Microvascular pathology in Friedreich cardiomyopathy.

Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocyte hypertrophy, fiber necrosis, and inflammatory infiltration, sections show fibrosis and disorganized capillaries. We examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69. Immunohistochemistry with an antibody to CD34 allowed quantitative counts of capillary profiles for a comparison with cardiomyocyte counts in the same field. Capillary counts (mean +/- standard deviation [SD]) in normal controls were 1926 +/- 341/mm(2), while mean cardiomyocyte counts were 2003 +/- 686/mm(2). The median ratio of capillaries to cardiomyocytes was 1.0 (interquartile range [IQR]: 0.9-1.2). In FA, the number of cardiomyocytes/mm(2) was significantly less (704 +/- 361; p<0.001), and the median ratio of capillaries to heart fibers was 2.0 (IQR:1.4-2.4). There was a significant correlation of the expanded guanine-adenine-adenine trinucleotides (shorter allele, GAA1) with a younger age of onset, shorter disease duration, and lower cardiomyocyte counts. The ratio of capillaries to heart fibers was higher in patients with long GAA1 repeat expansions (e.g., 3.31 in GAA1 of 1200). Double-label immunofluorescence for CD34 and the fibroblast marker S100A4 revealed co-expression in endothelial cells, supporting endothelial-to-mesenchymal transition in the pathogenesis of cardiac fibrosis in FA. We propose that the pathogenesis of FA heart disease includes primary fibrosis.