Document Detail


Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study.
MedLine Citation:
PMID:  22240500     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin.
METHODS AND RESULTS: Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S(1)-S(2) protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation-repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P = 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution.
CONCLUSION: Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction-repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.
Authors:
John Gomes; Malcolm Finlay; Akbar K Ahmed; Edward J Ciaccio; Angeliki Asimaki; Jeffrey E Saffitz; Giovanni Quarta; Muriel Nobles; Petros Syrris; Sanjay Chaubey; William J McKenna; Andrew Tinker; Pier D Lambiase
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-11
Journal Detail:
Title:  European heart journal     Volume:  33     ISSN:  1522-9645     ISO Abbreviation:  Eur. Heart J.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-02     Completed Date:  2012-11-19     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  8006263     Medline TA:  Eur Heart J     Country:  England    
Other Details:
Languages:  eng     Pagination:  1942-53     Citation Subset:  IM    
Affiliation:
Department of Medicine, UCL, London, UK.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Animals
Arrhythmogenic Right Ventricular Dysplasia / genetics*
Case-Control Studies
Desmoplakins / deficiency,  genetics*
Electrocardiography
Female
Gene Deletion
Heart Conduction System / physiology
Heterozygote
Humans
Immunohistochemistry
Male
Mice
Mice, Inbred C57BL
Mice, Inbred Strains
Middle Aged
Mutation / genetics*
Reverse Transcriptase Polymerase Chain Reaction
Sodium Channels / physiology
Young Adult
Grant Support
ID/Acronym/Agency:
//British Heart Foundation; //Department of Health; //Wellcome Trust
Chemical
Reg. No./Substance:
0/Desmoplakins; 0/Sodium Channels
Comments/Corrections

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