall thickness 11.1 ± 2.5 mm. After a mean follow-up of 13 ± 6 years, LVEF ≤ 50% was observed in 12 patients. The main determinants of LVEF ≤ 50% were GAA repeat number on the shorter allele (odds ratio [OR] 1.007, 95% confidence interval [CI] 1.003–1.012, p = 0.002), LVEDD (OR 1.217, 95% CI 1.058–1.399, p = 0.006), and SWT (OR 1.352, 95% CI 1.016–1.799, p = 0.04). High-risk patients were predicted 5 years before LVEF ≤ 50% occurred: area under the curve of 0.91, 95% CI 0.85–0.97. Patients with GAA repeats > 800 were categorized as high risk, patients with 500 < GAA < 800 were high risk if LVEDD was ≥ 52.6 mm and SWT was ≥ 13.3 mm, and patients with GAA < 500 were low risk if LVEDD was < 52.6 mm and SWT was < 13.3 mm.

Conclusions

Echocardiographic follow-up combined with size assessment of GAA repeat expansions is a powerful tool to identify patients at high risk of developing LV systolic dysfunction up to 5 years before clinical symptoms. Further studies are mandatory to investigate if these patients would benefit from cardiac interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Durr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, Mandel JL, Brice A, Koenig M. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996;335(16):1169–75.

    Article  CAS  PubMed  Google Scholar 

  2. Pousset F, Legrand L, Monin ML, Ewenczyk C, Charles P, Komajda M, Brice A, Pandolfo M, Isnard R, Tezenas du Montcel S, Durr A. 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.

    Article  PubMed  Google Scholar 

  3. Filla A, De Michele G, Cavalcanti F, Pianese L, Monticelli A, Campanella G, Cocozza S. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet. 1996;59(3):554–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Isnard R, Kalotka H, Durr A, Cossee M, Schmitt M, Pousset F, Thomas D, Brice A, Koenig M, Komajda M. Correlation between left ventricular hypertrophy and GAA trinucleotide repeat length in Friedreich’s ataxia. Circulation. 1997;95(9):2247–9.

    Article  CAS  PubMed  Google Scholar 

  5. Tai G, Corben LA, Yiu EM, Milne SC, Delatycki MB. Progress in the treatment of Friedreich ataxia. Neurol Neurochir Pol. 2018;52(2):129–39.

    Article  PubMed  Google Scholar 

  6. Perdomini M, Belbellaa B, Monassier L, Reutenauer L, Messaddeq N, Cartier N, Crystal RG, Aubourg P, Puccio H. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia. Nat Med. 2014;20(5):542–7.

    Article  CAS  PubMed  Google Scholar 

  7. Piguet F, de Montigny C, Vaucamps N, Reutenauer L, Eisenmann A, Puccio H. Rapid and complete reversal of sensory ataxia by gene therapy in a novel model of Friedreich ataxia. Mol Ther. 2018;26(8):1940–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Deverman BE, Ravina BM, Bankiewicz KS, Paul SM, Sah DWY. Gene therapy for neurological disorders: progress and prospects. Nat Rev Drug Discov. 2018;17(10):767.

    Article  CAS  PubMed  Google Scholar 

  9. Tsou AY, Paulsen EK, Lagedrost SJ, Perlman SL, Mathews KD, Wilmot GR, Ravina B, Koeppen AH, Lynch DR. Mortality in Friedreich ataxia. J Neurol Sci. 2011;307(1–2):46–9.

    Article  PubMed  Google Scholar 

  10. Weidemann F, Liu D, Hu K, Florescu C, Niemann M, Herrmann S, Kramer B, Klebe S, Doppler K, Uceyler N, Ritter CO, Ertl G, Stork S. The cardiomyopathy in Friedreich’s ataxia—new biomarker for staging cardiac involvement. Int J Cardiol. 2015;194:50–7.

    Article  PubMed  Google Scholar 

  11. Reetz K, Abbas Z, Costa AS, Gras V, Tiffin-Richards F, Mirzazade S, Holschbach B, Frank RD, Vassiliadou A, Kruger T, Eitner F, Gross T, Schulz JB, Floege J, Shah NJ. Increased cerebral water content in hemodialysis patients. PLoS One. 2015;10(3):e0122188.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Reetz K, Dogan I, Hilgers RD, Giunti P, Mariotti C, Durr A, Boesch S, Klopstock T, de Rivera FJ, Schols L, Klockgether T, Burk K, Rai M, Pandolfo M, Schulz JB, EFACTS Study Group. Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study. Lancet Neurol. 2016;15(13):1346–54.

    Article  PubMed  Google Scholar 

  13. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ, G. Chamber Quantification Writing Group, American Society of Echocardiography’s Guidelines and Standards Committee, European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440–63.

    Article  PubMed  Google Scholar 

  14. Foppa M, Duncan BB, Rohde LE. Echocardiography-based left ventricular mass estimation. How should we define hypertrophy. Cardiovasc Ultrasound. 2005;3:17.

    Article  PubMed  PubMed Central  Google Scholar 

  15. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787–847.

    Article  PubMed  Google Scholar 

  16. Henry WL, Gardin JM, Ware JH. Echocardiographic measurements in normal subjects from infancy to old age. Circulation. 1980;62(5):1054–61.

    Article  CAS  PubMed  Google Scholar 

  17. Weidemann F, Rummey C, Bijnens B, Stork S, Jasaityte R, Dhooge J, Baltabaeva A, Sutherland G, Schulz JB, Meier T, Mitochondrial Protection with Idebenone in Cardiac or Neurological Outcome (MICONOS) Study Group. The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms. Circulation. 2012;125(13):1626–34.

    Article  PubMed  Google Scholar 

  18. Kipps A, Alexander M, 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(3):306–10.

    Article  PubMed  Google Scholar 

  19. McCormick A, Shinnick J, Schadt K, Rodriguez R, Addonizio L, Hirano M, Perlman S, Lin KY, Lynch DR. Cardiac transplantation in Friedreich ataxia: extended follow-up. J Neurol Sci. 2017;375:471–3.

    Article  PubMed  Google Scholar 

  20. Long A, Napierala JS, Polak U, Hauser L, Koeppen AH, Lynch DR, Napierala M. Somatic instability of the expanded GAA repeats in Friedreich’s ataxia. PLoS One. 2017;12(12):e0189990.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB, Clinical Management Guidelines Writing Group. Consensus clinical management guidelines for Friedreich ataxia. Orphanet J Rare Dis. 2014;9:184.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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.

    Article  PubMed  Google Scholar 

  23. St John Sutton M, Ky B, Regner SR, Schadt K, Plappert T, He J, D’souza B, Lynch DR. Longitudinal strain in Friedreich ataxia: a potential marker for early left ventricular dysfunction. Echocardiography. 2014;31(1):50–7.

    Article  PubMed  Google Scholar 

  24. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson CM, Lesser JR, Hanna CA, Udelson JE, Manning WJ, Maron MS. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51(14):1369–74.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all patients who participated in the study. Special thanks go to Sandra Benaich and Fabien Lesne, who helped with data handling, and Rachel Peat, for English editing.

Author information

Authors and Affiliations

  1. Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France

    Lise Legrand, Marie-Lorraine Monin, Richard Isnard, Gilles Montalescot & Francoise Pousset

  2. Genetics Department, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France

    Marie-Lorraine Monin, Claire Ewenczyk, Perrine Charles & Alexandra Durr

  3. ICM (Brain and Spine Institute), INSERM, CNRS, Pitié-Salpêtrière University Hospital, Sorbonne Université, Paris, France

    Alexandra Durr

  4. ICAN (Institute for Cardiometabolism and Nutrition), Pitié-Salpêtrière University Hospital, Paris, France

    Lise Legrand, Richard Isnard & Francoise Pousset

  5. ACTION (Allies in Cardiovascular Trials Initiatives and Organized Networks) Group, URC Lariboisière University Hospital, Paris, France

    Abdourahmane Diallo, Richard Isnard, Eric Vicaut & Gilles Montalescot

  6. Département de Cardiologie, Hôpital de la Salpêtrière, 47 boulevard de l’Hôpital, 75651, Paris Cedex 13, France

    Francoise Pousset

Authors
  1. Lise Legrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abdourahmane Diallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marie-Lorraine Monin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claire Ewenczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Perrine Charles
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard Isnard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eric Vicaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gilles Montalescot
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alexandra Durr
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Francoise Pousset
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francoise Pousset.

Ethics declarations

Funding

This study was supported by FP7 (7th Framework Programme) Grant HEALTH-F2-2010-242193 from the European Commission.

Conflict of interest

Lise Legrand, Abdourahmane Diallo, Marie-Lorraine Monin, Claire Ewenczyk, Perrine Charles, Richard Isnard, Eric Vicaut, Gilles Montalescot, Alexandra Durr, and Francoise Pousset declare that they have no potential conflicts of interest that might be relevant to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 88 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Legrand, L., Diallo, A., Monin, ML. et al. Predictors of Left Ventricular Dysfunction in Friedreich’s Ataxia in a 16-Year Observational Study. Am J Cardiovasc Drugs 20, 209–216 (2020). https://doi.org/10.1007/s40256-019-00375-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-019-00375-z

Search

Navigation