The pathogenesis of cardiomyopathy in Friedreich ataxia

Arnulf H. Koeppen, R. Liane Ramirez, Alyssa B. Becker, Sarah T. Bjork, Sonia Levi, Paolo Santambrogio, Patrick J. Parsons, Pamela C. Kruger, Karl X. Yang, Paul J. Feustel, Joseph E. Mazurkiewicz

Research output: Contribution to journalArticle

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Abstract

Friedreich ataxia (FA) is an autosomal recessive disease with a complex neurological phenotype, but the most common cause of death is heart failure. This study presents a systematic analysis of 15 fixed and 13 frozen archival autopsy tissues of FA hearts and 10 normal controls (8 frozen) by measurement of cardiomyocyte hypertrophy; tissue frataxin assay; X-ray fluorescence (XRF) of iron (Fe) and zinc (Zn) in polyethylene glycol-embedded samples of left and right ventricular walls (LVW, RVW) and ventricular septum (VS); metal quantification in bulk digests by inductively-coupled plasma optical emission spectrometry (ICPOES); Fe histochemistry; and immunohistochemistry and immunofluorescence of cytosolic and mitochondrial ferritins and of the inflammatory markers CD68 and hepcidin. FA cardiomyocytes were significantly larger than normal and surrounded by fibrotic endomysium. Frataxin in LVW was reduced to less than 15 ng/g wet weight (normal 235.4±75.1 ng/g). All sections displayed characteristic Fe-reactive inclusions in cardiomyocytes, and XRF confirmed significant regional Fe accumulation in LVW and VS. In contrast, ICP-OES analysis of bulk extracts revealed normal total Fe levels in LVW, RVW, and VS. Cardiac Zn remained normal by XRF and assay of bulk digests. Cytosolic and mitochondrial ferritins exhibited extensive co-localization in cardiomyocytes, representing translational and transcriptional responses to Fe, respectively. Fe accumulation progressed from a few small granules to coarse aggregates in phagocytized cardiomyocytes. All cases met the "Dallas criteria" of myocarditis. Inflammatory cells contained CD68 and cytosolic ferritin, and most also expressed the Fe-regulatory hormone hepcidin. Inflammation is an important factor in the pathogenesis of FA cardiomyopathy but may be more evident in advanced stages of the disease. Hepcidin-induced failure of Fe export from macrophages is a likely contributory cause of damage to the heart in FA. Frataxin replacement and anti-inflammatory agents are potential therapies in FA cardiomyopathy.

Original languageEnglish
Article numbere0116396
JournalPLoS One
Volume10
Issue number3
DOIs
Publication statusPublished - Mar 4 2015

Fingerprint

Hepcidins
Friedreich Ataxia
cardiomyopathy
Ferritins
Cardiomyopathies
Cardiac Myocytes
pathogenesis
Fluorescence
ferritin
X rays
Ventricular Septum
Zinc
Assays
X-radiation
Tissue
fluorescence
Macrophages
X-Rays
Inductively coupled plasma
Spectrometry

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Koeppen, A. H., Ramirez, R. L., Becker, A. B., Bjork, S. T., Levi, S., Santambrogio, P., ... Mazurkiewicz, J. E. (2015). The pathogenesis of cardiomyopathy in Friedreich ataxia. PLoS One, 10(3), [e0116396]. https://doi.org/10.1371/journal.pone.0116396

The pathogenesis of cardiomyopathy in Friedreich ataxia. / Koeppen, Arnulf H.; Ramirez, R. Liane; Becker, Alyssa B.; Bjork, Sarah T.; Levi, Sonia; Santambrogio, Paolo; Parsons, Patrick J.; Kruger, Pamela C.; Yang, Karl X.; Feustel, Paul J.; Mazurkiewicz, Joseph E.

In: PLoS One, Vol. 10, No. 3, e0116396, 04.03.2015.

Research output: Contribution to journalArticle

Koeppen, AH, Ramirez, RL, Becker, AB, Bjork, ST, Levi, S, Santambrogio, P, Parsons, PJ, Kruger, PC, Yang, KX, Feustel, PJ & Mazurkiewicz, JE 2015, 'The pathogenesis of cardiomyopathy in Friedreich ataxia', PLoS One, vol. 10, no. 3, e0116396. https://doi.org/10.1371/journal.pone.0116396
Koeppen, Arnulf H. ; Ramirez, R. Liane ; Becker, Alyssa B. ; Bjork, Sarah T. ; Levi, Sonia ; Santambrogio, Paolo ; Parsons, Patrick J. ; Kruger, Pamela C. ; Yang, Karl X. ; Feustel, Paul J. ; Mazurkiewicz, Joseph E. / The pathogenesis of cardiomyopathy in Friedreich ataxia. In: PLoS One. 2015 ; Vol. 10, No. 3.
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