The pathogenesis of cardiomyopathy in Friedreich ataxia.
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.
Research, Neurology, and Pathology Services, Veterans Affairs Medical Center, Albany, New York, United States of America; Departments of Neurology and Pathology, Albany Medical College, Albany, New York, United States of America.
Arnulf H
AH
Koeppen
Research Service, Veterans Affairs Medical Center, Albany, New York, United States of America.
R Liane
RL
Ramirez
Research Service, Veterans Affairs Medical Center, Albany, New York, United States of America.
Alyssa B
AB
Becker
Research Service, Veterans Affairs Medical Center, Albany, New York, United States of America.
Sarah T
ST
Bjork
San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
Sonia
S
Levi
San Raffaele Scientific Institute, Milan, Italy.
Paolo
P
Santambrogio
Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America; Department of Environmental Health Sciences, University at Albany, Albany, New York, United States of America.
Patrick J
PJ
Parsons
Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.
Pamela C
PC
Kruger
Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, New York, United States of America; Department of Environmental Health Sciences, University at Albany, Albany, New York, United States of America.
Karl X
KX
Yang
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, United States of America.
Paul J
PJ
Feustel
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, United States of America.
Joseph E
JE
Mazurkiewicz
D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005293:Ferritins / Q000378:metabolism; D005621:Friedreich Ataxia / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000473:pathology; D064451:Hepcidins / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism; D009205:Myocarditis / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D055815:Young Adult
D064451:Hepcidins; D005293:Ferritins; D007501:Iron