The Pathogenesis of Cardiomyopathy in Friedreich Ataxia

PLOS ONE, Mar 2015

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 (ICP-OES); 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.

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The Pathogenesis of Cardiomyopathy in Friedreich Ataxia

March The Pathogenesis of Cardiomyopathy in Friedreich Ataxia Data Availability Statement: All relevant data are within the paper. 0 1 Arnulf H. Koeppen 0 1 R. Liane Ramirez 0 1 Alyssa B. Becker 0 1 Sarah T. Bjork 0 1 Sonia Levi 0 1 Paolo Santambrogio 0 1 Patrick J. Parsons 0 1 Pamela C. Kruger 0 1 Karl X. Yang 0 1 Paul J. Feustel 0 1 Joseph E. Mazurkiewicz 0 1 0 1 Research, Neurology, and Pathology Services, Veterans Affairs Medical Center, Albany, New York, United States of America, 2 Departments of Neurology and Pathology, Albany Medical College, Albany, New York, United States of America, 3 Research Service, Veterans Affairs Medical Center, Albany, New York, United States of America, 4 San Raffaele Scientific Institute , Milan , Italy , 5 Vita-Salute San Raffaele University , Milan , Italy , 6 Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health , Albany , New York, United States of America, 7 Department of Environmental Health Sciences, University at Albany, Albany, New York, United States of America, 8 Center for Neuropharmacology and Neuroscience, Albany Medical College , Albany, New York , United States of America 1 Academic Editor: Kostas Pantopoulos, Lady Davis Institute for Medical Research/McGill University , CANADA 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; Xray 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 235.475.1 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. - Funding: Friedreich's Ataxia Research Alliance (FARA) supported all aspects of this work including staff salaries and purchases of supplies and services. FARA also supported the tissue donation program. National Ataxia Foundation supported the tissue donation program. National Institutes of Health supported the tissue donation program and pertinent laboratory work (grant number R01 NS069454). NDRI receives financial support from the National Institutes of Health (grant number 2 U42 OD011158). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Friedreich ataxia (FA) is an autosomal recessive disorder that is best known for its disabling neurological phenotype. The most common cause of death, however, is cardiomyopathy [1]. Friedreich [2] described hypertrophy and discoloration of the myocardium in 3 of his initial 6 patients with fatal course but did not consider the heart lesion part of the pathological phenotype. Eighty years later, Russell [3] established that chronic myocarditis in FA is an integral part of the disorder and stressed that the destructive process was focal and progressed in a piecemeal manner. The current report presents systematic observations on archival autopsy specimens that support myocarditis as an important mechanism in the pathogenesis of FA cardiomyopathy. The work confirms severe reduction of cardiac frataxin levels and the importance of iron (Fe), cytosolic and mitochondrial ferritins [46], and the iron-regulator (...truncated)


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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. The Pathogenesis of Cardiomyopathy in Friedreich Ataxia, PLOS ONE, 2015, Volume 10, Issue 3, DOI: 10.1371/journal.pone.0116396