title: Distinct fibrosis pattern in desmosomal and phospholamban mutation carriers in hereditary cardiomyopathies.
abstract: Desmosomal and phospholamban (PLN) mutations are associated with arrhythmogenic cardiomyopathy. Ultimately, most cardiomyopathic hearts develop significant cardiac fibrosis.
  
  
  
  To compare the fibrosis patterns of desmosomal and p. Arg14del PLN-associated cardiomyopathies with the pattern in hearts with other hereditary cardiomyopathies.
  
  
  
  A midventricular transversal slice was obtained from hearts of 30 patients with a cardiomyopathy with a known underlying mutation and from 8 controls. Fibrosis and fatty changes were quantitatively analyzed using digital microscopy.
  
  
  
  Hearts from patients with desmosomal mutations (n = 6) showed fibrosis and fibrofatty replacement in the left ventricular (LV) outer myocardium, mainly in the posterolateral wall, and in the right ventricle. A similar phenotype, but with significantly more severe fibrotic changes in the LV, was found in the PLN mutation group (n = 8). Cardiomyopathies associated with lamin A/C (n = 5), sarcomeric (n = 8), and desmin (n = 3) mutations all showed a different pattern from that of the desmosomal and PLN mutation carriers. The posterolateral LV wall appeared to be the most discriminative area with fibrosis and fatty changes predominantly at the outer compact myocardium in 13 of 14 hearts with desmosomal and PLN mutations (93%), in 0 of 13 hearts with lamin A/C and sarcomeric mutations (0%), and in 1 of 3 desminopathic hearts (33%) (P < .001).
  
  
  
  Desmosomal- and PLN-associated cardiomyopathies have a fibrosis pattern distinct from the patterns in other hereditary cardiomyopathies. The posterolateral LV wall appeared to be the most discriminative region between mutation groups. These results may provide a roadmap for cardiac imaging interpretation and may help in further unraveling disease mechanisms.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Sepehrkhouy
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Johannes M I H
authors.initials: JMIH
authors.lastname: Gho
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: van Es
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Nicolaas
authors.initials: N
authors.lastname: de Jonge
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: van der Smagt
authors.affiliation: Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Buijsrogge
authors.affiliation: Netherlands Heart Institute, Utrecht, the Netherlands.
authors.forename: Richard N W
authors.initials: RNW
authors.lastname: Hauer
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Roel A
authors.initials: RA
authors.lastname: de Weger
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands; Netherlands Heart Institute, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: a.vink@umcutrecht.nl.
authors.forename: Aryan
authors.initials: A
authors.lastname: Vink
mesh_terms: D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics*; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D003896:Desmosomes / Q000235:genetics*; D005260:Female; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
keywords: Fibrosis; Genetics; Heart; Histology; Mutation; cardiomyopathy