Cardiomyopathy is the leading cause of death in Friedreich's ataxia. This autosomal recessive disease is caused by a homozygous guanine-adenine-adenine trinucleotide repeat expansion in the frataxin gene (chromosome 9q21). One untoward effect of frataxin deficiency is the lack of iron (Fe)-sulfur clusters. Progressive remodeling of the heart in FA, however, may be more specifically related to sarcoplasmic Fe overload. The Fe-containing inclusions in a small percentage of cardiomyocytes may not represent purely mitochondrial accumulation of the metal. The objective of the present study was to re-examine the contribution of Fe to cardiomyocyte hypertrophy, fiber necrosis, and myocardial scarring, using a combination of X-ray fluorescence, slide histochemistry of Fe, and immunohistochemistry of 2 Fe-related proteins. Polyethylene glycol-embedded human cardiac tissues from the left and right ventricular walls, ventricular septum, right atrium, and atrial septum were studied using qualitative and quantitative X-ray fluorescence. Tissues were recovered from the polyethylene glycol matrix, re-embedded in paraffin, and sectioned for visualization of Fe, ferritin, and ferroportin. X-ray fluorescence showed quantifiable levels of Fe and zinc. Regions of significantly increased Fe (1 to 4 mm2) were irregularly distributed throughout the working myocardium. Fe granules were sparse in conductive tissue. Zinc signals remained unchanged. Robust cytosolic ferritin reaction product occurred in many fibers of the affected regions. Ferroportin displayed no response except in fibers with advanced Fe overload. These observations are at variance with the concept of selective Fe overload only in cardiac mitochondria. In conclusion, Fe-mediated damage to cardiomyocytes and myocardial scarring are more likely due to cytosolic Fe excess. © 2012 Elsevier Inc.
Ramirez, R. L., Qian, J., Santambrogio, P., Levi, S., & Koeppen, A. H. (2012). Relation of cytosolic iron excess to cardiomyopathy of friedreich’s ataxia. American Journal of Cardiology, 110(12), 1820–1827. https://doi.org/10.1016/j.amjcard.2012.08.018