The significance of intercalated discs in the pathogenesis of Friedreich cardiomyopathy

Arnulf H. Koeppen, Alyssa B. Becker, Paul J. Feustel, Benjamin Gelman, Joseph E. Mazurkiewicz

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)171-176
Number of pages6
JournalJournal of the Neurological Sciences
Volume367
DOIs
StatePublished - Aug 15 2016

Fingerprint

Friedreich Ataxia
Cardiomyopathies
Cardiac Myocytes
Adherens Junctions
Myocardium
Fascia
Fluorescence Microscopy
Desmoglein 2
Electron Microscopy
Vinculin
Actinin
Ventricular Septum
Desmosomes
Connexin 43
Sarcomeres
Mechanical Stress
Connexins
Gap Junctions
Cardiomegaly
Cadherins

Keywords

  • Cardiomyopathy
  • Connexin 43
  • Friedreich ataxia
  • Gap junctions
  • Intercalated discs
  • N-cadherin

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

The significance of intercalated discs in the pathogenesis of Friedreich cardiomyopathy. / Koeppen, Arnulf H.; Becker, Alyssa B.; Feustel, Paul J.; Gelman, Benjamin; Mazurkiewicz, Joseph E.

In: Journal of the Neurological Sciences, Vol. 367, 15.08.2016, p. 171-176.

Research output: Contribution to journalArticle

Koeppen, Arnulf H. ; Becker, Alyssa B. ; Feustel, Paul J. ; Gelman, Benjamin ; Mazurkiewicz, Joseph E. / The significance of intercalated discs in the pathogenesis of Friedreich cardiomyopathy. In: Journal of the Neurological Sciences. 2016 ; Vol. 367. pp. 171-176.
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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.

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