TY - JOUR
T1 - The significance of intercalated discs in the pathogenesis of Friedreich cardiomyopathy
AU - Koeppen, Arnulf H.
AU - Becker, Alyssa B.
AU - Feustel, Paul J.
AU - Gelman, Benjamin B.
AU - Mazurkiewicz, Joseph E.
N1 - Funding Information:
Tissue specimens were obtained through a formal donation program supported by Friedreich's Ataxia Research Alliance and National Ataxia Foundation. The authors wish to thank the families who generously agreed to donate autopsy specimens to advance research in FRDA. Dr. David Lynch, Dr. Kim Lin, Ms. Kim Scheldt, and Ms. Juliana Shinnick, Children's Hospital of Philadelphia, Philadelphia, PA, USA, made available clinical data and the heart biopsy sample identified as No. 4 in Table 1 . Research grants for this work came from Friedreich's Ataxia Research Alliance and National Institutes of Health (grant No. R01NS069454 ) (to AHK). The National Disease Research Interchange is supported by a grant from the National Institutes of Health (grant No. 2U42 OD011158 ). The work was completed in the laboratories of Veterans Affairs Medical Center, Albany, NY, USA, the University of Texas Medical Branch, Galveston, TX, USA, and the Albany Medical College, Albany, NY, USA.
PY - 2016/8/15
Y1 - 2016/8/15
N2 - Friedreich ataxia (FRDA) is an autosomal recessive disorder with a complex clinical and neuropathological phenotype, but the most frequent cause of death is cardiomyopathy. The principal autopsy findings in FRDA hearts are concentric hypertrophy, enlargement of cardiomyocytes, myofiber necrosis, inflammatory infiltration, scarring, and random accumulation of iron. In addition, the myocardium shows generalized disorganization of intercalated discs (ICD), the Velcro-like end-to-end connections of heart fibers that provide mechanical cohesion and ionic coupling. The principal components of ICD are fascia adherens junctions (FAJ), desmosomes, and gap junctions. Frataxin deficiency in FRDA may cause improper assembly of ICD early in life, making hearts vulnerable to mechanical stress in childhood and adolescence. We studied the ICD in the myocardium of left ventricular wall (LVW), right ventricular wall, and ventricular septum in 18 genetically confirmed FRDA patients (age of death, 10 to 87 years) and 12 normal controls (age of death, 13 to 69 years). In cases with juvenile onset, electron microscopy and immunohistochemistry of N-cadherin and vinculin, two abundant FAJ proteins, showed enlargement of ICD, discontinuity, and hyperconvolution. Reaction product of the desmosomal protein desmoglein 2 was similar. The distribution of the gap junction protein connexin 43 at ICD was also irregular and displayed abnormal lateralization to the plasma membranes of cardiomyocytes. Confocal immunofluorescence microscopy of α-actinin, affinity fluorescence microscopy of actin with rhodamine-labeled phalloidin, and electron microscopy, revealed the principal integrity of sarcomeres of the myocardium in FRDA. In two late-onset long-surviving FRDA patients (ages 79 and 87), clinical cardiomyopathy was absent, and ICD were normal. The described observations in patients with a broad range of disease onset and duration allow us to conclude that faulty assembly of ICD interferes with proper end-to-end adhesion of cardiomyocytes of the growing heart and contributes to the pathogenesis of FRDA cardiomyopathy.
AB - Friedreich ataxia (FRDA) is an autosomal recessive disorder with a complex clinical and neuropathological phenotype, but the most frequent cause of death is cardiomyopathy. The principal autopsy findings in FRDA hearts are concentric hypertrophy, enlargement of cardiomyocytes, myofiber necrosis, inflammatory infiltration, scarring, and random accumulation of iron. In addition, the myocardium shows generalized disorganization of intercalated discs (ICD), the Velcro-like end-to-end connections of heart fibers that provide mechanical cohesion and ionic coupling. The principal components of ICD are fascia adherens junctions (FAJ), desmosomes, and gap junctions. Frataxin deficiency in FRDA may cause improper assembly of ICD early in life, making hearts vulnerable to mechanical stress in childhood and adolescence. We studied the ICD in the myocardium of left ventricular wall (LVW), right ventricular wall, and ventricular septum in 18 genetically confirmed FRDA patients (age of death, 10 to 87 years) and 12 normal controls (age of death, 13 to 69 years). In cases with juvenile onset, electron microscopy and immunohistochemistry of N-cadherin and vinculin, two abundant FAJ proteins, showed enlargement of ICD, discontinuity, and hyperconvolution. Reaction product of the desmosomal protein desmoglein 2 was similar. The distribution of the gap junction protein connexin 43 at ICD was also irregular and displayed abnormal lateralization to the plasma membranes of cardiomyocytes. Confocal immunofluorescence microscopy of α-actinin, affinity fluorescence microscopy of actin with rhodamine-labeled phalloidin, and electron microscopy, revealed the principal integrity of sarcomeres of the myocardium in FRDA. In two late-onset long-surviving FRDA patients (ages 79 and 87), clinical cardiomyopathy was absent, and ICD were normal. The described observations in patients with a broad range of disease onset and duration allow us to conclude that faulty assembly of ICD interferes with proper end-to-end adhesion of cardiomyocytes of the growing heart and contributes to the pathogenesis of FRDA cardiomyopathy.
KW - Cardiomyopathy
KW - Connexin 43
KW - Friedreich ataxia
KW - Gap junctions
KW - Intercalated discs
KW - N-cadherin
UR - http://www.scopus.com/inward/record.url?scp=84976492017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84976492017&partnerID=8YFLogxK
U2 - 10.1016/j.jns.2016.06.006
DO - 10.1016/j.jns.2016.06.006
M3 - Article
C2 - 27423584
AN - SCOPUS:84976492017
SN - 0022-510X
VL - 367
SP - 171
EP - 176
JO - Journal of the Neurological Sciences
JF - Journal of the Neurological Sciences
ER -